API Textbook of Medicine [9th Edition] 9350250748, 9789350250747

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API Textbook of Medicine

Editor-in-Chief

Yash Pal Munjal

9

th

EDITION

The Association of Physicians of India NOTICE The editors have checked the information provided in the book and to the best of their knowledge, it is as per the standards accepted at the time of publication. However, in view of the continuous changes in medical knowledge and the possibility of human error, there could be variance. In view of the possibility of human error by the authors, editors, or publishers of the work herein, or changes in medical knowledge, neither the authors, editors, publisher, nor any other party who has been involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Hence readers are requested to confirm information, particularly laboratory values and drug dosages from the product information sheet included in the package of each drug they plan to administer and from other sources as well, particularly in connection with new or infrequently used drugs. The editor takes no responsibility for the views expressed or the material submitted by the various contributors to this API Textbook of Medicine, Ninth Edition. © All rights reserved. This book is protected by copyright. No part of it may be reproduced in any manner or by any means, without written permission from the Editor-in-chief. First Edition: 1969 Ninth Edition: 2012 ISBN 978-93-5025-074-7 Published by:

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API Textbook of Medicine Ninth Edition EDITOR-IN-CHIEF

Yash Pal Munjal MD, FICP, MAMS, FIAMS, FACP, FIACMS, FRCP (Edin)

Medical Director and Hon. Senior Consultant Diabetes & Life Style Disease Centre Banarsidas Chandiwala Institute of Medical Science, Kalkaji, New Delhi Senior Consultant Diabetologist, Delhi Heart and Lung Institute Past President of Association of Physicians of India Past Dean of Indian College of Physicians Hon. Professor of Indian College of Family Physician EXECUTIVE EDITOR

Surendra K. Sharma MD, PhD

Professor and Head, Chief, Division of Pulmonary, Critical Care and Sleep Medicine Department of Medicine, All India Institute of Medical Sciences, New Delhi, India EDITORS A.K. Agarwal

R.K. Singal

MD, FICP, FRCP (Edin)

MD, FRCP, FICP, FACP

Head, Department of Medicine and Dean Postgraduate Institute of Medical Education & Research Dr RML Hospital, New Delhi, India

Senior Consultant and Head Department of Medicine Dr BL Kapur Memorial Hospital New Delhi, India

Pritam Gupta MD (Medicine)

Shyam Sundar

Senior Consultant and Head, Department of Medicine Sunder Lal Jain Hospital, New Delhi, India

MD, FRCP, FAMS, FNA, FSc, FNASc

Professor of Medicine Institute of Medical Sciences Banaras Hindu University, Varanasi Uttar Pradesh, India

Sandhya A. Kamath MD, FICP

Dean and Professor, Department of Medicine Lokmanya Tilak Municipal Medical College & Municipal General Hospital, Mumbai, Maharashtra, India

Subhash Varma MD, FICP

Professor and Head Department of Internal Medicine PGIMER, Chandigarh, India

Milind Y. Nadkar MD, FICP

Professor of Medicine Chief of Rheumatology and Emergency Medicine Seth GSMC & KEM Hospital, Mumbai, Maharashtra, India ASSISTANT EDITORS Ghan Shyam Pangtey

Anupam Prakash

MD

MD (Medicine), PGCC (Hospital Management), FICP

Associate Professor, Department of Medicine Lady Hardinge Medical College & Associated Hospitals New Delhi, India

Associate Professor, Department of Medicine Lady Hardinge Medical College & Associated Hospitals New Delhi, India

EMERITUS EDITOR

Siddharth N. Shah MD, FICP, FACP (Hon.), FRCP (Edin.)

Postgraduate Teacher in Diabetes, University of Mumbai Consulting Physician and Diabetologist SL Raheja Hospital and All India Institute of Diabetes Saifee Hospital, Bhatia Hospital, Sir Hurkisondas N. Hospital Visiting Consultant Central Railway and Western Railway Hospitals, Mumbai, Maharashtra, India

Editors-In-Chief

Late Dr. R.J. Vakil

Late Dr. K.K. Datey

Late Dr. Shantilal J. Shah

1st and 2nd Edition

3rd Edition

4th Edition

Dr. G.S. Sainani

Dr. Siddharth N. Shah

5th and 6th Edition

7th and 8th Edition

Dr. Y.P. Munjal 9th Edition

PREFACE Over four decades ago, a new compendium of medicine was published under the aegis of Association of Physicians of India. This was due to the vision and hard work of the stalwarts at that time. The first edition of the book was edited by an internationally famed physician Dr Rustam Jal Vakil. The book was well accepted all over the country. Enthused by the response of Indian physicians, eight more editions of the book have been published. Each new edition was an attempt to improve and incorporate the changing profile of medicine. In the last decade, the progress has far outstripped the progress made in the previous decades. It is in this milieu of continuous change that I have the pleasure of presenting to you the 9th edition of the popular, API Textbook of Medicine. The book is completely revised, updated and better illustrated. There are around 2200 pages with nearly 1588 figures and 1384 tables. There has been a marked 20% increase in the number of figures and nearly 100 new tables have been added than the last edition. This has been done so that the information is easily understood and the reading is not a strain. The book has been divided into 28 sections and each section deals with a special set of medical disorders. An entirely new section has been added,‘Clinical Approach to Key Manifestations’. This section deals with the common symptoms and signs with regard to how to scientifically and systematically analyse the problem to arrive at a definitive diagnosis in a timely and cost-effective manner. New authors have been requested to contribute new chapters so that the book is entirely re-written in most of the parts and some of the chapters have been exhaustively revised by the previous authors. A few chapters and figures have been reproduced from the 8th edition. I, on my own behalf and on behalf of the Editorial Board of the 9th edition, express our thanks to the erstwhile Editor-in-Chief, Dr Siddharth N Shah of the 8th Edition for having given us this permission. The explosion of knowledge in medicine is phenomenal and fast so it outpaces the printed textbook of medicine. Therefore the 9th edition endeavours to reflect on some of these changes occurring in medicine during the preceding few years. A number of new chapters have been added like Non Invasive Ventilation under Critical Care. Pharmacotherapy of Cardiovascular Diseases has been added in the section of Cardiology. In the Section of Gastrointestinal Disorders, a new chapter on the Gastrointestinal Symptoms due to Systemic Diseases has been added. The Neurology section has been enriched by adding a chapter on Neuroimaging and separate chapters have been written covering Amyotrophic Lateral Sclerosis and Hyperkinetic Movement Disorders. In the field of Rheumatology, Emergencies have been discussed as a separate chapter altogether which reflects the new way of thinking of treatment and diagnosis of various rheumatic emergencies. The section of Medical Genetics has been thoroughly revised and updated. Genetics is better understood and human genome has been completely delineated. This has tremendous potential for change in the way we practice medicine. Vascular Injury to Kidney and Chronic Dialysis under the section of Nephrology have been discussed in separate chapters because of the better understanding and growing importance of various facets of kidney disorders and diagnosis. An entirely new chapter on Nano Technology and Nano Medicine has been added which is going to be a new paradigm in the field of Clinical Pharmacology. The other sections have been duly revised and updated so that they provide contemporary information and clinical thinking. The expanse of medicine is vast and varied. The presentation of all disorders in a concise and systematic manner in a book of this size has to be a joint collaborative effort. This has been possible due to the support, constructive criticism and useful editorial guidance from all the members of my editorial team for which I am grateful to them. I am especially indebted to Prof. SK Sharma who has been instrumental in guiding and planning this assignment at the cost of his precious time despite his multifarious academic activities. Dr AK Agarwal and Dr RK Singal have been closely associated and have provided useful inputs and suggestions in preparation of this book for which I am grateful to them. Dr Milind Y Nadkar and Dr Sandhya A Kamath provided useful inputs as to how to circumvent some of the key issues while editing a book of this nature because of their past experience of the 8th Edition of the Textbook. Dr Shyam Sundar, Dr Subhash Varma and Dr Pritam Gupta were forthcoming in their help and suggestions for which I owe my thanks to them. Dr Siddharth N Shah, the Emeritus Editor has guided and supported whenever his help was sought for in the production of this book. I am obliged to him for all his help. The Sectional Editors were generous with their time and suggestions while the authors of chapters contributed their chapters in time and as per the common format which was agreed upon. For all this, I convey my sincere thanks to them.

In the era, of information technology, in consonance with the international practice, a new website for the book,‘API Textbook of Medicine’, has been created (www.apitextbook.com). It is a novel feature starting from this edition with online access which will be easily available to all those people who purchase the book. Periodically, the website will be upgraded and new information will be added. During the entire course of past three years of compiling of this book, my wife Dr Rama Munjal, son Dr Akshay Munjal and daughter Er. Jaya Munjal were a source of great strength and motivation. They showed tolerance and forbearance at all times during the preparation of this book. For all their support I wish to place on record my heartfelt thanks. On the completion of this major task, I feel more humble and ever so grateful to the Governing Body of API for having given me this opportunity to carry out this job for and on behalf of our organisation.

Dr Yash Pal Munjal Editor-in-Chief API Textbook of Medicine 9th Edition

ACKNOWLEDGEMENTS The 9th Edition of the API Textbook of Medicine is now available to you.This has been possible due to the collaborative, co-operative and untiring efforts of the Editorial team and many others. On the occasion of the successful completion of this marathon job, it would be appropriate to acknowledge and express my gratitude to all those who have helped in getting this job well done. I am especially grateful to Dr Anupam Prakash and Dr Ghan Shyam Pangtey. They have been associated from the stage of conceptualisation and planning to the final production of this manuscript and have provided unstinted help all through this exercise with dedication and commitment. Dr AP Misra, Dr Anurag Saxena, Dr DG Jain and Dr Sumit Singla have provided useful help at various stages which is duly acknowledged. The task of proof reading and organising the manuscripts was painstakingly and continuously carried out by Mr RK Gupta, Mr DK Sahu, Mr MS Muddur and other members of their team. The efforts of Mr RK Gupta especially stand out and I would like to express my thanks to all of them. I would like to express my thanks to Mr Sanjeev Chaudhry of ‘Initials’ for having done the initial type setting of the book. The final production of the book has been possible due to the hard work put in by the staff of Jaypee Brothers Medical Publishers. The good work done deserves our appreciation and gratitude to Shri Jitendar P Vij, Chairman and Managing Director of Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, which is now the second largest Medical Publishers in the world. Mr Tarun Duneja (Director Publishing) has been instrumental in getting the final shape of the book. The other members of Jaypee Brothers, Ms Shikha Gupta (Editor), Mr Manoj Pahuja and Mr Ankit Kumar (Graphic Designers), Mr Pramod Kumar Rout and Mr Kapil Dev Sharma (DTP Operators), and Mr KK Raman (Production Manager) have done a marvellous job and put in hard work in the production of this book. They were receptive and wore the brunt of this task willingly. They coordinated with the office of editorial board as a team and carried out the instructions diligently. They deserve our appreciation and thanks. I would like to express my sincere thanks to my Secretary, Ms Pushap Lata, for having taken up the additional responsibility with a smile on her face at all times. Ms Neha Garg, who joined at a later stage in the book production, was enthusiastic and co-ordinated the work very effectively and efficiently both in compiling as well as proof reading in the final stages of the book. I would be failing in my duty if I do not express my sincere thanks to Shri Autar Krishna, Chairman and Shri Bhuwan Mohan, Secretary of Shri Banarsidas Chandiwala Sewa Smarak Trust Society for providing the office space and allowing the use of infrastructure during the entire course of the publication of this assignment. Not only they provided the infrastructural support but they also encouraged me in my task as the ‘Editor-in-Chief’ of this book. The help of Sectional Editors for editing the section diligently and providing editorial inputs which were very useful and timely is highly appreciated. I would like to extend our thanks on behalf of the Editorial Board and the authors who have been provided useful assistance by their colleagues in preparation of their respective manuscripts.

Dr YP Munjal and the Editorial Board

Chapter

Section

Assisted By

Authors

06

Section 2 CLINICAL APPROACH TO KEY MANIFESTATIONS Haemoptysis

J.S. Guleria

Randeep Guleria

06

Section 3 DIAGNOSTIC IMAGING Positron Emission Tomography

Shamim Ahmed Shamim

Rakesh Kumar

03

Section 8 BONE DISORDERS Rickets and Osteomalacia

Gaurav Aggarwal

Bindu Kulshreshtha

09 10 19 28

Section 12 CARDIOLOGY Pharmacotherapy of Cardiovascular Disorders Heart Failure Acute Myocardial Infarction Disorders of Myocardium

Bimalpreet Kaur Ragavendra Baliga Naveen Kumar Gupta Ajay Bahl Uma Nahar Saikia

J.C. Mohan Donald Kikta Gurpreet Singh Wander K.K. Talwar

11

Section 14 HEPATOLOGY Non-Alcoholic Fatty Liver Disease

Harshal Rajekar

Yogesh K. Chawla

03

Section 15 HAEMATOLOGY Splenomegaly—A Clinical Approach

Brijesh Arora

Lalit Kumar

03

Section 16 HIV AND AIDS Pathophysiology and Clinical Features

Sonali Sanghavi

U.L. Wagholikar

06

Section 19 NEPHROLOGY Secondary Glomerular Diseases

Sonal Sharma Amit K. Dinda

O.P. Kalra

10 16

Section 20 NEUROLOGY Cerebrovenous Thrombotic Disorder Fungal and Parasitic Diseases of Nervous System

D. Nagaraja Ashok Panagariya

23

Demyelinating Diseases of Nervous System

Rita Christopher Parul Dubey Vipin Satija Prachi Mehndiratta

04

Section 21 ONCOLOGY Principles of Drug Treatment of Cancer

Ankur Behl

Lalit Kumar

03

Section 23 PULMONARY MEDICINE Pulmonary Disorders—Diagnostic Procedures

Archana Ahluwalia

Gautam Ahluwalia

07

Section 28 MISCELLANEOUS Adult Immunisation

Surendra K. Sharma

R.K. Singal

Man Mohan Mehndiratta

SECTIONAL EDITORS VOLUME 1 Section

Editor

Page

1.

Introduction

Yash Pal Munjal

1

2.

Clinical Approach to Key Manifestations

A.K. Agarwal

9

3.

Diagnostic Imaging

Raju Sharma

63

4.

Clinical Pharmacology

B.B. Thakur

119

5.

Immunology

Sita Naik

137

6.

Medical Genetics

Shyam Swarup Agarwal

169

7.

Critical Care Medicine

Surendra K. Sharma

223

8.

Bone Disorders

S.N.A. Rizvi

293

9.

Diabetes Mellitus

Anil Bhansali

319

10.

Endocrinology

Nikhil Tandon

397

11.

Dermatology

Vibhu Mendiratta

461

12.

Cardiology

Gurpreet Singh Wander

555

13.

Gastroenterology

Rakesh Tandon

769

14.

Hepatology

Rajesh Upadhyay and S.K. Sarin

841

15.

Haematology

Rajat Kumar

915

16.

HIV and AIDS

Alaka Deshpande and B.B. Rewari

1011

VOLUME 2 17.

Infectious Diseases

Shyam Sundar and Subhasish Kamal Guha

1039

18.

Disorders of Metabolism

B.K. Sahay

1227

19.

Nephrology

Vinay Sakhuja

1281

20.

Neurology

M.V. Padma Srivastava

1343

21.

Oncology

S.K. Bichile

1555

22.

Psychiatric Medicine

Yash Pal Munjal

1635

23.

Pulmonary Medicine

Surendra K. Sharma

1685

24.

Rheumatology

Rohini Handa

1803

25.

Nutrition

S.V. Madhu

1895

26.

Poisoning and Toxicology

N.P. Singh

1933

27.

Environmental Medicine

Randeep Guleria

1989

28.

Miscellaneous

R.K. Singal

2037

API Textbook of Medicine

CONTRIBUTORS O.C. Abraham MD MPH Department of Medicine Unit 1 and Infectious Diseases Christian Medical College, Vellore Tamil Nadu, India Philip Abraham MD DNB FCPS FICP Consultant Gastroenterologist and Hepatologist PD Hinduja National Hospital and Medical Research Centre, Mumbai Maharashtra, India S.K. Acharya DM Professor and Head Department of Gastroenterology All India Institute of Medical Sciences New Delhi, India Prabha Adhikari MD Professor and Head Department of Medicine Kasturba Medical College, Mangalore Karnataka, India C. Adithan MD DNB PhD Professor and Head Department of Pharmacology, JIPMER Puducherry, India

x

Vikas Agarwal MD Associate Professor Department of Immunology Sanjay Gandhi Postgraduate Institute of Medical Science, Lucknow Uttar Pradesh, India

Alan F. Almeida MD MNAMS FISN Section Co-ordinator, Nephrology Section Department of Medicine P.D. Hinduja National Hospital and Medical Research Centre, Mumbai Maharashtra, India

Amita Aggarwal MD Additional Professor (Clinical Immunology) Department of Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India

Y.K. Amdekar MD DCH Medical Director B.J. Wadia Hospital for Children, Mumbai Consultant Paediatrician Jaslok Hospital and Research Centre, Mumbai Maharashtra, India

Ashutosh Nath Aggarwal MD (Medicine)

A.C. Ammini MD DM (Endo) Professor and Head Department of Endocrinology and Metabolism All India Institute of Medical Sciences New Delhi, India

DM (Pulmonary Medicine)

Associate Professor of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India Praveen Aggarwal MD (Medicine) Professor Department of Emergency Medicine All India Institute of Medical Sciences New Delhi, India

P. Advaitham MD DM Professor and Head Department of Gastroenterology Madurai Medical College, Madurai Tamil Nadu, India

Aparna Agrawal MD (Medicine) Director Professor Department of Medicine Lady Hardinge Medical College and Associated Hospitals New Delhi, India

S.H. Advani MD DNB FICP PhD FNAMS Director Medical Oncology Jaslok Hospital and Research Centre Mumbai, Maharashtra, India

Gautam Ahluwalia MD (Medicine) Medical Officer In-charge Emergency Services, Dayanand Medical College and Hospital, Ludhiana Punjab, India

A.K. Agarwal MD FICP FRCP (Edin) Head of Department of Medicine Dean, PGIMER, Dr RML Hospital New Delhi, India

Jamal Ahmad MD (General Medicine) DM (Endocrinology)

M.B. Agarwal MD MNAMS Department of Haematology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India

Professor of Endocrinology Director Centre for Diabetes and Endocrinology Faculty of Medicine, Jawaharlal Nehru Medical College Hospital Aligarh Muslim University, Aligarh Uttar Pradesh, India

Shyam Swarup Agarwal MD FRCP FAMS FNA FNASc Senior Medical Consultant and Honorary Director (Academics and Research) Vivekananda Polyclinic and Institute of Medical Sciences, Lucknow Uttar Pradesh, India

Mansoor Ahmed MD Medical Officer Department of Cardiology PBM Group of Hospitals Associated to SP Medical College, Bikaner Rajasthan, India

Sanjay K. Agarwal MD Professor and Head Department of Nephrology All India Institute of Medical Sciences New Delhi, India

Parag Aland Department of Nuclear Medicine Jaslok Hospital and Research Centre 15, Mumbai Maharashtra, India

Deepak Amrapurkar MD (Medicine) DM (Gastro) DNB Consultant Gastroenterology and Hepatology Bombay Hospital and Medical Research Centre, Mumbai Maharashtra, India A.C. Anand MD (Medicine) DM (Gastroenterology) FICP FACP FACG

Senior Consultant (Medicine) Armed Forces Medical Services Army Hospital (R and R), Delhi Cantt New Delhi, India Inder S. Anand MD FRCP DPhil (Oxon) Professor of Medicine University of Minnesota Medical School Director, Heart Failure Program VA Medical Center 111C Minneapolis MN 55417 Late M. Paul Anand FRCP (Lond) FRCP (Ed) FICA (USA) FICP FIMSA FCCP (USA) FISCD

Physician Cardiologist Everest Chambers, Mount Pleasant Road Malabar Hill, Mumbai Maharashtra, India Dharamvir Singh Arya MD Assistant Professor Department of Pharmacology All India Institute of Medical Sciences New Delhi, India Vivek Arya MD Associate Professor Department of Medicine PGIMER and Dr Ram Manohar Lohia Hospital New Delhi, India Naved Aslam MD Associate Professor of Cardiology Dayanand Medical College and Hospital Unit Hero DMC Heart Institute, Ludhiana Punjab, India

Anuj Kumar Bansal DM (Oncology) Department of Medical Oncology Institute Rotary Cancer Hospital (IRCH) All India Institute of Medical Sciences New Delhi, India

Ashu Seith Bhalla MD Additional Professor Department of Radiodiagnosis All India Institute of Medical Sciences New Delhi, India

K.K. Raja Babu MD Ex Professor and Head Department of Dermatology Gandhi Hospital/Gandhi Medical College, Hyderabad Andhra Pradesh, India

Atma Ram Bansal MD DM (Neurology) Associate Consultant Institute of Neurosciences Medanta – The Medicity, Gurgaon Haryana, India

Rajvir Bhalwar MD MNAMS PhD Professor and Head and Senior Advisor in Preventive Med and Epidemiology Department of Community Medicine Armed Forces Medical College, Pune Maharashtra, India

V.K. Bahl MD DM (Cardiology) Professor and Head Department of Cardiology All India Institute of Medical Sciences New Delhi, India

Beena Bansal MD DM Department of Endocrinology Medanta – The Medicity, Gurgaon Haryana, India

Anil Bhansali DM (Endocrinology) Professor and Head Department of Endocrinology, Postgraduate Institute of Medical Education and Research Chandigarh, India

N.O. Bansal MD (Medicine) DM (Cardiology)

Ragavendra Baliga MD MBA FRCP

DNB (Cardiology)

FACC FRS (Med)

Professor and Head of Cardiology Grant Medical College and J.J. Group Hospitals, Mumbai Maharashtra, India

Assistant Division Director Division of Cardiovascular Medicine Professor of Internal Medicine The Ohio State University Columbus, OH, USA Amal Kumar Banerjee MD DM FACC FESC Senior Consultant and Intervention Cardiologist, AMRI Hospital, Salt Lake, Kolkata West Bengal, India

Reema Bansal Advanced Eye Centre Postgraduate Institute of Medical Education and Research Chandigarh, India

Ashok Kumar Bajaj MD FICAI Ex Professor Dermatology and STD MLN Medical College, Allahabad Uttar Pradesh, India

P.P. Bapsy MD DM Senior Consultant Medical Oncologist Apollo Hospital, Bengaluru Karnataka, India

B.K. Bajaj MD (Medicine) DM (Neurology) Associate Professor (Neurology) Department of Neurology Postgraduate Institute of Medical Education and Research and Dr RML Hospital New Delhi, India V. Balakrishnan MD, DM Professor of Gastroenterology Digestive Diseases Institute Amrita Institute of Medical Sciences (AIMS),Kochi Kerala, India Pradeep Bambery MD FRCP (Glasg) FRACP Professor Department of Internal Medicine Postgraduate Institute of Medical Education and Research, Chandigarh, India Associate Professor of Medicine Rural Medical School (Bundaberg Campus) The University of Queensland Acting Director of Medicine Bundaberg Hospital Queensland, Australia Debabrata Bandyopadhyay MD Professor and Head Department of Dermatology, Venereology and Leprosy RG Kar Medical College, Kolkata West Bengal, India Samar Banerjee MD Professor, Department of Medicine, Specialist, Diabetic Clinic Vivekananda Institute of Medical Sciences, Kolkata West Bengal, India

Pallavi Bhargava MD Diplomate American Board of Internal Medicine and Infectious Diseases Consultant Infectious Diseases HIV and Travel Medicine Deenanath Mangeshkar Hospital, Pune Maharashtra, India Nadir E. Bharucha MD (Bom) FAMS (India) FRCP (Lond) FRCP Neurology (Canada)

Sandeep B. Bavdekar MD Professor of Paediatrics Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India

Diplomate American Board of Neurology and Psychiatry (N) Professor and Head Department of Neurology Bombay Hospital Institute of Medical Sciences, Mumbai Head Department of Neuroepidemiology Medical Research Centre Bombay Hospital, Mumbai Maharashtra, India

Usha K. Baveja MD MNAMS Senior Consultant Pathology and Lab Medicine, Medanta – The Medicity, Gurgaon Haryana, India

Atul Bhasin DNB (Internal Medicine) MNAMS Senior Consultant Department of Internal Medicine Dr BL Kapur Memorial Hospital New Delhi, India

H.S. Bawaskar MD Bawaskar Hospital and Research Center, Mahad Maharashtra, India

Deepak Kumar Bhasin MD DM FAMS FASGE Professor Department of Gastroenterology Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India

Rahul Ramnik Baxi DM Department of Endocrinology Diabetes and Metabolism Christian Medical College, Vellore Tamil Nadu, India D.P. Bhadoria MD (Medicine) DM (Pulmonary/Critical Care Medicine)

Eesh Bhatia MD DNB (Endocrinology) Professor Department of Endocrinology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India

Professor Maulana Azad Medical College Lok Nayak, GB Pant, GNEC and CNBC Hospitals New Delhi, India

Jagriti Bhatia MD Assistant Professor Department of Pharmacology All India Institute of Medical Sciences New Delhi, India

Ashit M. Bhagwati MD (Med) FICP (India)

Shobna J. Bhatia MD (General Medicine) DM (Gastro) Professor and Head Department of Gastroenterology Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India

FICA (USA) ADHA (Hosp Adm)

Consulting Physician and Intensivist Bhatia Hospital, Sir Hurkisondas Hospital Smt Motiben B Dalvi Hospital, Mumbai Maharashtra, India

Contributors

K. Govind Babu MD DM (Onoclogy) Associate Professor of Medical Onoclogy Kidwai Memorial Institute of Oncology, Bengaluru Karnataka, India

xi

API Textbook of Medicine

Vijayalakshmi Bhatia MD Professor Department of Endocrinology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India Neerja Bhatla MD Department of Obstetrics and Gynaecology All India Institute of Medical Sciences New Delhi, India Mohit Bhatt MD DM Consultant and Head Department of Neurology Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai Maharashtra, India Jina Bhattacharyya DM Associate Professor Department of Haematology Guwahati Medical College, Guwahati Assam, India Prabhash Chandra Bhattacharyya MD Senior Consultant Physician Down Town Hospital, Guwahati Assam, India Prasanta Kumar Bhattacharya MD (General Medicine) PhD (Cardiology)

Professor of Medicine, Gauhati Medical College, Guwahati Assam, India S.K. Bhattacharya MD Medical Officer WHO, South East Asia Regional Office Indraprastha Estate New Delhi, India Lata S. Bichile MD FICP Consultant Rheumatologist, Saifee Hospital, Mumbai Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India S.K. Bichile MD FICP Consultant Haematologist Saifee Hospital and Bhatia Hospital, Mumbai Maharashtra, India Aspi R. Billimoria MD Hon. Cardiologist Conwest and Manjula Badani Jain Hospital, Mumbai Maharashtra, India Anita M. Borges MD FRCPath Consultant Histopathologist SL Raheja Hospital, Mumbai Director Centre of Excellence in Histopathology Piramal Diagnostic Sevices Ltd, Mumbai Maharashtra, India

xii

Nishigandha Burute MD Consultant Radiologist Jankharia Imaging, Mumbai Maharashtra, India

Ashok Chacko MD MNAMS (Gastro) DM (Gastro) Professor and Head Department of Gastrointestinal Sciences Christian Medical College, Vellore Tamil Nadu, India Partha Pratim Chakraborty MD Assistant Professor Department of Medicine Midnapore Medical College and Hospital Paschim Medinipur West Bengal, India Hemraj B. Chandalia MD FACP Endocrinologist and Diabetologist Jaslok, Breach Candy and Saifee Hospitals Director, Diabetes Endocrine Nutrition Management and Research Centre (DENMARC), Mumbai, Maharashtra, India P. Sarat Chandra MCh Additional Professor Department of Neurosurgery All India Institute of Medical Sciences Visiting Professor, International Neurosciences Institute Hannover, Germany Laxmisha Chandrashekar MD DNB Assistant Professor Department of Dermatology and STD Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Puducherry, India Mammen Chandy MD Professor Department of Haematology Christian Medical College, Vellore Tamil Nadu, India S.M. Channabasavanna MD DPM FAMS Professor Emeritus in Psychiatry Ex Director and Vice Chancellor National Institute of Mental Health and Neuro Sciences, Bengaluru Karnataka, India Mitali Chatterjee MD PhD Associate Professor Department of Pharmacology Institute of Postgraduate Medical Education and Research, Kolkata West Bengal, India Sarit Chatterjee MD DNB (General Medicine) Consulting Physician and Assistant Professor Department of Medicine PGIMER, Dr RML Hospital New Delhi, India Anil Chaturvedi MD FICP FIACM FIAMS Senior Consultant Preventive and Internal Medicine Delhi Heart and Lung Institute New Delhi, India Ved Chaturvedi MD DM Chief Consultant Armed Forces Medical Services Army Hospital RR New Delhi, India

Dhruva Chaudhry MD DNB DM (Pulmonary and Critical Care)

Senior Professor and Head Department of Pulmonary and Critical Care Medicine Pt BDS PGIMS, Pt BDS University of Health Sciences, Rohtak Haryana, India Uday Chaudhuri MD DNB DPN Assistant Professor Vivekanand Institute Medical Sciences Visiting Psychiatrist RK Mission Sewa Prathisthan Hospital, Kolkata West Bengal, India Yogesh K. Chawala MD Director Postgraduate Institute of Medical Education and Research Chandigarh, India Anuj Chawla MD (Physiology) DNB (Physiology) MNAMS FCGP

Associate Professor Department of Physiology Armed Forces Medical College, Pune Maharashtra, India Rajesh Chawla MD FCCM FCCP EDIC Consultant Intensivist Apollo Hospitals New Delhi, India Vaibhav C. Chewoolkar MD Assistant Professor Department of Medicine Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India S.K. Chhabra MD (Pulmonary Medicine) Head, Department of Cardiorespiratory Physiology Viswanathan Chest Hospital Vallabhbhai Patel Chest Institute Delhi, India Shibba Takkar Chhabra MD DM (Cardiology) Assistant Professor Dayanand Medical College and Hospital Unit Hero DMC Heart Institute, Ludhiana Punjab, India Sanjat S. Chiwane MD (Medicine) DM (Cardiology)

Associate Consultant Department of Cardiology Artemis Health Institute, Gurgaon Haryana, India Dharma R. Choudhary MD DM Haematologist and BMT Physician BL Kapur Memorial Hospital New Delhi, India Gourdas Choudhuri MD DM FICP FAMS FACG FRCPI

Professor and Head Department of Gastroenterology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India

S.N. Chugh MD MNAMS FICP FICN FIACM FISC Senior Professor and Pro Vice Chancellor Pt BD Sharma University of Health Sciences, Rohtak Haryana, India S. Criton MD Professor and Head Department of Dermatology Amala Institute of Medical Sciences, Thrissur Kerala, India Sanjay D’ Cruz MD DNB DM (Nephrology) MAMS Associate Professor Department of Medicine Government Medical College and Hospital Chandigarh, India M.K. Daga Professor Department of Medicine Maulana Azad Medical College New Delhi, India Ashwin Dalal MD (Paediatrics) DM (Medical Genetics) Head Diagnostics Division Centre for DNA Fingerprinting and Diagnostics, Hyderabad Andhra Pradesh, India P.M. Dalal MD FICP FAMS FAHA Senior Consultant, Neurologist and Research Director LKMM Trust Research Centre Lilavati Hospital, Mumbai Maharashtra, India Debashish Danda MD (Medicine) DM (Clinical Immunology)

Professor and Head Clinical Immunology and Rheumatology Christian Medical College, Vellore Tamil Nadu, India Ashok Kumar Das MD (General Medicine) Senior Professor of Medicine and Medical Superintendent Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Puducherry, India E. Mohan Das MD Psychiatry (AIIMS) Chief Consultant Elite Mission Hospital, Trichur Kerala, India Shyamal Kumar Das DM Professor and Head Department of Neurology Bangur Institute of Neuroscience, Kolkata West Bengal, India Siddharth Kumar Das MD Professor and Head Department of Rheumatology CSM Medical University, Lucknow Uttar Pradesh, India

Biswa B. Dash MD DNB MICOG Department of Obstetrics and Gynaecology All India Institute of Medical Sciences New Delhi, India Avinash Deo MD Consultant Medical Oncologist and Haematologist Holy Family, Guru Nanak and Dhanwantari Hospital, Mumbai Maharashtra, India Anita Desai Department of Neurovirology National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru Karnataka, India Mukesh Desai MD DNB Prof. of Paediatric Haematology Oncology Hon. Haematologist Oncologist and Immunologist Chief Division of Immunology Department of PHO, BJ Wadia Hospital for Children, Mumbai Consultant Haematologist Nanavati Hospital Sir HN Hospital, Saifee Hospital Shrinivas B. Desai MD Head Department of Imaging and Interventional Radiology Jaslok Hospital and Research Centre, Mumbai Maharashtra, India Vinay H. Deshmane MS DNB FRCS (Glasg) MD (London) FICS

Consultant, Surgical Oncology PD Hinduja Hospital and Asian Institute of Oncology, Mumbai Maharashtra, India Alaka Deshpande MD MAMS FIMSA FICP Professor of Medicine and Chief HIV Unit, Grant Medical College and Sir JJ Gr of Govt Hospitals, Mumbai Maharashtra, India Richa Dewan Director Professor and Head Department of Medicine Maulana Azad Medical College New Delhi, India Anil Dhall MD (Medicine) DM (Cardiology) FACC FSCAI FCSI Director and Head Department of Cardiology Artemis Health Institute, Gurgaon Haryana, India Sandipan Dhar MD Consultant Dermatologist AMRI Hospital (Dhakuria), Kolkata West Bengal, India Pankaj Dhawan MD DNB DM Consultant Gastroenterologist and Co-ordinator of GI Endoscopy Jaslok Hospital and Research Centre, Mumbai Chief Interventional Gastroenterologist Digestive Diseases and Endoscopy, Mumbai Maharashtra, India

Radha K. Dhiman MD DM MNAMS FACG Additional Professor Department of Hepatology Postgraduate Institute of Medical Education and Research Chandigarh, India

Contributors

Ranjit Roy Choudhury MD Chairman Task Force for Research Apollo Hospitals Educational and Research Foundation Indraprastha Apollo Hospital, Hostel Complex New Delhi, India

Tuphan Kanti Dolai MD DNB DM Haematologist and BMT Physician Assistant Professor, Haematology Department NRS Medical College, Kolkata West Bengal, India Lakshman Dutt MD Shri Krishna Prasad Psychiatric Nursing Home and Research Center, Ahmedabad Gujarat, India Koushik Dutta MD DM Pulmonary/Critical Care Medicine Professor of Medicine Maulana Azad Medical College, Lok Nayak GB Pant, GNEC and CNBC Hospitals New Delhi, India Tarun Kumar Dutta MD Professor and Head Department of Medicine Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India S. Dwivedi MD (Internal Medicine, BHU) PhD (Cardiology BHU) FRCP (London)

Dean, Principal, Professor and Head Department of Medicine and Preventive Cardiology at Hamdard Institute of Medical Sciences and Research (Hamdard University) New Delhi, India C.E. Eapen MD DM (Gastro) Professor Department of Gastrointestinal Sciences Christian Medical College, Vellore Tamil Nadu, India Natasha Edwin MD Assistant Professor Department of General Medicine Christian Medical College, Vellore Tamil Nadu, India Veronica Franco MD MSPH FACC The Ohio State University Division of Cardiovascular Diseases, DHLRI 200, Section of Advanced Heart Failure and Transplantation, Section of Pulmonary Hypertension Columbus, OH 43210 USA Ankur Gadodia MD DNB Department of Radiodiagnosis All India Institute of Medical Sciences New Delhi, India M.J. Gandhi MD FAMS FICC FICP FICE Prof. Emeritus, Cardiology, Nanavati Hospital and Heart Institute. V.P. Gangadharan MD Department of Medical Oncology Lakeshore Hospital and Research Centre, Kochin Kerala, India Dwijendra Nath Gangopadhyay MD MS Professor Department of Dermatology School of Tropical Medicine, Kolkata West Bengal, India

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Dhiman Ganguly Department of Medicine Vivekananda Institute of Medical Sciences Ramakrishna Mission Seva Pratisthan, Kolkata West Bengal, India

Sankar Prasad Gorthi MD DNB Senior Advisor Med and Neurology Command Hospital (Central Command) Lucknow Cantt, Lucknow Uttar Pradesh, India

Naveen Kumar Gupta MD (Medicine) Jr Consultant Physician Dayanand Medical College and Hospital Unit Hero DMC Heart Institute, Ludhiana Punjab, India

Ajay Garg MD Consultant, Neuroradiology All India Institute of Medical Sciences New Delhi, India

Ravinder Goswami MD DM FNASc FASC Additional Professor Endocrinology and Metabolism All India Institute of Medical Sciences New Delhi, India

Rakesh K. Gupta Professor Department of Radiodiagnosis Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India

Gunjan Garg MD Department of Endocrinology All India Institute of Medical Sciences New Delhi, India Ravindra Kumar Garg MD DM Department of Neurology Chhatrapati Shahuji Maharaj Medical University, Lucknow Uttar Pradesh, India Rohit Kumar Garg MD Department of Neurology GB Pant Hospital New Delhi, India Taru Garg Associate Professor Department of Dermatology and STD Lady Hardinge Medical College and Associated Hospitals, Connaught Place New Delhi, India A.R. Gayathri MD FCCP FRCP FIAB Consultant Department of Respiratory Medicine Apollo Hospital, Chennai Tamil Nadu, India Muhammad Abid Geelani MCh (CTVS) Professor Department of CTVS GB Pant Hospital, Maulana Azad Medical College New Delhi, India Alakendu Ghosh MD Professor Department of Medicine and Head Department of Rheumatology Institute of Postgraduate Medical Education and Research, Kolkata West Bengal, India Kanjaksha Ghosh MD MRCP MRCPI FRCPath FACP FICP

Director Institute of Immunohaematology KEM Hospital, Mumbai Maharashtra, India Uday Chand Ghoshal MD DNB DM FACG Associate Professor Department of Gastroenterology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India

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B.K. Girdhar MD Senior Consultant Dermatology, STD and Leprosy Shanti Manglick Hospital, Agra Uttar Pradesh, India

R.K. Goyal MD Ex Professor and HOD Medicine JLN Medical College, Ajmer Rajasthan, India Chander Grover Department of Dermatology, Venerology and Lephrology University College of Medical Sciences and Guru Tegh Bahadur Hospital New Delhi, India N.K. Grover MS FICS FIAMS FIMSA Senior Consultant Surgeon Medical Director, Vinayak Hospital, Bengaluru Karnataka, India Subhasish Kamal Guha DTM & H MD Associate Professor Department of Tropical Medicine School of Tropical Medicine, Kolkata West Bengal, India Deb Sankar Guin Medical Officer cum Clinical Tutor Department of Neurology Bangur Institute of Neuroscience, Kolkata West Bengal, India P.D. Gulati MD FAMS FAIID FICAI FIMSA Senior Hon Consultant Tirath Ram Shah Hospital, Delhi Formerly Head Division of Nephrology Maulana Azad Medical College and Associated Hospitals New Delhi, India Randeep Guleria MD DM (Pulmonary and Critical Care)

Professor and Head Department of Pulmonary Diseases and Sleep Disorders All India Institute of Medical Sciences New Delhi, India

M.C. Gupta MD DM Dean and Head Faculty of Para Clinical Sciences Professor Department of Pharmacology Pt BD Sharma University of Health Sciences, Rohtak Haryana, India Nitin Gupta MS MCh Consultant, Gastroenterology Jaipur Golden Hospital New Delhi, India Piyush Gupta MD MAMS FIAP Professor of Paediatrics University College of Medical Sciences New Delhi, India Pritam Gupta MD (Medicine) Senior Consultant and Head Department of Medicine Sunder Lal Jain Hospital New Delhi, India Rajeev Gupta MD PhD Department of Medicine Fortis Escorts Hospital, Jaipur Rajasthan, India Subash Gupta MS FRCS Senior Consultant Liver Transplant and Gastrointestinal Surgery Indraprastha Apollo Hospital New Delhi, India Sudeep Gupta MD DM Professor of Medical Oncology and Convener Breast Cancer Working Group Tata Memorial Hospital,Mumbai Maharashtra, India Vaibhav Gupta MD Department of Gastroenterology Rockland Hospital New Delhi, India

Amod Gupta MS Advanced Eye Centre Postgraduate Institute of Medical Education and Research Chandigarh, India

Soneil Guptha MD FACC FESC FCCP FICA Dip Pharm Med Hon Director Jaipur Heart Watch Foundation, Jaipur Rajasthan, India

Ankur Gupta DM (Nephrology) Department of Nephrology All India Institute of Medical Sciences New Delhi, India

Anil Gurtoo MD Director Professor Department of Medicine Lady Hardinge Medical College Associate Hospital New Delhi, India

Dheeraj Gupta MD DM MAMS Additional Professor Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India

Ashutosh Halder MD DNB DM MAMS Associate Professor Department of Reproductive Biology All India Institute of Medical Sciences New Delhi, India

C.V. Harinarayan MD DM (Endo) FAMS Professor and Head Department of Endocrinology and Metabolism Sri Venkateswara Institute of Medical Sciences, Tirupati Andhra Pradesh, India N.K. Hase MD DNB Professor and Head Department of Nephrology Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India A.K. Hooda MD DM Senior Advisor (Medicine and Nephrology) Command Hospital (Eastern Command),Kolkata West Bengal, India Arun C. Inamadar MD DVD Professor and Head Department of Dermatology, Venereology and Leprosy Sri BM Patil Medical College, Hospital and Research Centre, BLDE University, Bijapur Karnataka, India Vara Prasad IR MD DM Consultant Rheumatologist NIMS, Hyderabad Andhra Pradesh, India Priya Jagia MD DNB (Radiology) Assistant Professor Department of Cardiac Radiology All India Institute of Medical Sciences New Delhi, India Ankit Jain MD DM Assistant Professor Department of Medical Oncology Regional Cancer Center, JIPMER Puducherry, India D.G. Jain MD FRCP (Dublin) FRCP (Glasgow) FICP FNCCP (Ind) FIMSA FIACM FCPS (DLT) Adjunct Visiting Professor of Medicine Kasturba Medical College, Mangalore and Manipal NAHE Deemed University Manipal Hony. Physician, Fortis Jessa Ram Hospital New Delhi, India Narender Pal Jain Associate Professor Department of Medicine Dayanand Medical College and Hospital, Ludhiana Punjab, India Naresh Jain MD Department of Dermatology and Venereology All India Institute of Medical Sciences New Delhi, India Sachin K. Jain Director Professor, Department of Medicine, LHMC New Delhi, India

Sanjay Jain MD DM MAMS Professor of Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India A.K. Jaiswal MD Professor and Head Department of Dermatology Venereology and Leprosy Vydehi Institute of Medical Sciences and Research Centre, Bengaluru Karnataka, India Bhavin Jankharia MD DMRD Consultant Radiologist Jankharia Imaging, Mumbai Maharashtra, India M.S. Jawahar MD MSc DLSHTM Deputy Director (Sr Gr) and Scientist ‘F’ Department of Clinical Research Tuberculosis Research Centre Indian Council of Medical Research, Chennai Tamil Nadu, India R.V. Jayakumar MD DM MNAMS FRCP Professor of Endocrinology Amrita Institute of Medical Sciences, Kochi Kerala, India Venu Gopal Jhanwar MD Consultant Psychiatrist Deva Mental Health Care/RKM Home of Service, Varanasi Uttar Pradesh, India Farah F. Jijina Professor and Head Department of Haematology Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India S.K. Jindal MD Professor and Head Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India Sadhna Joglekar MD Vice President Medical and Clinical Research GSK Pharmaceuticals Ltd, Mumbai Maharashtra, India George T. John MD DM FRCP FRACP Senior Consultant Department of Renal Medicine Level 9, Ned Hanlon Building Royal Brisbane and Women’s Hospital Herston Qld 4029 Anant Joshi MS (Ortho) D Ortho Master of Sports Sciences (USA) Cons Orthopaedic Surgeon and Arthroscopy Specialist Bombay Hospital, Mumbai Maharashtra, India

Jyotsna M. Joshi MD Professor and Head Department of Pulmonary Medicine TN Medical College and BYL Nair Hospital, Mumbai Maharashtra, India

Contributors

Rohini Handa MD DNB FAMS FICP FACR FRCP (Glasgow) Senior Consultant Rheumatologist Apollo Indraprastha Hospital New Delhi, India

Prashant P. Joshi MD (Medicine) MSc (Clinical Epidemiology, UNC, Australia)

Associate Professor in Medicine Senior Physician and Head Department of Medicine, Indira Gandhi Government Medical College, Nagpur Maharashtra, India Shashank R. Joshi MD DM FICP FACP FACE (USA) FRCP (Glasg)

Faculty, Department of Endocrinology Grant Medical College and Sir JJ Group Hospital, Consultant Endocrinologist, Lilavati and Bhatia Hospital, Mumbai Maharashtra, India Shilpa S. Joshi Director Mumbai Diet and Health Centre, Mumbai Maharashtra, India V.R. Joshi MD Director of Research and Cons Physician and Rheumatologist PB Hinduja National Hospital and Research Centre, Mumbai Maharashtra, India Jyotsana Department of Gastroenterology RML and PGIMER, Chandigarh New Delhi, India Madhulika Kabra MD Additional Professor Division of Genetics Department of Paediatrics All India Institute of Medical Sciences New Delhi, India J. Kalita DM Additional Professor of Neurology Department of Neurology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India O.P. Kalra MD DM (Nephrology) FAMS FISN FICP FIACM Commonwealth Fellow in Nephrology Leicester (UK) Professor of Medicine Head, Division of Nephrology University College of Medical Sciences and GTB Hospital Delhi, India Sandhya A. Kamath MD FICP Dean and Professor Department of Medicine Lokmanya Tilak Municipal Medical College and Municipal General Hospital, Mumbai Maharashtra, India Madhuchanda Kar MD (Medicine) PhD (Cancer Research) Senior Consultant Medical and Hemato-Oncologist Apollo Gleneagles Cancer Hospital, Kolkata West Bengal, India

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Premashis Kar MD DM PhD FRCP FACG FAMS FICPs Director Professor of Medicine and Gastroenterologist Department of Medicine Maulana Azad Medical College New Delhi, India

Gurudas Khilnani MD (General Medicine)

N. Karthik Department of Neurology National Institute of Mental Health and Neurosciences, Bengaluru Karnataka, India

Uday Khopkar MD Professor and Head of Dermatology KEM Hospital and Seth GS Medical College, Mumbai Maharashtra, India

Amit Kulkarni DNB DPM Consultant Psychiatrist Asha Parekh BCJ Hospital Santacruz west, Mumbai

Surender Kashyap MD DNB Principal-cum-Dean Professor and Head Pulmonary Medicine Indira Gandhi Medical College, Shimla Himachal Pradesh, India

Donald Kikta MD Division of Cardiology Case Western University Cleveland, OH, USA

J.S. Kulkarni MD Dip AV Med Principal Medical Officer WAC Formerly Principal Institute of Aerospace Medicine IAF, Bengaluru Karnataka, India

Upendra Kaul MD DM FCSI FICC FACC FAMS FSCAI Executive Director and Dean Cardiac Sciences, Fortis Escorts Heart Institute Okhla Road and Fortis Hospital, Vasant Kunj New Delhi, India Gurleen Kaur Internal Medicine Westlake Hospital, Illinois State, USA Vineet Kaur DNBE (Derm and Ven) Dip GUM (UK) Consultant Dermatologist and Member Advisory Board International Skincare Nursing Group The Skin Institute, Varanasi Uttar Pradesh, India Rohini Kelkar MD DPB Professor and Head Department of Microbiology Tata Memorial Centre, Mumbai Maharashtra, India

Professor and Head Department of Pharmacology RNT Medical College, Udaipur Rajasthan, India

Ashok L.Kirpalani MD (Medicine) MNAMS (Nephrology) Professor and Head of Nephrology Bombay Hospital Institute of Medical Sciences, Mumbai Maharashtra, India Suman Kirti MD FRCP (London) FRCP (Edin) FICP Senior Consultant Holy Family Hospital New Delhi, India Girisha K.M. MD DM (Medical Genetics) Consultant Genticist and Associate Professor Department of Paediatrics Kasturba Medical College, Manipal Karnataka, India Abhishek Kochar Assistant Professor Department of Medicine SP Medical College, Bikaner Rajasthan, India Dhanpat Kumar Kochar MD DN (VIENNA) Consultant Neurologist Kothari Medical and Research Institute, Bikaner Rajasthan, India

Raj Kubba MRCP (UK) FRCP (Edin) FRCP (Canada) Adjunct Associate Professor of Dermatology Boston University School of Medicine Boston,MA Consultant Dermatologist Delhi Dermatology Group, Kubba Clinic New Delhi, India

Bindu Kulshreshtha MD DM Assistant Professor Endocrinology, PGIMER and Dr Ram Manohar Lohia Hospital New Delhi, India Ajay Kumar MD DM MAMS FRCP (Glasgow) Senior Consultant Gastroenterology and Hepatology Indraprastha Apollo Hospital New Delhi, India Arohi Kumar Consultant Physician, Muzaffarpur Bihar, India Bhushan Kumar MD FRCP (Edin) Consultant Dermatologist, Silver Oaks Multi-Speciality Hospital, Mohali Punjab, India Jaya Kumar MD Department of Medicine All India Institute of Medical Sciences New Delhi, India Lalit Kumar MD DM FAMS FASc Professor of Medical Oncology Institute Rotary Cancer Hospital (IRCH) All India Institute of Medical Sciences New Delhi, India

S.V. Khadilkar MD Professor Department of Neurology Grant Medical College and Sir J.J. Group of Hospitals, Mumbai Maharashtra, India

Rakesh Kochhar MD DM Professor Department of Gastroenterology Postgraduate Institute of Medical Education and Research Chandigarh, India

Rajat Kumar MD (Med) DNB (Med) FICP FRCP (Edin) FRCP (London) FRCPC

Deepak Khandelwal MD Department of Endocrinology and Metabolism All India Institute of Medical Sciences New Delhi, India

Abraham Koshy MD DM Department of Gastroenterology Lakeshore Hospital and Research, Kochi Kerala, India

Professor Department of Medical Oncology and Haematology Cancer Care Manitoba Professor, University of Manitoba, Canada

P.D. Khandelwal MD Director, Professor of Medicine SMS Medical College, Jaipur Rajasthan, India

Jatin P. Kothari Department of Medicine PD Hinduja National Hospital and Medical Research Centre, Mumbai Maharashtra, India

Rakesh Kumar MD Associate Professor Department of Nuclear Medicine All India Institute of Medical Sciences New Delhi, India

Prakash Kothari MD PhD Professor and Head Department of Sexual Medicine Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India

R. Krishna Kumar MD DM FACC FAHA Clinical Professor and Head of Department Paediatric Cardiology Amrita Institute of Medical Sciences Ponekkara PO, Kochi Kerala, India

Shyam S. Kothari MD FACC Professor (Cardiology) All India Institute of Medical Sciences New Delhi, India

Rakshit Kumar Department of Medicine Maulana Azad Medical College New Delhi, India

Sudeep Khanna MD DM Senior Gastroenterologist Pushpawati Singhania Research Institute for Liver, Renal and Digestive Diseases New Delhi, India

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MD (Pharmacology) DHRM

Vijay Kher MD DM FAMS FRCPE Chairman Medanta Kidney and Urology Institute, Gurgaon Haryana, India

Uma Kumar Associate Professor of Medicine Head, Clinical Immunology and Rheumatology All India Institute of Medical Sciences New Delhi, India Vinod Kumar MD Emeritus Professor Department of Medicine St Stephens Hospital New Delhi, India

Ashok A. Mahashur MD FRCP Consultant Chest Physician PD Hinduja National Hospital and Medical Research Centre, Mumbai Maharashtra, India

U.V. Mani Professor and Head Department of Foods and Nutrition MS University of Baroda, Vadodara Gujarat, India

P.K. Maheshwari DM (Neurology) Department of Medicine SN Medical College and Hospital, Agra Uttar Pradesh, India

C.N. Manjunath MD DM Department of Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru Karnataka, India

Sunita Maheshwari ABP ABPC (USA) Senior Consultant Paediatric Cardiologist RXDX and Narayana Hrudayalaya, Bengaluru Karnataka, India M. Maiya FRCP (Lond) FRCP (Edin) FRCP (Glasg) FICP (Ind) FICC (Ind)

Vivek Kumar Department of Medicine Maulana Azad Medical College New Delhi, India

Consultant Physician Maiya Multispeciality Hospital, Bengaluru Karnataka, India

S. Lahiri Consultant Cardiology Delhi Heart and Lung Institute New Delhi, India

D. Maji MD DM Professor and Head of Department Medicine Vivekanand Institute of Medical Sciences, Kolkata West Bengal, India

Bashir Ahmad Laway MD DM (Endocrinology) Additional Professor Endocrinology Sher-i-Kashmir Institute of Medical Sciences, Srinagar Jammu and Kashmir, India Ramchandra D. Lele MRCP (Edin) FRCP Hon. Director of Nuclear Medicine and PET-CT Jaslok Hospital and Research Centre Hon Director, Dept of Nuclear Medicine and RIA, Lilavati Hospital and Research Centre Emeritus Professor of Medicine Grant Medical College and Sir JJ Hospitals, Mumbai Emeritus Professor of the National Academy of Medical Sciences, India Vikram R. Lele MD (Med) DRM DNB (Nucl Med) Head, Department of Nuclear Medicine Jaslok Hospital and Research Centre 15, Mumbai Maharashtra, India Yash Y. Lokhandwala DM (Cardiology) Arrhythmia Associates, Mumbai Quintiles Cardiac Safety Services, Mumbai Maharashtra, India Kaushal Madan Senior Consultant Department of Digestive and Hepatobiliary Science Medanta - The Medicity, Gurgaon Haryana, India S.V. Madhu MD DM (Endocrinology) Division of Endocrinology and Metabolism Department of Medicine University College of Medical Sciences and GTB Hosptal Delhi, India M. Mahapatra MD Associate Professor Department of Haematology All India Institute of Medical Sciences New Delhi, India

Govind K. Makharia MD DM DNB MNAMS Associate Professor Department of Gastroenterology and Human Nutrition All India Institute of Medical Sciences New Delhi, India Ishwar Chandra Malav DM Consultant and Interventional Cardiologist Bharat Vikas Parishad Hospital and Research Centre, Kota Rajasthan, India A.N. Malaviya MD FRCP (Lond) ACR ‘Master’ FACP FICP FAMS FNASc

Consultant Rheumatologist, ‘A and R Clinic’ and Visiting Senior Consultant Rheumatologist ISIC Superspeciality Hospital New Delhi, India Hemant Malhotra MD MNAMS FICP FUICC FIMSA Professor of Medicine and Head Division of Medical Oncology Birla Cancer Center SMS Medical College Hospital, Jaipur Rajasthan, India Prabhat Singh Malik Medical Oncology Institute Rotary Cancer Hospital (IRCH) All India Institute of Medical Sciences New Delhi, India Sourabh Malviya MD Department of Medicine All India Institute of Medical Sciences New Delhi, India R. K. Mani MD Director Department of Pulmonology, Critical Care and Sleep Medicine Artemis Health Institute, Gurgaon Haryana, India

Contributors

Sunil Kumar Professor Department of Radiodiagnosis Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India

Aijaz H. Mansoor MD Attending Cardiologist Fortis Escorts Heart Institute New Delhi, India B.G. Mantur Professor and Head Department of Microbiology Belgaum Institute of Medical Sciences, Belgaum Karnataka, India Neelam Marwaha MD FAMS Professor and Head Department of Transfusion Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India Dilip Mathai MD PhD FRCP FCAMS FIDSA FICP Professor of Medicine Infectious Disease Training and Research Centre Christian Medical College, Vellore Tamil Nadu, India Praveen Mathew Department of Gastroenterology KEM Hospital, Mumbai Maharashtra, India Vikram Mathews MD DM Professor of Clinical Haematology Department of Haematology Christian Medical College and Hospital, Vellore Tamil Nadu, India Prashant Mathur MD Consultant, MHRC, Ajmer, Rajasthan, India P.S. Mathuranath DNB DM (Neurology) Additional Professor of Neurology Sree Chitra Tirunal Institute for Medical Sciences and Technology,Thiruvananthapuram Kerala, India A.K. Meena MD DM Professor Department of Neurology Nizam’s Institute of Medical Sciences, Hyderabad Andra Pradesh, India Man Mohan Mehndiratta DM Professor of Neurology Department of Neurology GB Pant Hospital New Delhi, India

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Narinder K. Mehra Professor and Head Department of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi, India Vibhu Mendiratta MD (Dermatology and VD) Professor Department of Dermatology Lady Hardinge Medical College and Assoc Sucheta Kriplani and Kalawati Saran Children’s Hospital New Delhi, India Vandana Midha Professor Department of Medicine Dayanand Medical College and Hospital, Ludhiana Punjab, India

Alladi Mohan MD Chief Division of Pulmonary Critical Care and Sleep Medicine Professor and Head Department of Medicine Sri Venkateswara Institute of Medical Sciences, Tirupati Andhra Pradesh, India Bishav Mohan Professor of Cardiology Dayanand Medical College and Hospital Unit Hero DMC Heart Institute, Ludhiana Punjab, India

Aditya Prakash Misra Fortis Jessa Ram Hospital Gurudwara Road, Karol Bagh New Delhi, India

J.C. Mohan MD DM Department of Cardiology Ridge Heart Centre, Sunder Lal Jain Hospital Delhi, India

Anoop Misra MD Director and Head Department of Diabetes and Metabolic Diseases Fortis Flt Lt Rajan Dhall Hospital New Delhi, India

V. Mohan MD FRCP (UK) FRCP (Glasg) PhD DSc Chairman and Chief Diabetologist Dr Mohan’s Diabetes Specialities Centre President and Chief of Diabetes Research Madras Diabetes Research Foundation, Chennai Tamil Nadu, India

Ramnath Misra MD FRCP (London) Professor and Head Department of Clinical Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India U.K. Misra DM FAMS Professor and Head Department of Neurology Dean, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India Ambrish Mithal MD DM Chairman Division of Endocrinology and Diabetes Medanta – The Medicity, Gurgaon Haryana, India Amit Mittal MD DM Assistant Professor Department of Cardiology GB Pant Hospital, Maulana Azad Medical College New Delhi, India B.R. Mittal MD DRM DNB MNAMS FICNM Professor and Head Department of Nuclear Medicine and PET Postgraduate Institute of Medical Education and Research Chandigarh, India

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M. Modi MD (Medicine) DM (Neurology) Assistant Professor Department of Neurology, Postgraduate Institute of Medical Education and Research Chandigarh, India

Veena Mittal MD (Microbiology) Consultant and Head Zoonosis Division National Centre for Disease Control Formerly National Institute of Communicable Diseases Delhi, India

Vipul Mohan Department of Cardiology Ridge Heart Centre, Sunder Lal Jain Hospital Delhi, India K.M. Mohandas MD DNB Senior Consultant Medanta Institute of Digestive and Hepatobiliary Sciences Medanta – The Medicity, Gurgaon, Haryana Dean, Academic Tata Memorial Centre Mumbai Maharashtra, India Prasanta Raghab Mohapatra MD MAMS FNCCP FIAB FCCP (USA)

Department of Pulmonary Medicine Government Medical College and Hospital Chandigarh, India Niranjan P. Moulik Department of Medicine MS Ramaiah Medical College, Bengaluru Karnataka, India Sukumar Mukherjee MD FRCP FRCPE FICP FICN FISE FIAMS FSMF

Consultant Physician Research Calcutta Medical Research Institute Kothari Medical Centre Kolkata GD Diabetes Institute, Kolkata West Bengal, India Rita Mulherkar PhD Scientific Officer ‘G’ Mulherkar Lab Advanced Centre for Treatment Research and Education in Cancer Tata Memorial Centre, Navi Mumbai Maharashtra, India

Yash Pal Munjal MD FRCP (Edin) FACP FICP MAMS Director Diabetes and Life Style Disease Centre Banarsidas Chandiwala Institute of Medical Science New Delhi, India A. Muruganathan MD FRCP (Glasg) Adjunct Professor AG Hospital The Tamilnadu Dr Mgr Medical University, Chennai Tamil Nadu, India Milind Y. Nadkar MD FICP Professor of Medicine Chief of Rheumatology and Emergency Medicine Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India D. Nagaraja DM (Neuro) DPM (Psych) MAMS Professor of Neurology Ex Director, Vice Chancellor National Institute of Mental Health and Neurosciences, Bengaluru Karnataka, India T.S. Nagesh Assistant Professor Department of Dermatology Venereology and Leprosy Sapthagiri Institute of Medical Sciences, Bengaluru Karnataka, India Sita Naik MD Ex Professor of Immunology and Dean Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India Ranjith Nair MD DM Army Hospital (R and R), Delhi Cantt New Delhi, India Velu Nair MD Professor and Head Department of Clinical Haematology and Bone Marrow Transplantation Army Hospital (Research and Referral) Delhi Cantt New Delhi, India Praveen Namboothiri MD DM (Nephrology) Consultant in Nephrology Sankar’s SIMS Hospital and Research Institute, Kollam Kerala, India Shiva Narang Assistant Professor Department of Medicine University College of Medical Sciences GTB Hospital New Delhi, India R. Narasimhan MD FCCP FRCP FIAB Senior Consultant Department of Respiratory Medicine Apollo Hospital, Chennai Tamil Nadu, India

Ashish Kumar Panigrahi Assistant Professor Department of Medicine Aarupadai Veedu Medical College and Hospital Puducherry, India

K. Pavithran Senior Consultant Department of Dermatology MIMS Hospital, Calicut Kerala, India

A.S. Narula MD DM FACP Additional Director General Armed Forces Medical Services Professor of Medicine Army College of Medical Sciences New Delhi, India

Manotosh Panja MD DM FICP FACC Director, ICVS AMRI Hospital, Kolkata West Bengal, India

K. Pavithran MD DM Professor of Medical Oncology Amrita Institute of Medical Sciences and Research Centre, Cochin, India

Satish Kumar Parashar MD FACC FCSI Senior Consultant Cardiologist and Director Non-Invasive Cardiac Laboratory Metro Hospitals and Heart Institute New Delhi, India

Shubha R. Phadke MD (Paediatrics)

Swapan Kumar Niyogi Deputy Director National Institute of Cholera and Enteric Diseases, Kolkata West Bengal, India Mohd. Talha Noor MD DM Department of Gastroenterology Postgraduate Institute of Medical Education and Research Chandigarh, India

Falguni S. Parikh MD DNB MNAMS FICP Consultant Internal Medicine Kokilaben Dhirubhai Ambani Hospital, Mumbai Ex Associate Professor TN Medical College and BYL Nair Charitable Hospital, Mumbai Maharashtra, India

DM (Medical Genetics)

Professor Department of Medical Genetics Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India Pawan Poddar MD DM Department of Cardiology Postgraduate Institute of Medical Education and Research Chandigarh, India

Nagaraja Rao Padaki MD DM Chief of Hepatology and Nutrition Asian Institute of Gastroenterology, Hyderabad Andhra Pradesh, India

Purvish M. Parikh MD DNB FICP PhD ECMO CPI MB Medical Oncologist and Haematologist BSES GH Municipal Hospital, Mumbai Maharashtra, India

Pramod Kumar Pal MD Additional Professor of Mental Health and Neurosciences, NIMHANS, Bengaluru Karnataka, India

R. Porkodi MD DM Professor and Head Department of Rheumatology Madras Medical College, Chennai Tamil Nadu, India

Rakesh Parikh MRCP FCPS PDCR Chief Consultant Diabetologist SK Soni Hospital and D Clinic, Jaipur Rajasthan, India

FAMS FIAN

Tanvi Pal MD Consultant Paediatric Dermatologist Delhi Dermatology Group, Kubba Clinic New Delhi, India

Kirti C. Patel MD (Mumbai) FRCP (UK) Honorary Physician Bharatiya Arogya Nidhi Hospital Juhu and BSES Hospital, Mumbai Maharashtra, India

Aparna Palit MD Associate Professor Department of Dermatology, Venereology and Leprosy Sri BM Patil Medical College, Hospital and Research Centre, BLDE University, Bijapur Karnataka, India Ashok Panagariya MD DM (Neurology) FRCP (UK) Professor and Head Department of Neurology SMS Medical College, Jaipur Rajasthan, India A. Pandey Postgraduate Department of Medicine SN Medical College and Hospital, Agra Uttar Pradesh, India

Kirti M. Patel MD Professor of Medical Oncology BJ Medical College, Ahmedabad Dy Director(Medical) and Chief of Medical Oncology, Gujarat Cancer and Research Institute, Ahmedabad Gujarat, India Lekha Adik Pathak Former Director, Professor and Head Department of Cardiology Grant Medical College & JJ Group of Hospitals Head of the Department of Cardiology Nanavati Heart Institute, Mumbai Maharashtra, India

S. Prabhakar MD (Medicine) DM (Neurology) Professor and Head Department of Neurology Postgraduate Institute of Medical Education and Research Chandigarh, India M.P. Ram Prabhu MD Department of Medical Oncology Institute Rotary Cancer Hospital (IRCH) All India Institute of Medical Sciences New Delhi, India Anupam Prakash MD (Medicine) PGCC (Hospital Management) FICP

Associate Professor of Medicine Lady Hardinge Medical College and Smt. Sucheta Kriplani Hospital New Delhi, India Shruti Prem Consultant Haematology Department of Medical Oncology Regional Cancer Centre, Thiruvanathapuram Kerala, India

Nikhil Prakash Patil MS (Gen Surgery) MRCS (England) Department of Cardiothoracic and Vascular Surgery GB Pant Hospital, Maulana Azad Medical College New Delhi, India

Susanne A. Pulimood MD Department of Dermatology Venereology and Leprosy Christian Medical College,Vellore Tamil Nadu, India

Ghan Shyam Pangtey MD Associate Professor Department of Medicine LHMC and Associated Hospitals New Delhi, India

Binoy J. Paul MD PhD DNB Additional Professor Rheumatology Division Department of Medicine Medical College, Calicut Kerala, India

Ratna Dua Puri MD (Paeds) DM (Medical Genetics) Consultant Geneticist Center of Medical Genetics Sir Ganga Ram Hospital New Delhi, India

Gopi Krishna Panicker Manager-Research Quintiles Cardiac Safety Services, Mumbai Maharashtra, India

Apoorva Pauranik MD DM Associate Professor and Neurophysician MGM Medical College, Indore Madhya Pradesh, India

Ramesh Balwant Pandit Hon. Consultant New Bombay’s MGM Hospital Fortis Hiranandani Hospital, Mumbai Maharashtra, India

Contributors

G. Narsimulu MD FICP FIACM Senior Consultant Rheumatologist Ex Prof and Head Rheumatology NIMS, Hyderabad Andhra Pradesh, India

Pendsey Sharad Purushottam MD (Medicine) Dip Diabetology (Yugoslavia) MDDG (West Germany)

Diabetes Clinic and Research Centre ‘Shreeniwas’, opp Dhantoli Park, Nagpur Maharashtra, India

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D. Raghunadharao MD DM Head Department of Medical Oncology Nizam’s Institute of Medical Sciences,Hyderabad Andhra Pradesh, India M. Raghunath MSc PhD Scientist F and Head Endocrinology, Instrumentation and Isotope Divisions National Institute of Nutrition, Hyderabad Andhra Pradesh, India Abhay Narain Rai MD MRCP (UK) FRCP (Glasgow) Ex Professor and Head of Medicine and Principal AN Magadh Medical College, Gaya Bihar, India Madhukar Rai Professor Department of Medicine Institute of Medical Sciences Banaras Hindu University, Varanasi Uttar Pradesh, India

Shaji V. Ramachandran MSc PhD Professor of Haematology Department of Haematology Christian Medical College and Hospital, Vellore Tamil Nadu, India B.S. Ramakrishna MD DM PhD FAMS Department of Gastrointestinal Sciences Christian Medical College, Vellore Tamil Nadu, India M. Ramam Additional Professor Department of Dermatology and Venereology All India Institute of Medical Sciences New Delhi, India

Ramesh Roop Rai MD DM (Gastro) Professor and Head Department of Gastroenterology Fortis Hospital, Jaipur Rajasthan, India

B.S. Rama Murthy MD DMRD DNB Consultant Radiologist Srinivasa Ultrasound Scanning Centre, Bengaluru Karnataka, India

Senthil Rajappa MD DNB DM Head Department of Medical Oncology Indo-American Cancer Center Banjara Hills, Hyderabad Andhra Pradesh, India

Bharath Rangarajan MD DM ECMO Medical Oncologist Mazumdar Shaw Cancer Center Narayana Hrudayalaya, Bengaluru Karnataka, India

C. Panchapakesa Rajendran MD DM Professor and Head Department of Rheumatology SRM Medical College, Potheri Tamil Nadu, India G. Rajesh Associate Professor Digestive Diseases Institute Amrita Institute of Medical Sciences (AIMS) Ponekkara PO Kochi Kerala, India S. Rajesh MD Department of Rheumatology Madras Medical College, Chennai Tamil Nadu, India S. Rajeswari MD DM Reader in Rheumatology Madras Medical College and Govt. General Hospital, Chennai Tamil Nadu, India Rajesh Rajput MD DM (Endocrinology) FICP FIACM FIAMSA Senior Professor and Head Department of Medicine and Endocrinology (PGIMS), Rohtak Haryana, India A. Ramachandran MD PhD DSc MNAMS FICP (London) FRCP (Edinburg)

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Prema Ramachandran Director Nutrition Foundation of India New Delhi, India

Chairman and Managing Director of India Diabetes Research Foundation and Dr A Ramachandran’s Diabetes Hospital, Chennai Tamil Nadu, India

D. Rama Rao MD FICA FIMSA FICC FICP Consultant Physician and Cardiologist Karnataka, India M. Hanumantha Rao Professor and Head Department of Anaesthesiology and Critical Care Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati Andhra Pradesh, India Murlidhar S. Rao MD FACP FCCP FICP FICC FCSI President and Senior Consultant Dhanvantari Charitable Trust Hospital, Gulbarga Karnataka, India U.R.K. Rao MD (Med) Director Sri Deepti Rheumatology Center, Hyderabad Andhra Pradesh, India G.K. Rath MD Professor and Head Department of Radiotherapy and Chief Institute of Rotary Cancer Hospital (IRCH) All India Institute of Medical Sciences New Delhi, India V. Ravi MD FAMS FASc Professor and Head Department of Neurovirology National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru Karnataka, India

K. Ravishankar MD Consultant In-charge The Headache and Migraine Clinic Jaslok Hospital and Research Centre Lilavati Hospital and Research Centre, Mumbai Maharashtra, India D. Raja Reddy FRCS (Edin) FRACS Senior Consultant Neurosurgeon Apollo Hospital, Hyderabad Andhra Pradesh, India B.B. Rewari MD Associate Professor Department of Medicine PGIMER and Dr Ram Manohar Lohia Hospital New Delhi, India S.N.A. Rizvi MD FICP FISN FIAMS Senior Consultant Physician and Nephrologist Apollo Hospital and Sanjeevan Medical Research Centre New Delhi, India Camilla Rodrigues MD Consultant Microbiologist PD Hinduja National Hospital and Medical Research Centre, Mumbai Maharashtra, India Rakesh Roy MD (Pharmacology) Department of Palliative Care, Cancer Centre, Kolkata West Bengal, India Priscilla Rupali MD DTM and H Professor of Medicine Christian Medical College and Hospital Department of Medicine Unit 1 and Infectious Diseases, Vellore Tamil Nadu, India M. Sabir MD Professor Department of Medicine MAMC AGROHA, India B.K. Sahay MD FICP FAMS FACP Ex Professor and Head Department of Medicine Osmania Medical College and General Hospital, Hyderabad Andhra Pradesh, India Manisha Sahay MD DNB MAMS Professor and Head Department of Nephrology Osmania Medical College and General Hospital, Hyderabad Andhra Pradesh, India Rakesh K. Sahay MD Professor of Endocrinology Osmania Medical College, Hyderabad Andhra Pradesh, India Tapan Kumar Saikia MD Head of Medical Oncology and Director of Research Prince Aly Khan Hospital AGA Hall, NESBIT Road, Mumbai Maharashtra, India

Director General Medicine Department Jaslok Hospital and Research Centre, Mumbai Emeritus Professor of Medicine Grant Medical College & JJ Hospital, Mumbai Maharashtra, India R. Sajithkumar MD PhD Chief, Infectious Diseases Govt. Medical College Hospital, Kottayam Kerala, India Vinay Sakhuja MD DM Dean and Head of Nephrology Postgraduate Institute of Medical Education and Research Chandigarh, India A.M. Samuel MD (Ped) DCH FAMS Ex Director Bio Medical Group Bhabha Atomic Research Centre, Mumbai Maharashtra, India Rakesh Sanghadiya Shri Krishna Prasad Psychiatric Nursing Home and Research Center, Ahmedabad Gujarat, India Vivek Anand Saraswat MD DM Department of Gastroenterology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Uttar Pradesh, India Kavitha Saravu MD DNB Associate Professor Department of Medicine Kasturba Medical College Manipal University Karnataka, India Rajiv Sarin Professor In-Charge Cancer Genetics Unit, Advanced Centre for Treatment Research and Education in Cancer Tata Memorial Centre, Navi Mumbai Maharashtra, India Anurag Saxena MD (Medicine) FICP Senior Consultant Physician Fortis Jessa Ram Hospital New Delhi, India Renu Saxena MD Professor and Head Department of Haematology All India Institute of Medical Sciences New Delhi, India Sumit Sengupta Consultant, Chest Physician AMRI Hospital, Kolkata West Bengal, India M.S. Seshadri Professor and Head Department of Endocrinology Diabetes and Metabolism CMC Hospital, Vellore Tamil Nadu, India

V. Seshiah MD FRCP (G) DSc (Hony) Director Dr V Seshiah Diabetes Research Institute,Chennai Tamil Nadu, India

Varun Shandal MD Department of Nuclear Medicine All India Institute of Medical Sciences New Delhi, India

K.K. Sethi MD DM FHRS FACC Director of Cardiology Delhi Heart and Lung Institute New Delhi, India

P.S. Shankar MD Emeritus Professor of Medicine Rajiv Gandhi University of Health Sciences Based at MR Medical College, Gulbarga Karnataka, India

Nusrat Shafiq MD DM (Clinical Pharmacology) Department of Pharmacology Postgraduate Institute of Medical Education and Research Chandigarh, India Ashok Shah MD Professor Department of Respiratory Medicine Vallabhbhai Patel Chest Institute University of Delhi Delhi, India

S.K. Shankar MD FAMS FNASc FIC Path Professor of Neuropathology National Institute of Mental Health and Neurosciences, Bengaluru Karnataka, India G. Shanmugasundar DM Department of Endocrinology Postgraduate Institute of Medical Education and Research Chandigarh, India

Hardik Shah Hon. Assistant Professor Department of Nephrology Bombay Hospital Institute of Medical Sciences, Mumbai Maharashtra, India

Atul Sharma MD DM Additional Professor Department of Medical Oncology Institute of Rotary Cancer Hospital (IRCH) All India Institute of Medical Sciences New Delhi, India

Nalini S. Shah Professor and Head Department of Endocrinology Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India

Bhawna Sharma MD DM (Neurology) Associate Professor Department of Neurology SMS Medical College, Jaipur Rajasthan, India

Pankaj Manubhai Shah MD Medical Oncologist Director, Gujarat Cancer and Research Institute Civil Hospital Campus, Ahmedabad Gujarat, India Samir R. Shah MD DM Consultant Gastroenterologist Jaslok and Breach Candy Hospital, Mumbai Maharashtra, India Sharad Shah MD MRCP RCPS MRCP (Ed) Hon. Gastroenterologist Jaslok Hospital Mumbai Maharashtra, India Siddharth N. Shah MD FICP FACP (Hon) FRCP (Edin) Postgraduate Teacher in Diabetes University of Mumbai Consulting Physician and Diabetologist SL Raheja Hospital and All India Institute of Diabetes, Saifee Hospital Bhatia Hospital, Sir Hurkisondas N Hospital, Mumbai Maharashtra, India Viral Shah Department of Endocrinology Postgraduate Institute of Medical Education and Research Chandigarh, India Shalimar DM Department of Gastroenterology All India Institute of Medical Sciences New Delhi, India

Contributors

G.S. Sainani MD FRCP (Lond & Edin) Hon FRCP PhD DSc

M.P. Sharma MD DM FAMS FICP FIMSA FACG Department of Gastroenterology Rockland Hospital New Delhi, India Navneet Sharma MD MNAMS Additional Professor, Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India Raju Sharma MD MNAMS Professor Department of Radiodiagnosis All India Institute of Medical Sciences New Delhi, India Sangeeta Sharma Professor and Head Department of Neuropsychopharmacology Institute of Human Behavior and Allied Sciences New Delhi, India Sanjiv Sharma MD (Radiology) Professor and Head Department of Cardiac Radiology All India Institute of Medical Sciences New Delhi, India Surendra K. Sharma MD PhD Professor and Head Department of Medicine Chief, Division of Pulmonary, Critical Care and Sleep Medicine All India Institute of Medical Sciences New Delhi, India

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Vinod K. Sharma MD FAMS Professor and Head Department of Dermatology and Venereology All India Institute of Medical Sciences New Delhi, India

Navneet Singh MD DM MAMS Assistant Professor Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India

Ashit Sheth MD DPM Consulting Psychiatrist Bombay Hospital, Mumbai Maharashtra, India

N.P. Singh MD FICP MNAMS FINSA Director Professor of Medicine Maulana Azad Medical College and Associated, Lok Nayak Hospital New Delhi, India

A. Shobhana MD IDCC Consultant Critical Care and Stroke Medicine Institute of Neurosciences, Kolkata West Bengal, India Garima Shukla Associate Professor Department of Neurology Neurosciences Centre All India Institute of Medical Sciences New Delhi, India

M.K. Singhi MD Professor and Head Department of Skin, STD and Leprosy Dr SN Medical College, Jodhpur Rajasthan, India Rajiv Singla MD DNB MNAMS Department of Medicine Maulana Azad Medical College New Delhi, India Rupak Singla MD (TB and Chest Diseases) DNB (Respiratory Medicine)

Sandeep Singh MD DM Additional Professor (Cardiology) All India Institute of Medical Sciences New Delhi, India

Head, Department of Tuberculosis and Respiratory Diseases LRS Institute of Tuberculosis and Respiratory Diseases New Delhi, India

Jamshaid A. Siddiqui Department of Transplant Immunology and Immunogenetics All India Institute of Medical Sciences New Delhi, India

S.K. Singh Department of Endocrinology and Metabolism Institute of Medical Sciences Banaras Hindu University, Varanasi Uttar Pradesh, India

Sumeet Singla MD DNB MNAMS Consultant Physician Air India New Delhi, India

R.K. Singal MD FRCP FICP FACP Senior Consultant and Head Department of Medicine Dr BL Kapur Memorial Hospital New Delhi, India

Sumit Singh MD DM (Neurology) Head of Neuromuscular Disorders Institute of Neurosciences Medanta – The Medicity, Gurgaon Haryana, India

Ajeet Singh Medical Officer Allergy and Pulmonary Division Department of Medicine SMS Medical College, Jaipur Rajasthan, India

Surinder Singh MD Professor of Anaesthesia Indira Gandhi Medical College, Shimla Himachal Pradesh, India

Sanjib Sinha MD DM Additional Professor of Neurology National Institute of Mental Health and Neurosciences, Bengaluru Karnataka, India

Surjit Singh MD Professor of Paediatrics Paediatric Allergy Immunology Unit Advanced Paediatrics Centre Postgraduate Institute of Medical Education and Research Chandigarh, India

Pradyot Sinhamahapatra Assistant Professor Department of Rheumatology Institute of Postgraduate Medical Education and Research, Kolkata West Bengal, India

Surjit Singh Professor Department of Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India

C. Snehalatha MSc DPhil DSc Head of the Department of Biochemistry Research, Director of India Diabetes Research Foundation and Dr A Ramachandran’s Diabetes Hospital, Chennai Tamil Nadu, India

Virendra Singh Professor Allergy and Pulmonary Division Department of Medicine SMS Medical College, Jaipur Rajasthan, India

Rajeev Soman MD Consultant Physician PD Hinduja Hospital, Mumbai Maharashtra, India

A.K. Singh MS Mch (Neurosurgery) Executive Director Department of Neurosciences Fortis Hospital, Noida and Vasant Kunj New Delhi, India Daljit Singh Professor of Neuro Surgery GB Pant Hospital New Delhi, India Guneet Singh Consultant Intensivist Indraprastha Apollo Hospitals New Delhi, India Gurmohan Singh DNBE (Derm and Ven), Dip GUM (UK)

Consultant Dermatologist and Member Advisory Board International Skincare Nursing Group The Skin Institute, Varanasi Uttar Pradesh, India

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Raminder Singh MD Professor of Medicine and Chief of Geriatric Services Seth GS Medical College and KEM Hospital, Mumbai Maharashtra, India

B.S. Singhal MD FRCP (London) FRCP (Edin) FAMS Professor and Head Department of Neurology Bombay Hospital, Mumbai Maharashtra, India

Inderpaul Singh MD DNB Department of Pulmonary and Critical Care Medicine Pt BDS, PGIMS, Pt BDS University of Health Sciences, Rohtak Haryana, India

Vivek Pal Singh Department of Medicine Postgraduate Institute of Medical Education and Research Dr RML Hospital New Delhi, India Yudh Dev Singh MD FIACM DIT Professor (Internal Medicine) SKN Medical College and General Hospital,Pune Maharashtra, India

Sanjeev Sinha MD Associate Professor Department of Medicine All India Institute of Medical Sciences New Delhi, India

Ajit Sood MD (Medicine) DM (Gastro) Professor and Head Department of Gastroenterology Dayanand Medical College and Hospital, Ludhiana Punjab, India Rita Sood MD Professor Department of Medicine All India Institute of Medical Sciences New Delhi, India

K.K. Talwar MD DM Director, Professor and Head Department of Cardiology Postgraduate Institute of Medical Education and Research Chandigarh, India

G.R. Sridhar MD DM Director Endocrine and Diabetes Centre,Visakhapatnam Adjunct Professor of Bioinformatics Andhra University College of Engineering Andhra Pradesh, India

A.B. Taly MD DM Professor of Neurology Department of Neurology National Institute of Mental Health and Neurosciences, Bengaluru Karnataka, India

M.V. Padma Srivastava MD DM FAMS Professor Department of Neurology All India Institute of Medical Sciences New Delhi, India

Nikhil Tandon MD Professor of Endocrinology All India Institute of Medical Sciences New Delhi, India

D.K.S. Subrahmanyam MD Additional Professor Department of Medicine, JIPMER Puducherry, India

P.N.Tandon MD FRCS DSc (hc) FAMS FNASc FASC FTWAS Consultant Neurosurgeon Metro Hospital Department of Neuro Surgery New Delhi, India

A.P. Sugunan Scientist ‘E’ Regional Medical Research Centre (ICMR), Port Blair Andaman and Nicobar Islands, India

Rakesh Tandon MD PhD FRCP (Edin) FAMS FICP FAGA Head, Department of Gastroenterology Pushpawati Singhania Research Institute for Liver, Renal and Digestive Diseases New Delhi, India

T.K. Suma Additional Professor Department of Medicine Govt TD Medical College, Vandanam Kerala, India

Shruti M. Tandan MD FNB (Critical Care) Intensivist Jaslok Hospital and Research Centre, Mumbai Maharashtra, India

Jamshed D. Sunavala MD FCCP (USA) FICP FISE Head of Department Critical Care Medicine Jaslok Hospital and Research Centre Hon Physician and Intensivist Breach Candy Hospital, Mumbai Hon Physician, BD Petit Parsee General Hospital, Mumbai Maharashtra, India

Sunil Taneja Department of Hepatology Postgraduate Institute of Medical Education and Research Chandigarh, India

Shyam Sundar MD FRCP FAMS FNA FSc FNASc Professor of Medicine Institute of Medical Sciences Banaras Hindu University, Varanasi Uttar Pradesh, India Dipika Sur MD Deputy Director National Institute of Cholera and Enteric Diseases, Kolkata West Bengal, India Vikas Suri MD Assistant Professor Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India Rupjyoti Talukdar MD Consultant Pancreatologist and Gastroenterologist (Fellowship, Mayo Clinic, Rochester, USA) NEMCARE Hospital, Guwahati Assam, India

Uma Tekur MD MNAMS Director, Professor and Head Department of Pharmacology Maulana Azad Medical College New Delhi, India Kamlesh Tewary MD FICP FIAMS Professor and Head Department of Medicine SK Medical College, Muzaffarpur Bihar, India Ashish K. Thakur Consultant Interventional Cardiologist The Mid Yorkshire NHS Trust and Yorkshire Heart Centre England, UK B.B. Thakur MD FICP FIAMS FIACM FISPA Consultant Physician Cardio-Diabetologist and 4 Juran Chapra, Muzaffarpur Bihar, India Devinder Mohan Thappa MD DHA MNAMS Professor and Head Department of Dermatology and STD Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Puducherry, India

R. Thara MD Director Schizophrenia Research Foundation, Chennai Tamil Nadu, India Urmilla Thatte MD Professor and Head Department of Clinical Pharmacology TN Medical College and BYL Nair Hospital,Mumbai Maharashtra, India

Contributors

D. Sreeramulu MSc PhD Endocrinology and Metabolism Division National Institute of Nutrition Indian Council of Medical Research, Hyderabad Andhra Pradesh, India

Nihal Thomas MD MNAMS DNB (Endo) FRACP (Endo) FRCP (Edin) Professor in Endocrinology Diabetes and Metabolism Christian Medical College, Vellore Tamil Nadu, India Sanjeev V. Thomas MD DM Professor of Neurology Sree Chitra Tirunal Institute for Medical Sciences and Technology,Thiruvananthapuram Kerala, India Anil Kumar Tripathi Professor Department of Medicine Nodal Officer (Art centre) Chhatrapati Sahuji Maharaj Medical University, Lucknow Uttar Pradesh, India J.K.Trivedi MD MRC Psych (UK) FAPA (USA) FAMS (India) Professor Department of Psychiatry Chhatrapati Shahuji Maharaj Medical University (Formerly KG Medical University), Lucknow Uttar Pradesh, India Pankaj Tyagi MD DM (Gastroenterology) Consultant Gastroenterology Sir Ganga Ram Hospital New Delhi, India Sanjay Tyagi MD DM Director, Professor and Head Department of Cardiology GB Pant Hospital Maulana Azad Medical College New Delhi, India Seema Tyagi Associate Professor Department of Haematology All India Institute of Medical Sciences New Delhi, India Vrajesh Udani MD Consultant – Child Neurology and Epilepsy Diplomate of the American Board of Neurology with Special Competence in Child Neurology PD Hinduja National Hospital and Medical Research Centre, Mumbai Maharashtra,India Farokh E. Udwadia MD FCPS FRCP (Edinburgh) FRCP (London) Master FCCP FACP FAMS DSc Consultant Physician and Physician In-Charge of ICU Breach Candy Hospital, Mumbai Consultant Physician, Parsee General Hospital, Mumbai Maharashtra, India xxiii

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Rajesh Upadhyay MD MRCP (UK) FRCP (Glasgow) FICP Senior Consultant and Chairman Department of Gastroenterology Jaipur Golden Hospital New Delhi, India Vihang N. Vahia MD DPM MAPA Honorary Professor of Psychiatry Cooper Hospital and GS Medical College Visiting Psychiatrist: Breach Candy Hospital Lilavati Hospital and Sir Hurkison Das Hospital, Mumbai Maharashtra, India P.P. Varma MD DNB DM (Nephrology) MNAMS FICP FISN Army Hospital (R and R) New Delhi, India Subhash Varma MD FICP Professor and Head Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India Varsha MSc PhD RD CNIS Founder Chair Indian Institute of Nutritional Sciences B. Vengamma DM (Neuro) Director and Dean Professor and Head Department of Neurology Sri Venkateswara Institute of Medical Sciences, Tirupati Andhra Pradesh, India S.Venkataraman MD DM (Neurology) FICA FICP FIAN Consultant Physician and Neurologist Mata Chanan Devi Hospital New Delhi, India S.K. Verma Professor Cancer Research Institute, HIHT University Uttarakhand, India

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Shailendra P. Verma Lecturer Department of Medicine, CSMMU, Lucknow Uttar Pradesh, India Deepti Vibha Department of Neurology Institute of Liver and Biliary Sciences New Delhi, India J.C. Vij MD (Medicine) DM (Gastroenterology) Senior Consultant Gastroenterology and Endoscopy Pushpawati Singhania Research Institute for Liver, Renal and Digestive Diseases New Delhi, India V.K. Vijayan MD (Med) PhD DSc FAMS Director Vallabhbhai Patel Chest Institute New Delhi, India R. Kasi Visweswaran MD DM Senior Consultant Nephrology Ananthapuri Hospital and Research Institute, Thiruvananthapuram Kerala, India Amit Vora MD DM DNB Glenmark Cardiac Centre, Mumbai Maharashtra, India R.S. Wadia MD FIAN FICP Department of Neurology Ruby Hall Clinic, Pune Maharashtra, India U.L. Wagholikar Consultant Histopathologist, India Rama Walia Assistant Professor Department of Endocrinology Postgraduate Institute of Medical Education and Research Chandigarh, India

Gurpreet Singh Wander MD (PGI) DM (Cardio) Professor and Head of Cardiology Dayanand Medical College and Hospital Unit Hero DMC Heart Institute, Ludhiana Punjab, India Vidhyadhar Watve MD DPM FIPS Poona Hospital and Research Centre, Pune Maharashtra, India Naveet Wig Additional Professor Department of Medicine All India Institute of Medical Sciences New Delhi, India Pushpa Yadav MD Consultant in Medicine and Associate Professor Dr. Ram Manohar Lohia Hospital New Delhi, India M.E. Yeolekar MD (Medicine) MNAMS FICP Director NEIGRIHMS, Shillong Meghalaya, India Sanjay Zachariah MD (Medicine) Assistant Professor Department of Medicine SUT Academy of Medical Sciences Vencode, Vattapara, Thiruvananthapuram Kerala, India Abdul Hamid Zargar Professor and Head Department of Endocrinology Director, Sher-i-Kashmir Institute of Medical Sciences, Srinagar Jammu and Kashmir, India

Contributors

CONTENTS SECTION 1: INTRODUCTION 1.

The Practice of Medicine Yash Pal Munjal

2

SECTION 2: CLINICAL APPROACH TO KEY MANIFESTATIONS 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13

Pain—Mechanisms and Management D. Rama Rao, Niranjan P. Moulik Headache K. Ravishankar Chest Pain Sanjay Tyagi, Amit Mittal Acute Abdomen—Non-Surgical Causes Sumeet Singla, A.K. Agarwal Cough Suman Kirti Haemoptysis Randeep Guleria, Jaya Kumar Jaundice Aparna Agrawal Upper Gastrointestinal Bleeding J.C. Vij Fever of Unknown Origin Priscilla Rupali Generalised Lymphadenopathy S.K. Verma Dizziness and Vertigo M. Maiya Syncope Pushpa Yadav, Vivek Arya Coma B. Vengamma

10 12 16 20 25 29 32 39 42 47 49 53 57

SECTION 3: DIAGNOSTIC IMAGING 3.1 3.2 3.3 3.4 3.5 3.6

Conventional Radiology Ashu Seith Bhalla, Ankur Gadodia Ultrasound in Medicine B.S. Rama Murthy Computed Tomography Bhavin Jankharia, Nishigandha Burute MRI in Medicine Raju Sharma, Ankur Gadodia Nuclear Imaging B.R. Mittal Positron Emission Tomography Rakesh Kumar, Varun Shandal

64 78 84 91 100 113 xxv

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SECTION 4: CLINICAL PHARMACOLOGY 4.1 4.2 4.3 4.4 4.5 4.6

Introduction and Scope of Clinical Pharmacology Ranjit Roy Choudhury, Urmilla Thatte Rational Use of Drugs Sangeeta Sharma Adverse Drug Reactions and Pharmacovigilance M.C. Gupta Prescribing in Special Situations Uma Tekur New Drug Development Sadhna Joglekar Pharmacoeconomics Gurudas Khilnani

120 123 125 128 133 135

SECTION 5: IMMUNOLOGY 5.1 5.2 5.3 5.4 5.5 5.6 5.7

An Overview of the Immune System Sita Naik General Concepts of Immunoinflammatory Disorders Ramnath Misra Immunology of Infectious Diseases Sita Naik Primary Immunodeficiency Disorders—A Clinical Approach Surjit Singh Laboratory Investigations in Immune-Mediated Diseases Amita Aggarwal Pharmacological Manipulation of the Immune System Mitali Chatterjee Immunology of Organ and Haematopoietic Stem Cell Transplantation Narinder K. Mehra, Jamshaid A. Siddiqui

138 146 149 151 155 159 164

SECTION 6: MEDICAL GENETICS 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 xxvi

Introduction to Medical Genetics Shyam Swarup Agarwal Mendel and Beyond Ratna Dua Puri Clinical and Molecular Cytogenetics Ashutosh Halder Genetic Tests Ashwin Dalal Inborn Errors of Metabolism Madhulika Kabra Molecular Genetics, Human Genome Project and Genomic Medicine Girisha K.M. Gene Therapy Rita Mulherkar Genetic Counselling and Prenatal Diagnosis Shubha R. Phadke Pharmacogenomics and Personalised Medicine C. Adithan Cancer Genetics Rajiv Sarin

170 173 180 189 193 201 206 209 215 217

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 7.12

Basic Considerations in Critical Care R.K. Mani Monitoring of Critically Ill Patients M. Hanumantha Rao Fluid and Electrolyte Balance in Health and Disease Sanjay Jain Acid-Base Disorders Alladi Mohan, Surendra K. Sharma Enteral and Parenteral Nutrition in Critically Ill Patients Shilpa S. Joshi Acute Respiratory Failure Ashit M. Bhagwati Sepsis and Acute Respiratory Distress Syndrome Alladi Mohan, Surendra K. Sharma Mechanical Ventilation Surender Kashyap, Surinder Singh Non-Invasive Ventilation Dhruva Chaudhry, Inderpaul Singh Hypotension and Shock Anil Dhall, Sanjat S. Chiwane Cardiopulmonary Resuscitation Ashit M. Bhagwati Brain Death and Support of the Brain-Dead Organ Donor Rajesh Chawla, Guneet Singh

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Contents Contributors

SECTION 7: CRITICAL CARE MEDICINE 227 232 239 246 251 256 263 271 277 282 289

SECTION 8: BONE DISORDERS 8.1 8.2 8.3 8.4 8.5 8.6

Bone and Mineral Metabolism in Health and Disease Deepak Khandelwal, Ravinder Goswami Investigations and Diagnosis of Bone Disorders Sukumar Mukherjee Rickets and Osteomalacia Bindu Kulshreshtha, Sachin K. Jain Osteoporosis S.N.A. Rizvi Developmental Disorders of Bone Rakesh K. Sahay Miscellaneous Bone Disorders C.V. Harinarayan

294 299 305 309 313 316

SECTION 9: DIABETES MELLITUS 9.1 9.2 9.3 9.4 9.5

Epidemiology and Basic Considerations of Diabetes A. Ramachandran, C. Snehalatha Pathogenesis of Type 1 Diabetes Mellitus V. Mohan, Rakesh Parikh Pathogenesis of Type 2 Diabetes Mellitus Hemraj B. Chandalia Clinical Features and Diagnosis of Diabetes Mellitus D. Maji Lifestyle Modifications in Management of Diabetes B.K. Sahay

321 324 327 331 336 xxvii

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9.6 9.7 9.8 9.9 9.10 9.11 9.12 9.13 9.14 9.15 9.16 9.17 9.18 9.19 9.20 9.21

Oral Anti-Diabetic Drugs Anil Bhansali, Viral Shah Insulin Therapy Rama Walia Newer Modalities of Treatment in Type 2 Diabetes Mellitus Anil Bhansali, G. Shanmugasundar In-Hospital Management of Diabetes Mellitus Nihal Thomas, Rahul Ramnik Baxi Hypoglycaemia Siddharth N. Shah Diabetic Ketoacidosis, Hyperosmolar Hyperglycaemic State and Lactic Acidosis Rajesh Rajput Infections in Diabetes Mellitus Samar Banerjee Macrovascular Complications of Diabetes Murlidhar S. Rao Microvascular Diseases—Pathogenesis of Chronic Complications Suman Kirti Diabetes and Kidney Disease Jamal Ahmad Diabetic Retinopathy Amod Gupta, Reema Bansal Diabetic Neuropathy Manish Modi Sexual Dysfunction in Diabetes Shashank R. Joshi The Diabetic Foot Pendsey Sharad Purushottam Diabetes and Pregnancy V. Seshiah Prevention of Diabetes Mellitus Yash Pal Munjal

339 343 347 350 354 359 364 368 372 375 377 382 385 387 390 393

SECTION 10: ENDOCRINOLOGY 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11. xxviii

Basic Considerations of Endocrinology Ashok Kumar Das Endocrine Disorders—A Clinical Approach M.S. Seshadri Disorders of Hypothalamus and Pineal Gland Abdul Hamid Zargar, Bashir Ahmad Laway Disorders of Anterior Pituitary R.V. Jayakumar Disorders of Posterior Pituitary G.R. Sridhar Disorders of Thyroid Glands Nikhil Tandon, Gunjan Garg Disorders of Parathyroid Glands Ambrish Mithal, Beena Bansal Disorders of Adrenal Glands Eesh Bhatia, Vijayalakshmi Bhatia Disorders of Puberty A.C. Ammini Disorders of Growth and Development Nalini S. Shah Disorders of Gonads Shashank R. Joshi

398 403 407 410 417 419 430 433 442 446 452

11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18

Introduction and Principles of Diagnosis in Dermatology Vibhu Mendiratta Cutaneous Infections Vineet Kaur, Gurmohan Singh Infestations and Insect Bites Devinder Mohan Thappa, Laxmisha Chandrashekar Eczemas Ashok Kumar Bajaj Drug Reactions M. Ramam Abnormal Vascular Responses A.K. Jaiswal, T.S. Nagesh Papulosquamous Disorders K. Pavithran Autoimmune Bullous Disorders K.K. Raja Babu Disorders of Pigmentation Bhushan Kumar Disorders of Skin Appendages Raj Kubba, Tanvi Pal Cutaneous Responses to Physical Factors S. Criton Genodermatoses Vibhu Mendiratta Skin in Connective Tissue Diseases Sandipan Dhar Skin in Systemic Diseases Uday Khopkar Leprosy B.K. Girdhar Sexually Transmitted Infections Vinod K. Sharma, Naresh Jain Premalignant Conditions and Malignant Tumours of the Skin Arun C. Inamadar, Aparna Palit Therapy of Dermatological Diseases M.K. Singhi

462

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SECTION 11: DERMATOLOGY 470 475 480 487 491 494 498 501 507 512 515 520 526 534 541 546 549

SECTION 12: CARDIOLOGY 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8

Basic Considerations in Cardiology Upendra Kaul, Aijaz H. Mansoor Cardiovascular Diseases—A Clinical Approach G.S. Sainani Electrocardiology M.J. Gandhi Exercise Testing Yash Pal Munjal Echocardiography Satish Kumar Parashar Cardiac Imaging Priya Jagia, Sanjiv Sharma Nuclear Cardiology Vikram R. Lele, Parag Aland Cardiac Catheterisation and Angiocardiography Lekha Adik Pathak, N.O. Bansal

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12.9 12.10 12.11 12.12 12.13 12.14 12.15 12.16 12.17 12.18 12.19 12.20 12.21 12.22 12.23 12.24 12.25 12.26 12.27 12.28 12.29 12.30 12.31 12.32 12.33

Pharmacotherapy of Cardiovascular Disorders J.C. Mohan, Vipul Mohan Heart Failure Donald Kikta, Veronica Franco Heart Failure Management Veronica Franco, Ragavendra Baliga Acute Rheumatic Fever R. Krishna Kumar Valvular Heart Disease (I) C.N. Manjunath Valvular Heart Disease (II) V.K. Bahl, Ishwar Chandra Malav Infective Endocarditis Shyam S. Kothari Atherosclerosis K.K. Sethi, S. Lahiri Ischaemic Heart Disease Inder S. Anand, Shibba Takkar Chhabra Acute Coronary Syndrome Gurpreet Singh Wander, Naveen Kumar Gupta Acute Myocardial Infarction Gurpreet Singh Wander, Naved Aslam Hypertension M. Paul Anand Management of Hypertension Sandhya Kamath Secondary Hypertension B.B. Thakur, Arohi Kumar Bradyarrythmias Yash Y. Lokhandwala, Gopi Krishna Panicker Tachyarrhythmias Amit Vora Sudden Cardiac Death Ashish K. Thakur Congenital Heart Disease Sunita Maheshwari Heart in Systemic Disease Aspi R. Billimoria Disorders of Myocardium K.K. Talwar, Pawan Poddar Diseases of the Pericardium Sanjay Tyagi, Amit Mittal Surgical Management of Heart Disease Muhammad Abid Geelani, Nikhil Prakash Patil Diseases of the Aorta Manotosh Panja Vascular Disorders of the Extremities Gurpreet Singh Wander, Bishav Mohan Pregnancy and Heart Disease Amal Kumar Banerjee

615 621 624 629 637 643 652 661 666 673 677 685 691 698 702 707 713 716 724 728 737 746 750 757 764

SECTION 13: GASTROENTEROLOGY 13.1 13.2 xxx

Clinical Approach—Gastrointestinal Disorders A.C. Anand Investigations—Gastrointestinal Disorders Ashok Chacko

770 774

13.4 13.5 13.6 13.7 13.8 13.9 13.10 13.11 13.12 13.13 13.14

Endoscopy—Diagnostic and Therapeutic Utility Gourdas Choudhuri Diarrhoea and Malabsorption B.S. Ramakrishna Constipation—Diagnosis and Management Uday Chand Ghoshal Gastrointestinal Bleeding Rakesh Kochhar, Mohd. Talha Noor Oesophageal Disorders Shobna J. Bhatia, Praveen Mathew Diseases of the Stomach and Duodenum Pankaj Dhawan Diseases of the Pancreas V. Balakrishnan, G. Rajesh Functional Gastrointestinal Disorders Philip Abraham Abdominal Tuberculosis Govind K. Makharia Inflammatory Bowel Disease Ajit Sood, Vandana Midha Ischaemic Bowel Disorders Deepak Kumar Bhasin Gastrointestinal Symptoms in Systemic Diseases Rakesh Tandon, Sudeep Khanna

777 782 787

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13.3

791 799 806 813 819 823 829 834 837

SECTION 14: HEPATOLOGY 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 14.9 14.10 14.11 14.12 14.13 14.14 14.15

Basic Considerations of Hepatobiliary Disorders Vivek Anand Saraswat Hepatobiliary Disorders—A Clinical Approach Nagaraja Rao Padaki Hepatobiliary Disorders—Investigations Radha K. Dhiman Hepatobiliary Disorders—Imaging Shrinivas B. Desai Acute Viral Hepatitis Deepak Amarapurkar Chronic Viral Hepatitis Rajesh Upadhyay, Nitin Gupta Chronic Non-Viral Hepatitis C.E. Eapen Alcoholic Liver Disease Nitin Gupta, Rajesh Upadhyay Cirrhosis of the Liver Philip Abraham Extra-Hepatic Portal Venous Obstruction Sharad Shah Non-Alcoholic Fatty Liver Disease Yogesh K. Chawla, Sunil Taneja Acute Liver Failure S.K. Acharya, Shalimar Inherited Metabolic Disorders of the Liver P. Advaitham Parasitic Diseases of the Liver Samir R. Shah Toxic and Drug Induced Liver Injury Abraham Koshy

842 846 851 855 862 867 870 873 878 883 885 888 892 895 898 xxxi

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14.16 14.17 14.18 14.19 14.20

Liver Transplantation Subash Gupta, Ajay Kumar Pregnancy and Liver Disease Ramesh Roop Rai Liver in Systemic Disease Premashis Kar, Rajiv Singla Tumours of the Liver Kaushal Madan, Pankaj Tyagi Diseases of Gall Bladder and Biliary Tract Rakesh Tandon

899 901 905 908 911

SECTION 15: HAEMATOLOGY 15.1 15.2 15.3 15.4 15.5 15.6 15.7 15.8 15.9 15.10 15.11 15.12 15.13 15.14 15.15 15.16 15.17 15.18 15.19 15.20

xxxii

Haematopoiesis Shaji V. Ramachandran, Vikram Mathews Anaemia—A Clinical Approach Renu Saxena, M. Mahapatra Splenomegaly—A Clinical Approach Lalit Kumar, Anuj Kumar Bansal Iron Deficiency Anaemia Subhash Varma Megaloblastic Anaemia Tarun Kumar Dutta Hereditary Haemolytic Anaemia M.B. Agarwal Acquired Haemolytic Anaemia Farah F. Jijina Aplastic Anaemia Dharma R. Choudhary, Tuphan Kanti Dolai Acute Leukaemia S.H. Advani Chronic Myeloid Leukaemia and Other Myeloproliferative Disorders Tapan Kumar Saikia Myelodysplastic Syndromes Rajat Kumar, Seema Tyagi Chronic Lymphocytic Leukaemia M. Mahapatra, Renu Saxena Lymphoid Neoplasms Bharath Rangarajan, Purvish M. Parikh Plasma Cell Dyscrasias Pankaj Manubhai Shah Bleeding Disorders Kanjaksha Ghosh Platelet Disorders S.K. Bichile Disorders of Coagulation Jina Bhattacharyya Hypercoagulable Disorders Mammen Chandy Transfusion Medicine Neelam Marwaha Haematopoietic Stem Cell Transplantation Velu Nair

916 922 926 928 933 938 947 952 956 963 966 970 974 979 984 987 990 996 1000 1004

16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8

Epidemiology O.C. Abraham, Susanne A. Pulimood Virology, Immunology and Diagnosis V. Ravi, Anita Desai Pathophysiology and Clinical Features U.L. Wagholikar Antiretroviral Therapy B.B. Rewari, Sanjeev Sinha Drug Resistance Alaka Deshpande Non-Opportunistic Infections Anil Kumar Tripathi, Shailendra P. Verma Opportunistic Infections Natasha Edwin, Dilip Mathai Non-Pharmacologic Interventions and Prevention R. Sajithkumar

1012

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SECTION 16: HIV AND AIDS 1014 1017 1023 1026 1029 1032 1036

SECTION 17: INFECTIOUS DISEASES A. 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8

General Considerations Basic Considerations of Infections Subhasish Kamal Guha Laboratory Diagnosis of Infections Camilla Rodrigues Syndromic Approach to Infectious Diseases Rajeev Soman Anti-Microbial Therapy—An Overview Jagriti Bhatia, Dharamvir Singh Arya Infections in the Immunocompromised Host Ghan Shyam Pangtey, Anupam Prakash Hospital Acquired Infections/Nosocomial Infections A. Shobhana Prevention of Health Care Associated Infections B.B. Rewari, Usha K. Baveja Hospital Infection Control Rohini Kelkar

1042 1044 1048 1051 1058 1060 1063 1067

B. Bacterial Infections 17.9 17.10 17.11 17.12 17.13 17.14 17.15 17.16

Staphylococcal Infections Rita Sood Streptococcal Infections Abhay Narain Rai Pneumococcal Infections D.P. Bhadoria, Koushik Dutta Meningococcal Infections R.K. Singal, Vivek Pal Singh Gonococcal Infections Chander Grover Typhoid Fever (Enteric Fever) Swapan Kumar Niyogi Bacillary Dysentery Pankaj Tyagi, Jyotsana Cholera S.K. Bhattacharya, Dipika Sur

1069 1072 1074 1077 1080 1083 1086 1088 xxxiii

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17.17 17.18 17.19 17.20 17.21 17.22 17.23

C. 17.24 17.25 17.26 17.27 17.28 17.29 17.30 17.31 17.32 17.33 17.34

D. 17.35 17.36 17.37

E. 17.38 17.39 17.40 17.41 17.42 17.43 xxxiv

Diseases Caused by Gram-Negative Enteric Bacilli Richa Dewan, Vivek Kumar Haemophilus Influenzae Infections M. Sabir, Mansoor Ahmed Legionnaires’ Disease P.S. Shankar Plague and Other Yersinia Infections Veena Mittal Clostridial Infections M.K. Daga, Rakshit Kumar Diphtheria Sandeep B. Bavdekar Pertusis—Whooping Cough Y.K. Amdekar

1090 1094 1097 1099 1102 1107 1109

Miscellaneous Bacterial Infections Syphilis Debabrata Bandyopadhyay Non-Syphilitic Treponematoses Taru Garg Leptospirosis A.P. Sugunan Lyme Disease, Rat Bite Fever, and Other Spirochaetal Infections Kamlesh Tewary Anaerobic Infections R. Sajithkumar Atypical Mycobacteria P.D. Khandelwal Brucellosis B.G. Mantur Donovanosis Dwijendra Nath Gangopadhyay Actinomycosis and Nocardiosis A. Muruganathan Bartonella Infections Pallavi Bhargava Melioidosis Kavitha Saravu

1111 1115 1117 1120 1122 1124 1125 1127 1129 1132 1134

Rickettsial, Chlamydial and Mycoplasma Infections Rickettsial Infections Raminder Singh Chlamydial Infections T.K. Suma Mycoplasma Infections Dilip Mathai

1135 1138 1141

Viral Infections Basic Considerations of Viral Diseases Usha K. Baveja Herpes Virus Infections Aditya Prakash Misra Human Papilloma Virus and Parvovirus Infections Neerja Bhatla, Biswa B. Dash Bird Flu and Swine Flu Sandhya Kamath Dengue M.E. Yeolekar Ebola and Marburg Infections Partha Pratim Chakraborty

1143 1148 1151 1155 1158 1161

17.45 17.46 17.47 17.48 17.49 17.50 17.51

F. 17.52 17.53 17.54 17.55 17.56 17.57

G. 17.58 17.59 17.60 17.61

H. 17.62 17.63

Japanese Encephalitis U.K. Misra, J. Kalita Rabies Tarun Kumar Dutta, Ashish Kumar Panigrahi Viral Gastroenteritis Prabhash Chandra Bhattacharyya, Rupjyoti Talukdar Mumps Falguni S. Parikh Measles (Rubeola) R.K. Goyal, Prashant Mathur Smallpox Ramesh Balwant Pandit Lymphocytic Choriomeningitis and Other Arena Virus Infections Deepti Vibha, Garima Shukla Prion Diseases P.K. Maheshwari, A. Pandey

1163 1166 1170

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17.44

1171 1172 1174 1175 1176

Protozoal Diseases Malaria A.K. Agarwal, Sarit Chatterjee Amoebiasis and Giardiasis M.P. Sharma, Vaibhav Gupta Leishmaniasis Shyam Sundar Toxoplasmosis Madhukar Rai Trypanosomiasis Prashant P. Joshi Cryptosporidiosis, Trichomoniasis, Balantidiasis and Isosporiasis Atul Bhasin

1177 1185 1188 1192 1195 1198

Helminthic Diseases Ankylostomiasis, Ascariasis and Other Nematodal Infestations Narender Pal Jain Tapeworm and Hydatid Diseases Anurag Saxena Filariasis and Other Related Infestations Sanjay Zachariah Schistosomiasis/Bilharziasis Kirti C. Patel

1200 1207 1211 1216

Fungal Infections Systemic Fungal Infections Shruti Prem, Rajat Kumar Pneumocystis Jirovecii Infections Prasanta Raghab Mohapatra

1218 1224

SECTION 18: DISORDERS OF METABOLISM 18.1 18.2 18.3 18.4 18.5

Basic Considerations of Metabolism B.K. Sahay Inborn Errors of Carbohydrate Metabolism Siddharth N. Shah Lipids and Lipoprotein Metabolism Soneil Guptha Disorders of Purine and Pyrimidine Metabolism R.V. Jayakumar Iron Metabolism and Iron Overload Syndrome Mukesh Desai

1228 1229 1232 1240 1243 xxxv

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18.6 18.7 18.8 18.9 18.10 18.11 18.12

The Porphyrias Dhanpat Kumar Kochar, Abhishek Kochar Wilson’s Disease Sanjib Sinha, A.B. Taly Lysosomal Storage Disorders Prasanta Kumar Bhattacharya Inherited Disorders of Membrane Transport S.K. Singh Amyloidosis Manisha Sahay Disorders of Adipose Tissue and Obesity Shashank R. Joshi Metabolic Syndrome Anoop Misra

1253 1257 1263 1266 1271 1275 1279

SECTION 19: NEPHROLOGY 19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 19.10 19.11 19.12

Kidney—Structure and Functions Sanjay K. Agarwal Kidney Disease—A Clinical Approach Vijay Kher Acute Kidney Injury Alan F. Almeida, Jatin P. Kothari Chronic Kidney Disease Ashok L. Kirpalani, Hardik Shah Primary Glomerular Diseases Vinay Sakhuja, Sanjay D’ Cruz Secondary Glomerular Diseases O.P. Kalra Urinary Tract Infections R. Kasi Visweswaran, Praveen Namboothiri Nephrolithiasis and Urinary Tract Obstruction P.D. Gulati Vascular Injury to Kidney A.S. Narula, A.K. Hooda Polycystic Kidney Disease and Inherited Tubular Disorders P.P. Varma, Ranjith Nair Dialysis for Chronic Renal Failure N.K. Hase Renal Transplantation George T. John

1282 1286 1291 1295 1302 1310 1316 1319 1323 1327 1333 1339

SECTION 20: NEUROLOGY 20.1 20.2 20.3 20.4 20.5

xxxvi

Basic Considerations in Neurology R.S. Wadia Neurological Disorders—A Clinical Approach M.V. Padma Srivastava Clinical Neurophysiology J. Kalita, U.K. Misra Neuroimaging Rakesh K. Gupta, Sunil Kumar Epilepsy Sanjeev V. Thomas

1345 1351 1357 1364 1371

20.7 20.8 20.9 20.10 20.11 20.12 20.13 20.14 20.15 20.16 20.17 20.18 20.19 20.20 20.21 20.22 20.23 20.24 20.25 20.26 20.27 20.28 20.29 20.30 20.31 20.32

Disorders of Speech Apoorva Pauranik Disorders of Cranial Nerves Sankar Prasad Gorthi, Sundaram Venkatraman Ischaemic Cerebrovascular Diseases P.M. Dalal Haemorrhagic Cerebrovascular Diseases M.V. Padma Srivastava, Ajay Garg Cerebrovenous Thrombotic Disorder D. Nagaraja, N. Karthik Bacterial Meningitis and Brain Abscess Ravindra Kumar Garg Neurotuberculosis Shyamal Kumar Das, Deb Sankar Guin Neurosyphilis S. Prabhakar, M. Modi Acute Viral Infections of Central Nervous System Nadir E. Bharucha Slow Virus Infections and Prion Diseases S.K. Shankar Fungal and Parasitic Diseases of Nervous System Ashok Panagariya, Bhawna Sharma Raised Intra-Cranial Pressure and Hydrocephalus Daljit Singh Dementia P.S. Mathuranath Extrapyramidal Disorders B.S. Singhal Hyperkinetic Movement Disorders Mohit Bhatt Cerebellar Disorders Pramod Kumar Pal Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases B.K. Bajaj Demyelinating Diseases of Nervous System Man Mohan Mehndiratta, Rohit Kumar Garg Nutritional and Toxic Disorders of the Nervous System U.K. Misra Metabolic Disorders of Nervous System Vrajesh Udani Intra-Cranial Space Occupying Lesions P. Sarat Chandra, P.N. Tandon Head Injury A.K. Singh Myelopathies S.Venkataraman Peripheral Neuropathy A.K. Meena Disorders of Autonomic Nervous System Garima Shukla Myasthenia Gravis Sumit Singh, Atma Ram Bansal Diseases of Muscles S.V. Khadilkar

1383 1390 1401

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20.6

1411 1418 1422 1428 1434 1437 1443 1446 1451 1454 1459 1464 1468 1477 1482 1490 1496 1505 1511 1518 1529 1540 1543 1546

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SECTION 21: ONCOLOGY 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 21.9 21.10 21.11 21.12 21.13 21.14 21.15 21.16 21.17 21.18

Basic Considerations of Oncology S.H. Advani Principles of Cancer Biology and Pathology Anita M. Borges Cancer Screening and Prevention Atul Sharma, M.P. Ram Prabhu Principles of Drug Treatment of Cancer Lalit Kumar, Prabhat Singh Malik Principles of Radiotherapy G.K. Rath Head and Neck Cancers V.P. Gangadharan Breast Cancer Vinay H. Deshmane Tracheobronchial and Lung Cancers Kirti M. Patel Tumours of the Gastrointestinal Tract (Stomach and Oesophagus) K.M. Mohandas Colorectal Cancer K. Govind Babu Genitourinary Cancers Sudeep Gupta Gynaecological Malignancies P.P. Bapsy, Ankit Jain Soft Tissue Sarcomas Avinash Deo Cancer of Unknown Primary Site Hemant Malhotra Paraneoplastic Syndromes Senthil Rajappa, D. Raghunadharao Cancers in the Predisposed Host K. Pavithran Oncological Emergencies Avinash Deo Supportive Care in Cancer Madhuchanda Kar, Rakesh Roy

1556 1561 1565 1568 1576 1579 1581 1586 1594 1598 1601 1606 1613 1616 1622 1626 1629 1632

SECTION 22: PSYCHIATRIC MEDICINE 22.1 22.2 22.3 22.4 22.5 22.6 22.7 22.8 xxxviii

Basic Considerations in Psychiatry Ashit Sheth Anxiety Disorders Uday Chaudhuri Bipolar Mood Disorders Lakshman Dutt, Rakesh Sanghadiya Somatoform Disorders Vihang N. Vahia, Amit Kulkarni Psychotic Disorders and Schizophrenia R. Thara Delirium, Dementia and Other Cognitive Disorders Venu Gopal Jhanwar Substance Related Disorders S.M. Channabasavanna Psychiatric Emergencies J.K. Trivedi

1636 1640 1645 1649 1652 1657 1661 1670

22.10

Psychotherapy Vidhyadhar Watve Biological and Somatic Treatments of Psychiatric Disorders E. Mohan Das

1674 1678

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22.9

SECTION 23: PULMONARY MEDICINE 23.1 23.2 23.3 23.4 23.5 23.6 23.7 23.8 23.9 23.10 23.11 23.12 23.13 23.14 23.15 23.16 23.17 23.18 23.19 23.20

Respiratory System—Structure and Functions S.K. Chhabra Pulmonary Disorders—A Clinical Approach Jyotsna M. Joshi Pulmonary Disorders—Diagnostic Procedures Gautam Ahluwalia, Surendra K. Sharma Upper Respiratory Tract Infections D.G. Jain Bronchial Asthma Virendra Singh, Ajeet Singh Chronic Obstructive Pulmonary Disease Surendra K. Sharma Pneumonia Dhiman Ganguly, Sumit Sengupta Suppurative Pleuro-Pulmonary Diseases Dheeraj Gupta, Navneet Singh Pulmonary Tuberculosis M.S. Jawahar Fungal Infections of Lungs Ashok Shah Diffuse Interstitial Lung Disease S.K. Jindal Eosinophilic Lung Disease and Tropical Pulmonary Eosinophilia Farokh E. Udwadia Occupational and Environmental Lung Diseases Ashutosh Nath Aggarwal Sarcoidosis V.K. Vijayan Sleep Related Breathing Disorders R. Narasimhan, A.R. Gayathri Pulmonary Embolism and Deep Vein Thrombosis Jamshed D. Sunavala, Shruti M. Tandan Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall Alladi Mohan Atelectasis and Pulmonary Fibrosis Rupak Singla Benign and Malignant Tracheobronchial Tumours Lalit Kumar, M.P. Ram Prabhu Cor Pulmonale Sandeep Singh

1686 1690 1695 1701 1704 1711 1719 1726 1734 1740 1745 1751 1754 1758 1764 1767 1774 1784 1790 1798

SECTION 24: RHEUMATOLOGY 24.1 24.2 24.3

Basic Considerations of Rheumatology Rohini Handa Soft Tissue Rheumatism and Regional Rheumatic Pain Syndromes Ved Chaturvedi Low Backache C. Panchapakesa Rajendran, S. Rajeswari

1804 1808 1813 xxxix

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24.4 24.5 24.6 24.7 24.8 24.9 24.10 24.11 24.12 24.13 24.14 24.15 24.16 24.17

Osteoarthritis Siddharth Kumar Das Gout and Other Crystal Arthritides U.R.K. Rao Rheumatoid Arthritis A.N. Malaviya Spondarthritides Milind Y. Nadkar Sjögren’s Syndrome Uma Kumar Systemic Lupus Erythematosus V.R. Joshi Antiphospholipid Syndrome Vikas Agarwal Systemic Sclerosis R. Porkodi, S. Rajesh The Vasculitides Pradeep Bambery Mixed Connective Tissue Disease and Overlap Syndromes G. Narsimulu, Vara Prasad IR Inflammatory Muscle Diseases Alakendu Ghosh, Pradyot Sinhamahapatra Rheumatic Manifestations of Systemic Diseases Debashish Danda Miscellaneous Rheumatic Disorders Binoy J. Paul Emergencies in Rheumatology Lata S. Bichile, Vaibhav C. Chewoolkar

1818 1822 1829 1844 1851 1853 1860 1863 1867 1876 1879 1883 1886 1891

SECTION 25: NUTRITION 25.1 25.2 25.3 25.4 25.5 25.6 25.7 25.8 25.9

Nutrition—Basic Considerations S.V. Madhu Assessment of Nutritional Status Prema Ramachandran Protein Energy Malnutrition Piyush Gupta Water Soluble Vitamins Milind Y. Nadkar Fat Soluble Vitamins Ghan Shyam Pangtey Minerals, Trace Elements and Antioxidants M. Raghunath, D. Sreeramulu Food Allergy and Food Intolerance U.V. Mani Eating Disorders Anupam Prakash Enteral and Parenteral Nutrition Varsha

SECTION 26: POISONING 26.1 26.2 xl

AND

1896 1900 1904 1909 1913 1917 1922 1924 1927

TOXICOLOGY

Poisoning—Basic Considerations and Epidemiology N.P. Singh, Gurleen Kaur Aluminium Phosphide Poisoning S.N. Chugh

1934 1936

26.4 26.5 26.6 26.7 26.8 26.9 26.10 26.11 26.12 26.13 26.14

Organophosphorous Poisoning Surjit Singh Corrosive Poisoning Rakesh Kochhar Alcohol Poisoning Pritam Gupta, Ankur Gupta Plant Poisoning D.K.S. Subrahmanyam Drug Overdose Nusrat Shafiq Snake Bite Poisoning H.S. Bawaskar Scorpion Sting H.S. Bawaskar Fluorosis D. Raja Reddy Lathyrism U.K. Misra, J. Kalita Epidemic Dropsy Navneet Sharma Heavy Metal Poisoning Praveen Aggarwal Miscellaneous Poisoning Subhash Varma, Vikas Suri

1939 1941 1944

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26.3

1947 1950 1955 1960 1965 1970 1972 1974 1983

SECTION 27: ENVIRONMENTAL MEDICINE 27.1 27.2 27.3 27.4 27.5 27.6 27.7 27.8 27.9 27.10 27.11

Basic Considerations of Environmental and Occupational Diseases Randeep Guleria Climate Change—Health and Disease Anil Gurtoo Environmental Pollution Ashok A. Mahashur Air-Borne Pollutants and Smoke-Related Hazards Rajeev Gupta Drowning, Near-Drowning and Submersion Injury Yudh Dev Singh Electric Shock and Lightning Injury Naveet Wig, Sourabh Malviya Effects of Extremes of Temperature Rajvir Bhalwar High Altitude Medicine Anuj Chawla Aviation Medicine J.S. Kulkarni Radiation Hazards A.M. Samuel Environmental Disasters M.E. Yeolekar, Milind Y. Nadkar

1990 1993 1998 2001 2006 2008 2011 2017 2024 2028 2034

SECTION 28: MISCELLANEOUS 28.1 28.2

Geriatric Medicine Vinod Kumar Sexual Medicine Prakash Kothari

2038 2042 xli

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28.3 28.4 28.5 28.6 28.7 28.8 28.9 28.10 28.11 Index

xlii

Sports Medicine Anant Joshi Diet in Medical Diseases Siddharth N. Shah Care of Terminally Ill Anil Chaturvedi Exercise and Yoga in Health and Disease S. Dwivedi, Shiva Narang Adult Immunisation R.K. Singal, A.K. Agarwal Perioperative Management Prabha Adhikari Law and Medicine N.K. Grover Travel Medicine Yash Pal Munjal Nanotechnology and Nanomedicine Ramchandra D. Lele

2046 2050 2058 2061 2063 2069 2073 2077 2081 I–1

Section

1

Introduction The Practice of Medicine Yash Pal Munjal

1.1 INTRODUCTION The history of practice of medicine is as old as the history of mankind. Over the years, medicine has gradually evolved and the modern medicine in its present form came into existence about 400 years ago. The last century has seen tremendous progress which is phenomenal and a lot more than in the preceding three centuries. Despite this explosion of knowledge, medicine still remains ‘an art and science’ to be practiced with compassion, empathy, and effective communication with the patient. In today’s practice, the patient is an informed partner in the plan of his management. This sea change in the medical practice is due to the emergence of new technologies which facilitate a physician to delve into the disease at its molecular level with the help of various biochemical, immunological, and genetic tests. There has been a marked improvement in the imaging technology. We have travelled a long distance from the time of conventional radiology to an era of PET and SPECT scanning. These have improved our capabilities to look into every nook and corner of the body and its organs.This has helped in arriving at a correct diagnosis and also to evaluate the functional status of the organ system. All these investigations with their sensitivity and specificity have armed the clinician to arrive at a diagnosis, plan effective treatment and prevent disease, if possible. Not only science has made rapid strides in diagnosis but also there has been a very significant improvement in the therapeutic modalities. The growing knowledge of genetics and immunology has enabled the clinician to provide treatment based on the molecular defect and individualising therapy accordingly. The advent of information technology and internet has changed the way we learn medicine and keep our knowledge up-to-date about the latest innovations in medicine. It has given us the capability of maintaining medical records in a comprehensive manner so that they are more useful to the patient as well as help the doctor to follow the patients very effectively. Difficult clinical problems can be solved easily. Patient’s records can be transmitted to other institutions and doctors for information.Telemedicine as a discipline has a great relevance, particularly in the context of developing countries, especially India, where there is a shortage of trained and expert medical manpower. This helps to provide medicare to patients in remote places where trained personnel are not available. Even sitting at one place, a senior surgeon can guide surgical procedures at more than one centre.

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In this phenomenal progress of scientific knowledge, the basic goal remains to diagnose and treat the patient effectively and as early as possible. In this exercise, due consideration has to be given to the quality of life achieved and cost benefit ratio. It is the latter part which is the practice of the ‘art’ of medicine. This is learnt and mastered by practice, experience, and gradual understanding of the diverse human nature over the years.

The Practice of Medicine Yash Pal Munjal AMALGAMATING THE ART AND SCIENCE OF MEDICINE The scientific technology has enabled the physician to arrive at a diagnosis at the molecular level. It is now possible to understand the cause and complex mechanisms involved in the pathogenesis of disease. This constitutes the science of medicine. Once the diagnosis is established, the doctor has to inform the patient about the diagnosis, plan of management, and prognosis. He has to get the concurrence from the patient for the line of management to be followed. It is this communication skill of the clinician which wins confidence, faith and builds a healthy relationship between the doctor and the patient. This is an ‘art’ to be nurtured. The task of a physician becomes rather delicate especially in situations which involve management of incurable and terminal stages of diseases. In a situation like this, the scientific knowledge at the command of a doctor is to provide adequate and effective relief from symptoms. The doctor and his team should not be carried away by the life-saving procedures used in the hospitals. In such situations, the doctor has to inform the relatives and the patient about the gravity and prognosis of the terminal diseases in a manner that the patient can understand and discuss with his doctor properly. It is an exercise to prepare the relatives and the patient to face the grave situation with forbearance and equanimity. This exercise has to be carried out by the doctor with all the compassion and empathy at his command so that he is able to communicate to the patient effectively and subtly. The doctor who can handle such delicate situations effectively earns the respect of the patient and the family. This is in true sense of the word an ‘art’ which a doctor has to imbibe and master over the years. PRINCIPLES OF MEDICAL PRACTICE Clinical Evaluation The art of clinical evaluation has to be learnt and mastered by everyone studying medicine. This forms the basic foundation on which the future course and technological advancement can be used effectively and rationally in a cost effective manner. Therefore, it is absolutely essential for every practising doctor not to lose sight of this part of clinical medicine thinking that technological advances can take away the importance of clinical examination. The clinical evaluation of a patient comprises of two major aspects: 1. History of sickness of the patient 2. Comprehensive physical examination History The history of illness should include all the facts of medical significance in a chronological order and in a comprehensive way. Eliciting the history of the patient is an art which a doctor develops over a period of time. He should be able to guide the patient and to encourage him to narrate the history of his

The history taking and talking to the patient is the first step towards developing an effective and unique doctor-patient relationship. The patient is encouraged at all times to narrate his condition in detail. This will give him the satisfaction of having communicated to the doctor all about his sickness. The feeling that the doctor was receptive to his condition and sickness helps in building a rapport between the patient and the doctor. Physical examination The physical examination should be carried out at a place which is comfortable, ensures privacy and maintains dignity of the patient. It has to be comprehensive and complete from head to toe. The physical examination has to identify the clinical signs of disease and confirm the structural and functional changes. The clues may have been provided by the patient in his history. There are no shortcuts in physical examination as they may lead to major errors in diagnosis. Competence in physical examination comes by knowledge, experience, and following the methods of clinical examination in all its detail. Progress of clinical disease alters the physical signs from time to time and therefore a good clinician must carry out the physical examination repeatedly and periodically. Not only the ethical attributes of the clinician but also an alert mind is absolutely mandatory for getting the best information from the physical examination. The success of a good history and physical examination yields information which prepares the clinician to prescribe diagnostic tests which will clinch his diagnosis rather than unnecessary and multitude of tests which cause unnecessary escalation of cost and add to confusion (Figure 1). The clinical examination provides useful input to the clinician about the line of investigation and whether to give credence to some symptom and physical sign or not depends not only on his knowledge but also is an art of medical practice.

Figure 1: Hippocrates (460–380 BC).

Investigations The investigations have significantly improved in their sensitivity and specificity so as to provide accurate diagnosis. The diagnostic tests help clinicians to:  Establish the diagnosis  Assess the degree of malfunction and extent of disease  Make a rational plan for management which may be medical, surgical, or palliative  Assess the benefit of therapeutics and interventions.

The Practice of Medicine

illness with all its details in a manner which is useful and easily comprehensible. He guides the patient to give the details rather than getting into trivia which may be irrelevant to the medical problem. He may pose questions which guide the patient to narrate the relevant details. To complete the history, personal, past, and family history have to be recorded. The family history is important as it can provide useful clues to certain genetic disorders as well as certain communicable diseases which may be transmitted from one member of the family to the other. Similarly, the details of history provided by the family members may be helpful especially in dealing with psychological disorders.

A good clinician is able to plan the investigations which are essential and appropriate in a given clinical situation. After the results of constellation of tests are available he should be able to interpret them in the clinical context. The judicious use of investigations limits the cost and helps to arrive at a diagnosis in an effective and useful manner. Decision-Making in Clinical Practice A physician has to take decisions at various stages during the clinical course of sickness. These have to be in consonance with the informed consent of the patient. The first level of decisionmaking is to arrive at a provisional diagnosis based on the history and physical examination. At this level, he has to plan the investigations as well as start provisional treatment so that there is no further deterioration in the condition of the patient. As soon as the results of investigative procedures are available, his clinical skill is once again called into play to arrive at a definitive diagnosis by following the principle of deductive science and plan a definitive course of treatment. This is the second level of decision-making. After the treatment has been initiated and continued, the response can be an improvement in the condition of the patient or there may be no change in the condition of the patient or it may get worse. This is the next level of decision-making where the doctor has to review his previous diagnosis, order fresh investigations so that missing link is detected. In case the patient shows benefit of treatment then he has to decide how long to continue the treatment so that the patient is restored to his health. Not only the subjective improvement but also an objective assessment has to be made based on the clinical and laboratory parameters which have to be decided by him. Evidence Based Medicine This concept means that the clinical decisions to be taken are fully supported by data that is derived from prospectively designed randomised controlled clinical trials over a fairly long period of time. This is in marked distinction to the previous concept of following the treatment based on one’s experience and bias towards one form of treatment than the other. It is imperative for today’s doctor to take decisions based on hard outcome data from large clinical trials. To get this implemented many National and International Organisations have formulated Practice Guidelines which help the physician and other members of his team in making a diagnosis and taking appropriate therapeutic decisions. These guidelines provide the framework for managing patients with a diagnosis or clinical symptoms and also help to create a standard of medical care so that all patients get the benefit of cost effective and proven therapies. They help to protect the doctors from frivolous charges of medical malpractice and cost overruns due to

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unplanned treatment. However, these guidelines have to be used with caution and must be based on the clinical constellation of a particular clinical condition. In case more than one options are available for treatment which is scientifically proven, the physician cannot be faulted for choosing one option for the other option. In planning a treatment, the other factors which have to be taken into consideration are the age and sex of the patient and associated medical conditions, and drug-drug interaction. Assessment of the Success of Treatment Previously the assessment of result was based on clinical examination and subjective feelings. Nowadays the evaluation is based on hard outcomes data to judge the success of treatment. This is in the form of prevention of morbidity and mortality. In case of chronic illnesses where cure is not possible, assessment of treatment is based on not only the symptomatic relief but also by finding out that if the progress of the disease has been stalled and complications have been prevented. Another parameter which helps in assessing the benefit of treatment is the quality of life which the patient enjoys after the treatment. Therefore, summing up in today’s context, it is predominantly an objective outcome assessment as compared to the olden times. There are certain modifying situations which can change the parameters of assessment like the age and sex of the individual.The delivery of medical care has to be assessed in the context of available resources and infrastructure. It is essential and obligatory for the doctor to provide compassionate care with empathy, understanding and constant dialogue with the patient (this is always possible) even with limited resources and infrastructure. MEDICAL ETHICS As soon as the foundation of the modern system of medicine was laid the practice of medicine was ‘put into guiding principles’ by the famous Hippocratic Oath. If we delve into the ancient Indian literature, similar guidelines were propounded much earlier by Sushruta/Charak Samhita, Aryabhatta Smriti, etc. (Figures 2A and B).They have elaborated on various aspects of code of conduct, qualities of physician as well as human aspects of relationship. Among the qualities and characteristics of physician, special emphasis was laid on character (purity, honesty, and integrity), qualification (knowledge, skill, and experience), professional attitude (alert, responsive, communicative, and responsible), and behaviour (friendly,

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B

Figures 2A and B: (A) Sushruta (800 BC); (B) Charak (300 BC).

respectful, and compassionate). The basic tenets of these guidelines were to ‘provide patients good doctors’. The good doctors are supposed to make patient care their first concern and, therefore, they need to be competent (good medical education). They should keep their knowledge and skills up-todate (continuing medical education). They should maintain good relationship with the patients and professional colleagues, be honest particularly to themselves and act with integrity (Ethics of Medicine). The various national and international agencies have provided guidelines for the practice of doctors in their respective countries. In India, the Code of Conduct has been framed by the Medical Council of India. This is modified from time to time based on the socio-cultural needs and advancement of medical knowledge. The responsibilities and duties of a doctor formulated by various organisations are based on the following principles enumerated in Table 1. Table 1: Responsibilities and Duties of a Doctor Patient care should be your first priority Keep the dignity and privacy of every patient and he should be dealt with politeness and consideration Do not be judgmental. Listen to the patients and respect their information Communicate in a manner the patients understand and make patients equal partners in decision-making Keep your professional knowledge and skills up-to-date You must practise and manage patients to the level of competence and knowledge acquired by you Refer patients at appropriate time to a higher centre or a super specialist at the earliest possible occasion, if required Keep the information given to you confidential and to be divulged only under extremes of circumstances Do not abuse your position as a doctor Your dealings with the colleagues and pharmaceutical industry should not raise conflict of interest and your conduct should be in the best interest of the patient Provide adequate information and take ‘informed consent’ before any drug trial or ‘off label use’ of any drug

Implementing Medical Ethics Medical ethics are also concerned with the standards of care and the ethical issues raised by the practice of medicine. Recent scientific knowledge and their usage have thrown many difficult ethical problems which are still in the process of debate. In these situations the doctor has to decide based on his belief and the sociocultural milieu. Some of the issues under debate are cloning, genetic medicine, abortion, care of the brain dead for organ transplant, and need of live tissues. Another issue which is a matter of concern and debate is the issue of assisted suicide or euthanasia. In clinical practice the ethics come into play in three vital areas. The clinical ethics are concerned with the relationship between the doctor and the patient. Another area is the conduct of research on patients which is guided by the research ethics while public health ethics deal with the health of the community, state, or country as a whole. CLINICAL ETHICS In clinical ethics, four principles are important and they can be abbreviated to autonomy, beneficence, non-maleficence, and justice.

Informed consent It is the fundamental right of an individual that his body is inviolable. Therefore, a doctor needs to have permission from the individual for his examination, investigations and therapeutic procedures including interventions and surgeries. The patient has to be informed about the method adopted for diagnosis and the line of his management. In case, there are more than one options for treatment then the details of all the options with their pros and cons have to be explained. This communication must be done in a manner that the patient understands and in his language. After this, he should give his consent in writing to carry out that treatment or procedure. Legally and morally, the patient has the absolute right to take a decision about what is right or wrong for him. Sometimes, the choice of the patient may seem irrational and not in accordance with the professional advice. But it should not be construed that he lacks the capacity and mind to take appropriate decision for himself. In situations where he is incapacitated to take a decision on his own, e.g. in children, unconscious patients or insane individuals, the treatment may be planned in consultation with the explicit permission of the relatives. In case the relatives are not available then a group of physicians may take a decision on behalf of the patient depending on the local laws and culture. Confidentiality The details of the history, treatment, and prognosis have to be kept confidential. All communications and other records relating to the patient’s care are to be treated as confidential documents. This information can be shared between health care professionals if the patient is referred to another institution or a consultant. In other situations, the authorisation in writing by the patient is a must. The confidentiality clause can be rescinded for due process of law and in cases of insurance or a medical claim. This right of confidentiality has been over-ruled in cases where the condition is infectious (e.g. HIV or AIDS) by right to healthy life of the other person who is likely to be in his contact or where the community interest suffers. Beneficence This means acting in the best interest of the other person. In clinical ethics, it means the benefit of individual patient based on the patients’ point of view as well. In situations where there is a conflict of interest between the benefit of the individual patient over that of the community, the declaration of Geneva by World Medical Association entitles a doctor to follow the dictum “Health of my patient will be my first consideration”. Non-Maleficence This means do no harm. In traditional medicine, the concept followed is ‘primum non nocere’. In the practice of medicine beneficence and non-maleficence have to be balanced (benefit versus risk). Relevant information on the above two grounds

must be shared with the patient so that he is able to make an informed decision. Justice This means availability and access to the health care by every individual irrespective of caste, creed, social and economic status. It mandates an equitable distribution of health care resources. One associated concept is that of utility, i.e. greatest good for the greatest number must be evaluated for an individual patient. Justice means being fair to him and it involves evaluation of the needs of the patient, respecting his rights as well as the merit.

The Practice of Medicine

Autonomy The respect and dignity of the patient has to be maintained at all times. Truthful communication with the patient is always a must though it is not essential to inform him of the facts in the first instance especially in critical illnesses or certain disorders (HIV) which have a lot of social stigma attached.

PUBLIC HEALTH ETHICS Public health involves the health of the community, state or country as a whole; no direct doctor patient relationship exists. This involves preventive measures like education, mass vaccination, mass screening for diseases and precautions to be taken at the community level. In prevention of certain lifestyle diseases like diabetes, coronary artery disease and obesity, there may be a conflict of interest with the corporates who are dealing with the marketing and advertisement of such substances like alcohol, tobacco, junk food, etc. To resolve these situations of conflict of interest social organisations and medical professionals may have to lobby with the politicians to educate the society to demand action against the sale, marketing and use of these substances if necessary, by laws. In India, a major step has been implemented that all advertisements pertaining to tobacco and its derivatives (e.g. cigarettes, bidis, hookah and chewing tobacco) have been banned and even at the individual level their use at public places is prohibited (by law). Restrictive measures may at times become a necessity. In an explosion of epidemic to prevent its further spread certain legislations may have to be passed. This was recently amplified and implemented in cases of severe acute respiratory syndrome (SARS) and avian flu. Such interventions are for the good of the general community at large. Another important aspect of public health ethics is the uniform and equitable distribution of funds for various disorders with a view that maximum people may draw benefit. RESEARCH ETHICS The conduction of research is a vital component of medical practice. It may provide a sound basis of care for a better and more effective treatment for subsequent patients.The principles of information, beneficence, non-maleficence and justice should be strictly adhered to in all research protocols. The guidelines for conduct of good research have been formulated and must be strictly followed. The patients consenting for trial should be offered due care and they must be compensated both for their time, travel and reimbursement of the other expenditure incurred by them. Such reimbursement should not appear to be an inducement to the patient, health care institutions and the doctors. END OF LIFE SITUATIONS A doctor is faced with the dilemma of communicating the diagnosis of certain incurable diseases or a disease in its terminal stage to the patient and/or his relatives. In such situations, the

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doctor must be sure about the diagnosis that the disease is incurable, or it has advanced to such an extent that it is in its terminal stage. The doctor is not necessarily bound to divulge the complete information at the time of first contact with the patient, but it is imperative for him that he must confide, educate the patient and the relatives about the gravity of situation and its consequences. This can be done slowly and progressively. The physician should provide this information in a manner that it is easily understood by the patient and other persons attending him so that they can appreciate the gravity of the situation. The doctor should be willing to discuss the details and answer necessary questions of the patient or his family members. This exercise has to be done with compassion, empathy, and it is an art which a physician has to master and practice by knowledge and understanding. The doctor sometimes gets overwhelmed with the prospect and availability of advanced life saving methods (e.g. ventilators, pacemakers, etc.) in an aggressive manner. But it is always important for him to remember the basic fact about the gravity of the sickness and its consequences. Symptomatic and pain relief have to be addressed aggressively to provide comfort to the patient round the clock. During the terminal stages of any disease it is not only the medical treatment which has to be provided but religious, cultural and other supportive measures also have to be used judiciously, and they should be facilitated so that the patient and his relatives are at peace and comfort. ENVIRONMENTAL MEDICINE A number of chronic and infectious diseases are emerging and posing a threat to the health of countries. It is believed that due to rapid industrialisation and urbanisation which has led to the degradation of the environment polluting the air, water, and significant lowering of the hygiene. According to WHO estimates, nearly one-fourth (24%) of the global disease burden and 23% of all deaths can be ascribed to environmental factors. This deterioration in the environment can lead to a spurt in the infectious diseases, chronic non-communicable diseases, and trigger certain genetic disorders due to mutation of genes. Due to global warming and increasing carbon dioxide in the atmosphere, it is estimated that the prevalence of vector borne diseases, like malaria and some of the infectious diseases, are likely to increase manifold. The environmental factors that lead to genetic variation concerning the cholesterol synthesis may precipitate increase of coronary artery disease significantly. A physician has to be well-versed with the various environmental pollutants, environment at work place, and have a working knowledge of some of the environmental and occupational diseases. DISASTER MANAGEMENT

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The environment and nature are friendly to the human beings most of the times but at times the ravages of nature can bring death, destruction and disease in a sudden and unexpected manner. Some natural disasters that have struck in the recent times where thousands of lives were lost—Tsunami in South India and Sri Lanka and a few years later we had a very severe Tsunami and earthquake in Japan. These natural disasters led to the outbreak of many infectious diseases and there was an associated increase in vector borne illnesses. The marvel of

technological advancement by science is useful to the mankind most of the time but due to an accident it may lead to a disaster. To mention a few examples of technology related disasters are—the Gas leak in Bhopal (MP) in 1984 the so called Union Carbide Gas Leak, the Chernobyl Russian Nuclear Power Plant Explosion in 1986, and the radiation spread by the damage of the Nuclear reactors in the area of Tsunami in Japan in 2011 have led to disastrous consequences. Man himself can unleash disasters like the bombing of Hiroshima and Nagasaki in Japan, chemical and biological warfare. It is the management of such emergencies in which there are mass casualties that it needs courage, presence of mind and a well-planned action so that misery can be minimised. In this situation, the health care professionals have to work in close collaboration with the society. The various phases in which the emergency management has to be carried out are described below. Mitigation Mitigations are concerted efforts to prevent hazards from developing into disasters altogether or to reduce the effects of disasters when they occur. The mitigation phase differs from the other phases because it focuses on long-term measures for reducing or eliminating risk. Mitigation is the most cost efficient method for reducing the impact of hazards while it may not always be feasible. Preparedness It is to train people to fight the disease and, therefore, it involves planning, organising, training, equipping, exercising, evaluation and improvement over a period of time. It helps to ensure coordination and increased capability to deal with disasters, terrorist attacks and man induced disasters. Response This phase includes the mobilisation of the necessary emergency services and first responders in the disaster area. Recovery The recovery phase aims at restoring the affected area and population to its normal state.The focus of this phase is different from response phase, recovery efforts are started after immediate needs are addressed. In recent years there has been a shift in emphasis from response and recovery to strategic risk management and reduction. There is more emphasis on community participation rather than a Government centred approach. Efforts involve the provision of emergency management training for first responders, the creation of a single emergency telephone number and the establishment of standards for emergency medical staff, equipment and training. The physician therefore has to learn how to handle acute emergencies especially in situations where there are mass casualties. In India, the Disaster Management Authority of India has been set up by the Government of India to deal with such situations and prepare the infrastructure in the country. MEDICAL GENETICS The study of genes and their function in health is called Genetics in Medicine while the understanding of the aberrations in the function and structure of genes is Medical Genetics. The advent of medical genetics has profound

The understanding of genetic disorders and how we can manipulate them has provided a new dimension to the art of genetic counselling in which the patient can be briefed about the likelihood of the genetic disorders which the offspring is likely to suffer. In case it is possible to correct the genetic defect the same may be done by genetic engineering. If it is as yet not correctible then counselling can be done about the consequences of the genetic disorder and its prognosis so that the parents can take appropriate decision at the beginning of the conception. Another important area of genetics is pharmacogenomics. It deals with pharmacological manipulation of the genes for correction of

of learning skills for a clinician who can take the benefit of the same at a place and time of his convenience. Video conferencing provides useful tool for interactive learning and teaching a large number of students at different locations by an expert in the field from a common site. Live case demonstrations and procedures can be learnt by direct telecast.The other advantage is that one can assess his grasp of the subject by taking web based examinations in the privacy of his chamber. The internet has also served the purpose of educating the patients about their sickness and disease.

The Practice of Medicine

influence on our understanding of the pathophysiology of disease and has opened new vistas of therapy especially the concept of planning and executing individual requirement based therapy. The greatest breakthrough was achieved in the spring of 2003 when complete sequencing of human genome was officially announced and released. This has ushered in an era of immense possibilities of not only cloning of species but repairing of many organ systems. The science of genetics has provided us the speed to understand the pathogenesis of disease epidemics. The discovery of new variant of coronavirus as a causative agent for SARS and the virus of avian flu; this has helped to quickly plan the management of these conditions.

COMPLEMENTARY AND ALTERNATIVE SYSTEMS OF MEDICINE Complementary and alternative medicine (CAM) is a diverse group of health care medical systems which does not conform to the commonly practised modern system of medicine. CAM is used and practised globally and in one survey it was found that 36% of people opted for CAM in the year 2002 in USA, while in a recent survey in UK, homoeopathy was used as a method of treatment in approximately 48% of patients. If we include faith, spiritual healing and prayers, then the number goes to approximately 62%. In India, this percentage is much higher and the various commonly used alternative systems of medicine are Ayurveda, Unani, Siddha, Homoeopathy (Figure 3), religious, yogic practices, and household remedies. Systems from other countries, such as accupuncture, reflexology, and osteopathy, have also been used quite frequently in recent times.

(a) Genetic defects or management of certain disease states especially cancer (b) Choosing the appropriate medicine for a particular disease based on the genetic profile of the individual (c) Another aspect of this is the use of stem cells. Stem cells are totipotent cells which can grow up into various tissues. These are now being used in many areas of clinical medicine like coronary artery disease, diabetes mellitus, healing of the wounds and rejuvenating organs. Stem cells are being extracted from the cord blood on the birth of the child. These can be preserved for a number of years and are capable of providing treatment or repair of certain damaged organs at a later stage in life. These stem cells provide the individual with homologous graft. The interaction between the genes and environmental factors i.e. phenotype can predispose to the common chronic diseases of the 21st century like obesity, diabetes, hypertension, and coronary artery disease which can be partially prevented or ameliorated by modifying the lifestyle factors. CONTINUING MEDICAL EDUCATION The science of medicine is galloping at a fast pace and, therefore, it is essential for the practising physician to learn new skills and knowledge so that he can serve the best interest of his patients. A doctor has to keep learning all through the time he is practising. The avenues available for medical education these days consist of learning from the peers in the field, the books and journals which are being brought at a fast pace. The technological advancement has significantly improved the way one can learn medicine. The availability of internet and video conferencing has added new tools with great potential

Figure 3: Christian Friedrich Samuel Hahnemann, Founder of Homoeopathy (1755-1843).

The large acceptance of CAM therapy is due to the perception that it does not have side effects (which may not always be true); it is easily accessible and comparatively cheaper form of therapy. All these therapies are based on perception and individual beliefs. The other major disadvantage and shortcoming of this therapy is that it is not backed by clinical evidence and poor or no standardisation of the medicines is done. Since this form of therapy is used very widely and frequently, therefore gradually and universally people and politicians are taking it up and certain regulatory bodies are established. In India, also there is a registering body which registers the doctors

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who are trained in Homoeopathy, Ayurvedic, or Unani systems of medicine. The government is making efforts to put these forms of medical management on scientific basis and trying to amalgamate it with the modern system of medicine. This concept of integrated health care is being developed. Therefore, today’s physician has to know the good and bad of CAM so that he can keep abreast with the changing times and practice of medicine. Integrated Health Care This concept of amalgamated complementary and alternative medicine with modern system of medicine in a manner that it is useful to the patient is gradually evolving itself. How effective and useful will it be to medical profession and patients? The coming few years may answer this question a little more definitively. The 21st Century Physician The science based technology has expanded at a very fast pace in the later part of 20th century. The cytomolecular basis of disease is better understood. The progress in imaging modalities

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has improved the sensitivity and specificity of tests.The complete sequencing of genes, the ease and the cost with which it can be mapped and modified have raised immense possibilities of even managing certain incurable and difficult clinical conditions. It has opened vistas of individualised and highly specific treatment.The use of stem cell therapy has enabled to cure and repair organs. This relentless progress is likely to continue during this century. Therefore a physician has to be well informed and trained in these advances and their rationale use. In this backdrop, the importance of clinical skills to provide a good humane treatment with kindness, justice, and autonomy, to the patient will remain of prime importance for centuries to follow. RECOMMENDED READINGS 1.

Blank L, Kimball H, McDonald W, et al. Medical professionalism in the new millennium: A physician charter 15 months later. Ann Intern Med 2003; 138:839.

2.

Bligh J. Learning about science is still important. Medical Education 2003; 37:944-5.

3.

BMA Ethics Department. Medical Ethics Today: The BMA’s Handbook of Ethics and Law; 2nd Ed. London: BMJ Publishing; 2004.

Section

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Clinical Approach to Key Manifestations Section Editor: A.K. Agarwal 2.1 Pain—Mechanisms and Management D. Rama Rao, Niranjan P. Moulik 2.2 Headache K. Ravishankar 2.3 Chest Pain Sanjay Tyagi, Amit Mittal 2.4 Acute Abdomen—Non-Surgical Causes Sumeet Singla, A.K. Agarwal 2.5 Cough Suman Kirti 2.6 Haemoptysis Randeep Guleria, Jaya Kumar 2.7 Jaundice Aparna Agrawal 2.8 Upper Gastrointestinal Bleeding J.C. Vij 2.9 Fever of Unknown Origin Priscilla Rupali 2.10 Generalised Lymphadenopathy S.K. Verma 2.11 Dizziness and Vertigo M. Maiya 2.12 Syncope Pushpa Yadav, Vivek Arya 2.13 Coma B. Vengamma

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Pain—Mechanisms and Management D Rama Rao, Niranjan P Moulik

Pain serves to protect the body from harm and promotes healing of damaged tissues. The International Association for the Study of Pain defines pain as ‘an unpleasant sensory and emotional experience associated with tissue damage and/or described in terms of such damage’. It is important to recognise that pain is a perception and not a sensation. The perception of pain is believed to be the summation of sensory-discriminative component (e.g. location, intensity, quality), a motivationalaffective component (e.g. depression, anxiety), and a cognitiveevaluative component (e.g. thoughts concerning the cause and significance of pain). The patient’s account of pain should be evaluated and treated as per the patient’s perception of pain. This can be irrespective of the existence and severity of tissue damage. A noxious stimuli is sensed by the body’s ‘nociceptive’ system and generates a physiological and behavioural response. This stimulus can be generated by traumatic, inflammatory, neoplastic or other mechanisms, and sustained by neuroplastic changes even after healing. It is believed that it is this neuroplasticity which maintains chronic pain, although the exact pathophysiology of chronic pain is yet to be elucidated.

Although, pain being a subjective phenomenon, is not easy to assess, a variety of validated pain scales are available to assist in the measurement of pain. Pain assessment tools include simple unidimensional scales or multidimensional questionnaires.

Nociceptive stimuli are carried by primary afferent neurons the cell body of which lie in the dorsal root ganglia (Figure 1).These are small diameter nerve fibres, type A delta and C fibres and are usually free nerve endings found in the skin, muscle, joints and some visceral tissues/organs.The processes of transduction, transmission, modulation and perception are all involved in the activation of the sensory system. The first order neurons relay to the axons of second order neurons, the cell bodies of which lie in the thalamus and they in turn transmit the sensations to the somatosensory cortex in the post-central gyrus of the cerebrum. However, there are considerable areas of modulation in the central as well as the peripheral components of the pain pathways; and these form the basis for differing action of various pain-alleviating therapies.

TREATMENT Pain treatment can be divided into pharmacological, nonpharmacological and alternative medicine approaches.Acute pain effectively responds to nonsteroidal anti-inflammatory drugs (NSAIDs) or to mild-to-moderate efficacy opioids. Acetaminophen and NSAIDs are effective in mild-to-moderate intensity pain while opioids can be used for moderate-to-high intensity pain. A combination of NSAID and opioid can be used for severe intensity pain and has been found to be beneficial in achieving adequate pain relief. Common NSAIDs usually block both cyclooxygenase-1 and -2 enzymes and hence, COX-2 inhibitors were developed. However, use of COX-2 inhibitors has fallen into disrepute and the traditional NSAID like ibuprofen, diclofenac, nimesulide, naproxen, ketorolac, indomethacin continues to be used.

Nociceptive pain primarily involves injury to somatic or visceral tissues. However, neuropathic pain results from direct injury or dysfunction of the nervous system (central or peripheral). Pain is classified usually as acute (short-duration and usually remittent) or chronic (longer duration and persistent). ASSESSMENT OF PAIN A comprehensive assessment is required for optimal pain management. The aim is to have a clear understanding of the patient’s pain problem, in terms of its aetiology, pathophysiology and syndrome. This requires a detailed history, and systemic examination is carried out to unravel the pain characteristics, impact of pain on multiple domains, relevant pre-morbid conditions, existing co-morbidities, history of substance use, previous investigations carried out and treatment taken. 10

Unidimensional scales include the numeric rating scale, the visual analogue scale and the faces pain scale. The former two include pictorial line scales which the patient uses and marks the intensity on a scale of 1 to 10 or no pain at all to worst possible pain.The faces scale has pictures of 6 to 8 different facial expressions depicting a range of emotions again along a 0 to 10 linear scale. It is particularly useful for use in young children, patients with language barriers, or having mild-to-moderate cognitive impairment. The multidimensional pain scales/questionnaires detail a more comprehensive pain assessment and apart from the intensity of pain also focus on the location and quality and effect of pain on mood and function. They are a bit time-consuming and cognitively-impaired and uneducated may find them difficult. The McGill Pain questionnaire and the Brief Pain Inventory are two such well-validated multidimensional pain measurement tools.

Chronic or persistent pain benefits transiently with these agents. Physiotherapy measures and physical treatments can be offered for chronic pain, while behavioural and psychological therapies do play a significant role as adjuncts in chronically depressed patients. Stimulation therapies like acupuncture and transcutaneous electrical nerve stimulation (TENS) have also been found to be beneficial. Apart from the NSAID and opioids which are also used for chronic pain, other pharmacological agents used include antidepressants (tricyclics, serotonergic uptake inhibitors and selective norepinephrine reuptake inhibitors), membrane stabilising agents like carbamazepine, gabapentin and pregabalin, local lidocaine plasters/patches. The commonly used drugs along with their dosages are listed in Table 1. Despite the availability of numerous analgesic drugs, the clinical relief to patients for chronic pain has remained far from

Pain—Mechanisms and Management Figures 1A and B: Pain signals are transmitted to the brain by two main pathways. The lateral system (A) is made up of long thick fibres that transmit information about the onset of injury and its precise location and intensity. They are designed to carry a rapid flow of pain signals to the thalamus to stimulate an immediate anti-nociceptive response. The medial system (B) is composed of phylogenetically older fibres that carry slower signals and probably transmit information related to the persistence of injury and level of response induced.

Table 1: Commonly Used Drug Dosages for Pain Anti-depressants Tricyclic anti-depressants—amitriptyline 10 to 25 mg bedtime, increase step-wise to 150 mg twice/day Duloxetine 30 mg twice/day, increase to 120 mg/day. Venlafaxine: 25 mg tid Anti-convulsants Carbamazepine 200 mg tid; Clonazepam 0.5 mg tid; Gabapentin 100 to 300 mg at bedtime to 3,600 mg/day in 3 divided doses; Pregabalin: 75 mg twice daily to 600 mg/day Opioid agonist Tramadol 50 mg once or twice to maximum of 400 mg/day Morphine Analogues: Morphine 30 mg every 4 hours or as needed; Codeine 200 mg every 3 to 4 hourly. Nonsteroidal anti-inflammatory drugs: Aspirin 650 mg 4 to 8 hourly Contd...

Contd... Indomethacin 50 mg 8 hourly Piroxicam 20 mg 24 hourly Ketoprofen 50 mg 8 hourly Ibuprofen 400 mg 6 hourly Diclofenac 50 mg 8 hourly

satisfactory. Researchers are presently investigating role of nerve growth factor monoclonal antibodies, targeting sodium and calcium membrane ion channels and mechanisms based on activated microglia (non-neuronal cells implicated in the pathophysiology of chronic pain) to achieve breakthrough in alleviating chronic pain. RECOMMENDED READINGS 1.

Burgess G, Williams D. The discovery and development of analgesics: new mechanisms, new modalities. J Clin Invest 2010; 120: 3751-7.

2.

Recommendation for pharmacological management of neuropathic pain: An overview and literature update. Robert Dworkin, AK Bannox Joseph Audette et al. Mayo Clin Proceedings 2010; 85 (3): S3-S14.

11

2.2 INTRODUCTION Headache is one of the most common of human complaints. It could be due to a number of causes ranging from a mild head injury to a serious brain tumour or more often it could be a disorder unto itself such as migraine. Headaches can be primary or secondary. Primary headaches are benign headaches where clinical examination and investigation including imaging are normal, e.g. migraine, tension-type headache and cluster headache. Secondary headaches have an underlying structural, vascular, metabolic or infective cause, e.g. headaches due to brain tumours, meningitis or subarachnoid haemorrhage. Approximately 90% of headaches seen in practise are primary headaches. The skull, much of the pia-arachnoid, the dura over the convexity of the brain, and the parenchyma of the brain are insensitive to pain. The pain-sensitive structures in the head are given below: 1. The skin, subcutaneous tissue, muscles, extracranial arteries, and the periosteum of the skull. 2. The intracranial venous sinuses, especially in the pericavernous region. 3. Parts of the dura at the base of the brain and the arteries within the dura and pia-arachnoid. 4. The middle meningeal and superficial temporal arteries. 5. The structures of the eye, the ear, the nasal cavities, and the sinuses. 6. Optic, oculomotor, trigeminal, glossopharyngeal, vagus and the first three cervical nerves. Sensory stimuli are conveyed to the central nervous system through the trigeminal nerve, particularly the first and to some extent the second division; they carry impulses from the forehead, orbit, anterior and middle cranial fossa. A specific classification system — ‘the classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain’ was proposed by the International Headache Society in 1988 and the same was revised in the year 2004. All headache disorders have been organised into 14 major groups and divided into 257 different subtypes. Groups 1 to 4 cover primary headaches and groups 5 to 14 cover secondary headaches. APPROACH TO THE PATIENT WITH HEADACHE History Pattern recognition is most important for headache diagnosis. The same patient can have more than one type of headache. It is better to generate a routine set of questions under pre-set headings. The following aspects of the history are important in arriving at a diagnosis.

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Temporal Profile The mode of onset and progression are critical in deciding whether one is dealing with a benign or a serious headache. A

Headache K Ravishankar chronic recurrent headache or a chronic non-progressive daily headache represents a primary headache, such as migraine, cluster headache or tension-type headache. Sudden onset of a severe headache suggests possible vascular involvement such as a subarachnoid bleed or an acute infective cause like meningitis. There are some forms of primary headaches which may have a sudden onset such as coital headache or crash migraine and although the suddenness and severity may suggest an organic illness, it may be possible to diagnose them in retrospect only after their recurrent nature manifests. Progressively worsening headache suggests increasing intracranial pressure or uncontrolled systemic disease. Although presence of focal or lateralising features makes the diagnosis easier, it is the subacute headache which is more difficult to interpret. These headaches develop over weeks or months and the aetiology could be benign or serious. Therefore, specific information regarding progressive worsening needs to be sought. Some headaches like cluster headache may occur at the same time everyday. In some the headaches may increase towards the evening as with tension-type headache, and in some like migraine, the headaches may occur first thing in the morning and awaken the patient from sleep. Rare primary headaches like cluster headaches and their variants are grouped together as trigemino-autonomic cephalgias ( TACs). These are short-lasting and occur several times in a day and are diagnosed by their characteristic pattern and associated autonomic features like conjunctival injection, lacrimation or rhinorrhoea. The age of onset is also important. Migraine begins at a younger age and is more common in females aged 25 to 40 years whereas tension-type headache is common in middle age. Headaches beginning after 50 years of age should be investigated for potential secondary causes. Any change in headache pattern should always raise suspicion of an organic pathology. The longer the history the more the likelihood of a benign underlying cause. When the head pain is chronic and occurs on a daily or near daily basis for more than 15 days per month, one uses the label of chronic daily headache (CDH). It is essential to establish if we are dealing with primary CDH or secondary CDH. The following entities are included under the heading of long-lasting primary CDH: 1. Chronic migraine 2. Chronic tension-type headache 3. Hemicrania continua 4. New daily persistent headache All these conditions may present with or without medication overuse. When faced with a patient who has CDH, it is essential

Location and Type of Headache The type of pain, its location and severity are important for diagnosis. Unilateral pulsating or throbbing headaches indicate an underlying vascular involvement as in migraine but migraine headaches are also known to be bilateral. Other vascular headaches can also be throbbing in nature. Cluster headaches are almost always unilateral in the same location during a cluster period, and rarely shifts sides.Tension-type headaches are diffuse, dull and generally bilateral. With secondary headaches, the location of the headache, the nature and severity would vary depending on the anatomical location of the lesion and the mechanism involved in pain production. In addition to getting the patient to describe the site and quality of the pain, rating the severity on a 10-point scale is useful in assessing progress of the headache and in gauging the response to treatment. The Accompaniments In all patients with headache, one must establish the presence or absence of nausea, vomiting, hypersensitivity to light and noise and associated neurological involvement. Absence of an established history of recurrent headaches or precipitation by triggers should prompt consideration of an underlying organic cause. Associated features like fever, arthralgias and malaise suggest systemic disease. Associated neurological deficits or auras, such as transient visual symptoms or hemisensory deficits, support a diagnosis of migraine with aura. Other neurologic accompaniments need appropriate investigations to differentiate between complicated migraine and transient ischaemic attacks (TIAs), vascular anomalies or a seizure disorder. The typical behaviour of a migraine patient who tries to sleep undisturbed in a dark room is in contrast to that of the patient with a cluster headache who cannot stay still and keeps pacing around. A positive family history can provide a clue to the diagnosis of migraine. Headache that occurs regularly just before or during the menstrual periods is likely to be menstrual migraine. Hypertensive headache is more common in the morning, sinusitis headache is worse on bending, eyestrain headache occurs more towards the evening and the headache of cervical arthritis is more intense after a period of inactivity. Provoking and Relieving Factors Primary headaches such as migraine can frequently be provoked by missing meals or going out in the hot sun. Trigger factors in the Indian setting are listed in Table 1. Medical History Careful questioning for systemic illnesses is essential, e.g. malignancy anywhere in the body should raise the possibility of cerebral metastases. Likewise vascular headaches in a patient with a history of spontaneous abortions or thromboembolic events should raise the possibility of antiphospholipid antibody syndrome. Systemic diseases can be a contraindication to the

use of certain drugs, e.g. beta blockers would be contraindicated in a diabetic or an asthmatic. Table 1: Migraine Triggers Food items

Food additives Alcohol Hormonal changes Physical exertion Visual stimuli Auditory stimuli Olfactory stimuli Sleep Weather changes Head or neck trauma Hunger Stress and anxiety

Headache

to determine the duration of the headache. With an arbitrary time limit of 4 hours, daily headaches can be grouped as shortlasting (< 4 hours) or long-lasting (> 4 hours). Examples of shortlasting CDH are cluster headache and other TACs. Recurrent attacks of short duration head pain would favour the diagnosis of cluster headache or one of its variants like chronic paroxysmal hemicrania.

Cheese, dairy products, paneer (cottage cheese), citrus fruits, chocolates, onions, sea food Monosodium glutamate (MSG), aspartame, nitrates, caffeine Red wine, beer Menstruation, ovulation Excessive exercise, fatigue Bright lights, glare Loud noise or music Perfumes and certain odours Too much or too little

EXAMINATION OF THE PATIENT WITH HEADACHE Routine examination helps exclude hypertension, meningitis, or systemic febrile illnesses. Additional examination may be necessary in order to increase the yield in headache patients. Palpation over the head and neck is necessary to detect tender trigger-points; auscultation over the skull, the carotid and vertebral vessels can identify bruits; temporomandibular joint and cervical spine palpation for tenderness and movement limitations; look for temporal artery tenderness; check the mental status, the cranial nerves and look for asymmetry in power and look for reflexes. INVESTIGATION OF THE PATIENT WITH HEADACHE Certain features in the history or examination (Table 2) should raise the suspicion of ominous disease and warrant further work-up. These are termed as danger signals’ or ‘red flags’. Table 2: Headache Danger Signals Sudden onset of a new severe headache Progressively worsening headache or change in the pattern of the headache Headache that is unresponsive to treatment Onset of headache with exertion, such as sexual activity, coughing or sneezing Onset of headache after 50 years of age Headache associated with change in neurological status Headache with abnormal examination findings

Laboratory Testing The CBC, erythrocyte sedimentation rate (ESR) and relevant blood chemistry should be obtained in all patients. It helps to rule-out unsuspected systemic diseases. In an elderly patient suspected with giant cell arteritis, ESR and C-reactive protein are helpful. Cerebrospinal Fluid Examination Cerebrospinal fluid (CSF) examination must be considered in patients when there is fever or associated cranial nerve deficit. Opening and closing pressures must be documented, particularly in cases of pseudotumour cerebri or idiopathic intracranial hypertension which can sometimes present with

13

intractable migraine-like headache and may not always be associated with papilloedema.

to severe unrelenting migraine attacks that last more than 72 hours.

Neuroimaging Imaging must be done whenever there are danger signals. Avoid imaging scans if there is a history of similar headaches in the past or if examination is normal, or if the headache improves with treatment.

Management Once trigger factors are identified, preferably with the help of a ‘headache diary or headache calendar’, drug treatment needs to be selected depending on the severity and the level of disability. Ideal management of migraine should concentrate on three major areas:

Magnetic resonance imaging (MRI) is now rapidly becoming the standard diagnostic test for head and face pain, particularly with the advantage of non-invasive evaluation of the vasculature by MR angiography and MR venography. An MRI has many advantages over a CT in a headache patient. In the appropriate setting one must investigate further with digital subtraction angiography (DSA). PRINICIPAL HEADACHE VARIETIES Primary Headaches Migraine Migraine manifests with recurrent headaches associated with nausea, vomiting, photophobia or phonophobia with or without an aura. It is more common in women (2 to 3:1) and a family history is often present (60% of cases). Attacks begin in late childhood, adolescence and early twenties. Majority of the patients with migraine, 80% have migraine without aura. Clinical features Migraine should always be thought of as a complex neurological disorder with headache being one of the common presenting features. There may be other accompanying neurological, gastrointestinal or autonomic features as shown in Table 3. Table 3: Accompaniments of Migraine Gastrointestinal: Anorexia, nausea, vomiting, diarrhoea Visual disturbances: Blurring, photophobia Motor abnormalities Brainstem features: Vertigo, ataxia, diplopia, dysarthria Autonomic disturbances: Hypertension, hypotension, tachycardia, bradycardia, nasal congestion, and peripheral vasoconstriction Fluid retention Psychological upsets, confusional states

The typical attack of migraine consists of a sequence of events divided into four different phases, that blend imperceptibly with each another: the prodrome, the aura, the headache and the postdrome. Pathophysiology The possibility that a migraine attack may be initiated by cortical spreading depression is the most favoured hypothesis. This condition is a transient disruption of neuronal activity in the brain accompanied by a flux of sodium, calcium ions into the cells. This results in a brief burst of electrical activity followed by electrical silence, which progresses as an expanding concentric wave through the brain at the same rate as a developing migraine aura.

14

Migraine variants Depending on the accompanying neurologic deficit, there are different variants of migraine, such as hemiplegic migraine and basilar migraine. Status migrainosus is the term applied

1. Control of trigger factors 2. Treatment of the acute attack 3. Long-term prophylactic medication Pharmacotherapy For mild-to-moderate attacks, simple analgesics like aspirin or acetaminophen suffice. Combining with an anti-emetic like metoclopramide or domperidone, which increases gastric motility and enhances the absorption of other drugs, is more beneficial. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective in mild to moderate cases. For moderate-to-severe attacks, triptans and ergotamine are useful as abortive drugs. When the patient is vomiting, injectable diclofenac or ketorolac is recommended. Narcotic injections should not be used in migraine. Sumatriptan is a 5HT 1D agonist that blocks neurogenic inflammation in the trigemino-vascular system. It is available as 25 mg, 50 mg, and 100 mg tablets and as a nasal spray. Unlike ergotamine, it is effective when given at any time during the attack and has a better safety profile; it works rapidly and also relieves nausea, vomiting, photophobia and phonophobia. Recurrence of headache because of the short half-life is a major disadvantage with sumatriptan, but is less with the newer second generation triptans, like rizatriptan, eletriptan, zolmitriptan and naratriptan. Chest symptoms including tightness and pressure in the throat, neck and chest are more common with sumatriptan than with other triptans. Contraindications to triptans include ischaemic heart disease, uncontrolled hypertension or concomitant use of ergotamine derivatives or other 5-HT1 agonists. Rizatriptan is available as 5 mg and 10 mg tablets. Steroids may occasionally be used as alternatives when all other drugs fail. Recurrent episodes of migraine need simultaneous prophylactic treatment. Beta-blockers, calcium-channel blockers, methysergide, cyproheptadine, tricyclic antidepressants and anticonvulsants like divalproex and topiramate are used prophylactically. In most instances, prophylaxis need not be continuous, but is used for specific trial periods with drug-free intervals until the frequency is controlled. Tension-Type Headache Tension-type headache occurs more commonly in patients subjected to stress, anxiety and depression. It begins as episodes and progresses to a chronic form where headaches occur almost daily and do not appear to be associated with any overt psychological factors. Clinical features The headache is usually generalised and of long duration. The patient experiences a constant pain and obtain temporary relief with analgesics and sleep. There are no associated symptoms,

Treatment The physician should attempt to identify the stress or emotional problem underlying the headache. Anxiety may be controlled by use of a mild antidepressant. Depressed patients may benefit from a tricyclic antidepressant such as imipramine or amitriptyline. When sleep is disturbed, it is important to establish a normal sleep pattern using short-acting hypnotic agents. When tension-type headache is associated with an emotional problem, the patient should be referred for psychiatric evaluation and treatment. Cluster Headache Cluster headache is a devastating painful headache, mostly affecting men.The term ‘cluster headache’ reflects the clustering of headache attacks in time. It is considerably less common than migraine and begins in the second or third decade of life. There is a periodicity to the attacks with seasonal clustering. Typically pain peaks lasts from 30 to 180 minutes and may occur 1 to 3 times per day. The pain is usually spontaneous, but can be provoked by alcohol. Patients describe the pain as excruciating or penetrating and on the same side during each cluster. The pain is accompanied by lacrimation, rhinorrhoea or ptosis. Differential diagnoses include diseases of the orbit, tumours of the brainstem or occipitocervical junction, infiltration/infection of the brainstem and cavernous sinus disorders. MRI should be done in all patients with cluster headache. Treatment Symptomatic treatment includes oxygen inhalation at about 7 litres per minute, parenteral dihydroergotamine (DHE), or parenteral sumatriptan 6 mg. Zolmitriptan nasal spray has been found to be useful for the acute treatment of cluster headache. Drugs for the prophylactic therapy of cluster headache include: 1. Verapamil given in doses as required, starting with 120 to 240 mg daily. 2. Lithium carbonate in a dose of 150 mg twice daily with periodic check-up of drug levels and watch for side-effects. 3. Steroids are very effective in preventing attacks, but are not indicated for long-term use. 4. Methysergide is an effective medication in treating chronic cluster headaches; 2 mg is the starting dose and the dosage is gradually increased, but retroperitoneal fibrosis is a side-effect. 5. Divalproex and other anticonvulsants like topiramate have also been found to be useful in prevention of cluster attacks. Other Trigemino-Autonomic Cephalgias (TACs) and ShortLasting Headaches There are some head pains which are considered variants of cluster headache, but they differ in being very responsive to indomethacin and in their short duration and high frequency of attacks. The best example of this is chronic paroxysmal hemicrania which is characterised by frequent daily attacks of severe, short-lasting, unilateral, orbital, or temporal pain of 20 to 45 minutes duration with associated autonomic features. It is seen mostly in females and is usually responsive to indomethacin.

Secondary Headaches Raised intracranial pressure Any lesion that increases intracranial pressure is likely to cause a progressively increasing headache. Headache as a presenting feature will depend on the nature and location of the mass. Posterior fossa lesions raise intracranial pressure rapidly. The headache is usually generalised, may not fit into any particular pattern, slowly increases in intensity and leads to drowsiness and confusion following which focal neurological signs develop. Neuroimaging helps in the early detection of some of these lesions.

Headache

like vomiting, photophobia or phonophobia. The diagnosis can be established by a good history.

Intracranial haemorrhage Head trauma can lead to epidural or subdural haematomas. Intracerebral haemorrhage is usually sudden in onset and can produce incapacitating headache with focal neurological symptoms and depressed consciousness. A subarachnoid haemorrhage due to rupture of an aneurysm or arteriovenous malformation produces an explosive incapacitating headache with vomiting, decreased level of consciousness and signs of meningeal irritation.This possibility should be kept in mind in every patient who presents with sudden onset headache and the diagnosis must be confirmed by doing a CT or lumbar puncture. Meningitis The headache is usually accompanied by fever, stiff neck, vomiting, and the diagnosis is confirmed by CSF examination. Idiopathic intracranial hypertension Idiopathic intracranial hypertension or pseudotumour cerebri presents with headache and visual obscurations along with other signs of increased intracranial pressure. It usually occurs in young, obese women; CT/MRI reveals small ventricles and on examination the patient may have decreased vision and usually but not necessarily there is papilloedema. Lumbar puncture shows evidence of increased opening pressure. MR Venography is a must in these patients. Medication overuse headache Medication overuse headache has been variously referred to as analgesic/ergotamine/drug-rebound headache. The headache sufferer who consumes medications for acute attacks on a regular, repeated and predictable basis is at risk of developing chronic daily headaches that are caused by overuse of medication. The most significant feature is that the headache typically persists throughout the whole day, is present on waking and is described as a dull, diffuse headache. Complete withdrawal of the analgesic is the only effective treatment. Withdrawal headaches can be treated with NSAIDs and, if detoxification fails, in-patient treatment with chlorpromazine or intravenous dihydroergotamine or subcutaneous sumatriptan can be tried. RECOMMENDED READINGS 1.

Bigal ME, Lipton RB, Tepper SJ, Rapoport AM, Sheftell FD. Primary chronic daily headache and its subtypes in adolescents and adults. Neurology 2004; 63: 843-7.

2.

Headache Classification Subcommittee of the International Headache Society.The International Classification of Headache Disorders. Cephalalgia 2004; 24 (suppl. 1): 1-160.

3.

Ravishankar K. Headache pattern in India a headache clinic analysis of 1000 patients. Cephalalgia 1997; 17: 316-7.

4.

Ravishankar K. Optimising primary headache management. J Assoc Physicians India 2006; 54: 928-34.

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2.3

Chest Pain Sanjay Tyagi, Amit Mittal

INTRODUCTION Chest pain is a very common complaint most often caused by benign conditions, but occasionally it may be due to lifethreatening medical emergencies. Chest pain may be caused by almost any condition affecting the thorax, abdomen or internal organs. The approach to chest pain, therefore, is to exclude benign conditions and to rapidly identify and treat potentially fatal and serious conditions. So, it is critically important to distinguish the two major presentations of chest pain: emergent and nonemergent. Many patients are aware that it is a warning of potentially life-threatening disorders and seek evaluation for minimal symptoms. Other patients, including many with serious disease, minimise or ignore its warnings. Pain perception (both character and severity) varies greatly between individuals as well as between men and women. So chest pain as a symptom should never be dismissed without an explanation for its cause. CAUSES Chest pain may originate from the cardiovascular, pulmonary, gastrointestinal, neurologic, or musculoskeletal systems (Table 1). Table 1: Common Causes of Chest Pain Cardiovascular

Pulmonary

Acute coronary syndrome Aortic dissection Pericarditis and cardiac tamponade Stable angina pectoris

Pulmonary embolism Pneumothorax Pneumonia Pleurisy

Chest wall Costochondritis or Tietze’s syndrome Fibromyalgia Radiculopathy Herpes zoster Psychological Somatisation disorder Anxiety and panic disorders Hypochondriasis

Gastrointestinal Oesophageal reflux disease Hiatus hernia Cholecystitis Gastritis Pancreatitis Others Da Costa’s syndrome Bornholm disease

Overall, the most common causes are:  Chest wall disorders (i.e. those involving muscle, rib, or cartilage)

16



Pleural disorders



GI disorders (e.g. oesophageal reflux or spasm, ulcer disease, cholelithiasis)



Idiopathic



Acute coronary syndromes

PATHOPHYSIOLOGY The thoracic viscera provide afferent visceral input through the same thoracic autonomic ganglia as the chest wall. A painful stimulus in these organs is typically perceived as originating in the chest but because afferent nerve fibers overlap in the dorsal ganglia, thoracic pain may be felt (as referred pain) anywhere between the umbilicus and the ear, including the upper extremities. When the sensation is visceral in origin, many patients deny having pain and insist that it is merely ‘discomfort’. APPROACH TO THE PATIENT While the priority in any patient who presents with chest pain is to exclude catastrophic or life-threatening (cardiac) causes, non-life-threatening aetiologies, which may be functionally disabling, are much more common. The diagnosis of chest pain is difficult but the history often gives an indication of the underlying cause. If there is any suspicion of an acute coronary syndrome (ACS) or other serious cause or any concern regarding the patient’s general well being, then urgent hospital admission should be arranged. The history and physical examination, complemented by selected tests such as an electrocardiogram or chest radiograph help to reach an accurate diagnosis for most causes of chest pain, especially CAD, and to judge which patients are likely to have a benign aetiology (Tables 2 and 3). DESCRIPTION OF THE CHEST PAIN A thorough description of the pain is an essential first step in the diagnosis of chest pain. Quality of the Pain The patient with myocardial ischaemia often vigorously denies feeling chest ‘pain’. More typical descriptions include squeezing, tightness, pressure, constriction, strangling, burning, heartburn, fullness in the chest, a band-like sensation, knot in the centre of the chest, lump in the throat, ache, a heavy weight on the chest and toothache (when there is radiation to the lower jaw). In some cases, the patient cannot qualify the nature of the discomfort, but places his or her fist on the centre of the chest (the Levine sign). A ‘sharp’ or ‘stabbing’ pain with a pleuritic or positional component that is fully reproducible by palpation, in patients who have no history of angina or myocardial infarction, probably indicates a low-risk for the episode being ischaemic. Region or Location of the Pain Ischaemic pain is a diffuse discomfort that may be difficult to localise. Pain that localises to a small area on the chest is more likely of chest wall or pleural origin rather than visceral. Referred pain is an exception.

Cause

Suggestive findings

Diagnostic approach

Acute, crushing pain radiating to the jaw or arm Exertional pain relieved by rest (angina pectoris) S4 gallop Sometimes a systolic murmur Sudden, tearing pain radiating to the back Some patients have syncope, stroke, or leg ischaemia Pulse or BP may be unequal in the extremities Constant or intermittent sharp pain often aggravated by breathing, swallowing food, or supine position and relieved by sitting leaning forward Pericardial friction rub Fever, dyspnoea, fatigue, chest pain, recent viral or other infection Sometimes findings of heart failure, pericarditis, or both

Serial ECGs and cardiac markers Stress imaging test considered in patients with negative ECG findings and no elevation of cardiac marker Chest X-ray, transthoracic or transoesophageal echocardiography CT scan of aorta for confirmation ECG and echocardiography usually diagnostic

Cardiovascular Myocardial ischaemia (acute MI/unstable angina/angina) Thoracic aortic dissection Pericarditis

Myocarditis

Gastrointestinal Oesophageal reflux (GERD) Peptic ulcer

Pancreatitis

Pulmonary Pulmonary embolism Pneumonia

Pneumothorax Pleuritis

Other Musculoskeletal chest wall pain (including trauma, overuse, costochondritis) Herpes zoster infection

Recurrent burning pain radiating from epigastrium to throat that is exacerbated by bending down or lying down and relieved by antacids Recurrent, vague epigastric or right upper quadrant discomfort in a patient who smokes or uses alcohol excessively that relieved by food, antacids, or both Pain in the epigastrium or lower chest that is often worse when lying flat and is relieved by leaning forward Vomiting, upper abdominal tenderness Often history of alcohol abuse or biliary tract disease

Chest Pain

Table 2: Causes of Chest Pain

ECG, serum cardiac markers ESR, C-reactive protein Usually echocardiography Clinical evaluation, endoscopy Sometimes motility studies Clinical evaluation, endoscopy Sometimes testing for H. pylori Serum amylase and lipase Sometimes abdominal CT

Often pleuritic pain, dyspnoea, tachycardia Sometimes, mild fever, haemoptysis, shock Fever, chills, cough, and purulent sputum Often dyspnoea, tachycardia, signs of consolidation on examination Sometimes, unilateral diminished breath sounds, subcutaneous air May have preceding pneumonia, pulmonary embolism, or viral respiratory infection Pain with breathing, cough, pleural rub

D-dimer, echocardiography, CT scan of chest, chest X-ray, lower limb Doppler study Chest X-ray

Often suggested by history Pain typically persistent (typically days or longer), worsened with passive and active movement Diffuse or focal tenderness Sharp, band-like pain mid-thorax unilaterally Classic linear, vesicular rash Pain may precede rash by several days

Clinical evaluation

Chest X-ray Usually clinical evaluation

Clinical evaluation

Table 3: Clinical Features Associated with Specific Diagnostic Categories of Chest Pain Clinical Features

Cardiac

Diagnostic Category Gastrointestinal

Musculoskeletal

Predisposing factors

Smoking Alcohol use

Physically active New activity Overuse Repeated activity

Onset Duration Character

Male sex Smoking Hypertension Hyperlipidaemia Family history At consistent level of exertion Minutes Pressure or tightness

After meals or on an empty stomach Minutes to hours Pressure or gnawing pain

Relieved by

Rest, sublingual nitrate

Food, antacids

With or after activity Hours to days Sharp, localised and movement related Rest, analgesics, NSAID 17

The pain of myocardial ischaemia may radiate to the neck, throat, lower jaw, teeth, upper extremity, or shoulder. A wide extension of chest pain radiation increases the probability that it is due to myocardial infarction. Radiation to both arms is an even stronger predictor of acute myocardial infarction. Acute cholecystitis can present with right shoulder pain, although concomitant right upper quadrant or epigastric pain is more typical than chest discomfort. Chest pain that radiates between the scapulae may be due to aortic dissection. Temporal Elements The time course of the onset of chest pain may be a very useful distinguishing feature:  The pain associated with a pneumothorax or a vascular event such as aortic dissection or acute pulmonary embolism typically has an abrupt onset with the greatest intensity of pain at the beginning.  The onset of ischaemic pain is most often gradual with an increasing intensity over time. A crescendo pattern of pain can also be caused by oesophageal disease.  ‘Functional’ or nontraumatic musculoskeletal chest pain might have a much more vague onset.  The duration of pain is also helpful. Chest discomfort that lasts only for seconds or pain that is constant over weeks is not due to ischaemia. A span of years without progression makes it more likely that the origin of pain is functional.  The pain from myocardial ischaemia generally lasts for a few minutes; it may be more prolonged in the setting of a myocardial infarction.  Myocardial ischaemia may demonstrate a circadian pattern. It is more likely to occur in the morning than in the afternoon, correlating with an increase in sympathetic tone.

Severity The severity of pain is not a useful predictor of CAD. As many as one-third of myocardial infarctions may go unnoticed by the patient. ASSOCIATED SYMPTOMS

Relieving Factors Factors that make the pain better should be established:  Pain that is reliably and repeatedly palliated by antacids or food is likely to be of gastro-oesophageal origin.

Associated symptoms may not reliably distinguish between a cardiac and gastrointestinal origin of chest pain.  Belching, a bad taste in the mouth, and difficult or painful swallowing are suggestive of oesophageal disease, although belching and indigestion also may be seen with myocardial ischaemia.  Vomiting may occur in the setting of myocardial ischaemia (particularly transmural myocardial infarction), in addition to gastrointestinal problems such as peptic ulcer disease, cholecystitis, and pancreatitis.  Diabetic ketoacidosis, which can be precipitated by acute myocardial infarction, is another cause of vomiting.  Diaphoresis is more frequently associated with myocardial infarction than with oesophageal disease.  Dyspnoea: Exertional dyspnoea is common when chest pain is due to myocardial ischaemia and may precede the sensation of angina. Dyspnoea that occurs concurrently with chest pain may be due to myocardial ischaemia or a number of pulmonary disorders including diseases of the airways, lung parenchyma, or pulmonary vasculature.  Cough: The differential diagnosis of chest pain and cough includes infection, as well as congestive heart failure, pulmonary embolus, and neoplasm. Cough, hoarseness, or wheezing may also be the result of gastro-oesophageal reflux disease.  Syncope: The patient with myocardial ischaemia may present with presyncope. However, syncope associated with chest pain should raise a concern for aortic dissection, a haemodynamically significant pulmonary embolus, a ruptured abdominal aortic aneurysm, or critical aortic stenosis (particularly if the patient has a history of exertional dyspnoea).  Palpitations: Patients with ischaemia can feel palpitations resulting from ventricular ectopy, or may have an abnormal awareness of their sinus rhythm. While atrial fibrillation is associated with chronic CAD, new onset, isolated atrial fibrillation is uncommon in patients with acute myocardial infarction.  Psychiatric symptoms: Symptoms of panic disorder, generalised anxiety, depression, or somatisation may occur in patients with chest pain. Panic disorder is present in 30% or more of patients with chest pain who have no or minimal CAD; it may also coexist with CAD.



RISK FACTORS

Provoking Factors The patient should be asked about factors that provoke or make the pain worse:  Discomfort that reliably occurs with eating is suggestive of upper gastrointestinal disease.  Post-prandial chest pain may be due to gastrointestinal or cardiac disease; in the latter case it can be a marker of severe myocardial ischaemia (e.g. left main or three-vessel CAD).  Chest discomfort provoked by exertion is a classic symptom of angina, although oesophageal pain can present similarly.  Other factors that may provoke ischaemic pain include cold, emotional stress, meals, or sexual intercourse.  Truly pleuritic chest pain is worsened by inspiration and may be exacerbated when lying down.  Causes of pleuritic chest pain include pulmonary embolism, pneumothorax, viral or idiopathic pleurisy, pneumonia, and a pleuropericarditis.

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

distinguish gastrointestinal from ischaemic chest pain. On the other hand, pain that abates with cessation of activity strongly suggests an ischaemic origin. The pain of pericarditis typically improves with sitting up and leaning forward.



Pain that responds to sublingual nitroglycerin may be of either oesophageal or cardiac aetiology. Relief of pain following the administration of a ‘GI cocktail’ (e.g. viscous lidocaine and antacid) does not reliably

The clinical impression raised by the patient’s description of pain must be interpreted together with other aspects of the history, including risk factors for various aetiologies of chest pain.

CVS Examination A complete cardiac examination including auscultation and palpation should be performed in a sitting and supine position to establish the presence of a pericardial rub or signs of acute aortic insufficiency or aortic stenosis. Ischaemia may result in a mitral insufficiency murmur or an S4 or S3 gallop.

PAST HISTORY A past history of CAD, symptomatic gastro-oesophageal reflux, peptic ulcer disease, gallstones, panic disorder, bronchospasm, or cancer is very helpful in making a diagnosis. It is important to establish if the present symptoms are similar to those which occurred when the diagnosis was previously established. A history of diabetes mellitus should heighten the concern for a nonclassic presentation of CAD. It is important to exclude recent blunt trauma to the chest that can result in pneumothorax, disruption of the aorta, tracheobronchial tree, and oesophagus, myocardial or pulmonary contusion, or chest wall injury with associated musculoskeletal discomfort.



PHYSICAL EXAMINATION The focused physical examination is used to support or disprove hypotheses generated by the history. Thus, the extent of the examination is primarily determined by the diagnoses that are being considered. General Physical Examination  The general appearance of the patient suggests the severity and possibly the seriousness of the symptoms (e.g. pallor, diaphoresis, cyanosis, anxiety).  A full set of vital signs can provide valuable clues to the clinical significance of the pain, and may in some cases aid in establishing its origin.  A marked difference in blood pressure between the two arms suggests the presence of aortic dissection. So pulses are palpated in both arms and both legs, BP is measured in both arms. Carotid artery is auscultated for a bruit.  The neck is inspected for venous distension and venous wave forms are noted. Chest Wall Examination Palpation of the chest wall may evoke pain; if so the patient should be asked if this sensation is identical to the chief complaint. Chest wall tenderness may be present concomitantly with myocardial ischaemia. Hyperesthesia, particularly when associated with a rash, is often due to herpes zoster.

Chest Pain

Knowledge about such risk factors provides important information regarding disease likelihood, which may ultimately guide the type and extent of evaluation performed. The presence of hyperlipidemia, smoking, cocaine use, or a family history of premature CAD increases the risk for myocardial ischaemia. Hypertension is a risk factor for both CAD and aortic dissection. Cigarette smoking is a nonspecific risk factor for serious diseases; it is associated with CAD, thromboembolism, aortic dissection, pneumothorax, and pneumonia. A recent infection, especially viral or tuberculosis may precede an episode of pericarditis. Other risk factors for pericarditis include a history of chest trauma, autoimmune disease, recent myocardial infarction or cardiac surgery, and the use of certain drugs such as procainamide, hydralazine, or isoniazid. Age is an important risk factor for CAD; among patients older than 40 years, chest pain resulting from stable CAD or an acute coronary syndrome (unstable angina or myocardial infarction) becomes increasingly common. Men older than 60 years are most likely to suffer aortic dissection, while young men are at the highest risk for primary spontaneous pneumothorax.

Respiratory System Examination Determine if the breath sounds are symmetric and if wheezes, crackles or evidence of consolidation is present. Abdominal Examination A careful examination of the abdomen is important, with attention to the right upper quadrant, epigastrium and the abdominal aorta. Findings which Raise Suspicion of a Serious Aetiology of Chest Pain  

 

Abnormal vital signs (tachycardia, bradycardia, tachypnoea, hypotension) and pulsus paradoxus > 10 mmHg Signs of hypoperfusion (confusion, ashen colour, diaphoresis). Shortness of breath. Asymmetric breath sounds and pulses. New heart murmur.

DIAGNOSTIC TESTING ECG is important in critical evaluation of chest pain particularly when a cardiac aetiology is a possibility. Presence of ECG changes of ischaemia or infarction warrants admission to a CCU. Chest radiography (when cardiac or pulmonary disease is a consideration) may support the initial diagnosis and help avoid missing serious aetiologies of chest pain such as aortic dissection, pneumonia, pulmonary embolism or pneumothorax. Serial measurement of cardiac biomarkers, i.e. creatine kinase (CK), CK-MB and cardiac troponins (I and T) are useful in the emergency department for evaluation of acute chest pain. However, markers may take several hours after the onset of infarction to rise, hence treatment should not be delayed awaiting the results of enzyme levels. Other Useful Investigations Other useful investigations are:  Complete blood counts (to exclude anaemia) 

Renal function tests blood sugar



Liver function test (Cholecystitis) and amylase (pancreatitis)



Exercise electrocardiography and stress echocardiography for evaluation of coronary artery disease in non-acute chest discomfort



Endoscopy for gastrointestinal causes of chest pain.

KEY POINTS/CONCLUSION  With careful history taking and physical examination, supplemented by targeted diagnostic tests, chest pain caused by serious conditions can often be quickly identified for early and immediate treatment.  Immediate life threats must be ruled out first. Quick review of ECG is useful.  Some serious disorders, particularly coronary artery disease and pulmonary embolism, may not have a classical presentation.

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2.4

Acute Abdomen—Non-Surgical Causes

Acute abdomen is defined as a recent or sudden onset abdominal pain (usually within 24 to 72 hours) with frequently associated gastrointestinal symptoms and signs. Acute abdomen is taught classically as a ‘surgical’ topic. A significant number of patients presenting with acute abdominal pain suffer from non-surgical conditions. Hence, an effective approach to the patient with acute abdomen must take into account the realisation that 3 out of every 4 such patients will be suffering from disorders requiring non-surgical intervention.This chapter is focussed on the approach to non-surgical causes of acute abdominal pain. APPROACH TO DIAGNOSIS The most important attribute of the physician evaluating a patient with acute abdominal pain is the ability to think ‘out of the (abdomen) box’. One must be familiar with the various causes of this presentation and then proceed to refute or confirm the individual entities. A structured approach (Figures 1A to C) is easy to remember, fast, useful in resource-poor settings and minimises errors. Once a surgical cause has been excluded (no signs of peritonitis, perforation or obstruction), one can search for medical causes (Table 1). A non-rigid abdomen suggests a medical cause. However, certain surgical processes, initially confined to the visceral peritoneum, manifest as a non-rigid abdomen and only later progress to frank peritonitis when the parietal peritoneum is involved. Such a progression invariably portends the need for surgery.

Sumeet Singla, AK Agarwal –

Lateralised and radiating from back to front of abdomen—spinal pain associated with radiculopathy



Aggravating factors – Increased on deep inspiration/coughing—pleurisy, pleural effusion, pneumonia, spinal pain – Increased during menstruation—endometriosis – Increased in supine position—pancreatitis



Associated features – Vomiting—if vomiting precedes pain, a medical cause is more likely – Appetite—retention of appetite is more likely in a medical cause – Diarrhoea, dysentery—indicates infection or inflammation of the bowel – Rectal bleeding—seen in bowel ischaemia/infarction, inflammatory bowel disease

CLINICAL CLUES TO MEDICAL AETIOLOGIES History

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

Age >65 years consider coronary artery disease, abdominal atheroemboli causing mesenteric ischaemia/ infarction.



Sex in females specific causes like ectopic pregnancy, threatened abortion, endometriosis, ovarian cyst and pelvic inflammatory disease (PID) must be looked for; in males epididymo-orchitis, prostatitis, and varicocoele are common causes of lower abdominal pain.



Nature of the abdominal pain – Insidious onset, diffuse or midline pain—visceral pain – Colicky pain—acute enteritis – Dysaesthetic type of pain—radiculopathy, neuropathy



Radiation of the pain – To the back—pancreatitis, pericarditis – To the right shoulder—Budd-Chiari syndrome, congestive hepatomegaly – To the left shoulder—splenic infarct, massive splenomegaly – Testicular/penile radiation—epididymo-orchitis

Figure 1A: Approach to the diagnosis of a non-rigid acute abdomen.

Acute Abdomen—Non-Surgical Causes

Figure 1B: Algorithm for diagnosing medical causes of upper abdominal pain.

Figure 1C: Algorithm for diagnosing medical causes of lower abdominal pain. (Figure 1A, 1B, 1C based on Martin RF, Rossi RL. The acute abdomen. An overview and algorithm. Surg Clin North Am 1997; 77: 1227-43).

–

High grade fever with/without chills—suggests pyelonephritis, enteritis, pneumonia

abdominal wall haematoma), neuroleptics (neuroleptic malignant syndrome), drugs which can precipitate acute intermittent porphyria (barbiturates, phenytoin, rifampicin, oral contraceptives, etc).



Urethral/vaginal discharge—suggestive of pelvic inflammatory disease, STD.



Frequency and urgency of urine associated with dysuria/ haematuria/graveluria/lithuria—urinary tract infection.



Drug withdrawal—steroids (withdrawal may precipitate acute Addisonian crisis), narcotics, alcohol, and nicotine.



Bloody/unusually dark urine—haematuria, haemoglobinuria due to intravascular haemolysis, acute intermittent porphyria.





Drug history—nonsteroidal anti-inflammatory drugs (NSAIDs) (acute erosive gastritis), vincristine (recent chemotherapy), anti-coagulants (intra-abdominal or

Occupational exposure to heavy metals like lead (battery makers, brass makers, cable makers, foundry workers, paint factory workers and painters), mercury (tube light, CFL and mercury vapour lamp industry), arsenic (production of glass or wood preservation), copper (mining, electrical wires, electroplating industry), asbestos (miners, stone crushers,

21

  

insulations, asbestos sheet industry); risk of scorpion (black widow spider) or snake bites (common krait or Bungarus caeruleus)—farmers, rural areas, sleeping on the floor, living in mud huts. Recent travel to areas endemic for malaria, typhoid, enteric infections. Menstrual history—relation of pain with menses; amenorrhoea. Psycho-social history—unemployed, living alone, divorced, diminutive personality, treated for anxio-depressive disorders, underlying psychoses. In these groups, a higher possibility of psychosomatic causes exists.

Physical Examination The overall appearance of the patient can be very helpful. Patients whose pain is relieved by leaning forward may have pancreatitis. Most patients would be having tachycardia; unusual bradycardia should suggest typhoid, inferior wall myocardial infarction, drugs/toxins, and hyperkalaemia. Marked hypertension could signify porphyria, connective tissue disorders, uraemia, and hyperthyroidism. A patient may be dyspnoeic because of underlying pneumonia, pulmonary embolism, massive pleural or pericardial effusion, myocarditis, myocardial infarction, or metabolic acidosis (Kussmaul breathing). Tachycardia, mildly raised blood pressure and

Table 1: Differential Diagnosis of Medical Causes of Abdominal Pain

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Metabolic/Haematologic A. Familial metabolic Acute intermittent porphyria Haemochromatosis Hereditary angioneurotic oedema B. Endocrine Diabetic ketoacidosis Addisonian crisis Hyperthyroidism/hypothyroidism Hypercalcaemia (hyperparathyroidism) C. Haematologic Sickle cell crisis Acute haemolytic states Leukaemia Coagulopathies Inflammatory Conditions A. Infections Enteric infections Salmonella, typhoid fever Shigella Staphylococcal Yersinia Campylobacter Tuberculosis Viral enterocolitis Parasitic Spontaneous bacterial peritonitis Hepatitis (viral, Q fever, malarial) Mesenteric lymphadenitis Infectious mononucleosis Mumps AIDS-related disorders B. Non-infectious Acute rheumatic fever Systemic lupus erythematous Polyarteritis nodosa Henöch-Schoenlein purpura Inflammatory bowel disease Crohn’s disease Ulcerative colitis Pancreatitis Drug-and toxin-related Conditions Heavy metal poisoning—Pb, Hg, As, Cu NSAIDs Mushroom ingestion Staphylococcus toxin Black widow spider bite Anti-coagulants Narcotic, steroid withdrawal Neuroleptic malignant syndrome Krait envenomation

Referred: Extraperitoneal Causes A. Pulmonary Pneumonia Pulmonary embolism Pleurisy Spontaneous pneumothorax B. Cardiac Angina: acute myocardial infarction Pericarditis Myocarditis Congestive hepatomegaly C. Urologic Pyelonephritis Renal infarct Cystitis Prostatitis D. Obstetric, gynaecologic Non-pregnant Ovarian cyst Salpingitis Dysmenorrhoea Endometriosis First-trimester pregnancy Ectopic pregnancy Normal pregnancy Threatened/incomplete abortion E. Neurologic; spinal Multiple sclerosis Tabes dorsalis; gastric crisis Diabetic thoracic radiculopathy Herpes zoster Abdominal migraine Abdominal epilepsy F. Abdominal wall—rectus sheath haematoma, myositis G. Skeletal Thoracolumbar spine Osteomyelitis Hip—arthritis H. Adynamic ileus and pseudo-obstruction Uraemia Hypokalaemia Constipation I. Splenic infarct Functional Somatisation disorders Hypochondriasis Malingering

The examination of the cardiovascular and respiratory systems may provide very important information viz. rubs, rhonchi, crackles, and murmurs. Examination of the abdomen starts with a careful visual inspection of the skin looking for rashes, discolouration (Grey-Turner’s sign, Cullen’s sign), distension (ascites). Palpate the abdomen for assessing the site of maximal tenderness, presence or absence of rigidity, any intramural swelling/tenderness (haematoma of the rectus sheath), hepatosplenomegaly (leukaemia, malaria, or tuberculosis), shifting dullness (ascites), and costovertebral angle tenderness (pyelonephritis, pyonephrosis, or perinephric abscess). While a diffusely rigid abdomen strongly points to an underlying surgical cause, a soft, non-rigid abdomen increases the likelihood of a medical cause. As a corollary, when abdominal signs are minimal, but the patient’s distress is severe, the physician should consider a medical condition as the cause of pain. Abdominal bruits signify that vascular occlusion may be the cause of pain, as do splenic rubs. A digital rectal examination is not to be omitted. It provides an opportunity to look for perianal skin tags, fistulae and sinuses (Crohn’s disease), to detect blood in the anal canal [inflammatory bowel disease (IBD), colonic infarction], to examine the male external genitalia (epididymo-orchitis, varicocoele) and is especially useful in patients with lower abdominal pain (pelvic abscess, mass, prostatitis) and when a rigid abdomen prevents adequate examination. Likewise, per vaginum examination by a gynaecologist may provide valuable information. It is a good practice to involve a gynaecologist in the evaluation and management of young female patients with acute lower abdominal pain due to the far higher frequency of gynaecological (and hence, surgical) causes in this group. Finally, a neurological examination should be done in patients with gross neurological deficits (weakness of limbs or cranial muscles, sensory deficits, paraesthesiae, seizures and altered sensorium). Lack of objective clinical findings is most often due to observer error; but, if repeated

examinations (and laboratory investigations) do not yield anything, a non-organic cause must be considered. Table 2: Imaging Studies in Acute Abdominal Pain Retroperitoneal disease—CT scan Right upper quadrant and epigastric symptoms—Ultrasound Left upper quadrant symptoms—CT scan with IV contrast Left lower quadrant symptoms—CT scan with IV and oral contrast Right lower quadrant symptoms—Ultrasound Table 3: Clues to the Diagnosis of Medical Causes of Abdominal Pain Abdominal pain associated with: Neurological symptoms and signs—porphyria, snake (krait bite), plumbism, barium carbonate poisoning, collagen vascular disorders, illicit drug use Dark/cola coloured urine—porphyria, acute haemolysis, renal infarction Jaundice—cirrhosis with spontaneous bacterial peritonitis, congestive hepatomegaly, acute Budd-Chiari syndrome, acute hepatitis High fever with/without chills—acute pyelonephritis, atypical pneumonia, basal pneumonia, bacterial enterocolitis, malaria, typhoid fever Multisystem involvement—SLE, PAN Anaemia—sickle cell disease, leukaemia, haemolysis, plumbism, coeliac disease, inflammatory bowel disease Alcoholism—hepatitis, pancreatitis, abdominal tuberculosis, spontaneous bacterial peritonitis Dyspnoea—metabolic acidosis (DKA, sepsis, mesenteric ischaemia, poisonings), pneumonia, myocardial infarction Rectal bleeding—inflammatory bowel disease, enterocolitis, bowel infarction Diabetes—diabetic ketoacidosis, thoracic truncal radiculopathy, acute pancreatitis, acute inferior wall myocardial infarction, mesenteric ischaemia Arthritis—Henöch-Schoenlein purpura, connective tissue disorders, inflammatory bowel disease, reactive arthritis associated with enteric infections Pleural effusion—acute pancreatitis, congestive cardiac failure, disseminated tuberculosis, pulmonary embolism, pneumonia, empyema, SLE Ascites—acute pancreatitis, congestive cardiac failure, spontaneous bacterial peritonitis Skin rash—herpes zoster, Henöch-Schoenlein purpura, vasculitides Azotaemia or uraemia—prerenal causes (diarrhoea, dehydration, acute blood loss), acute glomerulonephritis, collagen vascular disorders Weight loss—tuberculosis, diabetes mellitus, AIDS, chronic liver disease, inflammatory bowel disease Recurrent episodes of acute abdominal pain—acute pancreatitis, porphyria, vaso-occlusive crisis of sickle cell disease, chronic lead poisoning, peptic ulcer, inflammatory bowel disease, mesenteric ischaemia

DIAGNOSIS Laboratory/radiologic investigations must be viewed as confirmatory rather than screening tools. Other than a haemogram and a routine urine examination, all other investigations need to be justified keeping in mind the diagnoses being sought. A low haemoglobin suggests blood

Acute Abdomen—Non-Surgical Causes

tachypnoea may be seen in an apprehensive patient. The elderly, diabetic, uraemic, and immunosuppressed may be normothermic despite being seriously ill. Next, the head and neck should be examined for intraoral lesions, icterus, cyanosis, lymphadenopathy, jugular venous pressure, smell of ketones in the breath, carotid bruits, and lead line on gums. Fundus should be examined for emboli and lipaemia retinalis. Nailbeds should be inspected for infarcts or splinter haemorrhages. Pallor may signify external or internal blood loss, plumbism, addisonian crisis, and haematologic causes such as sickle cell disease, leukaemia or acute haemolysis; patients suffering form chronic diseases such as cirrhosis, uraemia, AIDS and connective tissue disorders, who have become acutely ill, may also be anaemic. Pedal oedema signifies congestive cardiac failure or chronic liver disease. A general visual survey may help characterise the nature of rashes; photosensitive rash of acute intermittent porphyria; purpuric rash of Henöch-Schoenlein purpura or leukaemia; vasculitic rash of systemic lupus erythematosus, polyarterits nodosa or scleroderma; nodular painful rash of fat necrosis in acute pancreatitis; ulcers in sickle cell disease; vesicular rash of herpes zoster and eruptive xanthomas in hyperlipidemia. Examination of joints for active arthritis and of the spine for local tenderness, deformity and paraspinal muscle spasm (suggestive of spinal disease) is not to be missed.

23

loss or haemolysis. Leucocytosis is rather non-specific; however, a neutrophilic leucocytosis suggests an infectious pathology. A lymphocytic or monocytic leucocytosis would be more in line with a viral aetiology, such as infectious mononucleosis. Leucopenia portends a grave prognosis and may be due to severe sepsis, leukaemia, SLE or typhoid. Surgical illness is rare when both TLC and DLC are normal. A routine urine examination is useful in diagnosing urinary tract infections, urolithiasis, glomerulonephritis and diabetic ketoacidosis. An electrocardiogram should be obtained when evaluating a patient with risk factors/past history of atherosclerotic disease and may reveal inferior wall myocardial infarction, myocarditis or pericarditis. A radiograph of the chest is required if physical findings are suggestive of pneumonia, effusion, embolism or congestive cardiac failure. Serum amylase and lipase are required when acute pancreatitis is a strong possibility; beware of false positives due to nonpancreatic hyperamylasemia. Imaging helps to differentiate the two. In a patient with right hypochondrial pain with/ without jaundice and hepatomegaly, it is prudent to order serum bilirubin, AST, ALT, and ALP levels. Serum sodium and potassium estimation may help in diagnosing certain conditions. Hyponatremia may be seen in porphyria, acute Addisonian crisis, and diabetic ketoacidosis. Only 45% of patients in Addisonian crisis will have hyponatremia and potassium levels will be typically normal (as opposed to 65% who have hyponatremia and 95% who have hyperkalemia in chronic Addison’s insufficiency). Microscopic examination of the stool is useful in patients with fever and diarrhoea/ dysentery. Arterial blood gas estimation is useful for patients in cardio-respiratory distress, suspected illicit drug use, poisonings, and unexplained causes (unexplained metabolic acidosis is the hallmark of mesenteric ischaemia). In young female patients with lower abdominal pain with/without

24

amenorrhoea, it is mandatory to obtain a urine β-hCG test to rule-out pregnancy. Free fluid in the peritoneal cavity/pleural cavity should be tapped if the situation demands or if the diagnosis is unclear. In critically ill patients, peritoneal lavage is a good bedside test to detect peritoneal inflammation. A red cell count of ≥100,000/mm3 and/or a white cell count of ≥500 /mm3 in the lavage fluid represent a positive finding, as does the return of grossly purulent material, enteric contents, or other fluids that should not be present in the peritoneal cavity. A surgical cause, and the need for surgery, is then much more likely. Imaging of the abdomen should be a planned activity and not ordered blindly. When considering the use of imaging, the presence of localised symptoms can be useful in directing the choice of study as shown in Table 2. A simplified, syndromic approach for the diagnosis of medical causes of acute abdomen is shown in Table 3. RECOMMENDED READINGS 1.

Agarwal N, Andley M. Acute abdomen in non-surgical disorders. In: Agarwal AK, Singal RK, et al. editors. Emergency Medicine; 1st Ed. New Delhi: API (DSC ); Jaypee Brothers; 2005: pp 495-501.

2.

Hammond ZT, Brunt LM. Evaluation of acute abdominal pain. In: Doherty GM, Meko JB, Olson JA, et al. editors. The Washington Manual of Surgery; 2nd Ed. Washington; Lippincott Williams and Wilkins; 1999: pp 179-89.

3.

Hiatt JR. Management of the acute abdomen. Postgrad Med 1990; 87: 38-51.

4.

Martin RF, Rossi RL. The acute abdomen. An overview and algorithms. Surg Clin North Am 1997; 77: 1227-43.

5.

Powell DW. Approach to the patient with gastrointestinal disease. In: Goldman L, Ausiello D, editors. Cecil Textbook of Medicine; 22nd edn, Vol 1. Philadelphia: Saunders; 2004: pp 782-3.

6.

Purcell TB. Non-surgical and extraperitoneal causes of abdominal pain. Emerg Med Clin North Am 1989; 7: 721-40.

7.

Steinheber FU. Medical conditions mimicking the acute surgical abdomen. Med Clin North Am 1973; 57: 1559-67.

2.5

Cough Suman Kirti

Cough is a sudden, explosive, often-repetitive expiration, which helps to clear the tracheobronchial tree of secretions, irritants, foreign particles and microbes. Often called the watchdog of the respiratory tract, it is the commonest and most important respiratory symptom.

initiates airway inflammation, which sensitises the airway to other irritants, and both cause persistent cough. Gastrooesophageal reflux disease (GERD) causes cough by aspiration of gastric contents into the upper airways as well as vagal reflex secondary to acid in the distal oesophagus.

MECHANISM Cough can be initiated voluntarily or reflexively. The cough reflex has an afferent limb with receptors in the sensory distribution of trigeminal, glossopharyngeal, superior laryngeal, and vagus nerves, that carries impulses to the cough centre located in the tractus solitarius in the medulla of the brainstem, which is connected to the central respiratory generator. The efferent limb consists of the recurrent laryngeal nerve and the spinal nerves. Cough starts with a deep inspiration followed by glottic closure, relaxation of the diaphragm and muscle contraction against a closed glottis causing airway pressure to rise (50 to 300 mmHg). This causes marked rise in positive intrathoracic pressure that results in tracheal narrowing. As the glottis opens the large pressure differential between airways and the atmosphere coupled with tracheal narrowing produces rapid flow rates (600 to 800 km/hr) through the trachea. These shearing forces aid in the elimination of mucus and foreign materials.

Cough occurs whenever there is inflammation, constriction, infiltration or compression of the airways. Inflammation occurs due to infections like viral or bacterial bronchitis or bronchiectasis. Viral bronchitis is usually acute, but persistent inflammation can cause a prolonged cough. Pertussis can also cause prolonged cough in adults. Constriction and inflammation occur in asthma and the diagnosis is made clinically. Rarely, there is a cough-variant asthma where there is cough without wheezing or dyspnoea. Tropical pulmonary eosinophilia (TPE) also causes cough. Infiltration of airways with granulomas as in tuberculosis (TB), which is common in India or endobronchial sarcoidosis, or by neoplasms like bronchogenic carcinoma and carcinoid, also triggers cough. Extrinsic compression of airways from lymph node masses, mediastinal tumours or rarely aortic aneurysm also causes cough.

AETIOLOGY Exogenous irritants like smoke, fumes, dust, foreign bodies or endogenous irritants like upper airway secretions or gastric contents may trigger cough, by stimulating the receptors in the upper airway (pharynx or larynx) or inhalation or aspiration in the lower airways (tracheobronchial tree). Endogenous irritants from postnasal drip or gastric contents may go unrecognised and cough may continue. Prolonged exposure to irritants

Parenchymal lung diseases causing cough are pneumonia, interstitial lung disease and lung abscess. Congestive heart failure (CHF) can cause cough by interstitial as well as peribronchial oedema. A dry cough may occur with angiotensin-converting enzyme (ACE) inhibitors in 5% to 20% of users usually within a week or up to 6 months of starting the drug, possibly due to accumulation of bradykinin or substance P which are degraded by ACE. The angiotensin II receptor antagonists do not increase bradykinin levels and do not cause cough.

Figure 1: Acute cough algorithm for the management of patients ≥15 years of age with cough lasting 8 weeks. Modified from: Irwin RS et al. Chest 2006; 129: 1S-23S. (With permission).

fever, rash, cyanosis, clubbing. Oro-pharynx may show oro-pharyngeal mucus or erythema, ‘cobblestone’ mucosa (postnasal drip). Examination of the Chest Inspiratory stridor in upper airway disease, rhonchi or expiratory wheezing in lower respiratory disease, inspiratory crackles in lung parenchymal disease like pneumonia, interstitial lung disease (ILD) or pulmonary oedema. Examination of Blood and Stool Complete blood counts may reveal leucocytosis, high erythrocyte sedimentation rate, and marked eosinophilia in TPE and hemoparasites on peripheral smear. Stool examination may reveal helminths that cause TPE. Chest Radiography May reveal fibro-infiltrative or cavitatory lesions suggestive of TB, reticulo-nodular shadows with prominent hila suggestive of TPE, diffuse interstitial or alveolar disease, honey-combing or cysts as in bronchiectasis, or bilateral hilar adenopathy as in sarcoidosis, or a mass lesion.

Sputum Examination Purulent sputum is seen in CB, bronchiectasis, pneumonia and lung abscess. Haemoptysis occurs in the same conditions as well as in TB and tumours. Sputum eosinophils >3% in patients without asthma suggests NAEB. Gram-stain, acid-fast bacilli stain and sputum culture will identify bacteria, TB and fungal infections. Cytology will help in identifying malignancy. Pulmonary Function Tests Assess functional abnormalities of the lung. Reversible airflow obstruction is seen in asthma. If airflow rates are normal but there is strong suspicion of asthma broncho-provocation tests may be done with methacholine or cold-air inhalation or capsaicin to show bronchial hyper-reactivity. Restrictive pattern and abnormality in diffusion studies are seen in diffuse ILD. Oxygen saturation and arterial blood gas analysis are also useful in assessing lung function. Fibreoptic Bronchoscopy Helps diagnose endobronchial granulomas (TB, sarcoidosis, fungi), tumours, foreign bodies, and collection of secretions

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Table 1: Differential Diagnosis of Sub-acute and Chronic Cough Common Causes

Clinical Features

Transient airway hyper-responsiveness

Cough persistent for many weeks, resolves (e.g. post-viral upper-respiratory infection)

Rhinosinus infection/inflammation

Cough follows infection or exposure to allergen; post-nasal drip is common

Asthma Cough-variant asthma

Worse at night, on exercise, or following exposure to allergen, cold air or dust Absence of wheezing or dyspnoea, dry nocturnal cough, bronchial hyper-responsiveness

Non-asthmatic eosinophilic bronchitis

No variable airflow obstruction; no hyper-responsiveness; sputum eosinophils >3%; Increased CO2 in exhaled air

Chronic obstructive pulmonary disease

Usually seen in smokers. When smoking, and environmental irritants stop, cough eventually ceases

Gastro-oesophageal reflux

Heartburn, acid reflux, throat clearing, hoarseness or asymptomatic reflux

Pulmonary tuberculosis

Constitutional symptoms (fever, night sweats, weight loss, haemoptysis)

Bronchiectasis

Productive sputum, often purulent; cough (and sputum production) often positional

Tropical pulmonary eosinophilia

Cough, dyspnoea, wheeze, scanty sputum, blood and sputum eosinophilia, helminthic infestation

Bronchial carcinoma Less Common Causes

Cough worse than usual in a smoker; sometimes, new persistent cough

Repeated bronchial aspiration

Oesophageal disorders, neurological swallowing disorders

Pulmonary fibrosis

Patient is breathless; cough ‘dry’

Aspirated foreign body

May have no history of aspiration

Lung compression (e.g. pleural effusion, mass)

Sometimes positional

Drug-induced cough

ACE-inhibitors: dry cough; beta-blockers: cough and usually wheezing

Pneumocystis jiroveci

Immune deficient patients with persistent cough

Psychogenic

Patient otherwise well; no cough at night or when distracted; no response to cough suppressants

Based on: Symptoms and Signs. Medicine International (Indian Ed) 1995; 9: 222; Philp EB. Chronic cough. Am Fam Physician 1997; 56: 1395-1408.

and endobronchial biopsies and transbronchial lung biopsies helps in further diagnosis. High Resolution Computed Tomography (HRCT) Helps in diagnosing ILD and can confirm the presence of bronchiectasis. CT of para-nasal sinuses can help in diagnosing UACS. COMPLICATIONS The complications of coughing can be classified as either acute or chronic. Acute complications include cough syncope due to markedly positive intrathoracic and alveolar pressures, decreased venous return, and decreased cardiac output when cough is prolonged and forceful, insomnia, cough-induced vomiting, sweating, rupture of bullae causing pneumothorax, sub-conjunctival haemorrhage, cardiac arrhythmias, seizures, splenic and venous ruptures, disruption of surgical wounds, coughing defaecation, cough syncope and in women with a prolapsed uterus, urinary incontinence. Chronic complications are common and include abdominal or pelvic hernias, fatigue, fractures of lower ribs and costochondritis. TREATMENT Specific treatment can be given once the cause is evident such as stopping smoking or an ACE-I, or beta-blocker, treating postnasal drip or GERD, infections, bronchodilators for airway obstruction, inhaled glucocorticoids for NAEB, treating TB, TPE, sarcoidosis and ILD, tumours, bronchiectasis. In patients with chronic unexplained cough empirical therapy with 28

antihistamines, decongestants, nasal glucocorticoids, nasal ipratropium may help improve UACS. In the absence of an appropriate response, empirical treatment for asthma, NAEB and GERD can be tried. Symptomatic therapy for cough is given when the cause is unidentified or no specific treatment is available or there is sleep disturbance and distressing cough. Dextromethorphan or codeine are cough suppressants and provide relief in dry irritating cough. Productive cough should not be suppressed, as the sputum will be retained in the respiratory tract and result in reduced ventilation. Cough suppressants should be strictly avoided in obstructive airway disease. RECOMMENDED READINGS 1.

Chen HH, Jafek BW. Chronic cough. eMedicine SpecialitiesOtolaryngeology and facial plastic surgery-laryngology. http:// emedicine.medscape.com/article/1048560-overview. Accessed on June 4, 2010.

2.

Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008; 371: 1364-74.

3.

Dicpinigaitis PV, Colice GL, Goolsby MJ, Rogg GI, Spector SL, Winther B. Acute cough: a diagnostic and therapeutic challenge. Cough 2009; 5: 11.

4.

Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightlin CE, et al. Diagnosis and management of cough. Executive Summary: ACCP evidencebased clinical practice guidelines. Chest 2006; 129: 1S-23S.

5.

Nadri FR, D’Souza GA. Investigation of chronic cough in tropics: a cost effective analysis. Lung India 2007; 24: 11-6.

6.

Pavord ID, Chung KF. Management of chronic cough. Lancet 2008; 371: 1375-84.

2.6

Haemoptysis Randeep Guleria, Jaya Kumar

INTRODUCTION Haemoptysis is defined as coughing up of blood from the respiratory tract. It can range from streaks of blood in the expectoration to coughing up of large quantities of blood. Haemoptysis is alarming for the patient and can be caused by a spectrum of disorders ranging from a respiratory tract infection, bronchogenic carcinoma and rarely with systemic diseases which causes alveolar haemorrhage. Sometime, a minimal haemoptysis initially may be followed by a bout of massive haemoptysis which can be life-threatening. Massive haemoptysis is a medical emergency, most often due to asphyxiation which occurs due to flooding of the airways and alveoli with blood and also due to significant haemodynamic compromise. Despite a lot of focus on the management of massive haemoptysis the definition is highly variable. It is most commonly defined as expectoration of 100 to 600 mL of blood in 24 hours. The problem with this definition is that it is very difficult for a patient to quantify haemoptysis. Also the morbidity and mortality depends on the rate of bleeding, the condition of the underlying lungs and the ability of the patient to clear the airways of the blood rather than on the absolute quantity of blood loss. Any amount of haemoptysis which causes haemodynamic instability or respiratory embarrassment should be considered massive. Life-threatening haemoptysis is recommended as a better term which encompasses the quantity of haemoptysis, haemodynamic instability and impairment of gas exchange. The unpredictable course of haemoptysis with a possibility of potentially lifethreatening massive haemoptysis and the various serious aetiologies mandates a prompt and focused assessment and management.

submucosa of the bronchial wall. Bleeding from the pulmonary vasculature is less common and minimal as it is a low pressure system. Also hypoxic pulmonary vasoconstriction diverts blood away from the diseased portion of the lung. Massive haemoptysis originating from the pulmonary circulation is therefore uncommon. The bronchial circulation is a more important cause of significant haemoptysis as it runs along the bronchial tree and supplies blood to the airways. Inflammation in the airways leads to hypertrophy of the bronchial vessels and an increased propensity to bleed. Also being a high pressure system it leads to more profuse bleeding and accounts for most cases of massive haemoptysis.

AETIOPATHOGENESIS Vascular Anatomy It is important to understand the blood supply of the lung to get an idea of the mechanism of significant haemoptysis. The lungs have a dual blood supply from the pulmonary and bronchial circulation. The pulmonary circulation is a low pressure system which is responsible for gas exchange. The pulmonary arteries run along the bronchial tree and carry the entire cardiac output for oxygenation in the pulmonary capillaries, but the only interaction with the airways is at the level of the terminal bronchioles where the pulmonary capillary bed arises around the alveoli for gas exchange. The bronchial tree on the other hand carries a small portion of the cardiac output but has a pressure at par with the systemic pressure. The bronchial arteries arise from the aorta or the intercostals arteries and supplies blood to the airways, hilar lymph nodes visceral pleura and parts of the mediastinum. They branch along the bronchial tree and form an extensive plexiform network in the peri-bronchial space and in the

Various mechanisms are responsible for haemoptysis in active TB and post-tubercular sequelae:

Causes Haemoptysis has a varied aetiology with the common causes being tuberculosis (TB), bronchiectasis, bronchitis, bronchogenic carcinoma and pneumonia in different proportions depending on the population studied. The causes can be categorised according to the site of origin within the lung and the underlying disorder (Table 1). The frequency of the different causes of haemoptysis varies in the developed and developing world. Recent literature from the developed world shows TB to be an infrequent cause of haemoptysis. The leading causes of haemoptysis in these countries are bronchitis, pneumonia, bronchiectasis and bronchogenic carcinoma with TB accounting for only 1.4% to 8% in different studies. In our country and most of the developing world TB still remains the most common cause for haemoptysis. In a study from Lucknow, India, the TB accounted for 79.2% cases of haemoptysis followed by bronchogenic carcinoma.

A. Active tuberculosis 1. Bronchiolar ulceration and necrosis of adjacent vessels and alveoli. 2. Erosion of a vessel wall of a cavity. 3. Tubercular involvement of the vessel wall causes formation of aneurysms called Rasmussen’s aneurysm. Rupture of these aneurysms can cause massive haemoptysis. B. Sequelae of tuberculosis 1. Bronchiectasis due to destruction of the normal lung architecture by TB. 2. Aspergilloma formation in an old tubercular cavity. 3. Erosion of bronchial arteries due to healed, calcified nodes rupturing through the bronchial tree. 4. Scar carcinoma. 29

Table 1: Causes of Haemoptysis

Table 2: Differences Between Haemoptysis and Haematemesis

A. Pulmonary 1. Airway disease Bronchiectasis Bronchitis (acute and chronic) Neoplasms Bronchogenic carcinoma Endobronchial metastatic carcinoma Bronchial carcinoid Kaposi’s sarcoma Foreign body Airway trauma 2. Parenchymal disease Infectious Tuberculosis Pneumonia/lung abscess Aspergilloma Lung parasite (ascariasis, schistosomiasis) Inflammatory or immune disorders Wegener’s granulomatosis, SLE Good pasture’s syndrome Idiopathic pulmonary haemosiderosis Other pulmonary vasculitis 3. Vascular causes Pulmonary embolism Pulmonary arteriovenous malformation

Haemoptysis

Haematemesis

Clinical evidence of lung disease Bright red or pink blood Liquid clotted appearance

Clinical evidence of gastric or hepatic disease Brown to black, coffee ground appearance

Cough, breathlessness chest pain present

Nausea vomiting, abdominal pain

Malaena rare Examination shows macrophages or neutrophils

Malaena may be present Mixed with ingested food particles

Alkaline pH

Acidic pH

B. Cardiovascular Pulmonary hypertension per se, Mitral stenosis Tricuspid endocarditis Aortic aneurysm C. Trauma Chest injury Iatrogenic Percutaneous lung biopsy Bronchoscopy with bronchial biopsy or transbronchial lung biopsy Swan ganz catheterisation causing pulmonary artery perforation D. Miscellaneous Drug induced (anti-coagulants, penicillamine, bevacizumab, cocaine) Pulmonary endometriosis Cryptogenic

30

DIAGNOSTIC APPROACH A good history is very essential as it guides towards a likely aetiology. The first step is to distinguish haemoptysis (bleeding from the upper respiratory tract) from haematemesis (bleeding from upper G.I. tract) (Table 2). Once haemoptysis is confirmed the history should include assessment of the quantity of haemoptysis as an aggressive approach is required for massive haemoptysis. Also history of associated symptoms, including fever, cough, expectoration, dyspnoea, constitutional symptoms related to the underlying aetiologies helps the physician to narrow the differential diagnosis and develop a focused approach. History related to any suspected, underlying systemic illness, smoking, use of any drug, past illnesses like TB, severe or recurrent pneumonia should also be included. A complete physical examination including the vitals, general physical examination, respiratory and cardiovascular system is essential.

The priority in massive haemoptysis is to protect the airway, maintain ventilation and circulation and avoid the other lung from flooding. An evaluation for cause would follow once the patient is stabilised. Non-massive haemoptysis entails an evaluation for the cause of haemoptysis so as to start treatment for the same. Initial evaluation, depending on the presentation, should include—haemogram with haematocrit , white blood cell count and platelet count, erythrocyte sedimentation rate (ESR), arterial blood gas analysis, sputum for acid fast bacilli (AFB), Gram-stain, culture, and cytology, blood urea and serum creatinine, serum chemistry, HIV serology, autoimmune workup and urine analysis if systemic vasculitis is suspected; prothrombin time, partial thromboplastin for coagulation disorders; D-dimer for suspected pulmonary embolism. The evaluation for the aetiology begins with a chest radiograph and has changed drastically with the advent of computed tomography (CT) scans and bronchoscopy. When the chest radiograph is normal with a history suggestive of airway disease and there is no apparent risk factors for carcinoma lung the patient can be observed. No further evaluation is necessary if bleeding does not recur. Further evaluation with a contrast enhanced and high resolution computed tomography (HRCT) is indicated even if the chest radiograph is normal if bleeding recurs or if risk factors for carcinoma lung are present or the history is not compatible with bronchitis. When the chest radiograph shows parenchymal involvement sputum for AFB must be done. If the sputum is negative for AFB, the CT of the chest is required followed by treatment of the underlying disease, if a specific diagnosis is established. Further evaluation with bronchoscopy is advised when the CT chest does not suggest a specific diagnosis. When a chest radiograph reveals a mass, further evaluation with CT chest, bronchoscopy and a biopsy from the mass is indicated. CT scan of the chest specially contrast enhanced HRCT has changed the diagnostic algorithm for haemoptysis. CT scan can help diagnose several conditions where the chest radiograph is normal or help in further characterising lesions seen on the radiograph. These include bronchiectasis, lung carcinoma, sequelae of TB, aspergilloma, pulmonary aneurysm and lung nodule. In addition it may also help to direct fine needle aspiration cytology (FNAC) and biopsy. Also it may help in deciding the better mode of tissue sampling in a particular case, bronchoscopic biopsy or CT guided per-cutaneous biopsy. Flexible fiberoptic bronchoscopy (FOB) along with HRCT chest is the mainstay of diagnosis in patients with haemoptysis.

The rigid bronchoscopy is being more and more infrequently used as the flexible scope gives greater access to the distal airways, but it has the advantage of providing better airway control and suctioning and can be used to remove large clots or foreign bodies. Bronchial and pulmonary angiography is rarely done as a diagnostic test with the advent of CT and bronchoscopy. It is done when bronchial artery embolisation is planned to stop bleeding. Specific tests like CT pulmonary angiography, ventilation perfusion scan and echocardiography may be required depending on the underlying aetiology. MANAGEMENT The goal of the management is to stop the bleeding, prevent asphyxiation and to treat the underlying disorder. The most important step is to quantify the haemoptysis and ensure that airway, breathing and circulation are maintained. It is important to remember that a minor bleed may herald a massive, lifethreatening haemoptysis. Management of Non-Massive Haemoptysis Non-massive haemoptysis can be managed on an out-patients basis. However, the patient should be advised to report immediately to the emergency, if the haemoptysis increases or does not settle. The management is based on preventing further bleed from occurring and to find and treat the underlying cause. Basic investigations including a chest radiograph, haemogram and sputum for AFB must be done. Once the cause of haemoptysis is found appropriate treatment should be initiated. To prevent further bleeding cough suppressants, haemostatic agents and anxiolytic should be used. A broad spectrum antibiotic is given at times to prevent secondary bacterial infection in the lung. Management of Massive Haemoptysis It is a medical emergency, as it can cause sudden death by asphyxiation. The first step is to protect ABC—airway, breathing and circulation. Protection of the airway is of utmost importance, as asphyxiation is the most common cause of death in these patients. The steps in management include: 1. Airway protection and haemodynamic stability: The patient should be admitted in the intensive care unit. If the site of bleeding is known the patient should be placed in a lateral position with the bleeding lung in the dependent position. This helps to protect the non-bleeding lung from spillage. Endotracheal intubation with a wide bore tube is indicated in patients with massive ongoing haemoptysis, haemodynamic instability and inadequate gas exchange. This also helps in better airway protection, suction and resuscitation in case of cardio-respiratory arrest. 2. Localisation of the bleed and protection of the nonbleeding lung: Bronchoscopy is the procedure of choice to

identify the side and specific site of bleeding. If the side is identified but the specific site cannot be seen selective single intubation of the lung can be done to prevent flooding of the other lung. Double lumen endotracheal tube can be used in experienced centres when the side cannot be localised and bleeding persists. Rigid bronchoscopy may be required when there is massive bleeding because it is difficult to visualise the airway with an FOB in such a situation.

Haemoptysis

Bronchoscopy helps in the diagnosis when the radiology is normal or non-localising and if done acutely may help identify the source of bleeding. It is specifically useful in diagnosing endobronchial lesions, bronchitis and subtle mucosal abnormalities. A bronchoscopy should always be done in a patient with haemoptysis if there are risk factors for lung carcinoma even if the CT scan is normal.

3. Bronchoscopic measures to stop bleeding: Once the specific site of bleeding is located, specific measures can be used to control the bleeding.  Bronchial lavage with iced saline has been successfully used in several studies.  Vasoconstrictive agents like epinephrine can be used to control bleeding.  Bronchoscopic balloon tamponade: A 4 French, 100 cm fogarty catheter is inflated in the segmental/sub segmental bronchus leading to the bleeding site for 24 to 48 hours. It is deflated for several hours after 1 to 2 days and removed if bleeding does not recur.  Laser photocoagulation and electrocautery have been tried in endobronchial tumours to control bleeding. 4. Angiography and embolisation: Patients who continue to bleed despite above measures can be taken up for angiography to localise the bleed and the bleeder can then be embolised. This procedure is used as a bridge to surgery or in patients who are not candidates for surgery. It is considered to be semi-definitive as rebleeding can occur in 10% to 20% patients in the next one year. Currently bronchial artery embolisation is a commonly used method to stop massive haemoptysis in most centres. It is also used in patients who have recurrent moderate to massive haemoptysis and are not candidates for definitive surgery. 5. Surgery: It is the only definitive option in massive haemoptysis not responding to above mentioned measures. Unfortunately most patients are not fit for surgery which is contraindicated in patients with diffuse/ bilateral disease, active TB and in patients with poor respiratory reserve. Also the mortality and morbidity is much higher in emergent surgery in comparison to elective surgery in the non-bleeding patient. PROGNOSIS The outcome of haemoptysis varies in various series depending on the underlying aetiology, the number of patients with massive haemoptysis and the expertise of the treating centre. The mortality is 8% to 10% in various studies. The prognosis is improving with the newer modalities of treatment. All patients with haemoptysis, minimal or massive should be aggressively managed at well equipped centres to further improve the outcome. RECOMMENDED READINGS 1.

Bidwell JL, Pachner RW. Haemoptysis: Diagnosis and management. Am Fam Physician 2005; 72: 1253-60.

2.

Prasad R, Garg R, Singhal S, Srivastava P. Lessons from patients with haemoptysis attending a chest clinic in India. Ann Thorac Med 2009; 4: 10-12.

31

2.7 Jaundice is a common presentation of liver and biliary tract disease, characterised by yellowish discoloration of skin, sclerae and mucous membranes. It is clinically detectable when serum bilirubin is >3.0 mg/dL. It manifests more in tissues with – high elastic content (skin, sclera, blood vessels), high blood flow, low interstitial fluid and in fluids with high protein content (urine, sweat, semen, milk, exudates, etc.). It manifests less in paralysed parts and oedematous areas. Yellowing of the skin can also occur in carotenoderma (spares the sclera), with use of quinacrine and with excessive exposure to phenols. CLINICAL EVALUATION  Inspection should be done in bright day light to detect jaundice. 

Inspect the sclera, tongue, hard palate, skin and fingers.



Ask the patient to look down and inspect the unexposed portion of the sclera because bulbar conjunctiva can be discoloured due to dust.



Note whether the hue is lemon yellow (unconjugated hyperbilirubinaemia stains the tissues lightly because of its water insolubility); orange yellow (in patients with hepatocellular and cholestatic jaundice there is increase in conjugated bilirubin which penetrates body fluids more because of its water solubility), or greenish yellow (in prolonged cholestasis because of formation of biliverdin).

Aparna Agrawal 

In unconjugated hyperbilirubinaemia due to haemolysis, usually serum bilirubin is < 5 mg/dL. If it is more than this, check for combination of haemolytic anaemia with an inherited disorder of bilirubin metabolism—Gilbert’s syndrome or Crigler Najjar syndrome, coexistent renal and hepatocellular dysfunction or acute haemolytic crisis.

CLASSIFICATION AND CAUSES OF JAUNDICE These are given in Table 1. APPROACH TO JAUNDICE A careful history, physical examination and standard laboratory tests help us in arriving at an accurate diagnosis in >80% of patients. In adult patients with a new-onset jaundice, the following disorders account for >95% of the diagnosis: 

Viral hepatitis.



Alcohol-induced liver disease.



Drug induced liver disease.



Infections involving the liver including liver abscess and sepsis.



Chronic hepatitis (all causes).



Gall stones and their complications.



Pancreatitis.



Carcinoma of the pancreas.



Haemolytic anaemia.

I.

History



Staining of clothes by secretions is a good clue (specially urine, sweat, milk and semen).

The onset, evolution and duration of jaundice should be noted. The associated features should also be enquired into.



Look for high coloured urine and pale coloured stools (avoid early morning specimen).

History suggestive of acute viral hepatitis 

Low grade fever for 1 to 2 days, usually associated with headache, myalgias, anorexia, nausea and vomiting followed by jaundice.



Change in taste and smell of food.



Contact with individuals with jaundice.



Needle stick exposure or any injection, body piercing, tattoos, shared razors or tooth brushes.

Some Practice Points



Blood or blood product transfusions.





Intravenous drug abuse.



Health care professionals.



Sex with commercial sex workers, multiple partners or with individuals with hepatitis B or C.



History of sexually transmitted disease.



Travel to endemic areas or eating raw shell fish (especially for hepatitis A).



Occasionally, pain with or without swelling of joints and transient skin rash may indicate hepatitis B or C.

AETIOPATHOGENESIS Jaundice results from a disorder of bilirubin metabolism in the form of increased formation or a decrease in hepatic clearance of bilirubin. Unconjugated bilirubin is lipid soluble and it is converted to water soluble bilirubin mono-and-diglucuronide by conjugation, which allows its excretion into the bile.



32

Jaundice

In late stages of cholestatic or hepatocellular jaundice, despite high serum bilirubin levels, none can be detected in the urine.This is due to a third type of bilirubin—a bilirubin mono conjugate (not mono-and-diglucuronide), covalently bound to albumin, which is not filtered by the glomerulus, hence absent in the urine. The high elastic content of tissues is responsible for the disparity between the depth of jaundice in the skin and sclera and serum bilirubin levels during recovery from hepatitis or cholestasis.

Type

Cause

Pre-hepatic

↑ Bilirubin production Haemolysis (a) Intravascular haemolysis – G6PD deficiency, PNH, malaria – Blood transfusion – Ineffective erythropoiesis

Basic Laboratory Abnormalities

Jaundice

Table 1: Classification and Causes of Jaundice

Unconjugated ↑ SBR Normal STA + ALP

(b) Extravascular haemolysis – Pneumonia, PTE, resorption of haematomas, haemoglobinopathies Hepatic

(a) ↓ Hepatocellular uptake – Drugs (Rifampicin, probenecid, ribavirin) – Gilbert’s syndrome (b) ↓ Conjugation – Gilbert’s syndrome, Crigler-Najjar Syndrome I and II – Physiologic jaundice of newborn – Drugs (e.g. Indinavir) (c) ↓ Transport i. Congenital hyperbilirubinaemia – Dubin-Johnson syndrome – Rotor’s syndrome ii. Acute/ subacute hepatocellular disease – Viral hepatitis A-E, EBV, CMV, HSV – Hepatotoxins (ethanol, Amanita Phalloides) – Drugs – Dose dependent (Acetaminophen) Idiosyncratic (INH, phenytoin, etc.) – Ischaemia (hypotension, Budd-Chiari syndrome, hepatic veno-occlusive disease) – Metabolic disorders (Wilson’s disease, Reye’s syndrome) – Pregnancy related (AFLP, pre-eclampsia) iii. Chronic hepatocellular disease – Viral hepatitis (B, C, D) – Alcohol – Hepatotoxins (Vinyl chloride, Vit. A. hypervitaminosis) – Autoimmune hepatitis – Metabolic (haemochromatosis, Wilson’s disease, NASH, α1-antitrypsin deficiency) – Coeliac sprue

Conjugated ↑ SBR Normal STA+ALP

Mixed ↑ SBR (↑ SBR + ↑ STA ± ↑ ALP)

Cholestatic (a) Hepatic disorders with prominent cholestasis i. Diffuse infiltrative disease of liver – Granulomatous disease (Mycobacterial infection, Brucella, fungal disease, sarcoidosis, lymphoma, drugs, Wegener’s granulomatosis) – Amyloidosis – Malignancy ii. Inflammation of intrahepatic bile ductules and/or portal tracts – Primary biliary cirrhosis – Drugs (erythromycin, trimethoprim-sulphamethoxazole) – Graft versus host disease iii. Miscellaneous – Benign recurrent intrahepatic cholestasis – Intrahepatic cholestasis of pregnancy – Drugs (estrogen, anabolic steroids) – Total parenteral nutrition – Infections – Post-operative cholestasis – Vanishing bile duct syndrome (b) Obstruction of bile ducts i. Choledocholithiasis – Cholesterol gall stones – Pigment gall stones ii. Diseases of the bile ducts – Cholangiocarcinoma – Inflammation/Infection – Primary sclerosing cholangitis – AIDS cholangiopathy – Post surgical strictures iii. Extrinsic compression of the biliary tree – Neoplasms (pancreatic carcinoma, hepatocellular carcinoma, nodes at porta hepatis) – Pancreatitis – Vascular enlargement (e.g., aneurysm, cavernous transformation of portal vein) SBR = Serum bilirubin, STA = Serum transaminases, ALP = Alkaline phosphatase, AFLP = Acute fatty liver of pregnancy.

↑ SBR + ↑ STA + ↑ ALP

Conjugated ↑ SBR + Normal STA + ↑↑ ALP

33

History suggestive of chronic hepatitis/cirrhosis with portal hypertension  Recurrent jaundice.  Swelling of feet.  Distension of abdomen.  Massive haematemesis or melena may indicate portal hypertension and variceal bleed.  Amenorrhoea. History suggestive of alcohol-induced liver disease  Details of quantity and type of alcohol being consumed now or in the past should be obtained from the patient, friends and family members. (The threshold for alcoholinduced hepatic injury appears to be 30 gms/day for women and 60 gms/day for men if ingested over 5 to 10 years. Less, if additional factors for liver disease are present).  History of binge drinking and day time drinking should be noted.  History of withdrawal symptoms or seizures should be taken. CAGE criteria (cut down, annoyed, guilty, eye opener) should be looked for as indicators of excessive alcohol usage.  History suggestive of other alcohol related illness, e.g. pancreatitis, gastritis, peripheral neuropathy should be taken. History suggestive of drug induced liver disease  Review all prescription medications.  Enquire specifically about alternative forms of medicine being taken.  History of pruritic rash, joint pain or swelling related to some drug intake. History suggestive of infections/liver abscess  Fever moderate to high grade with chills/rigors, with dull aching pain right upper abdomen especially when associated with dysfunction of other organs.  Rule-out leptospirosis in patients with combined renal and hepatic dysfunction. History suggestive of cholestatic jaundice  High coloured urine with pale coloured stools.  Pruritus.  Colicky pain right upper abdomen associated with fever, rigors/chills (suggestive of choledocholithiaisis with ascending cholangitis). History suggestive of pancreatitis  Recurrent upper abdominal pain with radiation to the back.  History suggestive of steatorrhoea.  Fever with severe pain and distension of the abdomen may be suggestive of acute pancreatitis.

34

History suggestive of haemolytic anaemia  History of pale coloured urine with mild yellow discolouration of eyes.  History of anaemia not responding to haematinics and requiring regular blood transfusions.

  

History of recurrent jaundice or non-healing ulcer. Family history of anaemia. Known haemoglobinopathy or having artificial heart valves.

Miscellaneous  Age and sex: Type A hepatitis decreases as age advances but no age is exempt from hepatitis B and C. – A multiparous, middle-aged, obese female with dyspepsia may have gall stones. – Chances of malignancy increase with increasing age.  Occupation should be noted (particularly involving alcohol, other hepato-toxic industrial chemicals or contact with rats for Weil’s disease).  Painless jaundice—check for malignancy.  Significant weight loss—check for malignancy.  History of joint pain or swelling (check for hepatitis B or C, autoimmune hepatitis, drug induced hepatitis, inflammatory bowel disease with primary sclerosing cholangitis or granulomatous disorders such as sarcoidosis).  Diabetes, arthritis and pigmentation—check for haemochromatosis.  Chronic obstructive pulmonary disease with jaundice— suspect α1 antitrypsin deficiency.  Chronic diarrhoea with blood and mucous—rule-out primary sclerosing cholangitis.  Family history of liver disease (check for Wilson’s disease, haemochromatosis, α1 antitrypsin deficiency).  Family history of biliary disease. Jaundice after biliary tract surgery Check for:  Residual calculus  Traumatic stricture of bile duct  Sepsis  Drug induced hepatitis  Hepatic metastasis in case of malignancy Jaundice in a liver transplant recipient Causes:  Hepatocellular injury resulting from impaired organ preservation  Vascular occlusion in immediate postoperative period  Graft rejection  Obstruction of the bile ducts  Acute viral hepatitis especially cytomegalovirus infection  Immunosuppressive drug toxicity  Recurrent disease (e.g. Hepatitis B or C, primary sclerosing cholangitis) Jaundice in pregnancy The following causes are specific to pregnancy:  Hyperemesis gravidarum (first trimester; self limiting)  Intrahepatic cholestasis of pregnancy (third trimester; pruritus; resolves within 2 weeks of delivery; tends to recur with subsequent pregnancies)



Acute fatty liver of pregnancy (third trimester; may be fatal unless delivery is performed promptly) Pre-eclampsia (third trimester; associated with hypertension and proteinuria)

Figure 1: Clinical signs in jaundice.

 

HELLP syndrome (severe form of pre-eclampsia; urgent delivery is indicated) Hepatitis E induced fulminant hepatic failure is more common in pregnancy.

Jaundice



35

II. Examination There are many signs that we need to check in a patient present with jaundice (Figure 1). General examination  Anaemia may indicate haemolysis, chronic liver disease or malignancy.  Pedal oedema may indicate chronic liver disease, inferior vena cava obstruction due to malignancy or procoagulant state; severe anaemia with volume overload or hypoproteinaemia due to nutritional deficiency or malabsorption.  Lymphadenopathy may indicate an infectious aetiology, lymphoma, tuberculosis or sarcoidosis. An enlarged leftsupraclavicular node (Virchow’s node) or periumbilical nodule (Sister Mary Joseph’s nodule) suggests an abdominal malignancy.  Altered mental state may indicate hepatic encephalopathy, sepsis or brain metastasis in patients with late stages of malignancy.  Kayser-Fleischer (KF) ring is usually seen in Wilson’s disease.  Xanthomas in primary biliary cirrhosis.  Pigmentation of the shins and non-healing ulcer may indicate haemoglobinopathy. Hyperpigmentation may also be present in haemochromatosis or in primary biliary cirrhosis.  Erythema nodosum may be seen in tuberculosis, sarcoidosis or syphilis.  Migratory thrombophlebitis is suggestive of carcinoma of the body of pancreas. Abdominal examination  Dilated abdominal veins can be seen in: – Portal hypertension – Inferior vena cava obstruction (functional or organic— dilated and tortuous veins indicate organic obstruction). The direction of flow in the infraumbilical veins helps in distinguishing between portal hypertension (from abovebelow) and IVC obstruction (from below-up).  Severe right upper quadrant tenderness with respiratory catch on inspiration (Murphy’s sign) suggests cholecystitis or occasionally, ascending cholangitis.  Ascites may be due to: – Cirrhosis – Malignancy – Infections, e.g. tuberculosis, spontaneous bacterial peritonitis – Acute pancreatitis (Grey Turner’s sign, i.e. discolouration of the abdomen is highly suggestive).  Liver: In liver examination the following should be noted: (i) The size and consistency of the liver – hard liver indicates malignancy. – Shrunken liver indicates: (a) Cirrhosis (b) Fulminant hepatic failure 36

   







[Localised dilatation of the transverse colon (toxic megacolon), fulminant colitis and ileus associated with peritonitis or a perforated viscus may decrease the liver dullness without a decrease in liver size]. (ii) Massive hepatomegaly (>10 cm below the costal margin) may indicate: (a) Malignancy (primary/secondary) (b) Congestive liver (chronic congestive cardiac failure (CCF)/Budd-Chiari syndrome) (c) Alcoholic liver disease (d) Primary biliary cirrhosis (e) Prolonged extrahepatic cholestasis (f) Infiltrative disease of the liver – Myelofibrosis – Amyloidosis (especially when associated with macroglossia, peripheral neuropathy, malabsorption, CCF or proteinuria) (g) Chronic myeloid leukaemia Whether it is tender (infections, congestion, bile stasis) or not. Whether the surface is nodular (malignancy, cirrhosis) or smooth. Whether the edge is rounded or sharp. Whether the left lobe is palpable.A palpable left lobe suggests: – Chronic liver disease – Malignancy – Abscess/cyst – Obstruction of left hepatic vein Bruit over the liver indicates increased vascularity: – Acute alcoholic hepatitis – Hepatocellular cancer – Hepatic artery aneurysm – Hepatic arterio-venous fistula Friction rub over the liver suggests – Liver metastasis – Primary hepatocellular carcinoma – Infarction of the liver (as in sickle cell anaemia and polyarteritis nodosa) – Liver abscess – Haematoma around the puncture site. Check for pulsatile liver (indicative of significant tricuspid regurgitation)

Peripheral stigmata of chronic liver disease  Parotid enlargement  Gynaecomastia  Spider angioma (usually found in the distribution of superior vena cava; >12 in number indicate portal hypertension)  Paucity of axillary and pubic hair  Testicular atrophy  Palmar erythema  Dupuytren’s contracture Signs suggestive of decompensated liver disease Jaundice Ascites

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III. Laboratory Diagnosis Integration of the patient’s history, clinical examination findings and laboratory results is essential for accurate interpretation because non-specific aberrations in these tests may occur. We can divide all jaundiced patients into three broad categories of patients (Table 1). A. Isolated elevation of serum bilirubin (SBR) with normal serum transaminases (STA) and alkaline phosphatase (ALP) Hepatocellular disease or biliary obstruction is unlikely in these patients. If SBR is predominantly unconjugated (>80%) we need to check for haemolysis (Hb, peripheral smear, reticulocyte count, Coomb’s test, plasma and urine haemoglobin and other special tests for diagnosing the type of haemolytic anaemia). A detailed description is beyond the purview of this chapter. If there is no evidence of haemolysis on the peripheral smear, the diagnosis is congenital hyperbilirubinaemia in the absence of history of drug intake. These can be definitely diagnosed with the help of special enzyme assays, genetic studies and liver biopsy (black pigmentation on liver biopsy in Dubin-Johnson Syndrome). B. Increased serum bilirubin with increased serum transaminases and normal to mildly increased alkaline phosphatase The most likely cause is hepatocellular jaundice (Table 1). The patient needs to be evaluated for acute versus chronic liver disease and for aetiology. Two biochemical tests that suggest chronic liver disease are a low serum albumin (16 sec. prolonged). A bedside diagnosis of cirrhosis can be made when it is associated with two physical findings of ascites and asterixis. Serum globulin levels are elevated in cirrhosis, resulting in reversal of A:G ratio. Electrophoretic analysis shows increased γglobulin fraction in hepatocellular jaundice (versus raised α2and β-globulins in cholestatic jaundice). The other tests that need to be done in suspected hepatocellular jaundice are:  Viral markers (serological tests for hepatitis A-E viruses, viral load for hepatitis B and C especially, serological tests for cytomegalovirus and Epstein-Barr virus infection) should be done for suspected acute or chronic viral hepatitis.  If serum AST: ALT is > 2 : 1, suspect alcoholic hepatitis in the setting of alcoholism.

    

   

 

Anti-mitochondrial antibody positivity indicates primary biliary cirrhosis. ANA, anti-SMA (smooth muscle antibodies) and antiLKM Ab positivity suggests autoimmune hepatitis. Serum Fe, transferrin and ferritin are elevated in haemochromatosis. Serum ceruloplasmin is reduced in Wilson’s disease. Serum ALP: SBR of 4, in a young patient with Coomb’s –ve haemolytic anaemia and KF ring on slit lamp examination is suggestive of Wilson’s disease. α1-antitrypsin phenotype for α1-antitrypsin deficiency. Transglutaminase Abs for coeliac sprue. Serum α-fetoproteins for hepatocellular carcinoma. UGI endoscopy for any malignancy, evidence of portal hypertension (esophageal or gastric varices and portal gastropathy features). Doppler ultrasonogram to detect patency of hepatic veins, portal vein and inferior vena cava. Liver biopsy is especially indicated in patients with undiagnosed persistent jaundice. It permits diagnosis of viral hepatitis, alcoholic and non-alcoholic steatohepatitis, haemochromatosis, Wilson’s disease, α 1-antitrypsin deficiency, fatty liver of pregnancy, primary biliary cirrhosis, granulomatous hepatitis and neoplasms with the use of special stains. Though liver histology may be entirely normal in acute biliary obstruction, it may occasionally provide a clue to unsuspected biliary tract obstruction. Iron and copper content of the liver can also be measured. In patients with prolonged prothrombin time (PT)—a transjugular biopsy is advisable.

Jaundice

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Hepatic encephalopathy Oliguria, hepatic failure Altered behaviour Fetor hepaticus Asterixis Check for any masses in the abdomen. Genitalia must be examined and per rectal examination is a must for piles, growth or nodules in the pouch of Douglas. Jaundice with extrapyramidal neurological features suggests Wilson’s disease especially in patients born of consanguinous marriage and having KF ring.

C. Increased serum bilirubin with markedly elevated alkaline phosphatase with normal to mildly elevated serum transaminases It is suggestive of cholestatic jaundice.Prolonged prothrombin time which normalises on Vitamin K administration is suggestive of extra-hepatic biliary obstruction. Imaging studies are very important in this group of patients with ultrasonogram (USG) of the abdomen being the basic investigation. Dilated ducts on imaging confirm the diagnosis of biliary obstruction (i.e. distinguishes between intra-hepatic and extrahepatic biliary obstruction) and further imaging tests can be planned based on the availability of the procedure, presence or absence of dilated bile ducts on initial imaging, technical expertise, cost of the procedure and risk versus benefit of the procedure. The various imaging techniques available are:  Contrast enhanced computed tomography (CECT)  Magnetic resonance cholangiopancreatography (MRCP)  Endoscopic retrograde cholangiopancreatography (ERCP)  Percutaneous transhepatic cholangiography (PTC)  Endoscopic ultrasound (EUS)  Nuclear imaging studies

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Both ERCP and PTC permit direct visualisation of the biliary tree as well as the pancreatic ducts. Biopsy can be done from any suspicious lesion and therapeutic intervention can be done in the same sitting. ERCP is used for lesions distal to the bifurcation of the right and left hepatic bile ducts whereas PTC is preferable when the level of biliary obstruction is proximal to the common hepatic duct or altered anatomy precludes ERCP. The sensitivity and specificity of MRCP, ERCP and PTC are comparable.

haemoglobin level and some patients may require iron chelation if blood transfusion requirement is high. Bone marrow transplantation is an option for thalassaemia , being done in a few centres. 

Hepatocellular jaundice has to be treated as per the cause. Drug induced hepatitis has to be recognised and the offending drug needs to be stopped. Cessation of alcohol, administration of antiviral agents, phlebotomy

Table 2: Differences between the Three Basic Types of Jaundice Features

Haemolytic Jaundice

Hepatocellular Jaundice

Extrahepatic Cholestatic Jaundice

Colour of urine Colour of stools Pruritus Jaundice Antecedent history

Pale Normal – Lemon yellow H/o anaemia requiring blood transfusions (BT) Anaemia ++ Evidence of haemolysis ↑ 60 years), clinical evidence of severe bleeding and ulcers greater than 2 cm in size are associated with a poor outcome. Bleeding stops spontaneously in 70% to 80% of patients with peptic ulcers. In the remaining patients endoscopic therapy controls bleeding in 80% to 90%. Surgery is needed in about 5% to 10% of patients. Endoscopic therapy is the most effective method of controlling bleeding and to some extent preventing re-bleeding thereby reducing mortality. Endoscopic methods of controlling ulcer bleeding fall into three broad categories: (a) injection therapy, (b) thermal methods, and (c) mechanical devices. Injection Therapy Submucosal injection of diluted epinephrine (1: 10,000) is a simple, effective and widely practiced method of controlling bleeding. Local injection acts by a tamponade effect on nearby vessels thus causing haemostasis. Besides it causes vasoconstriction and platelet aggregation. It is recommended that a large volume (30 to 45 mL) of epinephrine solution be injected in the four quadrants near an actively bleeding or visible vessel. Endoscopic Thermal Therapy This can be divided into two categories: (i) contact thermal; and (ii) noncontact thermal modalities.

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Contact thermal modalities include heater probe coagulation and bipolar/multipolar electrocoagulation. Noncontact thermal

modalities consist of organ plasma coagulation (OPC) and laser therapy. Contact thermal methods are preferred as besides causing coagulation of tissue due to thermal heat, they also cause tamponade of vessels by direct probe pressure. Noncontact thermal methods are cumbersome and expensive and are not shown to be more efficacious. Mechanical Devices These include metal haemoclips, rubber band ligation, endoloops and sewing devices. Haemoclips have been widely used to treat active bleeding ulcers or visible vessels. They act by direct compression of opposing tissues or vessels causing thrombosis and haemostasis. Several studies have shown that a combination of endoscopic therapy such as injection plus thermal therapy or injection plus haemoclips application are superior to monotherapy alone. Pharmacological Therapy Proton pump inhibitors (PPI) due to their inhibitory action on hydrogen potassium adenosine triphophatase raise intragastric pH. They have been found effective when given in high doses intravenously for 72 hours after successful endoscopic treatment of an ulcer with high-risk bleeding signs. They reduce the recurrence of bleeding and need for blood transfusion but not the mortality rate. The recommended dose is 80 mg omeprazole given as an intravenous bolus followed by 8 mg per hour intravenous infusion. In patients with low-risk ulcer bleeding oral proton pump inhibitors in high doses are recommended. In one study it was shown that PPI if administered for 24 to 48 hours before endoscopy significantly lowered the prevalence of high-risk stigmata and decreased the need for endoscopic therapy but did not decrease the incidence of recurrent bleeding, surgery or mortality. HEALING OF PEPTIC ULCER Proton pump inhibitor therapy has similar healing rates for bleeding and non-bleeding ulcers. The long-term treatment of ulcers depends on their aetiology. Patients with bleeding ulcers who have been taking NSAIDs should discontinue them. Patients with H. pylori infection should receive therapy for H. pylori eradication. MANAGEMENT OF BLEEDING VARICES Oesophageal variceal bleeding should be controlled swiftly and promptly as continued bleeding is associated with high mortality. The first episode of variceal bleeding is associated with about 30% mortality. Haemostasis can be achieved by pharmacological treatment and endoscopic therapy. Pharmacological Treatment In the past, vasopressin, a powerful vasoconstrictor, was widely used to control bleeding from varices. The drug causes splanchnic arteriolar vasoconstriction leading to decrease in portal inflow and thus portal pressure. However, this drug is associated with myocardial ischaemia, mesenteric ischaemia and cerebrovascular accidents. Some of adverse effects of vasopressin can be reduced by concomitant use of nitrates, used as intravenous infusions, sublingual or transdermal route. It is rarely used now because of its adverse effect profile. This led to the development of a safer synthetic analogue—terlipressin

Somatostatin and its analogues Somatastatin is a naturally occurring peptide. Its exact mechanism of action is not clear. It causes an increase in splanchnic vascular resistance by causing vasoconstriction and decrease in portal blood flow. Somatostatin is given as an intravenous bolus of 250 ug followed by continuous infusion of 250 ug per hour and therapy is continued for two to five days. Boluses of 500 ug can be administered intermittently if fresh episodes of bleeding occur during the course of treatment. Octreotide, a synthetic analogue of somatostatin, has a longer duration of action, and has been found to be effective in controlling variceal haemorrhage. Octreotide is given in the doses of 25 to 50 ug/hour by a continuous intravenous infusion. Somatostain and octreotide should be started immediately while waiting for more definitive endoscopic therapies to be employed or when endoscopy is not possible due to nonavailability of trained personnel or contraindicated because of haemodynamic instability. They can also be used as an adjunct to endoscopic therapies. Both somatostatin and octreotide have an excellent safety profile, with low complication rates. Their use may cause hyperglycaemia and abdominal cramping. Endoscopic Therapy Endoscopic therapy is the cornerstone of controlling haemorrhage from varices. These are two principal forms of endoscopic treatment: (a) Endoscopic sclerotherapy (EST) (b) Endoscopic variceal band ligation (EVL) Endoscopic sclerotherapy (EST) It involves injection of sclerosing agents into the veins causing thrombosis and scarring. Various sclerosing agents used are ethanolamine oleate, aethoxyskerol, sodium tetradecyl sulphate, sodium morrhuate and absolute alcohol. Tissue adhesive such as N-butyl-cyanoacrylate have been used for sclerosing of gastric varices. Variceal injections are started at gastro-oesophageal junction and are restricted to distal 5 cm of oesophagus. Usually 1 to 2 ml of sclerosing agent is injected into each varix and a total of 10 to 15 mL is effective in controlling bleeding. Sclerotherapy is repeated usually at intervals of 2 to 3 weeks. Endoscopic sclerotherapy is associated with some local and systemic complications, which include retrosternal pain, transient dysphagia, fever and mild pleural effusions. Oesophageal stricture leading to dysphagia is seen in approximately 15% of patients. Bleeding from post-EST ulcers and oesophageal perforation are potentially life-threatening complications of endoscopic sclerotherapy. Endoscopic variceal band ligation (EVL) It involves applying rubber bands around varices which lead to occluding the veins mechanically. The elastic rubber band strangulates the varix producing thrombosis, inflammation, necrosis and finally sloughing of mucosa that heals by scar

formation. EVL is performed by using multiband ligating system. The banding device consists of a cylinder preloaded with 6 to 8 elastic bands. The cylinder is attached to the tip of the endoscope and bands are released by pulling a trigger wire of a device placed over the biopsy channel after the varix is sucked into the cylinder. EVL is associated with fewer complications than EST. The procedure is effective in controlling bleeding in 75% to 85% of patients. With the available pharmacological and endoscopic treatments, the rate of failure to control acute bleeding is approximately 10% to 20%. Balloon tamponade using Sangstaken-Blakemore balloon, though associated with complications, can accomplish haemostasis in a difficult situation, such as massive variceal bleeding. Transjugular intrahepatic shunt (TIPS) represents an artificial communication by placing a metallic stent between the hepatic and the portal vein. It is an effective method of controlling active bleeding from oesophageal and gastric varices. It also prevents recurrent variceal bleeding. Although the TIPS procedure needs expertise (not available at many centres in India), when placed successfully it can achieve haemostasis in 90% to 100% cases. TIPS is associated with longterm complications of thrombosis and occlusion of stent and hepatic encephalopathy. It is contraindicated in patient with poor cardiac function, pulmonary hypertension and polycystic liver disease.

Upper Gastrointestinal Bleeding

which has a longer biological half life and is administered in a dose of 1 to 2 mg every four hours. Terlipressin is as effective as other vasoactive drugs as well as endoscopic treatment. This drug has been found to be associated with improved survival in several randomised trials.

Prevention of Variceal Bleeding Non-selective beta-blockers such as propranolol and nadolol in doses that decrease the heart rate by 25% have been shown to be effective in preventing primary and secondary variceal haemorrhage. The majority of episodes of upper GI bleeding can be controlled with endoscopic and pharmacological therapy. Angiographic therapy or surgery may be needed in those patients where bleeding cannot be controlled or localised or in those with recurrent bleeding. Upper GI bleeding is a serious emergency which carries a high mortality. Overall survival is improving due to the availability of new therapeutic methods and improved medical care. RECOMMENDED READINGS 1.

Adler DG, Leighton JA, Davila RE, et al. ASGE guidelines: The role of endoscopy in acute non-variceal upper-GI haemorrhage. Gastrointest Endosc 2004; 60: 497.

2.

Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2003;139: 843.

3.

Gevers AM, De Goede E, Simoens M, et al. A randomised trial comparing injection therapy with hemoclip and with injection combined with hemoclip for bleeding ulcers. Gastrointest Endosc 2002; 55: 466.

4.

Lau JY, Sung JJ, Chan AC, et al. Stigmata of haemorrhage in bleeding peptic ulcers: An interobserver agreement study among international experts. Gastrointest Endosc 1997; 46: 33.

5.

Lin HJ, Lo WC, Lee Fy, et al. A prospective randomised comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med 1998; 158: 54.

6.

Sharara AI, Rockey DC. Gastro-oesophageal variceal haemorrhage. N Engl J Med 2001;345:669.

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2.9 Pyrexia or fever of unknown origin (FUO) remains an intellectual and diagnostic challenge. A developing country like India, with its burden of endemic diseases like tuberculosis, fungal infections and limited access to diagnostic facilities, requires a radically different approach from that of the developed countries for arriving at a diagnosis in a patient of FUO. DEFINITION In 1961, FUO was defined by Petersdorf and Beeson as fever greater than 38.3°C (101°F) documented on several occasions, for more than 3 weeks with no diagnosis despite 1 week of inpatient investigation. With the advent of acquired immunodeficiency syndrome (AIDS), complex surgical and ICU protocols and increased diagnostic investigations, Durack and Street proposed classifying FUO into four different categories: (1) classic FUO, (2) nosocomial FUO, (3) neutropaenic FUO and (4) human immunodeficiency virus (HIV) associated FUO. TYPES OF FUO Classic FUO: The newer definition is similar to the one proposed in 1961. Keeping in mind increasing diagnostic capabilities, this has been modified to fever greater than 38.3°C (101°F) for more than 3 weeks with no diagnosis after 3 outpatient visits or 3 days as inpatient in the hospital or 1 week of ‘intelligent and invasive’ ambulatory investigations. Nosocomial FUO: Fever greater than 38.3°C (101°F) on several occasions in a hospitalised patient receiving acute care, not manifesting or incubating an infection on admission with no diagnosis after 3 days of investigations, including 2 days’ incubation of cultures. Neutropaenic FUO: Fever greater than 38.3°C (101°F) on several occasions in a neutropenic (absolute neutrophil count 70%). Musculoskeletal Applications Applications in the musculoskeletal system include evaluation of internal derangement of joints (knee/hip/shoulder), soft tissue injury/inflammation, ligaments and tendons, bone marrow for marrow infiltration, bone infarcts or contusions. In

musculoskeletal neoplasms, the role of MR is to demonstrate the extent of the lesion prior to surgery rather than primary characterisation for which plain radiographs are the investigation of choice. MR evaluates compartmental involvement (e.g. extension of bone tumours into soft tissues and joints), skip lesions within the bone marrow and status of neurovascular bundle. Role of intravenous contrast in musculoskeletal system is in evaluation of infection (bone, joint or soft tissues) (Figures 7A and B) and evaluation of post-operative spine to differentiate between scar tissue from non-enhancing residual disc. Advanced musculoskeletal MR applications include MR arthrography. In MR arthrography joint cavity is distended by intra-articular injection of dilute gadolinium. It is extremely useful in demonstrating the glenoid and labral tears (shoulder and hip) and in evaluation of the post-operative meniscus. Hepatobiliary Applications MRCP uses heavily T2 weighted sequences such as HASTE (half Fourier acquisition with single shot turbo spin echo) or RARE (rapid acquisition with relaxation enhancement) to visualise

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Figures 5A to D: Tubercular spondylodiskitis lumbar spine in a 44-year-old male. Sagittal (A) and Axial T2W (B) image shows hyperintensity and irregularity involving the end plate of two contiguous vertebras, intervening disc with small epidural component. Axial (C) and sagittal (D) post-contrast images demonstrates intense enhancement of two contiguous vertebrae, intervening disc and extradural soft tissue. Also note presence of prevertebral abscess.

Figures 6A to C: Acute infarct in a 60-year-old male. Axial T2W (A) image shows hyperintensity seen involving the left parietotemporal lobes (MCA territory), with mild mass effect. Diffusion weighted (B) image shows hyperintensity and ADC maps (C) show hypointensity in the corresponding area suggestive of restricted diffusion (cytotoxic oedema).

static fluid in the biliary and pancreatic ducts as high signal intensity. The heavy T2 weighting provides very high (bright) signal of static fluid within the biliary and pancreatic ductal systems, while the background tissues have very low (dark) signal (Figures 8A and B).These images look analogous to endoscopic retrograde cholangiopancreatography (ERCP) images. 96

MRCP is now the primary tool in the evaluation of biliary obstruction (calculi, intrinsic and extrinsic masses), intrahepatic

bile duct diseases, post-surgical anatomic alterations, and congenital anomalies of the biliary and pancreatic tract. A potential use of MRCP is the demonstration of aberrant bile duct anatomy before cholecystectomy. MRCP is increasingly becoming the initial imaging modality for the biliary system, with ERCP reserved for only therapeutic indications. MRCP can be combined with other sequences for the comprehensive evaluation of the liver, biliary tree and pancreas. In

MRI in Medicine Figures 7A and B: Tubercular arthritis left sacroiliac joint in a 26-year-old female. Axial T2W (A) image shows hyperintensity involving the left sacral ala and the iliac bone, with joint widening and irregularities. Post-contrast (B) T1W image shows intense homogenous enhancement. Findings suggestive of infective sacroillitis.

Figures 8A and B: Chronic pancreatitis in a 37-year-old female. Axial T2W (A) and MRCP projectional (B) images show dilation of the main pancreatic duct (arrowhead) and side branches with a pseudocyst (arrow in B) involving the tail of the pancreas. These findings are suggestive of chronic pancreatitis.

choledocholithiasis/cholelithiasis, calculi appear as dark filling defects within the high-signal-intensity fluid. Benign strictures due to sclerosing cholangitis are multifocal and alternate with slight dilatation or normal-calibre bile ducts, producing a beaded appearance, whereas in malignant obstruction there is abrupt cut-off and eccentric wall thickening. The current limitation of MRCP is its relatively low spatial resolution. Multiphasic contrast enhanced MR is the investigation of choice for characterisation of focal liver lesions and to look for presence of focal lesion in cirrhotic liver. In cirrhotic livers, MR can be helpful in differentiating between regenerative, dysplastic nodules and hepatocellular carcinoma. Hepatocellular carcinoma enhances in the arterial phase, washes out in the portal venous phase and shows capsular enhancement in delayed phase. On the other hand peripheral nodular discontinuous enhancement of a lesion with delayed fill in is typical of haemangiomas (Figures 9A to D). Peripheral arterial phase enhancement and portal venous phase wash out is typical of metastases. MRI is considered a non-invasive diagnostic tool for quantification of iron concentration in haemochromatosis. Liver specific contrast agents (contrast

Figures 9A to D: Liver haemangioma in a 43-year-old female. Axial T2W (A), post-contrast arterial phase (B), venous phase (C) and delayed phase (D) images show a well-defined mass lesion involving the right lobe of the liver. Mass is hyperintense on T2W images. Arterial phase image shows nodular discontinuous peripheral enhancement similar to signal intensity of the aorta. Venous and delayed phases show progressive fill on the contrast in the lesion. Findings are suggestive of liver haemangioma.

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agents specific to the hepatobiliary or the reticuloendothelial system) add to the diagnostic capabilities of MR in problem cases. Gastrointestinal Applications MRI of the bowel has been an under explored field of application for years. High soft tissue contrast resolution, acquisition of multiplanar images and the possibility to obtain functional information make MR a useful imaging technique to evaluate small bowel pathology. Applications include MR enteroclysis, MR colonography and MR virtual colonoscopy. The absence of ionising radiation is an important advantage of MRI examinations because inflammatory diseases such as Crohn’s disease (CD) need to be followed up frequently, and are prevalent among young adults. MR enteroclysis (MRE) and MR colonography are emerging techniques for the evaluation (Figures 10A to C) of small and large intestinal diseases.

poor spatial resolution due to extremely low proton density of normal lung and strong susceptibility artefacts induced by the multiple air—soft tissue interfaces within the lung, and the consequences of cardiac and respiratory movement. The main indications for chest MRI include characterisation of mediastinal lesions that are equivocal on CT, evaluation of superior sulcus tumours, particularly if brachial plexus involvement is suspected and posterior mediastinal masses. Cardiovascular Applications Technical advances in MRI have led to increased application of this modality for comprehensive evaluation of cardiovascular diseases. Gradually, MRI has become the ‘gold standard’ for the assessment of numerous cardiovascular conditions. Important clinical indications of cardiac MRI include heart failure, ischaemic heart disease, myocardial viability, cardiac masses, congenital heart disease, and diseases of the myocardium, pericardium, valves and the entire vascular tree. Cardiac MR for ischaemic heart disease shows higher spatial resolution and sensitivity compared to stress thallium, particularly for subendocardial infarcts. Disadvantages include: longer scanning time, need for general anaesthesia, various contraindications including pacemaker. Urological Applications MRI is used as a problem-solving tool in renal imaging, to characterise indeterminate masses on ultrasound and computed tomography. MRI is an alternative to CT and is particularly useful in paediatric or pregnant patients, and in patients with renal insufficiency and when ionising radiation/ iodinated contrast is to be avoided. MR urography (MRU) is clinically useful in the evaluation of suspected urinary tract obstruction, haematuria, and congenital anomalies.

Figures 10A to C: MR Enteroclysis demonstrating tubercular small bowel stricture in a 20-year-old male. Tru-FISP (true fast imaging with steady-state precession) axial (A and B) and coronal (C) images show circumferential short segment wall thickening involving distal illeal loops.

Chest Applications A MRI does not substitute CT in the investigation of most thoracic conditions requiring cross-sectional imaging. MRI in chest has

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Pelvic Applications These include gynaecological conditions like pelvic pain or pelvic mass, especially to differentiate between uterine and adnexal masses, indeterminate adnexal masses on ultrasound, detection of adenomyosis (blurring and thickening of the junctional zone of uterus on T2 weighted images), differentiation between uterine fibroids and focal adenomyosis (fibroids appear well defined and hypointense on T2 weighted images while focal adenomyosis/adenomyomas appear poorly

Figures 11A and B: Endometriosis in a 24-year-old female. Axial T1W (A) and T2W (B) images show left adenaxal mass lesion. Mass is hyperintense on T1W images and shows mixed intensity (hyperintense upper part and hypointense lower part). These findings are suggestive of endometriosis.

MRI in Medicine

A

B

Figures 12A and B: Foetal MR showing corpus callosal agenesis with dorsal interhemispheric cyst at 30 weeks gestation. T2W MR axial (A) and sagittal (B) images show dorsal interhemispheric cyst with absence of corpus callosum and dilatation of occipital horn (colpocephaly).

defined and may show intermediate to hyperintense speckling on T2 weighted images). While both endometriosis and dermoids might appear hyperintense (bright) on T1 and T2 weighted images, endometriosis is identified on T1 fatsaturated images as hyperintense due to haemorrhagic contents (Figures 11A and B), while fat in dermoids is suppressed. Another important application is the staging of carcinoma cervix and endometrium. An important application of MR in the male pelvis includes the early detection of prostatic carcinoma using endorectal coils. Unlike other malignancies, prostatic carcinoma appears hypointense (dark) on T2 weighted images amidst the hyperintense peripheral zone. Early peri-prostatic spread, neurovascular invasion or seminal vesicle invasion is well detected on MR. Obstetric applications of MR include early detection of foetal anomalies, especially when there is difficulty in sonographic visualisation due to unusual lie of the foetus, complex congenital malformation or insufficient amniotic fluid. Foetal MR is especially beneficial in evaluation of the sonographically occult or indeterminate and complex congenital malformations (Figures 12A and B). Foetal MR has an established role in the evaluation of neurological and chest anomalies. RECENT ADVANCES MR at 3 Tesla Imaging at higher field strength (3.0-T MR) provides higher resolution and has already proved superior to 1.5-T systems in neuroradiologic and musculoskeletal applications. In the abdomen, 3.0-T MR imaging is beneficial for hepatic imaging, MRCP, angiography, diffusion-weighted imaging, and colonography.

Figures 13A and B: Takayasu’s arteritis in a 16-year-old female. Maximum intensity projections of post-contrast MR angiogram (A) and invert image of A (B) demonstrates the narrowing of the proximal left subclavian artery, infrarenal aorta, bilateral common iliac arteries and left renal artery.

WB-MRI (Whole-Body MRI) Technical improvements in the MR sequences, the remote movement of the imaging table, and the use of specialised surface coils have rendered whole-body screening with MRI a feasible method. Whole-body magnetic resonance imaging is an accurate, safe and fast technique for the demonstration of disease throughout the entire body. Whole-body MRI is used to depict metastases in disseminated metastasis and lymphoma. Whole-body MR angiography can be very helpful for detecting vascular diseases (atherosclerosis, vasculitis) in different anatomic regions of the body (Figures 13A and B). RECOMMENDED READINGS 1.

Adam A, Allison D. Grainger and Allison’s diagnostic radiology. 5th Ed. Churchill Livingstone, 2007.

2.

Sutton D. Textbook of Radiology and Imaging. 7th Ed. Churchill Livingstone, 2008.

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3.5 Nuclear Medicine is a field of medical practice where minute quantities of unsealed radioactive substances, which rely on the process of radioactive decay, are used for diagnosis, therapy and clinical research. These procedures provide supportive service to almost all branches of medicine. This unique ability of imaging and therapy is based on the cellular function and physiology rather than relying on the anatomy. Most diagnostic radionuclides emit gamma rays while radionuclides emitting beta particles are used in therapeutic applications. Radionuclides for use in nuclear medicine are produced either in nuclear reactors or in cyclotrons. The reactor produced radionuclides usually have longer half-lives, whereas those produced in cyclotrons have shorter half-lives. Radioisotopes are also generated by natural decay processes in dedicated generators, e.g. molybdenum/technetium or strontium/ rubidium. Radionuclides when combined with other chemical compounds form radiopharmaceuticals which on being administered to the patient, localise to specific organs or cellular receptors. These radiopharmaceuticals emit gamma rays that are detected externally by sophisticated instruments such as gamma camera or PET scanners.This process is unlike diagnostic radiographs where external radiation is passed through the body to form an image. Gamma camera is the basic equipment in nuclear medicine imaging. The uses of computers in conjunction with cameras provide data and information about the area of body being imaged. Planar studies provide a two-dimensional image whereas tomography provides three dimensional view of physiological and biochemical processes. Tomography is the process of producing a picture of a section through an object. It is performed either by transmitting X-rays through an object (transmission computed tomography, as in CT scanning), by measuring proton density (magnetic resonance imaging) or by tomographically detecting the distribution of radioactivity in a patient (emission computed tomography). The two most widely used emission tomographic studies are Single Photon Emission Computed Tomography (SPECT ) and Positron Emission Tomography (PET). The three major categories of emission imaging are projection, longitudinal and transverse section imaging. Longitudinal tomography involves sampling over a limited range of angles and usually involves motion of a detector system parallel to long axis of the body. Transverse section tomography involves rotation of the detector system around the body with slices oriented perpendicular to the patient’s long axis. The transaxial data is then rearranged to get coronal, sagittal (slice parallel to the patient’s long axis) or oblique algorithms. SPECT refers to tomography with standard nuclear medicine radiopharmaceuticals that emit single photons upon decay. Though emission tomography was reported by Kuhl and 100

Nuclear Imaging BR Mittal Edwards in 1963, but it was X-ray tomography introduced in 1973 by Hounsfield that had a tremendous impact in diagnostic imaging. Practical application of SPECT came into existence only after the advent of the modern computers and availability of rotating gamma camera system. The most apparent advantage of SPECT is its ability to remove the superimposition encountered in two-dimensional (planar) imaging leading to increased detection of lesions. The end result of the nuclear medicine imaging process is a “dataset” comprising one or more images. Multi-image datasets may be dynamic, representing a time sequence (cine or movie), a cardiac gated time sequence, or a spatial sequence where the gamma camera is moved relative to the patient. The computer provides quantitative information for each of the specific imaging techniques. Nuclear medicine images can be superimposed, using software or hybrid cameras, on images from other modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) to highlight the part of the body in which the radiopharmaceutical is concentrated. This is called image fusion or co-registration. Presently single photon emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography/computed tomography (PET/CT) equipments are available as single units that are able to perform both imaging studies simultaneously. The fusion imaging technique allows information from two different studies to be correlated and interpreted on one image, leading to more precise information and accurate diagnosis. Nuclear medicine imaging procedures often identify abnormalities very early in the course of a disease, long before some medical problems are apparent with other diagnostic tests. This early detection allows a disease to be treated early in its course when there may be a more successful outcome. Non-imaging procedures such as thyroid uptake tests, Glomerular filtration rate (GFR) estimations and haematological tests also form part of nuclear medicine. Some of the nonimaging functional studies like clearance studies, dilution techniques are other forms of in vivo diagnostic methods. Radioimmunoassay constitutes its in vitro application. Radioimmunoassay and radioimmunometric assay were the first methods based on saturation analysis/competitive limited reagent/radiolabelled analyte to measure picomolar concentrations of biomolecules which otherwise is beyond the reach of conventional chemistry. This laid the foundation of modern endocrinology. These assays are also used to measure levels of hormones, vitamins and drugs in a patient’s blood. Beyond diagnosis, nuclear medicine also offers therapeutic applications. However, such applications are limited to a few

HISTORY The origin of nuclear medicine stems from many scientific discoveries, most notably the discovery of “X-rays” in 1895 and the discovery of radioactivity in 1896 and “artificial radioactivity” in 1934. The first clinical use of artificial radioactivity was carried out in 1937 for the treatment of a patient with leukaemia at the University of California at Berkeley. The most fundamental principle of Nuclear Medicine is the tracer principle, invented by George Hevesy for which he received the Nobel Prize in 1944. Nuclear medicine gained recognition as a medical specialty in 1946 when a thyroid cancer patient’s treatment with radioactive iodine caused complete disappearance of the spread of the patient’s cancer. Although, the earliest use of Iodine-131 was devoted to therapy of thyroid cancer, its use was later expanded to include imaging of the thyroid gland, quantification of the thyroid function, and therapy for hyperthyroidism. Development of rectilinear scanner by Benedict Cassen and scintillation camera (Anger camera) by Hal O. Anger broadened the discipline of nuclear medicine into a full-fledged medical imaging specialty. Among many radionuclides that were discovered for medical use, none were as important as the discovery and development of technetium-99m. The development of generator system to produce Technetium-99m in the 1960s became a practical method for medical use. Today, Technetium-99m is the most utilised element in nuclear medicine and is employed in a wide variety of nuclear medicine imaging studies. By the 1970s most organs of the body could be visualised using nuclear medicine procedures. The concept of emission and transmission tomography, later developed into single photon emission computed tomography (SPECT), was introduced by David E. Kuhl and Roy Edwards in the late 1950s. More recent developments in nuclear nedicine include the invention of the PET scanner. Fusion imaging with SPECT and CT was developed by Bruce Hasegawa from University of California San Francisco (UCSF), and the first PET/CT prototype by D.W. Townsend from University of Pittsburg in 1998. DIAGNOSTIC NUCLEAR MEDICINE IMAGING A nuclear medicine study involves administration of a radionuclide into the body by intravenous injection, ingestion while combined with food, inhalation as a gas or aerosol (Tables 1 and 2). In some studies patient’s own blood cells are labelled with a radionuclide (leucocyte and red blood cell scintigraphy). Following administration, the radiotracer is distributed around the body and/or processed differently where disease or pathology is present. Focal increase in radiotracer accumulation results in a ‘hot-spot’ which represents increased physiological function. In some disease processes a ‘cold-spot’ may be visualised which represents nonconcentration of radiotracer.

Table 1: The Commonly Used Intravenous Radionuclides in Nuclear Medicine Radionuclide

Symbol

Half-life (T½)

Type of Emission

Energy (Kev) (Photon)

6.01 hours 13.2 hours 27.7 days 2.8 days

IT EC γ EC, γ

Tl

73 hours

EC

Ga

3.26 days

EC, γ

110 min 75 sec

β+ β+

140 159 320 171 245 69-83* 135 167 93 185 300 511 511

Technetium-99m Tc99m 123 Iodine-123 I 51 Chromium-51 Cr 111 Indium-111 In Thallium-201

201

Gallium-67

67

Fluorine-18 Rubidium-82

18

F 82 Rb

MRI in Medicine

diseases like thyrotoxicosis, thyroid cancer, metastatic bone pain, neuroendocrine tumours, rheumatoid arthritis and radio-immunotherapy for some cancers, etc.

IT = Isomeric transition; EC = Electron capture; γ = Gamma; β+ = Positron decay; *Mercury X-rays.

Table 2: The Commonly Used Gaseous/Aerosol Radionuclides in Nuclear Medicine Radionuclide

Xenon-133

Symbol

133

Xe

81m Krypton-81m Kr Technetium-99m Tc99m DTPA aerosols Technetium 99m Tc99m Technegas

Half-life (T½)

Type of Emission

Energy (Kev) (Photon)

5.24 days

γ and β–

13 sec 6.01 hours

IT IT

81 346 β– 190 140

6.01 hours

IT

140

γ = Gamma; β– = Negative decay; IT = Isomeric transition.

CLINICAL APPLICATIONS OF DIAGNOSTIC NUCLEAR MEDICINE Nuclear Medicine scans may be used to diagnose a number of medical problems. Some of the more frequently performed tests are highlighted below. This is not meant to be exhaustive, and for a more detailed account the reader may refer to the standard nuclear medicine text books, journals and periodicals. Positron Emission Tomography is discussed in a separate chapter of this section. Endocrine Applications Thyroid Thyroid scintigraphy generates one or more images of the thyroid obtained after injection/ingestion of the tracer. Common indications are: (a) Localisation of ectopic thyroid tissue (i.e. lingual) or to determine whether a suspected thyroglossal duct cyst is the only functioning thyroid tissue present. (b) To evaluate a neck or substernal mass. Radionuclide scintigraphy may be helpful to confirm if the mass is functioning thyroid tissue.

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(c) To assist in evaluation of congenital hypothyroidism. (d) Differentiation of thyroiditis (i.e. subacute or silent) and factitious hyperthyroidism from Graves’ disease and other forms of hyperthyroidism. (e) Functional evaluation of thyroid nodules and masses (Figure 1 shows a case of cold nodule of right lobe of thyroid gland). (f) Distinguishing Graves’ disease from toxic nodular goiter, a distinction of significance in determining the amount of Iodine-131 to be given as therapy for hyperthyroidism. (Figures 2 and 3). (g) Post-operative assessment of differentiated thyroid cancer. (h) Radioactive iodine uptake (RAIU) for calculating Iodine-131 therapy dose for treating hyperthyroidism. (i) Perchlorate discharge test for identification of organification defects. (j) Radioimmunoassay/radioimmunometric assay for measurement of free and total T3, T4 and TSH.

Figures 2A and B: 99m Technetium thyroid scintigraphy showing (A) enlarged thyroid gland with increased tracer uptake (B) technetium uptake calculated by drawing ROIs showed 10% uptake (Increased) suggesting hyperthyroidism.

Commonly used radiotracers for thyroid imaging are Tc99m (pertechnetate), Iodine-123 and Iodine-131. Thyroid evaluation is one of the most frequently performed nuclear medicine procedure. Thyroid scintigraphy plays an extremely important role in the classification of thyroid pathology. The radiation dose to the thyroid is meagre with Technetium-99m, but may be significant with Iodine-131. Hence, lower doses of Iodine-131are utilised and imaging is not ideal when this radioisotope is used.

Figure 3: 99mTechnetium thyroid scintigraphy showing tracer uptake in a nodule in the right lobe of thyroid gland. Rest of the thyroid gland doesn’t show tracer uptake. Findings are consistent with autonomously functioning toxic adenoma.

Parathyroid scintigraphy (a) Localisation of hyperfunctioning parathyroid tissue (adenomas) in primary hyperparathyroidism and in patients with persistent or recurrent disease. (b) Gamma probe guided surgery. Thallium-201 or Tc99m-sestamibi are the tracers employed for parathyroid imaging.

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Figure 1: 99mTechnetium thyroid scintigraphy showing a non-functional (Cold) nodule in the right lobe of thyroid gland. Rest of the thyroid gland shows homogenous tracer uptake.

Over 90% of the primary hyperparathyroidism is caused by a single parathyroid adenoma. Most of the parathyroid adenomas are identified by scintigraphy (Figure 4) and hence allows limited surgical approach rather than bilateral neck exploration, reducing the morbidity and hospital stay of these patients. Gamma probe guided surgery combined with intra-operative PTH assay has the potential for reduced hospital stay and patient morbidity. Parathyroid scintigraphy has lower specificity in the

MRI in Medicine Figure 4: Dual phase Tc99m sestamibi parathyroid scintigraphy shows focal tracer uptake in the region of the right lobe of thyroid. Tracer retention is noted in the lesion at 1 hour. The findings are consistent with large right inferior parathyroid adenoma.

Iodine-131 MIBG has a specificity of >95% in detection of functioning neuro-endocrine tissue (Figure 5) and is mandatory before considering radionuclide therapy with high dose Iodine131 MIBG. However, sensitivity is lower because of the limited spatial resolution and poor imaging characteristics of Iodine131. MRI is an excellent modality for the evaluation of adrenal medullary disorders but is incapable of providing the functional status of the lesion. Further, whole body evaluation is possible with scintigraphy.

Genitourinary Applications Dynamic renal scintigraphy provides information about the blood flow to the kidneys, parenchymal function and drainage from the collecting system. Static cortical scintigraphy is useful in evaluation of relative kidney function and morphological abnormalities. Common indications of renal scintigraphy are: (a) Diuretic renography for detecting urinary tract obstruction (ureteropelvic or vesicourethral). (b) Captopril renography to diagnose and prognosticate renovascular hypertension. (c) Evaluation of kidneys in prenatal Ultrasonography (USG) diagnosis of hydronephrosis. (d) Renal transplant evaluation. (e) Measure differential renal function in renal insufficiency. (f ) Renal cortical scintigraphy for detecting pyelonephritis and cortical scars (Figure 6 shows cortical scars). (g) Localisation of ectopic kidney and evaluation of anatomical abnomalities. (h) Radionuclide cystourethrography for vesico-ureteric reflux, (Figure 7 shows a case of right VUR). (i) Measurement of GFR/effective renal plasma flow (ERPF). (j) Detect testicular torsion vs. epididymo-orchitis.

Adrenal cortex Scintigraphy is useful in the evaluation of Cushing’s syndrome and Conn’s syndrome.

For most purposes the radiotracer used is Tc99m-DTPA or Tc99m-MAG3 or Tc99m- EC. For anatomical visualisation, the preferred radiotracer is Tc99m-DMSA though sometimes Tc99m-GHA may also be used if DMSA is not available.

Commonly used radiotracer for this is iodine-131 iodocho lestrol/ NP-59.With the advent of high resolution cross-sectional imaging like CT and MRI, the role of nuclear medicine in the evaluation of adrenal cortical pathologies has diminished. PET has an extremely important role in the evaluation of adrenal masses and has been shown to exceed CT/MRI in both sensitivity and specificity in evaluation of adrenal masses in known/ suspected malignancies.

Renal scintigraphy has the advantages of providing functional parameters like cortical function and GFR. It plays an extremely important role in the follow-up of patients. The radiation dose delivered by renal scintigraphy is often lower than radiographic procedure like micturating cysto-urethrogram (MCUG) and intravenous pyelograms (IVP). Renal scintigraphy is also less traumatic to the patients.

presence of thyroid adenomas. However, the use of subtraction scintigraphy allows reasonable differentiation of thyroid from parathyroid adenomas. Ultrasonography has high specificity in the diagnosis of parathyroid adenomas but has insufficient sensitivity and interobserver variability. CT and MRI are also used in the evaluation of parathyroid disorders. Adrenal medulla The important tumours of the adrenal medulla are Pheochromocytoma and Neuroblastoma. The nuclear scan is usually performed with Iodine-123/Iodine131 labelled Metaiodobenzylguanidine (MIBG). Tc99m HYNICTOC is also used for this.

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(a) Neoplastic disease: demonstration of skeletal metastasis from various solid malignancies like breast, prostate (Figure 8 shows a typical case of widespread skeletal metastases). (b) Early diagnosis of osteomyelitis (Figure 9). (c) Evaluation of diabetic foot for osteomyelitis vs. Charcot’s joint. (d) Evaluation of prosthetic implant for infection or sterile inflammation. (e) Detection of bone graft viability. (f ) Evaluation of metabolic bone diseases. (g) Identify occult bone trauma (sports injuries like stress fractures, occult fracture, shin splint). (h) Diagnosing avascular necrosis of the femoral head. (i) Evaluate arthritic changes and extent. (j) Evaluation of chronic regional pain syndrome (CRPS) (Reflex sympathetic dystrophy). (k) Measure extent of certain tumours and localise sites for biopsy in tumour patients. (l) Evaluation of otherwise unexplained bone pain, especially low backache. (m) Identify bone infarcts such as in sickle cell disease. (n) Distribution of osteoblastic activity before radionuclide therapy for bone pain. The commonly used radiotracer for bone scan is Tc99m-MDP. Skeletal scintigraphy is extremely sensitive but lacks specificity. With the advent of hybrid scanners, the information obtained from CT is used to increase the specificity of bone scintigraphy. To increase the specificity of bone scintigraphy, a second imaging agent may be used e.g.; positive bone scan patient, in a case of suspected prosthetic infection, may be subjected to labelled WBC scan.

Figure 5: Whole-body 131I MIBG scintigraphy obtained 48 hours after administration of MIBG showing a focus of tracer uptake in the right hypochondrium suggesting a functional neuro-endocrine tumour. The patient had right adrenal pheochromocytoma.

Ultrasonography is an inexpensive initial modality for evaluation of the genito-urinary system. However, operator dependence and inability to differentiate dilated unobstructed systems from obstructed systems mandate further evaluation with scintigraphy. IVP requires bowel preparation and contrast administration and doesn’t provide quantitative functional parameters as scintigraphy. Skeletal System Applications Bone scintigraphy evaluates the distribution of active bone formation in the body. Whole-body bone scintigraphy produces anterior and posterior planar images of the skeleton, both axial and appendicular. Multiphase bone scintigraphy usually includes blood flow images of the area of region of interest, immediate blood pool static planar images, and delayed images at 3-4 hours. Delayed images may be limited to the areas of interest or may include the whole body (planar or tomographic). Common indications are: 104

Cardiac Applications Myocardial perfusion imaging (MPI), multigated radionuclide ventriculography (MUGA), first pass study are the common procedures. Myocardial perfusion imaging: MPI identifies areas of reduced myocardial blood flow associated with ischaemia or scar. The relative regional distribution of perfusion can be assessed at cardiac stress, rest or both. Imaging can also be performed during acute events such as in the coronary care unit or emergency department. Common indications include: (a) Diagnosis of physiologically significant coronary artery disease (presence and severity). (Figure 10 shows a case of ischaemia in the inferolateral wall). (b) Determine prognosis (risk stratification based on extent and severity of myocardial perfusion abnormalities and left ventricular function. (c) Differentiate between coronary and non-coronary causes in patients with acute chest pain syndromes seen in the emergency room. (d) Cardiac risk assessment for patients undergoing major non cardiac surgery. (e) Differentiate ischaemic from idiopathic cardiomyopathy.

MRI in Medicine Figure 6: Tc99m DMSA static planar (arterior and posterior) and pinhole images of the kidneys showing smaller right kidney with break in cortical outline in the upper pole of right kidney suggestive of presence of a cortical scar.

(f) Assessment of viable myocardium overlying the infarction to consider revascularisation. (g) Evaluate the immediate and long-term effects of revascularisation procedures and medical or drug therapy. Myocardial perfusion imaging is a gate-keeper to invasive coronary angiography. With the advent of CT coronary angiography, there is an increase in the number of equivocal coronary lesion whose physiological significance needs to be evaluated with MPI. MPI, apart from providing information about the perfusion status, also provide various functional parameters like ventricular ejection fraction, systolic and diastolic volumes, myocardial mass and prognostic information. A normal stress MPI has less than 1% risk of contracting any major cardiac event.

Multigated equilibrium radionuclide ventriculography: MUGA is a procedure where patient’s red blood cells (RBCs) are radiolabelled and ECG gated cardiac scintigraphy is obtained. Parameters obtained from MUGA include (i) global ventricular ejection fraction, (ii) systolic and diastolic function indices, (iii) regional wall motion, (iv) ventricular volumes, (v) stroke volume ratios. Common indications are: (a) Evaluation of known or suspected coronary artery disease. (b) Distinguishing systolic from diastolic causes of congestive heart failure (CHF) in patients with known or suspected CHF. (c) Measure cardiac toxicity in patients undergoing chemotherapy. (d) Assessment of ventricular function in patients with valvular heart disease. (e) Monitoring response to surgery or other therapeutic interventions.

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Figure 7: Direct radionuclide cystography (DRCG) study showing left vesico-ureteric reflux. Tracer activity in the urinary bladder is noted refluxing into the left ureter and renal pelvis during the voiding phase of the study.

First pass studies help to identify and quantify shunts and evaluation of right heart failure. Thallium-201, Tc99m-sestamibi, Tc99m tetrofosmin are the radiotracers for myocardial perfusion imaging. MUGA study is performed with labelled erythrocytes. First pass study to evaluate right heart function or shunts can be performed with any Tc99m labelled tracer. MUGA study is the current gold standard for the evaluation of LV ejection fraction and is proving indispensable in the evaluation of patients undergoing cardio-toxic chemotherapy.

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Pulmonary Applications Perfusion scintigraphy measures the distribution of pulmonary arterial blood flow. Ventilation scintigraphy records the bronchopulmonary distribution of an inhaled radioactive

aerosol within the lungs. Pulmonary lung scintigraphy for pulmonary embolism assesses pulmonary perfusion and often includes ventilation scintigraphy. The most common indications are: (a) Determination of the likelihood of pulmonary embolism. (b) Quantify lung ventilation and perfusion as preoperative evaluation. (c) Evaluation of lung transplantation. (d) Right-to-left shunt evaluation. (e) Detect pulmonary complications of AIDS. (f ) Detect inhalation injury in burn patients. Lung perfusion scan is performed with Tc99m-microspheres of albumin while ventilation scan is performed either with Xenon 133 or with Tc99m-DTPA aerosols/technegas.

MRI in Medicine

(a) Evaluation of suspected acute cholecystitis. (b) Evaluation of suspected chronic biliary tract disorders. (c) Determine causes of jaundice and identify obstruction in the biliary passage. (d) Detection of bile extravasation. (e) Evaluation of congenital abnormalities of the biliary tree. (f ) Liver and gallbladder scans to evaluate liver and gallbladder function. (g) Liver (reticulo endothelial cells) scans for cirrhosis, noncirrhotic portal fibrosis (NCPF), tumours, space occupying lesions, etc. Scintigraphy suffers from limited anatomical resolution which precludes detection of small lesion and to localise the exact sites of biliary leaks. Some of the studies require many hours to complete. Gastrointestinal tract motility studies Gastrointestinal tract motility studies include oesophageal transit, gastro-oesophageal reflux studies, gastric emptying studies, intestinal and colonic transit studies. Gastrointestinal bleeding scans are used to identify bleeding into the bowel. Gastric emptying and motility: Radionuclide studies of gastric emptying and motility are the most physiologic studies available for studying gastric motor function. The study is noninvasive, uses a physiologic meal (solids with/without liquids), and is quantitative. Serial testing can determine the effectiveness of therapy. Indications for gastric emptying include: (a) Suspected gastroparesis (b) Poor diabetic control (c) Gastro-oesophageal reflux (d) Following response to therapy for previously documented motility disturbances

Figure 8: Tc99m-Methylene diphosphonate (MDP) bone scintigraphy showing multiple foci of increased tracer uptake involving several bones. The findings are consistent with widespread skeletal metastasis.

Inspite of the introduction of CT pulmonary angiography, ventilation-perfusion (V/Q) scintigraphy has continued to have important role. V/Q scan delivers far less radiation to the female breast than CT angiography. V/Q scan also serves as a baseline for the evaluation of response to anti-coagulants (Figure 11). Of late, the utility of V/Q scintigraphy has also been studied in parenchymal lung disease and asthma. One of the drawbacks of V/Q scan is the large number of indeterminate scans but with the advent of V/Q SPECT, the indeterminate scans have been reduced to 120 kcal/kg/day). Arginine hydrochloride 360 mg/kg, carnitine 50 mg/kg, Na-benzoate 350 mg/kg and Na-phenylbutyrate or Na-phenylacetate 250 mg/ kg should be started. The patient should be transferred to a referral centre. Citrulline may be used in the dose of 170 mg/kg per day in CPS and OTC deficiency. Anticonvulsants like sodium valproate should be avoided. NH3 level more than 400 μ mol/L In addition to the above measures, extracorporeal detoxification should be started as soon as possible. Use haemodialysis, if possible; otherwise, peritoneal dialysis. Long-term treatment of urea cycle defects Start low-protein diet containing essential amino acids early. Na-benzoate orally in a dose of 250-400 mg/kg/day and Naphenyl-butyrate orally in a dose of 250-500 mg/kg/day is also to be administered. Supplement vitamins (e.g. folic acid 500 μg/ day) and trace elements. If carnitine is low, supplement carnitine in the dose of 30-50 mg/kg. Consider lactulose as it binds intestinal ammonia due to acid pH. The target value of NH 3 is less than 80. Essential amino acids should be in the normal range. Organic Acid Disorders Emergency treatment in the hospital includes the following: (a) Interrupt catabolic state: High-dose energy substitution, usually glucose intravenous (exceptionally via nasogastric tube), if necessary with intravenous insulin. (b) Stop protein intake: In some disorders, the accumulation of toxic metabolites can be reduced by intestinal antibiotic treatment (metronidazole, colistin). (c) Ensure adequate fluid and electrolyte intake: Aim for a sodium concentration >140 mmol/L to reduce the risk of cerebral oedema. (d) Carry-out detoxifying measures depending on the disease and laboratory findings: Increased diuresis, dialysis, haemofiltration. (e) Consider specific drug treatment (vitamins, carnitine, etc.) depending on the disease and laboratory findings. Long-term treatment includes the following: (a) Diet: protein restriction, (b) If indicated give specific vitamins or co-factors, (c) Carnitine (50-100 mg/kg/day), and (d) Regular laboratory monitoring (depending on the disease). Disorders of Fatty Acid Oxidation The main therapy is prevention of fasting and catabolic states. In acute situations, intravenous glucose infusion (8-10 mg/kg/min) should be started without delay. In contrast, in patients with defects in LCAD metabolism, low fat diet supplemented with

medium chain triglycerides may be beneficial. Avoid valproate as an antiepileptic drug if possible. Mitochondrial Disorders Most approaches used for the treatment of mitochondriopathies have not been scientifically evaluated, and success is limited. General measures include avoidance of drugs that inhibit the respiratory chain, e.g. valproate, barbiturates, tetracyclines, chloramphenicol. L-Carnitine 50-100 (up to 200) mg/kg/day in 4 doses; avoid lactic acidosis by limiting excessive physical exercise, controlling fever, early and efficiently, and early treatment of seizures. Treatment regimen in acute lactic acidosis and suspected mitochondriopathy includes: coenzyme Q10 + riboflavin (in the neonate: 100 mg/day), vitamin C, carnitine, biotin (20 mg/day), phylloquinone or menadione and thiamine.

Inborn Errors of Metabolism

acetate and arginine. Intravenous preparations of sodium benzoate and phenyl acetate are not available in India. Oral sodium benzoate is available and can be used in the same dose.

Specific long-term treatment, though of uncertain efficacy, includes: coenzyme Q10 4-5 mg/kg/day in 2 doses, riboflavin 320 mg/kg/day in 4 doses, thiamine 25-100 mg/kg/day, tocopherol (vitamin E) 100-300 (up to 1,000) mg/day and Creatine 4-10 g/day (stop every 4th month), e.g. in mitochondrial myopathy. Corticosteroids are not indicated. Vitamin/Cofactor Therapy In certain IEM, enhancement of the activity of a mutant enzyme can be achieved by giving mega-doses of a vitamin cofactor required for enzyme’s action. One-third of the cases of homocystinuria due to cystathionine b-synthetase deficiency are pyridoxine responsive. Deficiency of multiple biotin-dependent carboxylases responds to 10 mg of biotin given daily. Some cases of methylmalonic acidaemia respond to pharmacological supplementation of intramuscular hydroxycobalamin in a dose of 1 mg per day. A diet low in fat and protein together with a trial of oral riboflavin (200-300 mg per day) and carnitine may be helpful in some patients with glutaric aciduria type I and II. Dietary Therapy and Enzyme Replacement Specific therapy will depend on the final diagnosis. Dietary therapy is required for PKU, MSUD, galactosaemia, homocystinuria, etc. Cost of the special diets is high and critical monitoring is required for effective management. Enzyme replacement therapy is available for many lysosomal storage (e.g. Gaucher’s, MPSI, MPSII, GSDII, Fabry’s, MPSVII) disorders with excellent results. Bone marrow/stem cell transplantation is another option for lysosomal storage disorders. Newborn Screening Newborn screening is a well-tested strategy for secondary prevention of IEM. Most developed countries test for IEM using TMS in addition to screening for congenital hypothyroidism and congenital adrenal hyperplasia. Samples are collected by heal prick 48 to 72 hours after birth. Early diagnosis and timely management prevents neurological sequelae and mortality. India does not have a national newborn screening programme presently. The ICMR has initiated a multicentric pilot project for newborn screening of 100,000 babies for congenital

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hypothyroidism and congenital adrenal hyperplasia to study the incidence of these disorders and also the feasibility of introducing such a programme in India. The Governments of Chandigarh and Goa, India have also initiated newborn screening programmes recently. Genetic Counselling and Prenatal Diagnosis As most IEM are autosomal recessive, the risk of recurrence in subsequent pregnancies is 25%. For X-linked disorders recurrence risk is 50% for male offspring. Prenatal diagnosis is possible by enzyme assay in chorionic villous biopsy or amniotic fluid cells. Mutation analysis on DNA extracted from chorionic villous sample or amniotic fluid cells is a more robust and preferred modality if causative mutations are known.

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RECOMMENDED READINGS 1.

Bruton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998. 102: E 69.

2.

Clarke JTR. The management of inherited metabolic diseases: a review. J Pediatr Obster Gyn. 2005; 31: 186-96.

3.

Graya RGF, Preecea MA, Greenb SH et al. Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neuro Neurosurg Psychiatry. 2000; 69: 5-12.

4.

Marburg JZ, Marburg GH. Vademecum metabolium. Manual of metabolic Pediatrics. Milupa, Schattaner 1999.

5.

Scriver CR, Beaudet AL, Sly WS Valle D. The Metabolic and Molecular Bases of Inherited Disease. Vol 1; 8th Ed. McGraw Hill; 2001.

6.

Stanton Segal, Karl S Roth. Inborn errors of metabolism: a new purview of internal medicine. J Neuro Neurosurg Psychiatry. 2000; 69: 5-12.

6.6

Molecular Genetics, Human Genome Project and Genomic Medicine Girisha KM

The understanding of the structure, function, regulation and variations in DNA is the key to the understanding of human health and disease. This chapter discusses the molecular basis of life, gives insight into genetic variation between individuals and its clinical implications. STRUCTURE OF DNA Deoxyribonucleic acid (DNA) is a long polymer of nucleotides. Each nucleotide is made up of a nitrogenous base [purines: adenine (A) and guanine (G); and pyrimidines: cytosine (C) and thymine (T)], a deoxyribose sugar, and a phosphate group. Ribonucleic acid (RNA) differs from DNA in having a ribose sugar in place of deoxyribose, and pyrimidine uracil (U) in place of thymine. Watson and Crick (1953) demonstrated how deoxynucleotides are assembled to form the double stranded helical structure of DNA, where sugar and phosphate molecules form two sides of the ladder that are held by strong phosphodiester bonds, and rungs of the ladder are formed by nitrogenous bases facing inside, being held together by hydrogen bonds that are weaker and separate during replication and transcription. The two strands run anti-parellel to each other with one strand having the orientation of 5’ to 3’ direction and the other of 3’ to 5’ direction (Figure 1). In human nucleated cells, approximately 2 metres of DNA is condensed about 10,000 times and packaged into chromosomes. The DNA is first wound around a histone protein core to form a nucleosome, which in turn forms a helical solenoid. The solenoids are organised into chromatin loops, which are attached to a protein scaffold and further packaged into chromosomes. DNA REPLICATION Replication of DNA is the key event for transmission of genetic information from parent cell to its progeny. The process leads to formation of two identical copies of the original DNA that get segregated into two daughter cells during cell division. The replication begins with uncoiling and separation of two strands of the DNA molecule by the enzyme helicase. Each strand of the DNA directs synthesis of its complementary copy through complementary base pairing (adenine pairs with thymine and cytosine pairs with guanine) resulting in formation of two DNA molecules (semi-conservative synthesis) identical to the original parent molecule. This process conserves the genetic information, and transmits it unchanged to each daughter cell. The key enzyme that carries out DNA synthesis is DNA polymerase. The process initiates at several sites simultaneously during the S (synthetic) phase of cell cycle. The synthesis of a new DNA strand proceeds in 5’ to 3’ direction. This leads to formation of one continuous strand (leading strand) which is the copy of the 3’ to 5’ strand; and the other strand is synthesised in parts (Okazaki fragments) that are later joined together by the enzyme DNA ligase.

Figure 1: Helical structure of the DNA showing the sugar-phosphate backbone and the nitrogenous bases. The DNA resembles a ladder with the sides formed by the phosphodiester bond between phosphoric acid and deoxyribose sugar and the rings formed by hydrogen bonds in-between the nitrogenous bases. Two hydrogen bonds are formed between adenine (A) and thymine (T) and three hydrogen bonds between guanine (G) and cytosine (C).

TRANSCRIPTION AND RNA PROCESSING Transcription is the process whereby genetic information stored in DNA is utilised for gene function. It leads to formation of RNA which migrates to cytoplasm for synthesis of proteins. The transcript of the coding DNA is known as messenger RNA. The mRNA is single stranded. It is synthesised by the enzyme RNA polymerase that adds complementary ribonucleotides to the RNA chain (uracil replaces thymine in mRNA). The particular strand of DNA that acts as a template for synthesis of mRNA is called ‘antisense strand’ so that the new molecule of mRNA is the copy of the other ‘sense strand’. The mRNA leaves the nucleus to cytoplasm after several processing events. The RNA processing includes removal of introns at specific splice sites in mRNA (splicing), addition of a methylated guanine nucleotide to the 5’ end of the molecule (5’ capping) and addition of about 200 adenylate residues at the 3’ end (polyadenylation). Now the mRNA molecule is ready to be translated. THE GENETIC CODE The 20 different amino acids in proteins are coded by the four different nucleotides (bases) in DNA (Figure 2). The sequence of triplet nucleotide bases in the DNA molecule that specifies the sequence of amino acids in the protein molecule is called the genetic code. The genetic code from DNA is transmitted to

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Figure 3: The genetic code: Triplet nucleotides in the mRNA form codons and code for specific amino acids. An amino acid may be coded by more than one codon and three codons stop the elongation of polypeptide chain. Figure 2: Central dogma of molecular biology.

codons of the mRNA during transcription which is then decoded into specific amino acids during translation. The codons on mRNA are non-overlapping, and are read as per translational reading frame. Among 64 possible triplet codons from 4 nucleotides, some code for same amino acid (degeneracy, since there are only 20 amino acids). Three codons code for termination of the polypeptide synthesis (stop codons). The process of transfer of genetic information from DNA to RNA to protein is sometimes referred to as ‘central dogma’ or ‘holy trinity’ of molecular biology (Figure 3). TRANSLATION The genetic code in the DNA (of a gene) is transmitted on to the codons of mRNA and these direct the synthesis of polypeptide chain by incorporating specific amino acids during the process of translation. In the ribosomes, the site of protein synthesis, the mRNA molecules with the help of specific transfer RNAs (tRNA) carrying the ‘anticodons’ for individual amino acids synthesise the polypeptide chain, originally directed by the genetic code in the gene. The polypeptide chains, thus synthesised, undergo several post-translational modifications (hydroxylation, methylation, glycosylation, proteolytic cleavage, etc.) to become functional proteins that are transported to their specific cellular locations.

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REVERSE TRANSCRIPTION In most situations, the genetic information flows from DNA to RNA. However, in certain types of viruses (retroviruses) genetic information can flow in reverse direction from RNA to DNA. This is termed reverse transcription or RNA-directed DNA synthesis and involves the enzyme reverse transcriptase. Some regions of the DNA serve as templates for synthesis of RNA, which in

turn act as templates for synthesis of DNA. This DNA may get integrated into nuclear DNA of other cells. GENE: THE FUNCTIONAL UNIT OF DNA A ‘gene’ may be conceptualised as the sequence of DNA that contains the information required for a functional product (Figure 4). The product encoded may be a polypeptide or RNA molecule. Previously, it was thought that the coding sequence of a gene lies in continuity, which is now known to be a rarity. Now, the ‘gene’ has been shown to consist of amino acid coding exons, intervening non-coding introns, promoter sequences at 5’ region that initiate transcription and other regulatory elements like enhancers, silencers, and locus control regions. Genes may overlap, may be found within another gene, or even the same sequence may be transcribed in reverse direction to produce another product. REGULATION OF GENE EXPRESSION The estimated 23,000 genes in each human cell control all the cellular processes in the living being. Their expression varies at different stages of development, and depending on the type of the cell/tissue. Several complex pathways are involved in controlling temporal and spatial expression of genes. Signalling molecules called transcription factors bind to regulatory sequences of DNA, nuclear receptors (hormones) or even specific ligands located at the cell surface for signal transduction. The transcription factors may bind to promoter elements (TATA, GC and CAAT boxes) of the specific genes located adjacent to the coding region (cis-acting) to regulate the pace of protein synthesis, or to enhancer or silencer elements located at a distance and act on both copies of the gene (transacting) to enhance or suppress the transcription. Transcription factors themselves are coded by genes and bind to DNA to regulate gene expression.

Gene activity may also be related to patterns of chromatin condensation. Heterochromatin is usually highly condensed and is characterised by histone modification that makes it inaccessible to transcription factors, whereas euchromatin is decondensed and transcriptionally more active. Though regulation of expression of most of the genes is mediated by transcription factors, regulation can also occur at various stages of protein synthesis, viz. RNA processing, transport, and translation. Alternative splicing is a mechanism where a gene can code for more than one protein or at varying rates. STRUCTURE AND ORGANISATION OF THE HUMAN GENOME The ‘human genome’ refers to the total genetic information in human cells. In simple terms, genome refers to the entire DNA content of the cell. It consists of the larger nuclear genome (3x109 bp) and the very small mitochondrial genome (16.6 kb). The nuclear genome encodes bulk of genetic information, most of which specifies synthesis of proteins of the body. Mitochondrial genome encodes its own transfer RNA, ribosomal RNA and few of its own polypeptides. Nuclear Genes It is estimated that there are about 23,000 genes in the entire nuclear genome. The size of the genes varies greatly, with small genes comprising of one to three exons (e.g. beta globin gene) and large genes with up to 79 exons (dystrophin gene, ~2.5 Mb). Unique single-copy genes are present in single copy (in the haploid set of chromosomes). These encode the polypeptides that are involved in a wide variety of cellular functions: enzymes, receptors, regulators, etc. Some others are members of multigene families. These arise through gene duplication events during evolution.These may be found in physically close clusters like alpha and beta globin genes on chromosome 16 and 11, respectively or dispersed throughout the genome like the HOX gene family, which are important developmental genes. The genes which encode the ribosomal RNAs are clustered as tandem arrays at the short arms of the acrocentric chromosomes and those encoding the transfer RNAs occur in numerous clusters throughout the genome. These constitute classic gene families. Genes encoding the human leukocyte antigens (HLA) and the T-cell receptor genes belong to the immunoglobulin gene superfamily. Pseuodogenes closely

resemble known structural genes but do not express. They are thought to have arisen either by duplication of genes that have lost function due to mutations or by insertion of complementary DNA sequences lacking promoter sequences. Extragenic DNA The sequences that represent all the genes of the human body constitute around 1.5% of the genome. The rest of the human genome is made up of repetitive DNA sequences that are predominantly inactive. These have also been referred to as junk DNA, but have some uncertain regulatory role.

Molecular Genetics, Human Genome Project and Genomic Medicine

Figure 4: Structure of a gene: A typical gene is made up of a promoter, a transcriptional start site, exons, introns, translational stop site and a Poly A signal.The promoter facilitates the binding of RNA polymerase to the gene during transcription; the transcriptional start site contains the initiation codon ATG, which marks the start of transcription. Exons encode the information for a functional protein. The 5’ and 3’ untranslated sequences play a role in gene regulation.

Tandem repeats The non-coding DNA may occur in tandem repeats or may be interspersed in the genome. Satellite DNA is clustered around the centromeres of certain chromosomes and contains very large series of tandemly repeated sequences that are transcriptionally inactive. Mini-satellites consist of repetitive sequences found at the telomeres of chromosomes. Highly polymorphic short tandem repeats of core units made up of 10-100 base pairs are used in DNA fingerprinting. Micro-satellite DNA consists of tandem repeats of 1-4 base pair sequences located throughout the genome. Highly repeated interspersed repetitive DNA Approximately one-third of the human genome is made up of two main classes of short and long repetitive DNA sequences that are interspersed throughout the human genome. These include several lakhs of copies of short interspersed nuclear elements (SINEs) and the long interspersed nuclear elements (LINEs). Mitochondrial DNA Mitochondria contain their own 16.6 kb circular DNA (mtDNA). It encodes for 37 genes including 2 for ribosomal RNA, 22 for transfer RNA and 13 for polypeptide sequences. It may be noted that most of the protein component of mitochondria are product of nuclear genes. DNA CLONING Cloning refers to selective amplification of a specific DNA fragment of interest to produce it in a large quantity for further analysis. This can be done by either one cell based in vivo amplification, or via polymerase chain reaction in vitro.

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To clone a segment of DNA, the first step is to generate DNA fragments. This can be done by various methods, the most popular being digestion with restriction enzymes that cleave the DNA into fragments at recognition sites specific to the enzyme. Enzymes that produce staggered (sticky) ends are used for DNA cloning. Next, a suitable vector (plasmid, bacteriophage, cosmid, bacterial or yeast artificial chromosome) is also digested with the same restriction enzyme. The sticky ends of the DNA fragment and the DNA of the vector are attached by the enzyme DNA ligase to generate a recombinant DNA molecule. The recombinant vector is then introduced into especially modified bacterial or yeast host cell that gets transformed. When the host cell multiplies, large quantities of DNA of interest or clones are also synthesised. The transfected cells are then screened for antibiotic resistance or sensitivity genes incorporated in the transforming vector or for the product of gene of interest. Specific clones containing the desired DNA inserts are then selected and cultured separately. This clone serves as the source of amplified DNA fragment of interest for further analysis. DNA Libraries DNA libraries contain a large number of clones representing entire repertoire of DNA/RNA derived from a given source. When whole DNA from nucleated cell is used as the source, the resultant product is called genomic DNA library. It may also be chromosome specific library if clones are prepared from sorted chromosomes. When mRNA is used to synthesise the DNA (complementary DNA (cDNAJ) and library is created from it, it is termed cDNA library. The cDNA library contains DNA sequences that are copies of transcribed mRNA. Specific clones from the library may be used for different purposes. VARIATIONS IN HUMAN GENOME Humans display a remarkable degree of genetic variation. The most obvious traits include height, blood pressure and skin colour. This also encompasses variation in disease traits and susceptibility to diseases, etc. Even though the sequence of human nuclear DNA is 99.9% similar between any 2 individuals; only 0.1% is sufficient for no. 2 individual to be alike. Mutations and Polymorphism Genetic variations originate from ‘mutation’ that is defined as a change in DNA sequence that is heritable. As a result of mutations, DNA sequences and genes may vary from personto-person. Different sequences on a particular location (locus) of the chromosome are referred to as alleles. A homozygote has the same allele on both members of a chromosome pair, but alleles differ in a heterozygote. The genotype refers to the alleles present at a given locus.

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generation to generation, whereas a somatic mutation (that can lead to cancer) is confined to somatic cells. Mutations in individual genes are classified on basis of sequence change and its consequence on protein product and its function. Substitution refers to replacement of a single nucleotide by another, and is the most common type of mutation. Transition refers to substitution of the same type of nucleotide (i.e. purine by purine, or pyrimidine by pyrimidine nucleotide). The reverse is transversion. Substitutions can result in a synonymous change (silent, with same amino acid retained in the protein product), or a non-synonymous change of amino acid. Non-synonymous mutations are missense when the altered amino acid affects protein function or stability, and nonsense when it leads to creation of a stop codon. A substitution may also affect the splice site leading to aberrant splicing of mRNA, or the promoter that leads to altered gene expression. Deletions involve the loss of one or more nucleotides. If it occurs in the coding sequence, it may disrupt the reading frame (frame shift mutation), unless the deletion affects nucleotides that are a multiple of three (in frame). Larger deletions involving a part or whole of the gene also occur. Insertion refers to addition of one or more nucleotides into a gene. Depending on the number of nucleotides inserted, the mutation may cause a shift in the reading frame. Expansion of triplet repeats is a form of insertion. It is described elsewhere in this section. Substitution, insertion and deletion may affect the splice site, either by activating a cryptic splice site or by abolition of a regular splice site. This may result in exon skipping, retention of intronic sequences and frame shift. Functionally, a mutation can lead to loss of function of a protein [deletion of dystrophin gene (some exons) in Duchenne muscular dystrophy], haploinsufficiency (50% of the protein product is insufficient for normal cellular function as in familial hypercholesterolaemia) or gain of function (as in achondroplasia), or rarely a dominant-negative effect where product of mutant gene in heterozygous state results in loss of activity of normal gene product of the corresponding allele as well.

If a locus has 2 or more alleles where the frequency of minor allele exceeds 1% in population, the locus is said to be polymorphic. Usually such alleles do not produce significant phenotypic effect (i.e. these are neutral in effect), but are presumed to be selected/ maintained in the population.These can serve as a useful genetic marker.

Single Nucleotide Polymorphisms Single nucleotide polymorphisms (SNPs, also pronounced as SNIPS) refer to single base differences in the DNA sequence, found throughout the human genome with a frequency of about 1 per 1000 bp, in more than 1% of the population. These are mostly biallelic and occur in both coding and non-coding regions of the genome. It is easy, fast and inexpensive to assay SNPs, and many sites can be assayed simultaneously and automated. They are almost always found near the genes of interest. Combination of SNPs can be used to construct haplotypes, or SNP profiles which serve as powerful tools to study linkage, genetic predisposition to multifactorial diseases, detection of submicroscopic chromosomal imbalances, pharmacogenetics, etc. More recently SNP microarrays have been extensively used for genome wide association studies.

Types of Mutations The variations in the human genome may be at the genomic level as in aneuploidy, chromosomal level as in translocations, or at the gene level as in point mutations. A germline mutation affects cells that produce gametes and is transmitted from

Copy Number Variations Being diploid, humans have two copies for any particular segment of DNA. However, in some areas, the number of copies of the particular segment varies between two human genomes (of two individuals). This phenomenon has now been termed

to methods suitable for study of functions of different genes identified in the genome. Functional genomics aims to study functions of a gene at biochemical, cellular and organismal level, including gene-gene interactions and gene-environmental interactions. The approach also takes into consideration the role of conserved genes in model organisms and human homologues. Transgenic (those which carry the gene of interest) and knock-out (where the gene of interest is absent or mutated) models provide invaluable insight into function of genes. Transcriptomics (study of total mRNA transcript of the cell) provides more scope for linking genes and their products into functional pathways and networks. Expression pattern also reveals how changes in gene expression coordinate the biochemical activities of the cell in health and disease. Development of microarray technology has provided useful means to study expression of thousands of genes at a time. The field of proteomics encompasses the analysis of protein expression, protein structure and protein interactions to understand the functions and interactions of genes. Metabolomics refers to the study of metabolites and metabolic networks (pathways).

HUMAN GENOME PROJECT It has been one of the most ambitious undertakings in the history of biomedical research. The Human Genome Project (HGP) began in 1991 and produced the first draft sequence of the human genome by 2001, well ahead of its scheduled date of completion. A completed, highly accurate sequence was unveiled in 2003. The entire data is now available in the public domain. In addition to sequencing of the entire human genome, the project had set several other objectives and areas of work as well: human gene maps and mapping of human inherited diseases, maps of model organisms, development of new DNA technologies, development of bioinformatics, comparative genomics and functional genomics. The project also had an ethical component to look into various issues arising out of genome research. The project has provided a map of genetic markers using many thousands of polymorphisms (variations) distributed throughout the genome. Additionally, more than 4 million SNPs have been identified in the human genome.

GENOMIC MEDICINE Each person has a unique genome, except for monozygotic twins, and hence different phenotype (physical traits). Its needs and responses with respect to nutrition, disease susceptibility, preventive care, disease phenotype, complications, treatment, response to drugs, are likely to be unique. All physicians will soon need to understand the concept of genetic variability, its interactions with the environment, and its implications for patient care. With sequence of the human genome now available and technology making it possible to sequence the whole genome of any individual, the practice of medicine will enter into a new era in which an individual patient’s genome will help determine the optimal approach to care, be it preventive, diagnostic, or therapeutic.

In addition to the human genome, genomes of several other organisms like Escherichia coli, Haemophilus influenzae, Saccharomyces cerevisiae (yeast), Caenorhabditis elegans, Drosophila melanogaster (fruit fly), mouse, rat, and zebra fish have also been sequenced. The genes in these organisms show significant homology to genes in humans and provide an opportunity to study candidate genes for human diseases (comparative genomics). These model organisms are also invaluable tools to study expression of genes and function of their protein products in normal development as well as their dysfunction in inherited disorders. Developments in molecular techniques and computational abilities have made gene mapping easier and faster. But it has also thrown many ethical, legal and social challenges. Completion of HGP project represents the beginning of an era of scientifically exciting, but socially complex, biomedical research and molecular medicine. POST-GENOMIC ERA OF ‘OMICS’ The major goal of HGP was to provide entire structure of human genome (structural genomics). But this is of limited use without knowing function of the genome. The emphasis has now shifted

Molecular Genetics, Human Genome Project and Genomic Medicine

copy number variation (CNV) and more and more such copy number variants are being uncovered by the use of array comparative genomic hybridisation technique that is being used widely. A CNV may vary in size from 1 kb to several mega bases and can occur anywhere in the genome. Usually they result from deletion-duplication events and are heritable. It is estimated that approximately 0.4% of the genome of unrelated people typically differs with respect to copy number. Like any other genetic variation, CNVs have been found to be associated with disease susceptibility and resistance. CNVs encompass more DNA than SNPs. CNVs can be limited to a single gene or include contiguous set of genes. CNVs can result in having either too many or too few of the dosage sensitive genes, which may be responsible for substantial amount of human phenotypic variability, complex behavioural traits, and disease susceptibility. It is often difficult to determine whether a particular CNV that is uncovered in a chromosomal array is pathogenic or not. A CNV that arose de novo in an individual with abnormal phenotype is likely to be pathogenic whereas a CNV that is inherited from an asymptomatic parent or a CNV that is found in other unaffected individual is likely to be a polymorphism.

With rapid progress in technologies to unravel the genome, proteome and even metabolome, there is a paradigm shift in the research focus from disease causing genes to modifier genes, structure to function, aetiology to pathogenesis, and disease diagnosis to susceptibility recognition. Though stem cell therapy and gene therapy still remain a dream despite over two decades of research, we are likely to see major discoveries demystifying human health and disease at an astonishing pace in the coming years. All the monogenic disorders and the underlying defects will be characterised enabling molecular diagnosis of all and prenatal diagnosis whenever indicated. This will open up new treatment options based on innovative strategies. Predictive testing is already possible for some disorders and the number is likely to increase in case of multifactorial diseases. The ultimate aim of understanding the human genome is to offer genomic medicine where the genetic make-up of an individual paves the way for a healthy lifestyle, prevention of disease, and optimal treatment of medical conditions. Simultaneously, progress in the medical field, in all likelihood will increase the debate on social and ethical issues involved. RECOMMENDED READINGS 1. 2.

Collins FS, McKusick VA. Implications of the human genome project for medical science. JAMA. 2001; 285: 540-4. Guttmacher AE, Collins FS. Genomic medicine—a primer. N Engl J Med. 2002; 347: 1512-20.

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6.7 INTRODUCTION There are more than 3000 genetic disorders caused by single gene defects. In addition, there are many other multifactorial disorders where genetic variation plays a significant role in the aetiology of the disease. The strategies of conventional treatment for genetic disorders often require life-long treatment and are expensive. Besides, for many disorders there is nothing to offer. The possibility of curing the genetic disorder by replacing the defective gene or repairing the mutation insitu appears to be much more logical. Recent advances in molecular biology have made gene therapy an achievable goal. Gene therapy, as yet, is an experimental modality of treatment where a functional gene is introduced into a cell to take over the function of the defective gene. The first gene therapy trial in humans was approved in 1989. Since then more than 1500 trials in various conditions have been carried out. These studies have provided the ‘proof of principle’ but safe and effective gene therapy for genetic disorders is still a long way to go. In addition to monogenic disorders, clinical trials using gene therapy are also being carried out for disorders like cardiovascular disease, diabetes mellitus, cancer and infectious diseases like human immunodeficiency virus (HIV). Gene therapy can be carried out to correct the genetic defect in a fertilised egg (Germline Gene Therapy), or in somatic cells (Somatic Gene Therapy). Due to fear of possible adverse effect on future generations and other social, ethical and legal issues, germline gene therapy is not permitted in any country at present. For somatic gene therapy, special guidelines for clinical trial protocols and permission of ethics committee and other regulatory bodies of the country may be essential. REQUIREMENTS FOR GENE THERAPY The prerequisites of successful human gene therapy (HGT), include selecting a therapeutically suitable gene (with a proven role in the pathophysiology of the disease), appropriate gene delivery system (e.g. viral and non-viral vectors to transfer the gene into the cells), efficacy and safety studies in appropriate animal models, and suitable manufacturing and analytical processes to produce well-defined HGT products for clinical investigations. It is only after successful pre-clinical trials for gene therapy in cell culture and animal models, that the therapeutic gene be tested in clinical trials.

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In monogenic disorders, addition of the wild type gene has shown some promise in several clinical trials. The first successful gene therapy trial for severe combined immunodeficiency syndrome (SCID) due to adenosine deaminase (ADA) deficiency was carried out in 1990. In this disorder, the wild type ADA gene was introduced in T-cells of the patient and the transduced cells were transferred back to the patient. This resulted in dramatic improvement in immune competence of the patient, so much so that she could attend the normal school. Once the

Gene Therapy Rita Mulherkar therapeutic gene is selected, the sequences which regulate expression of the gene, i.e. the promoter sequences also need to be selected. A tissue-specific promoter would regulate expression of the therapeutic gene in that particular tissue. A ubiquitous promoter, on the other hand, would express the gene in most tissues, e.g. a viral promoter such as cytomegalovirus (CMV) promoter. The choice of vector is equally important. Most efficient vectors are viral vectors which are modified in the lab to become non-pathogenic. Viruses have evolved over a period of time to efficiently utilise the cellular machinery for its own advantage and make numerous copies of itself in the cell. Thus a gene cloned in a viral vector also replicates itself along with the virus and either gets integrated in the host genome or remains in the nucleus as an episomal body. Adenoviral and adeno-associated virus vectors have been the most widely used vectors in clinical trials so far. IN VIVO AND EX VIVO DELIVERY OF A THERAPEUTIC GENE The therapeutic gene along with its regulatory sequences can be introduced into the patient either directly as naked deoxyribonucleic acid (DNA) or through a vector, which is injected intramuscularly or systemically. This is known as in vivo gene delivery. On the other hand, the therapeutic gene can be introduced into cells removed from patient’s body and manipulated in vitro before injecting them back into the humans. This is called as ex vivo gene delivery. In ex vivo gene delivery, there is scope for selectively expanding the cells carrying the transgene, and carry-out quality assurance procedures before administering it to the patient. Stem cells, because of their capacity to survive indefinitely, are good candidates for ex vivo gene therapy. Methods of Gene Delivery Techniques for gene (DNA) delivery into cells in culture have been the crux of success of recombinant (DNA) technology. Various chemical and physical methods have been used to introduce DNA into cells in vitro, the process being called transfection of cells. The cheapest and most widely used method in the laboratory is transfection via calcium phosphate precipitation where DNA is trapped in a fine precipitate and layered onto cells in culture. The DNA enters the cell via endocytosis. Other chemical methods include the use of cationic (positively charged) molecules, such as liposomes, which bind both to the negatively charged DNA on one hand and the negatively charged cell membrane on the other, thereby, facilitating DNA entry into the cell. Physical method, such as electroporation, is another commonly used method for introducing DNA into cells in culture. It is a technique where cells are mixed with the DNA construct and then briefly exposed to pulses of high electrical voltage. This creates transient, reversible pores on the cell surface allowing foreign DNA to enter the host cell. However, the most efficient method for DNA delivery is the use of viral vectors. These include retroviruses,

Depending on tropism, selected retroviruses can infect all dividing mammalian cells. They carry ribonucleic acid (RNA) as their genome which is converted to cDNA by the enzyme reverse transcriptase inside the infected cell. The cDNA of the virus along with the therapeutic gene, under appropriate regulatory sequences, gets incorporated in the host genome. Thereafter, the virus uses the host cellular machinery to make the therapeutic gene product. Adenoviruses, on the other hand, are DNA viruses; they enter the cell via membrane receptors and remain episomal (unintegrated in the host DNA) in the nucleus.The transduction efficiency (infectivity) of adenoviruses is much greater than that of retroviruses in human tissues. They also have the advantage of transfecting non-dividing cells. But they are immunogenic and do not last for long. Recently, vectors based on HIV lentivirus are being tested as they are the most efficient vectors. Viruses are made non-pathogenic by removing some structural genes from its genome. STRATEGIES FOR GENE THERAPY Gene therapy strategy for different diseases varies depending on the genetic information available for a particular disease. Various strategies employed for gene therapy are described below. Gene Augmentation Therapy For a disease caused by a mutation leading to loss of function, introduction of a functional copy of the gene into the patient’s cells will restore normal function of the cell. However, sustained, long-term expression of the therapeutic gene in an adequate and regulated amount is a major problem. For diseases like severe combined immunodeficiency syndrome (SCID) due to adenosine deaminase deficiency, and haemophilias, expression of even a small amount of protein is sufficient to ameliorate the symptoms. Such diseases are good candidates for gene therapy. Targeted Mutation Correction If a mutated gene produces a defective protein which by itself has the harmful effect, i.e. dominant negative effect, then the mutation has to be repaired. In this situation, introduction of a normal copy of the gene will not be effective. For this purpose, a normal copy of the gene is required to be targeted to the same location as the defective gene by homologous recombination. This approach has not yet been possible, although much research is continuing in this area. RNA Interference (RNAi) for Inhibiting Gene Expression RNA interference is the technology by which expression of the gene can be inhibited, so that the protein it codes for is not made. The system depends on introduction of doublestranded RNA (dsRNA) inside the cell which activates a cascade of events leading to destruction of the specific RNA molecule. The dsRNA may be in the form of silencing RNA (siRNA) or

short hairpin RNA, (shRNA) which is made synthetically and introduced into cells, like DNA, for gene therapy. The sequence of the dsRNA molecule is the same as the sequence of the RNA that is targeted to be destroyed. This approach could be of great benefit in diseases such as cancer, where proteins known to play a role in cell proliferation and anti-apoptosis can be manipulated by this technique. Also, knocking down of the genes which confer resistance to chemotherapy/ radiotherapy could sensitise tumour cells to treatment. Numerous trials blocking gene expression at RNA level are in progress and have shown promise.

Gene Therapy

such as Moloney murine leukaemia virus and adenoviruses which are the common cold viruses. Some important properties desired of an ideal vector are as follows: (a) should protect and deliver DNA into the cell without any alteration, (b) transit easily through cell membrane and from cytoplasm to nucleus, (c) persist in host cell nucleus, (d) be non-toxic (non-pathogenic, if viral) and non-immunogenic, and (e) be easy to produce in large quantities.

Gene Therapy for SCID In 1990, the first genetic disorder to be treated by gene therapy was ADA-SCID. The ADA mini gene was transferred by retroviral vector ex-vivo into peripheral blood lymphocytes from 2 patients undergoing enzyme replacement therapy. Longterm survival of transfected T- and B-lymphocytes, marrow cells, and granulocytes expressing the transferred ADA gene was demonstrated and resulted in restoration of cellular and humoral immunity. Although the haemopoietic stem cell would have been the ideal target cell for somatic cell gene therapy of the haematopoietic system, the use of T-lymphocytes as gene therapy vehicle was chosen since they represent the affected cells and known to be long survivors. Subsequently, 8 out of 10 children with ADA deficiency have been successfully treated following infusion of autologous CD34+ cells transduced with the ADA gene. More recently children with X-linked SCID have shown almost complete reconstitution of their immune system after receiving retrovirally transduced autologous CD34+ haematopoietic stem cells carrying a functional gamma chain of multiple cytokine receptor genes. These children are able to lead a normal life, have responded to several childhood immunisations and have shown good antibody response to infections. However, five of the 20 treated children subsequently developed a leukaemia-like disease after 3.5 years, probably due to the undesired activation of an oncogene by retroviral integration in the host genome. Gene Therapy for Lysosomal Storage Disorders Gene therapy is an attractive alternative in many lysosomal storage disorder patients who have responded poorly to bone marrow transplantation or enzyme replacement therapy. The primary goal is to introduce a normal copy of the gene for the lysosomal enzyme into a depot organ such as liver or muscle, so that there is sustained production and reconstitution of therapeutic levels of the enzyme in the affected tissues. A mouse model of Gaucher disease has been developed. In this model, chemically induced deficiency of glucocerebrosidase (GC) is created which results in accumulation of elevated levels of glucosylceramide (GL-1) in lysosomes of Kupffer cells. When these animals were administered mannose-terminated GC (cerezyme) there was reduction of GL-1 levels in liver. Gene transduction of hepatocytes with a plasmid DNA vector encoding human GC (pGZB-GC) achieved similar results. Based on pre-clinical studies, clinical trials are being carried-out where gene coding for GC is transferred to the haematopoietic cells. In one of the clinical trials, the GC gene was targeted via retroviral vector to CD34+ progenitor cells. Preliminary results indicate engraftment of genetically corrected cells in the patient. Further results are awaited.

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GENE THERAPY IN CANCER The largest number of gene therapy trials have been done in patients with cancer (about 65%). It may be not only because cancer is a genetic disease at somatic cell level, but more so out of desperation. Several approaches have been tried for this purpose, viz. (a) introduction of a gene to convert a prodrug to active cytocidal drug in tumour cells causing selective tumour cell destruction, (b) introduction of a multidrug resistant (MDR) gene in normal bone marrow cells to protect them from toxic effects of chemotherapy, (c) introduction of genes for enhancing antitumour immune responses, and (d) introduction of tumour suppressor gene, such as p53, mutation of which is related to several cancers. The latter therapy has even been approved in China for the treatment of head and neck cancer. FUTURE OF GENE THERAPY So far four patients have died related to gene therapy. In addition, the occurrence of leukaemia in successfully treated children with X-SCID has been a big dampner. Generally, reaction of the scientific community has been to go back to

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the bench.This has also served as an impetus to improve vectors and lay greater emphasis on in situ gene correction. Successes continue to be achieved in experimental models. Recently, it has been possible to cure sickle-cell disease in an experimental animal using transduced induced pleuripotent stem cells. The unbridled enthusiasm of the nineties has given way to more sober and more realistic expectations. So far the promise continues and the efforts are on. The success in treating SCID, and understanding the molecular basis of leukaemogenesis indicates that the dream may still come true. RECOMMENDED READINGS 1.

Agarwal SS. Gene therapy: how close to clinical reality? Natl Med J India. 2009; 22: 1-4.

2.

China offers alternative gateway for experimental drugs. Nature Biotech. 2006; 24: 117-8.

3.

http://www.wiley.co.uk/genmed/clinical/ This site gives the current status of ongoing gene therapy clinical trials.

4.

Mulherkar R. Gene therapy for cancer. Curr Sci. 2001; 81: 101-5.

5.

Ratko TA, Cummings JP, Blebea J; et al. Clinical gene therapy for nonmalignant disease. Am J Med. 2003; 115: 560-9.

6.8

Genetic Counselling and Prenatal Diagnosis

For most of the genetic disorders there is no curative treatment at present, or the treatment is cumbersome, costly and associated with risks. Also, many genetic disorders are associated with decreased life expectancy, and mental or physical handicap. Due to these reasons, families with a genetic disorder or those at risk of having an offspring with a genetic disorder, need information about the disease to help them cope with the problem and ways to prevent the occurrence or recurrence of the disorder. The process of communication of this information is genetic counselling. It is aimed to answer the questions of the family, viz. ‘Why did this happen to me?”, and “Will it recur in my family?’ As genetic disorders can involve any system of the body, it is important that clinicians in all specialities are able to identify clinical presentations which are due to, or can possibly be due to, genetic disorders, counsel them and refer them to a geneticist for appropriate investigations and advice where available. In this chapter the importance of genetic counselling in the management of genetic disorders is stressed and basic principles of genetic counselling are discussed. DEFINITION OF GENETIC COUNSELLING The American Society of Human Genetics defined genetic counselling as ‘a communicative process which deals with human problems associated with the occurrence and/or recurrence of a genetic disorder in a family’. This process involves an attempt by one or more appropriately trained persons to help an individual or a family to: (i) comprehend the medical facts, including the diagnosis, probable course of the disorder and available management; (ii) understand the manner in which heredity contributes to the disorder, and the risk of recurrence in the family; (iii) understand the alternatives for dealing with the risk of occurrence or recurrence; (iv) choose a course of action which seems to them appropriate in view of this risk, their family goals, ethical and religious standards and to act in accordance with the decision; and (v) make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder. It is clear from the above definition that the primary goal of the genetic counselling is to educate the concerned persons about the medical aspects of the genetic disorder in their family. The family can use the information in a meaningful way to cope with the disorder and the risk of recurrence in accordance with their psychosocial and religious background. A person who seeks genetic counselling is called consultand or ‘counsellee’, and the person who gives the advice is called the counsellor. In association with a medical specialist, persons with various backgrounds such as nursing, sociology, psychology or genetics can be trained as genetic counsellor.

Shubha R Phadke INDICATIONS FOR GENETIC COUNSELLING The following clinical presentations indicate the need for referral to a clinical geneticist and genetic counselling: 1. Congenital malformation: Lethal or non-lethal, isolated or multiple, prenatal or postnatal. 2. Still births/perinatal deaths with or without malformation. 3. Developmental delay or mental retardation with or without malformations, facial dysmorphism and/or neurological deficit. 4. Neurodegenerative diseases presenting as focal neurological deficit, ataxia, spasticity, hypotonia, seizures or psychomotor regression. 5. Mypopathies and muscular dystrophies. 6. A neonate or an infant with acute sickness, or failure to thrive or has recurrent episodes of vomiting, acidosis and/ or convulsions. 7. Ambiguous genitalia or abnormalities of sexual development like primary amenorrhoea and delayed puberty. 8. Infertility and poor obstetric history like recurrent spontaneous abortions and foetal losses. 9. Proportionate or disproportionate short stature. 10. Childhood deafness. 11. Known monogenic disorders like thalassaemia, Wilson disease, haemophilia A, mucopolysaccharidosis, etc. 12. Down's Syndrome and other chromosomal disorders. 13. Familial cancers or cancer prone disorders. 14. Relatives of an individual having a structural abnormality of a chromosome or chromosomes. 15. Any unusual disease of the skin, eyes, bones or unusual facial features. 16. Any disease which is familial. 17. Exposure to a known or possible teratogen during pregnancy. 18. Consanguineous marriage. 19. Advanced maternal age. 20. Carrier of a genetic disorder. 21. Positive screening test for a genetic disorder. STEPS IN GENETIC COUNSELLING The process of genetic counselling is quite complex. It requires correct diagnosis and latest information about medical and genetic aspects of the disorder. The steps of genetic counselling are as follows: 1. Accurate diagnosis of the proband (a) History taking (b) Pedigree drawing 209

2. 3.

4. 5.

6.

(c) Clinical examination (d) Biochemical, haematological, imaging and other necessary investigations. Chromosomal or DNA tests, as needed. Latest information about pathophysiology of the disease, available treatment, risk of recurrence, and availability of prenatal diagnostic test. Communicating the information in simple, layman’s language to the consultand and family members concerned. Giving the consult and a written or typed case summary which includes the case details, diagnosis and details of genetic counselling. Follow-up sessions may be needed to support the family, communicate new information, and observe any progression of the disease in the proband.

In addition to accurate diagnosis, consideration of many other issues like psychosocial, religious, educational and ethical are of paramount importance for effective genetic counselling. Success of genetic counselling depends on whether the consultand feels benefited by genetic counselling or not. Hence, it is important to assess the expectations of the consultand and to tailor the counselling accordingly, keeping in mind the psychosocial, religious and educational backgrounds of the consultand. Genetic counselling for some common genetic disorders is discussed below. This is to illustrate the principles of genetic counselling and various issues involved in the process. CASE-I Down’s Syndrome: A Common Chromosomal Syndrome and the Commonest Genetic Cause of Mental Retardation A 3-month-old infant was brought to the clinic with rapid breathing, feeding difficulty and excessive crying. The child had a pansystolic murmur in the left parasternal region and typical facial features like flat face, hypertelorism, upslant of eyes and Simian crease on both hands. The diagnosis was Down’s syndrome with ventricular septal defect with congestive cardiac failure. In addition to echocardiography and treatment of cardiac failure, the karyotype from blood was recommended. Karyotype is needed not only to confirm the diagnosis of Down’s syndrome but also to know the type of chromosomal abnormality. Ninetyfive per cent of Down’s syndrome cases are due to free trisomy 21 (47,+21) (Figure 1), and the risk of recurrence in siblings of

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Figure 1: Karyotype showing free trisomy 21.

such a child is 1%. Four per cent of Down's Syndrome cases are because of translocation of chromosome 21 to 14, 15, 21 or 22 (Figure 2). Karyotypes of both parents of such a case are essential. The risk of recurrence varies depending on the chromosome involved and sex of the carrier parent (Table 1). The karyotyping of parents of a child with free trisomy 21 is not indicated.

Figure 2: Partial karyotypes showing balanced translocation between chromosomes 14 and 21.

Table 1: Risk of Recurrence of Down’s Syndrome in the Offspring of a Parent with a Balanced Translocation Translocation t(14; 21) t(21; 22) t(21; 21)

Carrier Father

Carrier Mother

1% to 5% 1% to 5% 100%

15% 15% 100%

Genetic counselling The challenge in this case is to break the news of the diagnosis of Down’s syndrome to the parents. Further, the parents are to be advised regarding the need for surgical treatment of the cardiac defect, and associated problem of mental sub-normality and developmental delay which would become more pronounced as the child grows. Realistic information about mental abilities is essential. Though the intelligent quotient (IQ) of Down’s syndrome cases varies from 40 to 70 or more, most of the cases with Down’s syndrome are moderately retarded. Though late, they learn to walk, talk, carry-out self-care activities, and can also be taught to do simple repetitive tasks. They can work in a supervised and sheltered workplace. They can lead a loving, useful and happy life but need lifelong super vision. Importance of regular surveillance for hypothyroidism and hearing and ophthalmological problems needs to be stressed, but increased risk of leukaemia and atlanto-axial dislocation need not be told in the first visit as the risk of these conditions is very small. Risk of recurrence of Down’s syndrome in any subsequent pregnancy should be discussed after the karyotype report is available. Prenatal diagnosis in the next pregnancy can prevent recurrence and the family should be provided the information before planning the next pregnancy. Messages 1. The diagnosis of Down’s syndrome is obvious at birth and should be communicated to the family soon after birth.This helps in screening for major malformations immediately

CASE-II Prenatally Detected Mild Ventriculomegaly at 20 Weeks of Gestation on Routine Ultrasound Examination A 32-year-old lady married for 8 years, who conceived after treatment for infertility, came for routine ultrasonography (USG) at 20 weeks of gestation. In the first year of her marriage, she had two spontaneous abortions at 10 weeks of gestation. The USG showed mild ventriculomegaly. Hence, she was referred for genetic counselling. The first step of genetic counselling was to get a targeted ultrasonographic examination done to look for associated malformations. It showed mild dilatation of the lateral ventricles of the brain with open spinal defect and a large sac in the thoracolumbar region. There was no talipes equinovarus deformity or any major malformation of the heart, kidneys, abdominal wall, face, etc. Genetic counselling Meningomyelocoele is a major malformation which is often associated with Arnold-Chiari malformation and obstructive hydrocephalus. These defects are surgically treatable. But in spite of surgery after birth, many (50% or more) of the operated cases may have residual neurological defects including paraplegia, bladder-bowel incontinence and cognitive defects due to ventriculomegaly. In some cases hydrocephalus progresses rapidly, which may need destructive surgery for large head causing obstructed labour or may lead to stillbirth. The mother should be asked about the history of taking teratogenic drugs like anticonvulsants, and investigated for diabetes mellitus, as these are common risk factors for neural tube defect. Though the chance of chromosomal abnormality with isolated neural tube defect is low, prenatal chromosomal analysis by amniocentesis is recommended for proper counselling. If the family opts to continue the pregnancy regular follow-up USG examination, delivery at a good centre with good neonatal facilities, consultation with a paediatric surgeon or a neurosurgeon needs to be arranged. If the family opts for termination of pregnancy, foetal autopsy, or after delivery detailed clinical and radiological examination of the baby is essential for counselling regarding risk of recurrence in a subsequent pregnancy. The risk of recurrence

of isolated neural tube defect in the next pregnancy after the birth of one affected child is 5% and can be reduced by intake of folic acid by the mother during periconceptional period. If the meningocoele/meningomyelocoele is a part of a multiple malformation syndrome like spondylothoracic dysplasia or Meckel-Gruber syndrome then the risk of recurrence is 25%. Accurate diagnosis is also important to provide prenatal diagnosis during the next pregnancy which can be done ultrasonographically, as early as at 14 weeks. One USG at 16 to 18 weeks by an ultrasonographer with specialisation in prenatal diagnosis will be able to detect open neural tube defect with almost 100% sensitivity. Messages 1. One routine USG examination should be offered at 16 to 18 weeks of gestation for prenatal diagnosis of malformations.

Genetic Counselling and Prenatal Diagnosis

after birth and timely treatment. Of course giving the bad news of the birth of a child with mental sub-normality to the family, happy with the childbirth and an apparently normal looking neonate is a challenge to the paediatrician and obstetrician. 2. Chromosomal analysis of all children with Down’s syndrome is important to provide the risk of recurrence and prenatal diagnosis. 3. Prenatal diagnosis of Down’s syndrome is possible by doing karyotype analysis from chorionic villi or an amniotic fluid sample. 4. The primary care physician or a paediatrician can take up the responsibility of providing regular follow-up needed for children with Down’s syndrome. This includes clinical examination for associated abnormalities, investigations for iron deficiency anaemia, hypothyroidism and ophthalmologic and ear examinations.

2. Accurate diagnosis of associated malformations and foetal chromosomal analysis is important for giving information about prognosis of malformation. 3. The information about possible outcomes of the malformation, especially if the malformation is treatable, will help the family in deciding about continuation or termination of pregnancy. 4. The uncertainties in providing exact outcome in each case should be truthfully shared with the family. 5. The genetic counselling should be non-directive. Possibilities of good and bad outcomes should be told with their likelihood. Many other factors like presence of previous normal or similarly affected children, age of mother, history of infertility may affect the family’s decision. In this case, due to long period of infertility and two spontaneous abortions, the family may not take up the option of amniocentesis for karyotyping as it is an invasive procedure and associated with a small risk of abortion. 6. Autopsy of foetuses terminated after prenatal diagnosis of malformations is important not only for confirmation of prenatal diagnosis but also to look for associated malformations which may have been missed on USG, or may not be detectable on USG. Autopsy may change the diagnosis in about 30 to 50% foetuses, hence, essential for genetic counselling. CASE-III Pre-pregnancy Counselling for Family History of Huntington Chorea A couple married for 2 years and planning to raise a family came for genetic counselling. The husband was 32-year-old and the wife was 27-year-old. The husband’s brother who is 40-yearold had developed abnormal movements since the last 4 years and was diagnosed to have Huntington chorea. His father died at the age of 65 years, who suffered from similar problems for 10 years and had become bed-ridden. The couple wanted to know whether their child could have the same disease and whether it could be avoided. Genetic counselling The first step of genetic counselling is to draw a pedigree chart and confirm the diagnosis. A 3-generation pedigree chart was

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drawn which showed that two of the uncles of the consultand (husband in this case) were similarly affected and one of them was seen as an out-patient at the Department of Genetics. The family was asked to get the medical records of the affected uncle with his permission. The records confirmed the diagnosis of Huntington chorea by a neurologist as well as by DNA-based mutation analysis. The DNA test showed that the uncle with Huntington disease had 44 CAG repeats in HD gene and the other copy was normal (20 CAG repeats). This confirmed the presence of mutated HD gene in the family. Now, the question: What is the risk of Huntington disease mutation in the offspring of the couple? This will depend on whether the consultand himself is carrying the mutation or not. As Huntington disease usually manifests after 40 years of age, many individuals who carry the mutation will be clinically normal at 32 years of age. Hence, it is essential to test the husband’s DNA for HD mutation. If he is not the carrier of the mutation, he will not develop the disease in future and also there is no risk of Huntington disease in the offspring of the couple and prenatal diagnosis is not indicated. But if he is a carrier of mutation, then there is 50% chance that the offspring may inherit the mutated copy of the gene from him and develop the disease in future. The age of onset of symptoms depends on the number of CAG repeats and the number of repeats may increase when the mutation is transmitted from one generation to the next.The individuals with repeats around 80 may develop the disease in childhood. The birth of a child with HD mutation can be avoided by prenatally testing the mutation in chorionic villi at 10 to 12 weeks of gestation providing the couple an option for reproductive planning. All DNA-based tests have some error rate, usually around 1%. This opens a lot of issues for the family. First, pre-symptomatic diagnosis in the husband may cause major psychological problems as there is no treatment for the disease. Also, if this information if not kept private and confidential it may cause problems at the job, and for medical insurance, etc. Hence, the couple should be given time before opting for DNA testing. If after adequate counselling and careful deliberation the consultand wants to go for a DNA test, then it should be ordered. After the results are available, the couple should be explained the results, and post-test counselling should be provided. Continued psychological support may be needed. If the husband is the carrier of mutation, there is 50% risk of transmitting the mutation to the offspring. Many laboratories and also families are not comfortable with the idea of termination of a affected pregnancy as the foetus will not manifest the disease until 3 to 4 decades. This is ethically debatable, especially with the present pace of developments in the field of genetics, where new treatments for many genetic diseases are expected in the future. After discussing all these issues in a non-directive manner, the family may take their reproductive decision. The whole process may take many sessions to understand difficult scientific information and various complexities of the situation. Messages 1. DNA-based diagnosis is available for many single gene disorders and is useful for diagnosis of patient and prenatal diagnosis. 212

2. The confirmation of diagnosis in the proband or affected member of the family is an important first step before providing genetic counselling. 3. Mutation detection is essential for prenatal diagnosis based on DNA analysis. 4. The counselling should be non-directive and the family should make their own reproductive decisions. 5. The genetic counselling involves providing a lot of scientific information and probabilities, which may be a difficult task, for which very good communication skills are needed to be a good genetic counsellor. 6. The information provided during genetic counselling may be psychologically disturbing and adequate pre-test and post-test counselling is necessary. 7. Pre-symptomatic and prenatal diagnosis of late onset genetic disorders pose a lot of ethical, legal and social dilemmas and need to be dealt with sensitivity. 8. Pre-pregnancy counselling plays an important role in genetic disorders and is the most appropriate time for genetic counselling, as it provides time for organising investigations, understanding the situation and making appropriate decisions. CASE-IV Counselling for Familial Breast Cancer A 28-year-old married woman comes for genetic counselling as her 35-year-old sister is diagnosed to have carcinoma breast and her mother died of carcinoma breast at the age of 50 years. Pedigree chart showed that one sister of her mother had carcinoma of ovary. Her maternal uncle’s wife also had carcinoma breast. Genetic counselling Presence of three blood relatives with carcinoma breast and ovarian carcinoma suggests familial breast cancer. Note that the wife of her maternal uncle is not her blood relative and medical ailments in her do not influence the risk of genetic disorders in the consultand. Such an individual needs to be offered surveillance for carcinoma breast and ovaries as early detection may help in better treatment and improve outcome. This is the case where mutation detection in carcinoma breast related genes, namely, BRCA1 and BRCA2 is indicated. The BRCA1 and BRCA2 account for 50% and 30% of familial breast cancers, respectively. First the mutation has to be tested in one of the individuals with carcinoma breast (it can be done on the operated breast cancer tissue), and if the mutation is detected then DNA testing of the consultand and other probable carriers in the family (who are more than 18 years of age) needs to be discussed. The individuals who have the mutation need to be kept under close surveillance for carcinoma breast and ovaries as per accepted guidelines. The confirmed carriers of BRCA gene mutations can be offered even radical measures like prophylactic mastectomy or oophorectomy. Messages 1. Three or more family members with one type of cancer or related cancers should alert the clinician for the possibility of familial cancers and refer the family for genetic counselling.

3. Mutation detection in the individual with the cancer is important before the mutation-based screening can be offered to the unaffected family members. 4. Mutation testing for carcinoma breast and other familial cancers is technically demanding, costly and not easily available. Even if mutation detections not done, continued surveillance for early diagnosis can be offered to individuals with familial cancer. CASE-V A Couple with Three Recurrent Spontaneous Abortions in the First Trimester A non-consanguineous couple with three spontaneous abortions was referred for genetic testing. The chromosomal analysis from peripheral blood was done for both the spouses. The karyotype of the wife showed a balanced translocation between chromosomes 7 and 11 (Figure 3). Genetic counselling The balanced translocation in this case is likely to be the cause of recurrent spontaneous abortions in this case. The gametes of an individual with a balanced rearrangement may have unbalanced karyotype and the conceptus with a major chromosomal imbalance may not be compatible with life and abort spontaneously. As such individuals also have gametes with normal chromosomal complement, or balanced chromosomal complement, so they can have normal offspring as well. The risk of repeated abortions is about 30% but may vary depending on the chromosomes involved and their breakpoints. There is no treatment to prevent formation of unbalanced gametes or to prevent abortion. Some of the chromosomal imbalances may be small and such foetuses may not be aborted but may have malformations or a mental handicap. Hence, this couple should be offered prenatal karyotyping by amniocentesis if the pregnancy continues beyond the first trimester. The other options are use of donor ova (or sperms, if husband is the carrier of a balanced chromosomal rearrangement), or preimplantation diagnosis. The latter involves in vitro

fertilisation and single cell genetic test which in addition to being costly is also not easily available. The other treatable causes of recurrent abortion should also be simultaneously investigated as more than one cause may coexist. Investigations for toxoplasmosis, rubella and cytomegalovirus infections are not indicated as they do not cause recurrent abortions. Messages 1. About 5% of the couples with recurrent spontaneous abortions have one spouse with balanced chromosomal rearrangement. 2. If the karyotype is abnormal, there is no treatment but counselling, and prenatal diagnosis is needed. 3. One in 500 normal people have a balanced chromosomal translocation, and such carriers are usually phenotypically normal.

Genetic Counselling and Prenatal Diagnosis

2. The pointers towards the possibility of familial cancer include cancer at young age, co-occurrence of multiple primary cancers and bilateral cancers in paired organs, associated clinical features like hyperpigmentation of lips (Peutz-Jeghers syndrome), adenomatous polyposis colon, neurofibromatosis, etc.

4. The individual with balanced translocation is not at any risk of medical ailment due to chromosomal abnormality. 5. All attempts should be made while counselling such a couple to protect from blame or guilt in the family. 6. Chromosomal variants, such as long ‘Y’ chromosome, pericentric inversion of chromosome 9, etc. are not known to be associated with recurrent spontaneous abortions. CASE-VI A Family with a Two-year-old Child with Metachromatic Leukodystrophy A couple came with a 2-year-old son who was diagnosed as a case of cerebral palsy. The mother of the child was 6 weeks pregnant. The family wanted to know the risk of recurrence of a similar problem in the next child. The pedigree chart showed that the parents were cousins and their first child had a similar problem and had died at two- anda-half years of age. The proband (the affected child) was normally developing till about one year of age and was able to stand without support. Then he lost the milestones, and developed scissoring of lower limbs (Figure 4). There was hypertonia of limbs with exaggerated knee reflexes and absent ankle reflex. The deterioration continued. Magnetic resonance imaging (MRI) brain showed changes indicative of white matter involvement. The enzyme assay for metachromatic leukodystrophy showed deficiency of aryl sulphatase A which confirmed the diagnosis of metachromatic leukodystrophy. Genetic counselling Metachromatic leukodystrophy is an autosomal recessive disorder and the risk of recurrence to a subsequent child of these parents is 25%, i.e. 1 in 4. The prenatal diagnosis can be carried out by assaying the enzyme in chorionic villi at 11 weeks of gestation. If the foetus is found to be deficient in the enzyme, the family can take an appropriate decision according to their convictions.

Figure 3: A karyotype showing a balanced translocation between chromosomes 7 and 11.

If by DNA sequencing of the aryl sulphatase A gene (ARSA) mutations can be identified in the proband or his parents then prenatal diagnosis by mutation detection can be done. DNA-based prenatal diagnosis is more accurate than that by biochemical test (enzyme assay).

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variety of tissues can be collected from the foetus for chromosomal, DNA and biochemical analysis. These include chorionic villi (11-12 weeks of gestation) and amniotic fluid (16-20 weeks). Rarely, foetal skin, muscle, liver biopsy or blood sample may be collected for biochemical or tissue analysis. Analysis of foetal cells and foetal DNA from mother’s blood has become technically possible and can be used for foetal Rh typing. Prenatal diagnosis based on free foetal DNA in mother’s plasma is used not only for single gene disorders but also for aneuploidy detection.Preimplantation diagnosis is a good option for families who do not approve of termination of pregnancy. High resolution ultrasonography can detect a number of structural malformations of the central nervous system, gut, kidneys, limbs, spine and heart. Detection of associated malformations and chromosomal analysis is useful for providing counselling in a case with prenatally detected malformation. But for counselling regarding next pregnancy, examination of baby or foetus after delivery or termination (foetal autopsy) is important, because in 30% to 40% cases associated malformations may be missed or may not be detectable on ultrasonography. Figure 4: A child with metachromatic leukodystrophy. Note the scissoring of lower limbs.

Messages 1. All children with developmental neurological problems should not be labelled as cerebral palsy without evaluation, as many genetic disorders may manifest as developmental delay or mental retardation which superficially mimics cerebral palsy. 2. Presence of normal development followed by regression of milestones is characteristic of metabolic disorders.

RECOMMENDED READINGS

3. Presence of consanguinity, or similarly affected 2 or more siblings, suggests the possibility of an autosomal recessive disorder.

1.

Burke W. Taking family history seriously. Ann Intern Med. 2005; 143: 388-9.

2.

Ensenauer RE, Michels VV, Reinke SS. Genetic testing: practical, ethical, and counselling considerations. Mayo Clin Proc. 2005; 80: 63-73.

4. Confirmation of genetic metabolic disorder by enzyme assay of involved metabolic pathway is essential for diagnosis, genetic counselling and prenatal diagnosis.

3.

Martin JR, Wilikofsky AS. Integrating genetic counselling into family medicine. Am Fam Physician. 2005; 72: 2444.

4.

Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol. 2007; 110: 687-94.

5.

Skotko BG, Capone GT, Kishnani PS. Postnatal diagnosis of Down's Syndrome: synthesis of the evidence on how best to deliver the news. Down's Syndrome Diagnosis Study Group. Pediatrics. 2009; 124: e751-8.

PRENATAL DIAGNOSIS The availability of prenatal diagnosis for a number of genetic disorders has made counselling and decision-making easier. A

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CONCLUSION All cases in which a genetic disorder is diagnosed or suspected, a complete evaluation of the affected individual and genetic investigations are important. Genetic counselling is an integral part of management of a case with genetic disorder. It is the responsibility of the primary care physician to suspect cases with a probable genetic disorder and refer them to a clinical genetics centre. As the clinical geneticists are few in number, paediatricians, obstetricians and physicians may have to take up the responsibility of providing diagnosis and counselling for common genetic disorders.

6.9 Optimal therapy for major illnesses is still elusive. The drug therapy of psychiatric illnesses, cancer, hypertension and many other common diseases is associated with unsatisfactory response and undesirable adverse effects. Many approaches have been adopted to improve this condition. Among them the role of genetic factors in drug response is very important. PHARMACOGENETICS AND PHARMACOGENOMICS The action of a drug is regulated by several factors, namely drug metabolising enzymes, transporter proteins, receptors and several other mediators. These enzymes and proteins are encoded by genes in the deoxyribonucleic acid (DNA). A number of variations have been identified in the structure of genes encoding these factors. This can result in varying drug responses in each individual depending upon their genetic make-up. A genetic variation occurring in more than 1% of the population is termed as genetic polymorphism. The study of the effect of a single gene or genetic polymorphism on drug response is called pharmacogenetics. Study of the effect of variations in multiple genes, including whole genome approach, on drug response is called pharmacogenomics. It is predicted that application of pharmacogenomics in clinical practice may lead to individualised drug therapy (personalised medicine), thus, paving the way for improved effectiveness and reduced adverse drug reactions. PERSONALISED MEDICINE Personalised medicine is the science concerned with providing medical care tailored to the genomic and molecular profile of an individual patient. The physician selects the drug and its dosage using detailed information about the patient including clinical data, genotype or level of gene expression, drug profile, as well as genetic details of the causative organism, if any. The important pre-requisites for success of personalised medicine are valid biomarkers and availability of reliable, simple and affordable genetic tests. CLINICAL APPLICATIONS The clinical practice of personalised medicine has started to receive attention with more drugs being discovered using methods of pharmacogenetics. For a drug to be used clinically based on pharmacogenetic data, identification and establishment of a valid pharmacogenetic biomarker is necessary. Some of the drugs for which a valid pharmacogenetic biomarker has been identified are warfarin, irinotecan, carbamazepine, abacavir, azathioprine, trastuzumab, imatinib, maraviroc, rituximab, omeprazole, and clopidogrel. Oral Anticoagulant Drugs Warfarin, an oral anticoagulant is used in patients with cardiovascular disorders. The most common complication of warfarin includes bleeding manifestations. It is metabolised by the enzyme CYP2C9 encoded by the gene CYP2C9.

Pharmacogenomics and Personalised Medicine C Adithan Further, its activity depends on the enzyme epoxide reductase complex 1 encoded by the gene VKORC1. Variations in the nucleotide sequences of the coding region of these enzymes result in altered metabolism and activity of warfarin. Patients with the variant genotypes, such as CYP2C9 *1/*3 and VKORC1 AA have six-times lower dose requirement compared to the common genotypes of CYP2C9 *1/*1 and VKORC1 GG. The United States Food and Drug Administration (US-FDA) has made label changes in warfarin and recommended genetic testing for these two genes before initiation of warfarin therapy. Based on the genotype of the patient, the dose has to be adjusted to an optimum level of international normalised ratio (INR). Anticancer Drugs Irinotecan, an inhibitor of the enzyme topoisomerase 1 is used as an anticancer agent. It is a pro-drug and gets converted to an active form SN 38 which inactivates topoisomerase 1, and thus, inhibits DNA replication. The SN 38 gets inactivate by the process of glucuronidation by the enzyme UGT1A1. This enzyme is encoded by the gene UGT1A1. It was found that the variant genotype UGT1A1 *28/*28 was associated with impaired conjugation, and hence, results in higher plasma levels of SN38. This genotype was associated with greater haematological toxicity. This led to changes in the label of irinotecan by the US-FDA which also recommended genetic testing for patients who are to be started on treatment with irinotecan. Anticancer agents such, as azathioprine and 6-mercaptopurine are metabolised by the enzyme thiopurine methyl transferase enzyme (TPMT) encoded by the gene TPMT. Individuals with variant genotype of TPMT have reduced or absent enzyme resulting in high drug levels and greater myelo-toxicity. It is recommended to do a genotype or phenotype test for TPMT before starting thiopurine therapy. Other drugs where genetic testing is preferred, include trastuzumab, rituximab, imatinib and maraviroc. Trastuzumab, a monoclonal antibody targeting the HER2 protein is used in breast cancer patients who are over-expressing HER2/neu protein. It is more effective in the treatment of early stage HER2 positive breast cancer patients. Rituximab, a monoclonal antibody directed against the CD-20 protein in B-cell lymphocytes is approved for use in B-cell non-Hodgkin lymphoma and rheumatoid arthritis. The patients may be tested for expression of CD-20 protein by the B-cells for initiation of therapy with rituximab. Imatinib mesylate is used for treatment of chronic myeloid leukaemia which is associated with the chromosomal abnormality termed as ‘Philadelphia chromosome’ which produces mutant protein responsible for cell proliferation. Imatinib inactivates this overactive protein BCR-ABL-tyrosine kinase. Thus, testing for this genetic abnormality is necessary for treatment with imatinib mesylate.

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Antiretroviral Drugs Abacavir, the antiretroviral drug was found to have higher incidence of hypersensitivity reactions associated with patients having human leucocyte antigen (HLA)*5701.The development of high resolution HLA typing enabled identification of patients at risk for abacavir hypersensitivity and avoided adverse drug reactions. After the publication of PREDICT1 and SHAPE studies, there has been an increased demand for HLA typing tests for patients with human immunodeficiency virus (HIV) infection. Maraviroc, an antiretroviral drug, prevents entry of HIV into the host cell by binding the CCR5 protein on cell surface. The virus requires binding to CCR5 protein for cell membrane fusion and entry into host cell. Thus, the entry of CCR5 tropic viruses is inhibited. However, the viruses which are CXCR4 tropic do not respond to maraviroc and result in dominance of CXCR4 tropic strains. It is recommended to test for tropism of the virus strain in a patient before initiation of therapy with maraviroc. Omeprazole and Clopidogrel The proton pump inhibitor omeprazole is metabolised by CYP2C19 enzyme. Patients with variant genotype CYP2C19 *2/*2 have markedly reduced metabolism of omeprazole. This has been found to result in higher cure rates with anti-Helicobacter pylori regimen in such patients. For a patient with similar variant genotype CYP2C19 *2/*2, the anti-platelet drug clopidogrel can have reduced therapeutic effect due to reduced conversion to its active metabolite by the enzyme CYP2C19. In such patients, genotyping for CYP2C19 polymorphism would enable selection of a suitable alternative anti-platelet drug. Stevens-Johnson Syndrome Stevens-Johnson syndrome (SJS), a severe form of dermatological manifestation of hypersensitivity reaction to drugs, was found to occur with the anti-epileptic drugs, carbamazepine. Studies have shown a strong association between the HLA-B*1502 and occurrence of SJS in patients receiving this drug. This variant gene was found to occur at higher frequency in Hans Chinese, Malays and Thais. Based on strong association demonstrated, the US-FDA made label changes in carbamazepine and recommended testing for HLA-B*1502 in Asian populations before starting therapy with carbamazepine. This would help in identifying patients who are at risk of developing SJS with carbamazepine, and thus, avoid drug-induced morbidity. BARRIERS FOR PHARMACOGENETIC TESTING Although extensive studies are being done in the field of pharmacogenomics, the concept of personalised medicine is

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yet to be incorporated in clinical practice to a large extent. This can be attributed to factors, such as increase in cost of therapy due to inclusion of pharmacogenetic testing as part of drug therapy and difficulty in imparting the pharmacogenetic knowledge to clinicians on a wider scale. Further, availability of laboratory facilities to do pharmacogenetic tests is necessary for the widespread use of pharmacogenetics in clinical practice. Most clinicians prefer to rely on clinical and biochemical parameters for dose selection and empiric dose titration rather than testing for genetic make-up of the individual. The cost of genotyping could be a major limiting factor in application of pharmacogenetics on a larger scale in clinical practice. One alternative is to do bulk testing. The cost of genotyping 1000 DNA samples is approximately 0.3 to 0.5 USD (US Dollors) per genotype compared to 130 USD for testing of a single sample. This difference is due to the fixed price of the set-up of assay marker. Hence, patient samples can be analysed only when collected in large numbers. Several ethical issues arise with the application of pharmacogenetic methods. Categorisation of populations based on genotypes may result in exclusion of smaller groups of people from usage of drugs which are brought into the market based on pharmacogenetic tests. Further, revelation of genetic risk factors for late onset diseases and variation in drug response for such diseases may have profound psychological impact on the patient and affect the quality of life. This information can also lead to denial or increased cost of insurance policy coverage for such people. Pharmacogenomics and personalised medicine have many promising features but there are issues in their application on a larger scale for clinical practice. They can be solved only by further refining of the process involved in it and policy decision making by the government. RECOMMENDED READINGS 1.

Avigan MI. Pharmacogenomic biomarkers of susceptibility to adverse drug reactions: just around the corner or pie in the sky? Per Med. 2009; 6: 67-78.

2.

Ingelman-Sundberg M, Sim SC. Pharmacogenetic biomarkers as tools for improved drug therapy; emphasis on the cytochrome P450 system. Biochem Biophys Res Commun. 2010; 396: 90-4.

3.

Miller MP, Grant DM. The art and science of personalized medicine. Clin Pharmacol Ther. 2007; 81: 311-5.

4.

Ramasamy K, Narayan SK, Chanolean S. et al Severe phenytoin toxicity in a CYP2C9*3*3 homozygous mutant: first case report from India. Neurology India. 2007; 55: 408-9.

5.

Surendiran A, Pradhan SC, Adithan C. Role of pharmacogenomics in drug discovery and development. Indian J Pharmacol. 2008; 40: 137-43.

6.10 CANCER IS A GENETIC DISEASE Cancer is a ‘genetic disease’, as gene mutation/s and chromosomal alterations are the hallmark of all cancer cells. The term ‘genetic’ in this context refers to molecular pathology of the disease and not to transmission from generation to generation, as is often the case for hereditary diseases. It shall be noted that while all cancers are characterised by genetic alterations, only 2% to 5% of human cancers are hereditary. It is because the genetic alterations in cancers are acquired, and remain restricted to the somatic cell. The origin of hereditary cancers is discussed separately. The genes associated with causation of cancer are broadly classified into two types, viz.‘tumour suppressor genes’ (TSGs) and ‘proto-oncogenes’, based on their normal cellular function and mechanism of causation of cancer. Knowledge of specific genetic alteration/s which gives rise to a particular cancer has been of immense use in improving prognostic classification, and development of targeted therapy for several cancers. In case of hereditary cancers it can be used for detection of carrier status, genetic counselling and cancer prevention. MULTI-STEP CARCINOGENESIS AND CLONAL ORIGIN OF CANCER The process of carcinogenesis is characterised by three steps initiation, promotion and progression. Accumulation of 5-10 mutations in specific genes is invariably required for a normal cell to transform into a malignant phenotype as shown for the colon cancer model by Vogelstein (Figure 1). According to the clonal theory of cancer, cancer initiates from a single cell. It progresses through a series of mutations at successive cell divisions, with selection at each step, resulting in the

Figure 1: Multi-step carcinogenesis (Vogelstein’s colon cancer model).

Cancer Genetics Rajiv Sarin establishment of an autonomous, malignant clone with selective growth advantage which leads to formation of a tumour mass. During their long natural history, most cancers develop molecular heterogeneity due to development of subclones, ultimately leading to development of the ‘metastatic clone’ which eventually kills the individual. GENOMIC INSTABILITY Genomic instability is a cardinal feature of cancer. In certain hereditary cancer syndromes, the underlying defect mismatch repair pathway, as seen in hereditary non-polyposis colon cancer (HNPCC), or neucleotide excision repair pathway (NERP) as seen in xeroderma pigmentosa (XP), which results in genomic instability and cancer. In sporadic cancers, the genomic instability is often the result of accumulation of several mutational events during malignant transformation and progression. ONCOGENES AND TUMOUR SUPPRESSOR GENES Oncogene, the activated form of proto-oncogene, is the ‘accelerator switch’ of cell division while tumour suppressor gene (TSG) is the ‘natural brake’ of cell division (Table 1). Mutations in specific domains of proto-oncogenes, their amplification or translocation, sometimes leading to formation of fusion genes, result in gain of function and constitutive activation of mechanisms controlling cell proliferation. Germline point mutation in the cysteine rich extracellular domain or intracellular tyrosine kinase domain of RET proto-oncogene resulting in multiple endocrine neoplasia (MEN-2) syndrome is a classical example of oncogene driven hereditary cancer. A somatic mutation, or over-expression of oncogenes, is a common mechanism of sustained growth stimulus in sporadic cancers. Some clinically relevant examples include point mutations in phosphate binding loop of K-RAS in pancreatic, colon and lung cancer; catalytic kinase domain of epidermal growth factor receptor (EGFR) in head, neck, lung and pancreatic cancers; over-expression of C-ERBB2 in breast cancer and the BCR-ABL fusion gene in chronic mylogenous leukaemia (CML). In contrast to gain-in-function mutations of oncogenes, TSGs undergo loss-of-function when certain mutations or chromosomal alterations lead to diminution in normal activity of proteins controlling apoptosis (p53 protein); cell cycle regulation (RB protein), or DNA damage repair (BRCA1 or XP proteins), etc. Somatic mutation in p53 gene is one of the most frequently occurring genetic alterations in human cancers. TSGs are broadly classified as Gatekeeper or Caretaker genes based on their normal cellular function. As the names imply, the gatekeeper genes control critical events and check points in the cell cycle (RB, TP53, APC, etc.), while the caretaker genes maintain genomic integrity through their critical role in DNA repair (mismatch repair genes, nucleotide excision repair genes, BRCA1, etc).

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Table 1: Comparison Between Oncogenes and Tumour Suppressor Genes Oncogene (Activated Proto-oncogene)

Tumour Suppressor Gene

Encode components of a signalling pathway that regulate cell proliferation and control the machinery of cell cycle (e.g. MYC, RAS or EGFR, etc). Mutation or over-expression of a single allele results in gain of function which drives cell proliferation and malignant transformation

Regulate cell cycle progression (e.g. RB), apoptosis (e.g. p53) and DNA damage repair (e.g. BRCA1/2) Mutation or deletion of both alleles results in loss of tumour suppressor function thereby allowing malignant transformation

Examples

Examples

Point mutations (missense) KRAS in pancreatic and colon cancers RET in multiple endocrine neoplasia (MEN-2) syndrome

Point mutations (missense, nonsense, frameshift) TP53 in Li-Fraumeni syndrome RB1 gene in retinoblastoma BRCA1 and 2 in HBOC syndrome APC genes in familial adenomatous polyposis Mismatch repair genes in HNPCC

Gene amplification/over-expression NMYC in neuroblastomas C-ERBB2/HER2neu in breast cancer Chromosomal translocation ABL (9q34) to BCR (22q11) in CML MYC (8q24) to IgH (14q32) in Burkitt’s lymphoma FLI1 (11q24) to EWS (22q12) in Ewing’s sarcoma Aneuploidy Loss of chromosome 10 (PTEN) in glioblastomas

KNUDSON’S TWO HIT HYPOTHESIS FOR TUMOUR SUPPRESSOR GENE (RETINOBLASTOMA PARADIGM) Knudson proposed the “two hit hypothesis” to explain genesis of retinoblastoma, a childhood malignant tumour of the eye, and clinical features distinguishing hereditary from sporadic retinoblastoma. Hereditary form of retinoblastoma occurs at a younger age, generally in the first year of life and sometimes at birth; frequently arises in both eyes; and could be multifocal within each eye. In this form, first hit is the inherited germline mutation in one of the two alleles of RB genes present in all cells of the body and second-hit is the somatic mutation in second of RB gene in one of the retinal cells, resulting in development of retinoblastoma (Figure 2). This hypothesis explains why both alleles of a tumour suppressor gene are to

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Figure 2: Kundson’s two hit hypothesis in retinoblastoma.

Large genomic rearrangements BRCA1 and 2 in HBOC Mismatch repair genes in HNPCC Deletion WT1 in Wilm’s tumour SMAD4 in pancreatic and colon cancers

be inactivated for development of cancer and why most forms of hereditary cancer occur at a younger age, are frequently bilateral, and multiple as compared to their sporadic counterparts. It is important to note that while the mutation is recessive at cellular level (requiring both alleles to be inactivated), the inheritance pattern for cancer risk is autosomal dominant. Progeny of germline mutation carriers have 50% probability of inheriting the germline mutation (one mutated allele in each cell of the body). Subsequently a very high proportion of these carriers acquire the second inactivating mutation in one of the target organ cells (somatic mutation) resulting in 70% to 100% penetrance for cancer development in mutation carriers. EPIGENETIC REGULATION IN CANCER Epigenetic alteration refers to the change in genome (or gene expression), which is inherited by the daughter cells without any alteration in the DNA sequence. Common epigenetic modifications include DNA methylation of CpG islands (cytosine precedes Guanine) in the promoter region of a gene, thereby controlling gene expression, and acetylation of histones that could silence TSGs. Global genomic hypomethylation in the CpG islands of TSGs and specific histone modifications are commonly seen in many human cancers. Being reversible, these epigenetic changes are attractive drug targets with various drugs like histone deacetylase inhibitors undergoing evaluation in clinical trials. Analysis of epigenetic silencing of the MGMT gene by promoter methylation is now in clinical use to predict response to temozolamide chemotherapy for glioblastoma. HEREDITARY CANCER SYNDROMES AND GENETIC TESTING It is estimated that 2% to 5% of all cancers are hereditary, occurring as a result of germline mutation in one of the several TSGs (BRCA1, BRCA2, TP53, NF1, etc), or proto-oncogene. Vast majority of hereditary cancer syndromes are autosomal dominant (Table 2) with few rare syndromes associated with DNA repair defects being autosomal recessive (Table 3).

Genetic Syndrome

Malignancy (Lifetime Risk of a Cancer)

Phenotypic/Tumour Features

Hereditary breast ovarian cancer (HBOC) syndrome Incidence: 1 in 1000 Genes: BRCA1 (17q); BRCA2 (13q)

Breast cancer (70% to 80%), Ovarian cancer (40% to 60%) Male breast cancer, prostate, pancreas, colon, etc. (especially in BRCA2 carriers)

Cancer presents at young age, frequently bilateral and same person may develop breast and ovarian primaries BRCA1 associated breast tumours are generally ER, PR and C-ERBB2 negative (Triple –ve) and poorly differentiated

Hereditary non-polyposis colon cancer (HNPCC) syndrome Incidence: 1 in 400 Genes: One of the mismatch repair genes MSH2 (2p)

All cancers (70% to 90%) Colorectal cancer (30% to 75%)

Colon polyps in 30% cases but unlike FAP polyps in HNPCC rarely exceed few dozen

Endometrial cancer (20% to 40%) Other cancers: Gastric, brain, small bowel, pelvi-ureteric, hepatobilliary

Compared to sporadic cases, HNPCC associated colon cancer is generally right-sided (ascending or transverse colon) and at younger age Amsterdam -II Criteria for HNPCC – At least 3 first degree relatives with colon, endometrial, small bowel or pelvi-ureteric carcinoma – At least 2 generations affected – At least one affected person 12000 cells/ mm3 or presence of 10% immature forms) or leucopaenia (1,00,000) where white blood cells take-up K + , if the serum sample is stored at room temperature. It may be seen in the setting of an insulin dose being given just prior to taking a serum sample due to intracellular shift of K+. Causes of Hypokalaemia The causes of hypokalaemia may be classified into reduced K+ intake and increased K+ losses (Table 3). Decreased intake of K+ rarely causes hypokalaemia. The daily requirement is 40 to 120 mEq/L; however, the normal kidney is able to decrease the daily excretion of K+ in the presence of low intake. Clinical Manifestations The clinical manifestations tend to be proportionate to the degree of hypokalaemia. Patients are asymptomatic above the K+ level of 3.0 mEq/L. However, rapidly falling K+ levels or other conditions predisposing to arrhythmias can give rise to symptoms at a much higher level. The usual manifestations are described below: 1. Muscle weakness Hypokalaemia is one of the causes of acute flaccid paralysis starting in the lower limbs and progressing upwards. It can also lead to respiratory muscle involvement to cause respiratory failure or affect gastrointestinal muscles resulting in ileus. Other muscular manifestations include cramps, paresthesias and tetany. 2. Cardiac arrhythmias Various types of cardiac arrhythmias can be induced by hypokalaemia including atrial pre-mature complexes, ventricular pre-mature complexes, sinus bradycardia, paroxysmal atrial tachycardia, atrioventricular block and

3. Renal abnormalities Hypokalaemia can induce impaired urinary concentrating ability, increased ammonia production, increased renal bicarbonate production and hypokalaemic nephropathy. 4. Rhabdomyolysis Severe hypokalaemia (< 2.5 mEq/L) may induce rhabdomyolysis and myoglobinuria. Table 3: Causes of Hypokalaemia Decreased potassium intake Increased transcellular shift Metabolic alkalosis Insulin administration Beta-2 adrenergic agonists Increased potassium loss Renal Diuretics, especially loop diuretics Primary mineralocorticoid excess Metabolic acidosis Hypomagnesemia Amphotericin B Salt wasting nephropathy Polyuria Non-reabsorbable ions Extra-renal loss Excessive sweating: Generally insignificant, may be seen after heavy exercise when sweating is > 10 L per day Gastrointestinal losses, e.g. diarrhoea, nasogastric aspiration, vomiting Dialysis or plasmapheresis

Diagnosis Total body K+ depletion may result from renal or extrarenal causes. Most of the times, a good history and examination reveals the source of K+ loss (renal versus extrarenal). If the source is unclear, a 24-hour urinary K+ excretion may be of benefit. A 24-hour urinary K+ >20 mEq/L implies that renal potassium loss is the cause of hypokalaemia. The presence of metabolic acidosis is most often due to diabetic ketoacidosis or renal tubular acidosis type 1 or type 2. The transtubular potassium concentration gradient (TTKG) is used to evaluate the force for K+ secretion in the cortical collecting duct in the kidney. The electrocardiographic changes of hypokalaemia include flattening or inversion of T waves (early), prominent U waves, STsegment depression, prolonged PR interval and widening of QRS complex.These changes do not correlate well with plasma K+ levels. Treatment In the absence of an independent factor, causing transcellular K+ shifts, the magnitude of the deficit in body stores of K+ correlates with the degree of hypokalaemia. On an average, serum K+ decreases by 0.3 mmol/L for each 100 mmol reduction in total body stores, but the response is extremely variable. Oral correction is recommended in all non-urgent settings where patient does not have any arrhythmias or paralysis and

does not have any contraindication to oral supplementation. Intravenous K+ supplementation is used for profound, lifethreatening hypokalaemia and in patients who do not tolerate oral solution. Electrocardiogram (ECG) monitoring should be done with supplementation rates >20 mEq/hr. The concentration of administered potassium should be no more than 40 mEq/L in a peripheral vein or 60 mEq/L in a central vein. Infusion rates should be limited to 40 mEq/hr via central line. In all cases, serum K+ should be checked after 2 to 4 hours of ongoing replacement. Serum Mg2+ levels should be checked if hypokalaemia is refractory to correction. HYPERKALAEMIA Hyperkalaemia is a common and life-threatening electrolyte imbalance. Early recognition of this condition can allow for the initiation of corrective measures. Hyperkalaemia is defined as a serum K+ concentration of larger than 5.0 mEq/L. The normal concentration of K+ depends on the K+ intake, its excretion by the kidney, and by the balance between extra-cellular and intracellular spaces.

Fluid and Electrolyte Balance in Health and Disease

ventricular tachycardia (VT)/ventricular fibrillation (VF). Presence of concomitant coronary ischaemia, digitalis, increased beta adrenergic activity and hypomagnesemia increases the risk of arrhythmias.

Causes of Hyperkalaemia The causes of hyperkalaemia may be divided into two major groups as described in Table 4. In normal individuals, a phenomenon referred to as K + adaptation ensures a proportionate rise in K+ secretion by the kidney in response to an increase in ingested K+. Hence, in the presence of normal renal function, hyperkalaemia due to excess intake is rare. Of these metabolic acidosis is a frequently seen cause. In response to every 0.1 unit reduction in extra-cellular pH, the plasma K+ concentration will rise by 0.6 mEq/L (range 0.2-1.7 mEq/L). Table 4: Classification of Causes of Hyperkalaemia Hyperkalaemia due to excess release of intracellular potassium Metabolic acidosis Insulin deficiency and hypertonicity Tissue catabolism Exercise Beta-adrenergic blockade Drugs, e.g. succinylcholine, digitalis overdose Hyperkalaemic periodic paralysis Pseudohyperkalaemia Hyperkalaemia due to reduced renal clearance Renal failure Decreased effective circulating volume Impaired sodium reabsorption, e.g. primary hypoaldosteronism, adrenal insufficiency, secondary hypoaldosteronism, renal tubular acidosis, drugs (angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, potassium sparing diuretics) Increased chloride reabsorption, e.g. Gordon’s syndrome, cyclosporine Ureterojejunostomy

Clinical Manifestations Hyperkalaemia is associated with very few overt symptoms and signs, and these manifests only at very high levels or when the rise is rapid. Severe muscle weakness and paralysis may be seen in some cases. The primary cause of mortality in hyperkalaemia

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is cardiac rhythm disturbances. As a result, hyperkalaemia can be recognised by some typical ECG abnormalities. A tall and symmetrical T-wave is the first sign of hyperkalaemia. T-waves are usually taller than half of the preceding QRS complexes when considered significant and may appear tented in severe cases. Due to slowing of cardiac conduction, other subsequent changes ensue, including progressive lengthening of the PR interval and QRS duration, atrioventricular conduction delay and loss of P-waves, progressive widening of the QRS complex and merging of the T- and U-waves resulting in a ‘sine wave’ pattern. The terminal event is ventricular fibrillation or asystole. The level of K+ does not correlate with the degree and progression of ECG changes. Diagnosis The most common causes of hyperkalaemia, such as renal failure, drugs and transcellular K+ shift, are relatively simple to identify. Chronic hyperkalaemia not related to these aetiologies is usually due to impaired secretion of K+. Assessment of the TTKG is helpful to differentiate between decreased effective circulating volume (TTKG >10) and other causes (TTKG 7.5 mEq/L but may also occur at lower levels. The goals of therapy are to decrease membrane excitability; thereby preventing arrhythmias, shifting K+ to the intra-cellular space and promoting K + loss and removal of exogenous source of K+. 1. Membrane excitability is controlled by the infusion of 1000 mg (10 ml of a 10% solution) of calcium gluconate over 2 to 3 minutes. The effect begins within minutes but is short lived (only 30 to 60 minutes). The dose can be repeated if no change in ECG is noted within the next 5 to 10 minutes. This does not affect the levels of K+. 2. Insulin causes a shift of extra-cellular K+ into the cells by enhancing the effect of the Na +-K + ATPase pump. An infusion of 10 to 20 units of regular insulin in 20 to 50 g of dextrose can result in the fall of K+ by 0.5 to 1.5 mEq/L in 15 to 30 minutes. This effect peaks at 30 minutes and lasts several hours. Diabetic patients with hyperglycaemia may be given insulin alone. 3. Sodium bicarbonate is effective in shifting K+ into the intracellular space when given in hyperkalaemia associated with metabolic acidosis. The action begins within 30 to 60 minutes and persists for several hours. 4. Beta-2-adrenergic agonists promote the cellular uptake of K+. The onset of action is within 30 minutes and lasts for 2 to 4 hours. These drugs can be effectively used in the treatment of acute hyperkalaemia, lowering the plasma K+ concentration by 0.5 to 1.5 mEq/L.

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5. Removal of potassium can be achieved using loop or thiazide diuretics if renal function is adequate. Potassium binding resins, like sodium polystyrene sulfonates, are useful in binding dietary potassium in the gut and preventing its absorption. One gram of resin binds 1 mEq of K+ and releases 2 to 3 mEq of sodium. The usual dose is

25 to 50 g mixed in 20% sorbitol to prevent constipation. It lowers plasma K+ concentration by 0.5 to 1.5 mEq/L. A retention enema may also be used. 6. The most effective way of lowering K+ is by haemodialysis. Severe hyperkalaemia, not responding to conservative management, is an indication for haemodialysis. Peritoneal dialysis may be done in hypotensive patients but is only 15% to 20% effective. CALCIUM METABOLISM Calcium plays a vital role in body homeostasis. Diverse physiologic processes in body like muscle contraction, neuromuscular signaling, blood coagulation and hormone secretion take place because of calcium. Total body calcium is around 1 to 2 kg of which 99% is in the bones. The normal total levels of calcium in body are 8.5 to 10.5 mg/dL of which 50% is ionised.The remainder is ionically bound to negatively charged proteins (albumin and immunoglobulins) or loosely complexed with phosphate, citrate, sulphate or other anions. Intra-cellular calcium concentrations are 10,000 folds lower than extra-cellular levels. The levels are maintained by feedback mechanism involving parathyroid hormone and active vitamin D. Liver, kidneys, intestines and bones are the principle sites of metabolism. Causes of Hypocalcaemia The causes of hypocalcaemia can be classified according to the activity of parathyroid hormone (PTH) (Table 5). Table 5: Causes of Hypocalcaemia Low or absent parathyroid hormone (PTH) Parathyroid agenesis: Isolated/DiGeorge syndrome Parathyroid destruction: Radiation/surgical/infiltration by metastases/autoimmune process Decreased PTH release: Hypomagnesemia, activating calcium sensing receptor (CaSR) mutations High or ineffective PTH Chronic renal failure Vitamin D deficiency/resistance Pseudohypoparathyroidism Drugs: Calcium chelators, bisphosphonates, phenytoin, ketoconazole Severe acute hyperphosphataemia: Tumour lysis, rhabdomyolysis Miscellaneous Acute pancreatitis Hungry bone disease (after parathyroidectomy) Severe burns, sepsis, acute renal failure, extensive transfusions with citrated blood (transient)

Clinical Manifestations Hypocalcaemia may be asymptomatic if the decrease in serum calcium are relatively mild and chronic. Moderate-to-severe hypocalcaemia is associated with paresthesias, usually of the fingers and toes, and circumoral region. Tapping the inferior portion of zygoma produces twitching of perioral muscles (Chvostek’s sign). Carpal spasm can be induced by inflation of blood pressure cuff to 20 mmHg above the patient’s systolic blood pressure for 3 minutes (Trousseau’s sign). Life-threatening complications, like cardiac arrhythmias, bronchospasm, laryngospasm and seizures, may occur due to severe hypocalcaemia.

Management The treatment depends on the severity of hypocalcaemia, the rapidity with which it develops and accompanying complications. Acute symptomatic hypocalcaemia is treated with intravenous calcium gluconate 10 ml 10% wt/vol (90 mg) diluted in 50 ml of 5% dextrose or 0.9%; normal saline is given over 5 minutes. It may be followed by a continuous infusion of 5 ampules of calcium gluconate (450 mg) in dextrose 5% or normal saline 500 ml over 12 hours. Intra-muscular or subcutaneous route should be avoided due to chances of necrosis. Associated magnesium deficiency should also be corrected. Asymptomatic chronic hypocalcaemia can be treated with oral formulations containing calcium (1 to 2 g/day) and vitamin D2 or D3 (25,000 to 1,00,000 U daily) or calcitriol (1,25 dihydroxy vitamin D) 0.25 to 2 µg/day. Vitamin D deficiency is treated with oral supplementation of vitamin D (50,000 U 2 to 3 times per week for several months). HYPERCALCAEMIA It is a very common problem in day-to-day practice. It could be an incidental finding on laboratory testing or reflection of some serious underlying disease. Causes of Hypercalcaemia Broadly, the aetiology can be classified on the basis of either related to or unrelated to PTH (Table 6). Table 6: Classification of Aetiology of Hypercalcaemia Parathyroid hormone (PTH) related Primary hyperparathyroidism: Solitary adenomas/multiple endocrine neoplasia (MEN) Tertiary hyperparathyroidism (CKD with long-term stimulation of PTH) Lithium therapy Familial hypercalciuric hypercalcaemia PTH unrelated Malignancy associated: Solid tumours (breast, lung, kidney), blood disorders (myeloma) Vitamin D associated: Vitamin D intoxication, granulomatous disease like sarcoidosis, lymphomas High bone turnover: Hyperthyroidism, immobilisation, thiazides, vitamin A intoxication Excessive calcium intake: Milk alkali syndrome, total parenteral nutrition

Clinical Manifestations Hypercalcaemia is largely asymptomatic in half of the patients. Mild hypercalcaemia (upto 11 to 11.5 mg/dL) may present with vague symptoms like difficulty in concentration, personality changes or depression. Groans (constipation), moans (psychotic noise), bones (bone pain, especially if PTH is elevated), stones (kidney stones) and psychiatric overtones (including depression and confusion) are a common mnemonic for hypercalcaemic symptoms. Symptoms are common at calcium levels of 12 to 13 mg/dL, especially if they develop acutely and may include lethargy, stupor or coma, as well as gastrointestinal tract symptoms like anorexia, nausea, constipation or pancreatitis. Bone pains, pathologic fractures, polyuria or polydipsia may also occur. ECG changes in the form of short QT interval, widened Twaves and atrioventricular conduction disturbances may also occur. Severe hypercalcaemia (> 15 mg/dL) is life-threatening and coma or cardiac arrest could occur. Immediate measures should be taken to decrease the levels. Management The treatment of hypercalcaemia depends on the serum calcium levels, symptom presentation or rapidity with which it develops. Mild asymptomatic hypercalcaemia does not require immediate treatment. The steps in the treatment include hydration, diuretics like furosemide, bisphosphonates, calcitonin and glucocorticoids. Use of oral or parenteral phosphate is not recommended due to systemic toxicity of calcium-phosphate complex. Dialysis can be used as a useful therapy in emergency conditions where severe hypercalcaemia is associated with renal failure and is difficult to manage medically.

Fluid and Electrolyte Balance in Health and Disease

Diagnosis Besides measuring serum calcium, it is useful to determine albumin, phosphorus and magnesium levels. Each 1 g/dL reduction in the serum albumin concentration lowers the total calcium concentration by approximately 0.8 mg/dL (0.2 mmol/L) without affecting the ionised calcium concentration. Serum intact PTH measurements provide critical information in patients with hypocalcaemia, but can be interpreted correctly only when serum calcium is measured simultaneously. Suppressed PTH levels along with hypocalcaemia suggests absent or reduced PTH secretion as the cause of hypocalcaemia. Elevated PTH levels should direct to search for secondary hyperparathyroidism. Levels of 25-hydroxy vitamin D should be done if nutritional cause of hypocalcaemia is suspected. 1, 25 dihydroxy vitamin D levels are useful in patients with renal dysfunction and hypocalcaemia.

MAGNESIUM Magnesium is a critical co-factor in more than 300 enzymatic reactions in the human body and is essential to the normal functioning of the human body. The average daily intake of magnesium is 360 mg, out of which approximately one-third is absorbed through the small bowel. It is mainly excreted through the kidneys; with 15% to 25% ultrafiltrate magnesium reabsorption through the proximal tubule and 5% to 10% in the distal tubule. Approximately 1% of total body magnesium is present in the serum and interstitial space with the normal plasma magnesium concentration of 1.4 to 2.2 mEq/L. Magnesium is found in various dietary sources, best being green leafy vegetables. It is also found in nuts, soybean and whole grain foods. Hypermagnesemia Under normal physiological conditions, magnesium is excreted in the urine. Hypermagnesemia is seen when either the renal function is impaired or there is excess of magnesium load. Causes of hypermagnesemia Causes of hypermagnesemia are listed in Table 7. Clinical manifestations Depends on the serum magnesium concentration, symptoms can range from asymptomatic (4 mEq/L). Magnesium concentration of 4 to 6 mEq/L leads to nausea, headache, lethargy and sluggish deep tendon reflexes. Concentration of 6 to 10 mEq/L leads to somnolence, hypocalcaemia, hypotension and absent reflexes. Levels more than 10 mEq/L

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Table 7: Causes of Hypermagnesemia

Table 8: Causes of Hypomagnesemia

Renal failure: Hypermagnesemia up to 2 to 3 mEq/L is seen in endstage kidney disease. Severe hypermagnesemia is seen only if excess exogeneous magnesium load is given. Magnesium infusion: Parenteral infusion like treatment for preeclampsia, eclampsia Magnesium enemas and oral ingestion which exceeds the renal excretory capacity Hormonal: Primary hyperparathyroidism, diabetic ketoacidosis, adrenal insufficiency Tumour lysis syndrome Milk alkali syndrome

Gastrointestinal losses: Chronic diarrhoea especially if associated with dietary deficiency, malabsorption, steatorrhoea and small bowel resection

causes muscle paralysis, complete heart block, respiratory and cardiac arrest. Management Prevention is by avoiding magnesium loading in patients with impaired renal functions. Cessation of magnesium supplements in patients with normal renal function will allow restoration to normal levels. Intravenous calcium gluconate can be given as a magnesium antagonist. Haemodialysis may be required in patients with renal failure or with severe life-threatening hypermagnesemia. Hypomagnesemia Hypomagnesemia is especially common in intensive care unit settings with nutrition, diuretics, etc. In the presence of hypomagnesemia, kidney can decrease the renal excretion. Hypomagnesemia can occur in the setting of gastrointestinal or renal losses. However, it is often associated with other metabolic abnormalities like hypokalaemia, hypocalcaemia and metabolic acidosis. Causes of hypomagnesemia Causes of hypomagnesemia are listed in Table 8.

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Acute pancreatitis, alcoholic patients Renal losses: Loop and thiazide type diuretics, primary defect in renal tubular magnesium handling, Bartter’s and Gitelman’s syndrome Hormonal: Primary aldosteronism Hypercalcaemia: Resulting from increased reabsorption of calcium in the loop of Henle leading to hypomagnesemia Drugs: Aminoglycosides, amphotericin B, cisplatin, cyclosporine, pentamidine, proton pump inhibitors Hungry bone syndrome following parathyroidectomy

Clinical manifestations The clinical features of hypomagnesemia include tetany, positive Chvostek’s and Trousseau’s signs and generalised convulsion. ECG changes include widening of QRS complex, peaking of the T-waves, prolongation of PR interval and diminution of T-wave and ventricular arrhythmias, especially during myocardial ischaemia. hypomagnesemia can also present along with hypocalcaemia. Mild hypomagnesemia can lower the plasma concentration of calcium. Vitamin D deficiency is also noted in hypocalcaemic and hypomagnesemic patients. Management It is important to correct the underlying cause of hypomagnesemia, e.g. stopping the offending drug. Magnesium is replaced by oral route in asymptomatic patients or those with mild deficiency by sustained release formulations, dose being 2 to 4 tablets per day. Intravenous magnesium replacement is required in conditions like ventricular arrhythmias and tetany.

7.4

Acid Base Disorders Alladi Mohan, Surendra K Sharma

INTRODUCTION In critical care practice, a wide range of disorders affecting the acid-base balance are encountered. In addition to diseases that cause primary acid-base disorders, a number of disease states either predispose patients to develop these conditions or require the use of medications that alter renal, gastrointestinal, or pulmonary function and secondarily alter acid-base balance. The history and physical examination and measurement of blood and urinary indices allow identification of the underlying cause of these disorders in most cases. Arterial blood gas (ABG) analysis, considered to be one of the most precise measurements in medicine, is a crucial investigation that is frequently employed in the critical care setting. It provides valuable precise information regarding the acid-base, ventilation and oxygenation status of the patient. BASIC PHYSIOLOGICAL AND CHEMICAL CONCEPTS Interpretation of the ABG report requires a clear understanding of the basic concepts and physiological principles underlying the disorders of acid-base homeostasis, oxygenation and ventilation. A brief overview regarding the essential fundamental physiological concepts is provided and a practical approach for the bed-side interpretation of ABG results is described. Acid-Base Chemistry pH The concept of pH was put forward by the Danish chemist, Soren Peter Sorensen in 1909 to refer to the negative logarithm of hydrogen ion (H+) concentration.

Table 1: Relationship between pH and [H+] pH

[H+] (nmol/L)

6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8

158 125 100 79 63 50 40 31 25 20 15

Dissolved carbon dioxide (CO2) is in equilibrium with carbonic acid CO2 + H2O

Carbonic anhydrase ⎯⎯⎯⎯ → H2CO3–

→ ⎯ ⎯ ⎯⎯

Carbonic acid ionizes according to the equation Carbonic anhydrase H2CO3 H+ + HCO3– ⎯⎯⎯⎯ → By the law of mass action [H+] [HCO3–]

=

log K’

=

log K’

[H+] [HCO3–] log [H2CO3]

pH = – log [H ]

Overview of Acid-Base Balance in the Human Body The normal extracellular fluid (ECF) H+ concentration is 40 nmol/L. Under normal physiological conditions, the H + concentration varies little from its normal value due to the processes of acid-base regulation as maintenance of H + concentration at this level is considered to be essential for normal cellular processes. In order to achieve this, close interaction between three physiological systems of the body, namely, the chemical buffers of the body namely kidneys and the lungs is considered essential.

K’

Taking logarithm on both sides, we have

+

The pH is a ‘dimensionless representation’ of the H + concentration, it has no units and is just a number. There are several advantages of the expression pH compared to H+. Measured by the pH electrode, pH is related to the logarithm of H+ ‘activity’ rather than ‘concentration’ of H+ and this seems physiologically more appropriate. The relationship between pH and H+ is shown in Table 1. For each 0.1 pH unit increment, H+ falls by 20%; by remembering this relationship, the intermediate values can be derived accurately.

= [H2CO3 ]

Therefore, log [H+] + log

[HCO3–] [H2CO3]

and +

log [H ] =

[HCO3–] log K’ – log [H2CO3]

By changing signs on both sides of the equation, we have – log [H+] = – log K’ + log

[H2CO3–] [H2CO3]

+

Since – log [H ] is called pH and – log K’ is called pK, the equation can be re-written as [HCO3–] pH = pK + log [H2CO3 ] This has been called the ‘Henderson-Hasselbalch’ equation.

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The pK represents the pH at which maximum buffering capacity can be achieved for that reaction. Since the carbonic acid concentration is dependent on the amount of dissolved CO2 which in turn is dependent on its solubility and the partial pressure of carbon dioxide (PaCO 2) in the arterial blood. Therefore, in this equation, H2CO3 can be substituted by s x PaCO2, where, s = solubility coefficient. In the clinical setting, pK = 6.1; s = 0.0301. Therefore, [HCO3–] pH = 6.1 + log 0.0301 × PaCO2 The body responds to the perturbations in the acid-base balance by buffering, which is the immediate response followed by respiratory (alteration in ventilation) and renal (alteration in bicarbonate excretion) responses. The major buffer system in the ECF is the CO2-bicarbonate buffer system. Other buffer systems that play a role in buffering are protein and phosphate buffer systems. In the blood, concentration of phosphate is very low and it is quantitatively unimportant. Protein buffers in blood include haemoglobin and plasma proteins. Haemoglobin is an important blood buffer particularly for buffering CO 2. According to the ‘isohydric principle’, at a given moment, all buffer systems which participate in defense of acid-base changes are in equilibrium with each other. It is important to remember that the carbonate and phosphate salts in bone act as a long-term supply of buffer, especially during prolonged metabolic acidosis. NOMENCLATURE FOR CLINICAL INTERPRETATION OF ARTERIAL BLOOD GAS MEASUREMENTS The nomenclature for clinical interpretation of ABG measurements are listed in Table 2. Normal laboratory values and acceptable therapeutic ranges for pH and PaCO2 are shown

in Table 3. The typical alterations in the ABG results and the expected compensatory mechanisms in simple acid-base disorders are listed in Tables 4A and B. Table 2: Nomenclature for Clinical Interpretation of ABG Measurements: Acid-Base Status Acidosis is an abnormal process or condition which would lower arterial pH if there were no secondary changes in response to the primary aetiological factor Alkalosis is an abnormal process or condition which would raise arterial pH if there were no secondary changes in response to the primary aetiological factor Acidaemia = Arterial pH < 7.36 Alkalaemia = Arterial pH > 7.44 Simple acid-base disorders are those in which there is a single primary aetiological acid-base disorder Mixed acid-base disorders are those in which two or more primary aetiological disorders are present simultaneously Respiratory disorders are caused by abnormal processes which tend to alter pH because of a primary change in PaCO2 levels Metabolic disorders are caused by abnormal processes which tend to alter pH because of a primary change in HCO3– ABG = Arterial blood gas; PaCO2 = Partial pressure of carbon dioxide; HCO3– = Bicarbonate

Table 3: Normal Laboratory Values and Acceptable Therapeutic Ranges for pH and PaCO2 Variable

Mean

1SD

2SD

Acceptable Therapeutic Range

pH

7.40

7.38-7.42

7.35-7.45

7.30-7.50

PaCO2 (mmHg)

40

38-42

35-45

30-50

SD = Standard deviation; PaCO2 = Partial pressure of carbon dioxide

Table 4A: Expected Compensatory Mechanisms in Respiratory Acid-Base Disorders Acid-base Disorder

Initial Change

Compensatory Response

Respiratory acidosis

↑PaCO2

↑HCO3–

Equations for Expected Range of Compensation

Acute

For every 10 mmHg↑ in PaCO2, pH decreases by 0.08 units Expected pH = 7.4 – [0.008 × (PaCO2 – 40)]

Chronic

For every 10 mmHg↑ in PaCO2, pH decreases by 0.03 units Expected pH = 7.4 – [0.003 × (PaCO2 – 40)]

Respiratory alkalosis

↓PaCO2

↓HCO3–

Acute

For every 10 mmHg↓ in PaCO2, pH increases by 0.08 units Expected pH = 7.4 + [0.008 × (40 – PaCO2)]

Chronic

For every 10 mmHg↓ in PaCO2, pH increases by 0.03 units Expected pH = 7.4 + [0.003 × (40 – PaCO2)]

Table 4B: Expected Compensatory Mechanisms in Metabolic Acid-Base Disorders

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Acid-base Disorder

Initial Change

Compensatory Response

Equations for Expected Range of Compensation

Metabolic acidosis

↓HCO3–

↓PaCO2

↓PaCO2 = 1.2 ×  (HCO3–) Expected PaCO2 = [1.5 × (HCO3–) + 8] ± 2 (Winter’s formula)

Metabolic alkalosis

↑HCO3–

↑PaCO2

↑PaCO2 = 0.7 ×  (HCO3–) Expected PaCO2 = [0.7 × (HCO3–) + 21] ± 2

Calculating PaCO2 Variance First, the PaCO2 variance is determined by calculating the difference between the measured PaCO2 and 40; then, the decimal point is shifted two places to the left. Example: pH 7.06, PaCO2 = 74 74 – 40 = 34 PaCO2 variance = 0.34 pH 7.48, PaCO2 = 20 40 – 20 = 20 PaCO2 variance = 0.20 Calculating Predicted pH Predicted respiratory pH is calculated as follows. If the PaCO2 is greater than 40, half the PaCO2 variance is subtracted from 7.40. If PaCO2 is less than 40, the PaCO2 variance is added to 7.40. Examples: 1. pH 7.06, PaCO2 = 74 74 – 40 = 34 PaCO2 variance = 0.34 0.34 × ½ = 0.17 Predicted respiratory pH = 7.40 – 0.17 = 7.23 2. pH 7.48, PaCO2 = 20 40 – 20 = 20 PaCO2 variance = 0.20 Predicted respiratory pH = 7.40 + 0.20 = 7.60 Estimate of Base Excess/Deficit The difference between the predicted respiratory pH and the measured pH reflects the metabolic pH change. Normally, a 10 mEq/L variance from normal buffer baseline represents a pH change of 0.15. If the pH decimal point is moved two places to the right, a 10 (10 mEq/L) to 15 (0.15) relationship will be evident and this has been expressed as “ 2/3 relationship”. By determining the difference between the measured pH and the predicted respiratory pH, moving the decimal point two places to the right and multiplying by 2/3, base excess/deficit can be calculated. When the measured pH is greater than the predicted pH, it is termed as base excess. When the measured pH is less than the predicted pH, it is termed as base deficit.

Examples: 1. pH 7.06, PaCO2 = 74, predicted pH = 7.23 Difference between predicted and measured pH = 7.23 – 7.06 = 0.17 Applying 2/3 rule, 0.17 × 2/3 = 0.11 Base deficit = 11 mEq/L

Acid Base Disorders

Indices for Acid-Base Balance Indices for acid-base balance include PaCO2, actual bicarbonate, standard bicarbonate and buffer base. Standard bicarbonate is the measurement made in the clinical laboratory after the blood has been equilibrated at 37oC with a PaCO2 of 40 mmHg. Actual bicarbonate is calculated from PaCO2 and pH using HendersonHasselbalch equation. Base excess is defined as the number of mEq of acid or base needed to titrate 1 L of blood to a pH of 7.40 at 37oC while PaCO2 is held constant. For quick bed-side calculation, it can be assumed that at PaCO2 held constant at 40 mmHg, 7 mEq of acid or base are required to change pH by 1 unit (0.10). Base excess (or deficit), which is a true reflection of non-respiratory component of acid-base balance, is an estimate and not an actual measurement. Therefore, it will be reliable only if the measurements used to derive it, the pH and PaCO2 are estimated accurately. Base excess is determined as follows:

2. pH 7.48, PaCO2 = 20, predicted pH = 7.60 Difference between predicted and measured pH = 7.6 – 7.48 = 0.12 Applying 2/3 rule, 0.12 × 2/3 = 0.08 Base deficit = 8 mEq/L 3. pH 7.20, PaCO2 = 90 90 – 40 = 50 PaCO2 variance = 0.50 0.50 × ½ = 0.25 Predicted respiratory pH = 7.40 – 0.25 = 7.15 Difference between predicted and measured pH = 7.20 – 7.15 = 0.05 Applying 2/3 rule, 0.05 × 2/3 = 0.033 Base excess = 3 mEq/L Base excess/deficit calculation serves as a useful guide for bicarbonate administration. Anion Gap Anion gap (AG) represents the concentration of all the unmeasured anions in the plasma (Table 5) and is calculated by the following formula: AG = [Na+] – [Cl–] + [HCO3–] Normal AG is 12 ± 4 mEq/L. Conditions resulting in metabolic acidosis other than hydrochloric acidosis usually lead to a decrease in the serum bicarbonate concentration without a concomitant rise in serum chloride thereby increasing the AG. Table 5: Unmeasured Anions and Cations Contributing to the Anion Gap Unmeasured Anions

Unmeasured Cations

Serum proteins, mostly serum albumin (15 mEq/L) Organic acids (5 mEq/L) Phosphates (2 mEq/L) Sulphates (1 mEq/L) Total = 23 mEq/L

Calcium (5 mEq/L) Potassium (4.5 mEq/L) Magnesium (1.5 mEq/L) Total = 11 mEq/L

Delta Ratio Delta ratio is related to the AG and buffering, and is defined as: Delta ratio = increase in AG/decrease in bicarbonate A high delta ratio can occur when the bicarbonate levels are already elevated at the onset of the metabolic acidosis either due to a pre-existing metabolic alkalosis, or as a compensation for pre-existing respiratory acidosis. A low delta ratio occurs with hyperchloraemic normal AG acidosis (Table 6). DIAGNOSIS OF ACID-BASE DISORDERS Clinical Assessment Patients with acid-base disturbances (Tables 7A and B) may present with symptoms due to the aetiological causes that

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Table 6: Utility of Delta Ratio when Assessing Metabolic AcidBase Disorders Delta Ratio

Interpretation

10 mOsm/L is considered abnormal when calculated using this formula. Conditions causing increased osmolar gap metabolic acidosis include ethanol, ethylene glycol, methanol, acetone and propylene glycol poisoning. While a high AG, high osmolar gap metabolic acidosis is seen in methanol and ethylene glycol poisoning, normal AG, high osmolar gap metabolic acidosis is seen in isopropyl alcohol poisoning. Step 6: Determining whether other metabolic disturbances co-exist with an elevated anion gap acidosis A normal AG acidosis or a metabolic alkalosis may exist concurrently with an elevated AG acidosis. In this situation, corrected bicarbonate should be calculated as follows: Corrected HCO3– = measured HCO3– + (AG – 12) where, AG = anion gap If the corrected HCO3– is greater than 24, a metabolic alkalosis co-exists; if it is less than 24, then a normal AG metabolic acidosis co-exists.

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Step 7: Assessing the normal compensation by the respiratory system for a metabolic disturbance In simple metabolic acidosis, the measured PaCO2 will fall within the range predicted by Winter’s formula (Table 4B). If a

concurrent respiratory disturbance is also concurrently present, it would be defined by the direction the PaCO2 varies beyond the range predicted by Winter’s formula rather than the PaCO2 variation from the normal value of 40. In metabolic alkalosis, the magnitude of respiratory compensatory response is not easily predictable because degree of PaCO2 increase does not exhibit an exactly linear relationship with the HCO3-. However, for practical purposes, the following equation has been found to be useful to calculate the expected: PaCO2 = [0.7 × (HCO3–) + 21] ± 2 In compensated metabolic alkalosis, the measured PaCO2 is equivalent to the expected PaCO2. If the measured PaCO2 is higher than the expected PaCO2, the respiratory compensation is not adequate, and the condition is termed as a primary metabolic alkalosis with a superimposed respiratory acidosis. In primary metabolic alkalosis with a superimposed respiratory alkalosis, the PaCO2 is lower than the expected. TREATMENT The aetiological causes responsible for acid-base disturbances largely determine the status and prognosis in patients with acidbase disorders. Therefore, it is essential to recognise the underlying cause responsible for the disturbance so that specific treatment can be instituted. Metabolic Acidosis Metabolic acidosis may induce a wide range of adverse clinical effects, some of which may be life-threatening. In lifethreatening metabolic acidosis, exogeneous alkali therapy aims to prevent or reverse the detrimental consequences of severe acidaemia affecting the cerebral, respiratory, metabolic and cardiovascular systems. Intravenous sodium bicarbonate is the mainstay of alkali therapy and should be given judiciously in amounts that will return blood pH to a safer level of about 7.20. The distribution of HCO3– being 40% of the body weight, the amount of HCO3– required to return the serum concentration to normal can be calculated as follows: HCO3– deficit = Body weight (kg) × 0.4 × (desired HCO3– – measured HCO3–) Except in situations of extreme acidaemia, sodium bicarbonate should be administered as an infusion rather than a bolus; about 30 minutes must elapse following the completion of the infusion before its clinical effect can be judged. One-half of the calculated deficit can be replaced in 3 to 4 hours, if severe heart failure is not present. Subsequently, monitoring of the patient’s acid-base status will determine additional alkali requirements. Alterations in respiratory function, dyselectrolytaemia (especially hypokalaemia) and hypo-tension must be recognised and treated. Specific therapy is required in the setting of poisoning and overdosage. Chronic metabolic acidosis (e.g. chronic kidney disease) is treated with oral sodium bicarbonate. Metabolic Alkalosis Metabolic alkalosis is usually mild; when severe (pH >7.6) or rapidly developing it may be life-threatening. The chlorideresponsive metabolic alkalosis can be treated with intravenous

Respiratory Acidosis Treatment of respiratory acidosis is directed at improving ventilation using non-invasive or invasive ventilatory strategies; administration of bicarbonate can be harmful and should be avoided. Respiratory Alkalosis Treatment of respiratory alkalosis should be directed towards the underlying cause, identification and correction of electrolyte abnormalities that usually co-exist. Usually, reassurance, re-breathing from a bag or treating the underlying psychological stress is enough to alleviate respiratory alkalosis. Controlling fever, seizure activity and sepsis will also help. RECOMMENDED READINGS 1.

Adrogué HJ, Madias NE. Management of life-threatening acid-base disorders. First of two parts. N Engl J Med 1998; 338: 26-34.

2.

Adrogué HJ, Madias NE. Management of life-threatening acid-base disorders. Second of two parts. N Engl J Med 1998; 338: 107-11.

3.

Driscoll P, Brown T, Gwinnutt C,Wardle T. A Simple Guide to Blood Gas Analysis. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2002.

4.

Fall PJ. A stepwise approach to acid-base disorders. Practical patient evaluation for metabolic acidosis and other conditions. Postgrad Med 2000; 107: 249-50, 253-4, 257-8 passim. 5. Laski ME, Kurtzman NA. Acid-base disorders in medicine. Dis Mon 1996; 42: 51-125. 6. Mohan A, Sharma SK. An approach to interpret arterial blood gases. In Agarwal AK, editor Clinical Medicine Update 2006; Vol. IX. A publication of Indian Association of Clinical Medicine. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2006; pp 73-81. 7. Mohan A, Sharma SK. How to interpret blood gas data. In: Singal RK, editor Medicine Update. Mumbai: Association of Physicians of India; 2007:pp (17): 145-51. 8. Morganroth ML. An analytic approach to diagnosing acid-base disorders. J Crit Ill 1990; 5: 138-50. 9. Morganroth ML. Six steps to acid-base analysis: clinical applications. J Crit Ill 1990; 5: 460-9. 10. Narins RG, Emmett M. Simple and mixed acid-base disorders: a practical approach. Medicine (Baltimore) 1980; 59: 161-87.

Acid Base Disorders

saline administration. When alkalosis is severe, or there is a risk of volume overload, 1N hydrochloric acid administration may be required. Chloride-unresponsive alkaloses are more difficult to treat and treatment is directed at the underlying cause.

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7.5

Enteral and Parenteral Nutrition in Critically Ill Patients

Feeding is not considered medical therapy under ordinary circumstances. But when patients are critically ill and cannot eat themselves food takes the form of medical therapy. The incidence of hospitalised malnutrition is well documented, especially in critically ill patients. Despite the advances in medicine, definitive indications for the use of nutritional support are unclear. Use of enteral and parenteral therapies should be widespread for various reasons: 1. Protein calorie malnutrition is common in a variety of hospitalised patients. 2. Documented association between malnutrition and increased morbidity and mortality. 3. It seems intuitive that well-nourished patients would respond more favourably to therapeutic interventions than malnourished patients. 4. Nutritional support can be provided safely to a wide variety of patients. 5. Several randomised prospective clinical trials showed that nutritional support benefits the patients. Therefore, there is a clear-cut evidence base for the role of enteral and parenteral therapies in hospitalised as well as critically ill patients. Nutritional support is a delivery of formulated enteral or parenteral nutrients to appropriate patients for the purpose of maintaining/restoring nutritional status. ENTERAL NUTRITION By definition, enteral nutrition means ‘within or by the way of gastrointestinal (GI) tract’. In practice, enteral nutrition is generally considered tube feeding. The consensus of nutritional experts is that the GI tract is more physiologically and metabolically effective than the intravenous route for nutrient utilisation. Any disease process that adversely affects oral intake may ultimately lead to significant nutritional deprivation and depletion. Patients who cannot eat, will not eat, or should not eat, yet who have adequate function of the GI tract, are candidates for enteral tube feeding.

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Once the patient has been assessed and found to be a good candidate for enteral nutrition, the clinician selects the appropriate tube and route of access for tube placement. Enteral access selection depends on several factors as given below: 1. Anticipated length of time for which enteral feeding will be required 2. Degree of risk for aspiration or tube displacement 3. Presence or absence of normal digestion and absorption 4. Whether or not there is a planned surgical intervention 5. Administration issues such as formula viscosity and volume.

Shilpa S Joshi Advantages of Enteral Feeding Various advantages of enteral feeding are: (i) it is a preferred route of nutrition support as it is more physiologic, (ii) costeffective, (iii) safe, (iv) fewer side-effects as compared to parenteral nutrition, (v) maintenance of GI immune barrier, (vi) avoidance of central catheter related complications. The indications for enteral feeding are listed in Table 1. Table 1: Indications of Enteral Feeding Oral intake inadequate or contraindicated

Increased nutritional requirements Digestive and absorptive disorders

Metabolic and excretory disorders

Mechanical: stroke, central nervous system Disorders, coma, oropharyngeal and oesophageal disorders, partial or complete oesophageal or gastric obstruction Poor appetite: chemotherapy, radiation therapy, drug effect, nausea Transitional feeding: advance from parenteral to oral intake Psychological: anorexia nervosa, depression, Alzheimer’s disease Burns, trauma, sepsis, surgical or medical stress Inflammatory bowel disease, short bowel syndrome, pancreatitis, irradiated bowel, proximal and distal intestinal fistulae, immunocompromised syndromes Glycogen storage disease, hepatic encephalopathy, renal disease

Contraindications of Enteral Feeding Enteral feeding is contraindicated in patients with peritonitis, distal intestinal obstruction, intractable vomiting or severe diarrhoea. ASSESSMENT OF NUTRITIONAL NEEDS OF A PATIENT Before initiation of feedings, assessment of nutritional status of every patient is fundamental and includes some key components: nutritional history, anthropometric procedure, clinical examination, biochemical data, evaluation of weight loss and previous nutrient intake before admission, level of disease severity, co-morbid conditions, and function of the GI tract. Assessment of these parameters will help to document presence of malnutrition and will help clinician to select best method for providing nutrients and allows objective monitoring of nutritional efforts. These assessment are also needed to estimate caloric protein, micronutrient requirement and also help to select/make right kind of formula. FORMULA COMPOSITION Energy The target goal of enteral nutrition (defined by energy requirements) should be determined and clearly identified at

Males (kJ/day): REE = 278 + 58 (Wt) + 21 (H) -28.5 (Af) x SF Females (kJ/day): REE = 2734 + 40 (Wt) + 7.7 (H) -19.7 (Af) x SF where, kJ = Kilo Joules; REE = Required energy requirement; Wt = Weight in kilograms; H = Height in meters, Af = Activity factor, and SF = Stress factor Values for activity factor and stress factor for various diseases to be considered as standard are given below: Activity factor (AF) Stress factor (SF) Bed rest = 1.0 Post-operative with complication = 1.24 Ambulatory = 1.1 Skeletal trauma = 1.1-1.3 Active = 1.2-1.3 Sepsis = 1.3-1.6 Cancer = 1.2 where, 1 calorie is about 4.185 kJ. Efforts to provide more than 50% to 65% of goal calories should be made to achieve the clinical benefit of enteral nutrition over the first week of hospitalisation. Studies suggest that more than 50% to 65% of goal calories may be required to prevent increases in intestinal permeability in burn and bone-marrow transplant patients, to promote faster return of cognitive function in head injury patients and to improve outcome from immune modulating enteral formulations in critically ill patients. If unable to meet energy requirements (100% of target goal calories) after 7 to 10 days by the enteral route alone, consider initiating supplemental parenteral nutrition. Initiating supplemental parenteral nutrition before this 7 to 10 days period in the patients already on enteral nutrition does not improve outcome and may be detrimental to the patient. Proteins Proteins in the diet serve as a source of amino acids that body cannot make (essential amino acids) and provide nitrogen for the synthesis of other amino acid (non-essential amino acids). Insufficient protein intake can potentially affect all aspects of a patient’s care, for example, it can lead to muscle atrophy and can make it difficult to wean off the patient from ventilator. In addition to the importance of adequate amounts of protein is the quality of protein. Proteins can be modified in various ways in enteral formulation, for example intact protein, hydrolysed protein, amino acids. Intact proteins and protein isolates requires normal pancreatic enzymes to catabolise them into small polypeptides and free amino acids. Hydrolysed protein formulas can be directly absorbed into the blood stream. These feeds can be administered when the feeds are administered via jejunum and where only absorption of proteins takes place. IMMUNOMODULATORY AGENTS Glutamine and Branched Chain Amino Acids Glutamine and branched chain amino acids are amino acids found in skeletal muscles. These have been identified as key amino acids in preserving nitrogen balance during stress and injury. Numerous studies have indicated that glutamine is necessary to maintain integrity of intestinal mucosa, immune

function of lymphocytes to preserve muscle glutamine pool and to improve overall nitrogen balance. Arginine Arginine is a conditionally essential amino acid, i.e. it can be conditionally essential after injury. Human and animal studies have shown that increased intake of arginine after trauma decreases nitrogen losses and accelerate wound healing. Standard formulas contain arginine in the amount of 1 g and 2 g/L. Arginine enriched formulas contain 14 to 15 g/L. Nucleotides Nucleotides are added to some formulas as immunity enhancers. In animals, dietary supplementation of nucleotides has shown to facilitate growth and maturation of developing gut. Agents such as ribonucleic acid (RNA) nucleotides increase total lymphocyte count, lymphocyte proliferation and thymus function. Taurine Taurine is conditionally essential nutrient since it can be synthesised by dietary cysteine or methionine.

Enteral and Parenteral Nutrition in Critically Ill Patients

the time of initiation of nutritional support therapy. Energy requirements may be calculated by Harris Benedict equation, which is as follows:

EPA-DHA Omega-3 fatty acids eicosapentaenoic acid and docosohexaenoic acid displace omega-6 fatty acids from the cell membranes of immune cells. This effect reduces systemic inflammation through the production of alternative biologically less active prostaglandins and leukotrienes. Patients with acute respiratory distress syndrome and severe acute lung injury should be placed on an enteral formulation characterised by an anti-inflammatory lipid profile (i.e. omega3 fish oils, borage oil) and antioxidants. High Nitrogen Products These have increased proportions of branched chain amino acids. These products are used for patients with catabolic stress. Most of formulas contain a non-protein kcal: nitrogen ratio of 150:1 (with ranges between 100:1–200:1) which is thought to be optimal for patients. Most of the enteral formulations offer high nitrogen products. Patients who do not need high nitrogen formulas are likely to use amino acids for energy and increase urea production. As a result this formula should be given carefully to renal patients. Carbohydrates Carbohydrates (CHO) provide 30% to 90% of total calories of enteral formulas and in most of the formulas these are the principle source of energy. The main difference among the formulas is the form and composition of CHO. In general, the longer carbohydrate molecule are less osmotic, taste less sweet are require more digestion than the shorter ones. Lactase deficiency is most prevalent disaccharide deficiency and hence, most of the enteral formulas are lactose free. Fibre Enteral formulas containing fibre may have potentially clinical applications including ameliorating constipation and tube feeding-associated diarrhoea, improving mucosal healing in inflammatory bowel disease, supporting gut barrier of critical ill patient and increasing intestinal adaptation in short bowel

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syndrome. Predominant source of fibre of enteral formula is soya derived polysaccharides. Soluble fibre may be beneficial for the fully resuscitated, haemodynamically stable critically ill patient receiving enteral nutrition who develops diarrhoea. Insoluble fibre should be avoided in all critically ill patients. Both soluble and insoluble fibre should be avoided in patients at high-risk for bowel ischaemia or severe dysmotility. Lipids Fat is a dense source of energy and also serves as a vehicle for fat soluble vitamins and essential fatty acids. Most of the enteral formulas contain vegetable oil as primary source of fat. Vegetable oil is also a good source of essential fatty acids. Fat does not contribute to osmolality of enteral formula. Long Chain Triglycerides Vegetable oils are predominant source of fat in enteral formulas. Long chain triglycerides are slowly cleared from blood stream and require carnitine for its absorption. Medium Chain Triglycerides (MCTs) MCTs are 6 to 12 carbon long and are usually prepared from palm kernel or coconut oil. They offer many advantages over long chain triglycerides, as they are absorbed intact without appreciable pancreatic or biliary function and are subjected to more rapid clearance from blood stream. They are transported to the liver principally via portal venous system where they cross mitochondrial membrane and can be oxidised independent of carnitine. These should not be used in patients who are prone to high ketone levels as they produce ketone. Vitamins, Minerals and Trace Elements A combination of antioxidant vitamins and trace minerals should be provided to all critically ill patients receiving specialised nutritional therapy. Supplemental vitamins and minerals should be given when quantity of formula does not fulfil the requirement. Water Fluid balance in patients receiving enteral nutrition should be monitored. The daily water requirement for a healthy adult is 1 mL/kcal taken for approximately 30 to 32 mL/kg. Minimum of 30 mL of water every 6 hours is recommended as a flush for tube patency alone. Probiotics Administration of probiotic agents has been shown to improve outcome (most consistently by decreasing infection) in specific critically ill patient populations involving transplantation, major abdominal surgery, and severe trauma. No recommendations can currently be made for use of probiotics in the general intensive care unit population because of a lack of consistent outcome effect.

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PHYSICAL CHARACTERISTICS OF A FORMULA Osmolality Osmolality is a physical phenomenon of net permeability resulting in equilibrium across the cell membrane. It is a measure of concentration of free particles, molecule or ions in a given

solution in water. These particles include electrolytes, minerals, carbohydrates, proteins or amino acids and are expressed in milli osmoles per kilogram of water. All nutrients and dietary components except water contribute to osmolality solution. It has been widely thought that isotonic formulas (osmolality ranging from 280 to 320 milli osmoles/kg) are tolerated well than hyper or hypotonic formulas. Renal Solute Load Renal solute load refers to the constituents in the formula that must be excreted by the kidneys. Protein, sodium, potassium, and chloride are the major constituents of enteral formulas that contribute to the renal solute load. It is important, as there is obligatory water loss with each unit of solute. Nutritional Formulations A wide variety of commercially prepared formulas with variable sources and concentrations of protein, carbohydrate and fat are currently available. Polymeric Formulas Polymeric formulas are composed of intact proteins, disaccharides and polysaccharides and variable amount of fat. The osmolality of polymeric formula is usually lower than that of elemental formulas. These formulas require a functioning GI tract for digestion and absorption of nutrients. Polymeric formulas can be further subdivided into hypercaloric formulas, normocaloric formulas, etc. Pre-Digested Formulas Pre-digested formulas are composed of low molecular nutrients, have minimal residue and are thought to lead less stimulations of pancreatic and GI secretion and are less allergic than other formulas. These formulas have greater osmolalities than the polymeric formulas because of the small molecule weight of nutrients. Modular Products Individual macro-nutrients modules, such as glucose polymers, proteins, and lipids, are available as additives to foods and enteral formulas to change overall fuel composition. Disease Specific Formulas These products are designed for patients who have specific medical conditions that may require nutrient modifications. Formula Selections Selection of appropriate formulas is based on patient’s medical and nutritional status, digestive and absorptive capabilities indicate whether pre-digested or polymeric formulas can be used. Administration of Tube Feeding Proper administration of enteral formulas ensures safe delivery of desired nutrients, enhanced patient tolerance and optimal nutritional support. There are various methods of feeding the patients. Choice of technique depends upon GI function, feeding site, and ultimately patient’s response. 1. Bolus feeding Bolus feeding is rapid administration of large volumes of formula over a short period of time usually by syringe. This form of feeding is least cumbersome but is associated with

2. Continuous feeding Continuous infusion is controlled delivery of prescribed volume of formula at a constant rate over a continuous period of time using infusion pumps or gravity assisted sets. This method is considered advantageous since gastric cooling is minimised and few GI tract side effects are experienced. Continuous infusion into jejunum is more analogous to normal gastric emptying. 3. Intermediate infusions In intermediate feeding, total quantity of formula needed for 24 hours is divided into equal portions and required fractions are administered in 3 to 6 feedings. Each feeding is administered over 30 to 90 minutes period. Techniques of Feeding 1. Selection of appropriate formulas. 2. Elevate the head of the patient’s bed to at least 30 degree to horizontal levels before feeding begins. 3. Aspirate through nasogastric or gastrostomy tube before initiating feeding to determine whether retained gastric secretions are present. 4. Begin feeding schedule of 100 to 150 mL of isotonic or slightly hypertonic formulas every 4 hours. 5. Increase formula amount by 50 mL every 1 or 2 feeding up to 450 mL every 4 hours. 6. Flush the tube at least with 30 mL of water after feeding and every 4 hours to maintain patency. Complications of enteral feeding are shown in Table 2. Table 2: Complications of Enteral Feeding Mechanical complications

Blockage of tube Dislocation of tube Aspiration pneumonia

Gastrointestinal complications

Delayed gastric emptying Constipation Malabsorption

PARENTERAL NUTRITION Parenteral nutrition is a form of intravenous therapy that provides opportunity to replenish or maintain nutritional status. Parenteral nutritional was originally developed to nourish those whose GI tract was not capable of digesting and absorbing nutrients. Central parenteral nutrition is delivery of nutrients through the large diameter vein usually subclavian or superior vena cava. Peripheral parenteral nutrition is usually delivered through small veins usually in the forearm. Central parenteral nutrition is indicated when volume and concentration of solution preclude peripheral administration and when anticipated duration of therapy is greater than 7 days to 2 weeks and when substantial depletion of body fat and protein has occurred. Peripheral parenteral nutrition is preferred when solution concentration is less than 1000 mOsm/L and duration of therapy is less than 10 days.

RATIONAL OF PARENTERAL NUTRITION 1. The patient is well nourished before admission but after 7 days of hospitalisation enteral nutrition has not been feasible or target goal calories have not been met consistently by enteral alone. 2. On admission, the patient is malnourished and enteral nutrition is not feasible. A major surgical procedure is planned, the pre-operative assessment indicates that enteral nutrition is not feasible through the peri-operative period and the patient is malnourished. 3. Indications: The basic indications for the use of parenteral nutrition are required for nutrition when the GI tract is either not working or not available or not appropriate (Table 3). Table 3: Indications for Parenteral Nutrition Non functioning gut, e.g. paralytic ileus Malnourished patients after major abdominal surgery

Enteral and Parenteral Nutrition in Critically Ill Patients

increased possibility of aspiration, regurgitation and GI sideeffect. A rate of 30 mL/min or a volume of 500 to 750 mL per feed appears to mark physical tolerance limit.

Severe mucositis systemic chemotherapy, upper gastrointestinal strictures or fistulae and acute pancreatitis Patients with major resections of the small intestine (short bowel syndrome) before compensatory adaptation occurs Patients in the intensive care unit with systemic inflammatory response syndrome or multiple organ dysfunction syndromes.

PARENTERAL MACRONUTRIENTS Proteins/Amino Acids The primary function of protein in parenteral nutrition is to maintain nitrogen balance, thus, preventing skeletal muscle from being degraded from gluconeogenesis. Protein requirement can be very high during intensely catabolic state. A positive nitrogen balance may not be feasible during the first few days of the catabolic stress. A positive caloric balance is necessary to establish a positive nitrogen balance. For delivered amino acids to be incorporated into new protein rather than catabolise the ratio of non-protein calories to gram of nitrogen should approach 150:1. This ratio is based on the fact that 10% to 15% or more of required calories during catabolism are derived from protein breakdown. Commercial amino acids are available. Dilute solutions are most often used for peripheral administration. Amino acid profiles of parenteral solutions are based on Food and Agriculture Organisation – World Health Organisation (FAO-WHO) recommendations for optimal proportion of essential amino acids. Carbohydrates Primary function of parenteral carbohydrate is to serve as energy source. Optimum carbohydrate is an amount adequate to spare protein without exacerbating hyperglycaemia. Commercial carbohydrates consist of N-hydrate, dextrose monohydrate in sterile water. Fats Parenteral lipids provide as a source of essential fatty acids and calories. These can be substituted for dextrose calories for patients with glucose intolerance or used as concentrated caloric source for patients who require volume restriction. Fats

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have lower respiratory quotient than carbohydrates, which is a rational for use of lipids to provide large proportion of nonprotein calories in patients with respiratory failure. Because fat emulsions are isotonic, these can be administered through peripheral vein. Alternatively these may be directly added to parenteral nutritional solution. Electrolytes Electrolytes requirement for patients receiving total parenteral nutrition may vary depending on body weight, presence of malnutrition or catabolism, the degree of electrolyte depletion, change in organ function, ongoing electrolyte losses and disease process. Vitamins Vitamin requirements during parenteral nutrition therapy are uncertain because these are not based on balanced studies. Recommendations for parenteral nutritional therapy have been made by American Medical Association—Nutrition Advisory Group. Water Water requirements vary depending on the capacity of patient to excrete an osmotic load. Usually requirements are 30 ml/kg in normal adult or approximately 1 ml/kcal delivered. An additional 360 ml per day is recommended for each centigrade of temperature elevation. Also 300 to 400 ml of water per day may be necessary for new intra-celluloid fluid, if anabolism is being induced. Restriction of water is necessary during volume overload and presence of hyponatraemia. Patients who become hyperosmotic may need additional free water on daily basis. Trace Elements Trace elements are those nutrients that make-up less than 4 g or 0.01% of total body content. Individual trace elements may be supplemented in appropriate dose as specific patients deficiency dictates. Osmolality and Osmolarity While osmolality is most often used in reference to enteral feeding, osmolarity is preferred term for parenteral solutions.

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Body maintains serum osmolality between 280-300 mOsm/kL. To avoid the irritation to veins, solutions with osmolarity greater than 900 mOsm/L are not usually administered peripherally. Initiation of Parenteral Nutrition Prior to initiation of parenteral nutrition, a baseline biochemistry profile should be checked and fluid and electrolyte abnormalities should be corrected. Monitoring During the first week of parenteral nutrition (and subsequently if patient is unstable with respect to fluid and electrolyte or metabolic issues) the patient should be monitored intensively. Reintroduction of Diet Diet should be reintroduced in a graded fashion. COMPLICATIONS The complications of parenteral therapy can be divided into three categories: (i) technical—pneumothorax, malposition, subclavian artery puncture, air embolism etc; (ii) septic— catheter related sepsis, septic thrombosis; and (iii) metabolic – hyperglycaemia, hypoglycaemia, hyperkalaemia, hypophosphataemia, etc. With proper patient monitoring, most of these complications can be minimised. RECOMMENDED READINGS 1.

Barr J, Hecht M, Flavin KE et al. Outcomes in critically ill patients before and after the implementation of an evidence-based nutritional management protocol. Chest 2004; 125: 1446-57.

2.

Calo L, Bianconi L, Colivicchi F, et al. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: A randomised, controlled trial. J Am Coll Cardiol 2005; 45: 1723-8.

3.

Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition. Crit Care Med 2009; 37: 1-30.

4.

Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med 2006; 34: 2325-33.

5.

Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006; 34: 1033-8.

7.6

Acute Respiratory Failure Ashit M Bhagwati

INTRODUCTION

Table 1: Aetiology of Type 1 Respiratory Failure

Respiratory system is responsible for gas exchange in the human body. Inability to maintain a normal state of gas exchange leads to respiratory failure. Disorders involving the respiratory centre in the brain, peripheral nerves, respiratory muscles, airways, pleura, lung parenchyma and the chest wall can lead to compromise of gas exchange; thereby leading to a clinical scenario of acute respiratory failure (ARF). ARF is one of the most common life-threatening disorders encountered in the intensive care unit (ICU) and is associated with poor prognosis.

Respiratory System Airway disease: Asthma, COPD Parenchymal: Airspace: Pneumonia (bacterial, viral, mycoplasmal, fungal), atelectasis, bronchiectasis, and tumours Vascular: Pulmonary embolism, fat embolism, pulmonary arterial hypertension Pleura: Pneumothorax Chest Wall: Flail chest

DEFINITION Clinically, respiratory failure occurs when hypoxaemia (PaO2 is less than 60 mmHg), i.e. inadequate oxygenation of the blood or hypercarbia (arterial PCO2 is >50 mmHg), i.e. excess content of circulating carbon dioxide; or frequently, a combination of both types of gas exchange abnormalities occur. CLASSIFICATION ARF is classified as hypoxaemic respiratory failure (type 1), hypercapnic respiratory failure (type 2), post-operative/peri-operative respiratory failure (type 3) and shock-related respiratory failure (type 4). Respiratory failure is also classified as per its onset; acute or chronic respiratory failure. ARF refers to disorders of recent onset (hours to days). It suggests that respiratory failure has developed too rapidly for physiologic compensation to occur; therefore, pH is less than 7.3. Chronic respiratory failure develops overmonths to years, allowing compensatory mechanisms to improve oxygen transport and to buffer respiratory acidaemia; therefore the pH is slightly decreased. Sometimes, ARF may be superimposed on chronic respiratory failure. HYPOXAEMIC (TYPE 1) RESPIRATORY FAILURE Hypoxaemic respiratory failure (type 1) is defined as a condition in which the respiratory system exhibits a failure in its gas exchange function of oxygenation, PaO2/FiO2 35 breaths/min and with active use of accessory muscles of respiration. It is also associated with a normal or low PaCO2. The underlying physiologic aberration results from a disease process that involves the lung itself such as a ventilation-perfusion (V/Q) mismatch, shunting or diffusion impairment. The classic example of acute hypoxaemic respiratory failure is acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Aetiology Type 1 ARF is usually seen in diseases of the lung parenchyma, cardiovascular system and lower airways. The causes are due to low inspired concentration of oxygen (alveolar hypoventilation), impairment of diffusion, VA/Q mismatch, intrapulmonary shunting and low mixed venous oxygen content (Table 1).

Cardiovascular System Pulmonary oedema (cardiac failure), cyanotic congenital heart disease Miscellaneous: Obesity

Physiology The process of gas exchange has two components: the flow of gas between the atmosphere and the terminal airways; and the diffusion of gases between the terminal lung regions and the pulmonary capillary blood. The efficiency of gas exchange can be evaluated clinically by measuring the PAO2, PaCO2 and the alveolar-arterial (A-a) PO 2 gradient. Thus, patients with hypoxaemia may be divided into those with a normal gradient and those with an increased gradient (Table 2). The alveolar PO2 can be calculated from the alveolar air equation: PAO2 = (PB – PH2O) FiO2 – (PaCO2 /R) here, PAO2 is alveolar PO2; FiO2 is fraction of inspired oxygen; PB is barometric pressure (760 mmHg at sea level), PH2O is water vapour pressure (47 mmHg at sea level), and R is respiratory exchange ratio (assumed to be 0.8). Ventilation-perfusion mismatch and intrapulmonary shunting are the clinically important causes of hypoxaemia in ARF. Ventilation-Perfusion Mismatch In the presence of disease, the V/Q units vary. The low V/Q units contribute to hypoxaemia and hypercapnia as compared to high units where wastage of ventilation may occur without affecting the blood gases unless quite severe. If the patient is given 100% oxygen to breathe, there is a dramatic increase in the PaO2 as it eliminates low V/Q units, thereby correcting the hypoxaemia. Intrapulmonary Shunts Normally in health some degree of intrapulmonary shunting does occur, i.e. referred to as anatomical shunt accounting for 2% of the shunt. In addition, cyanotic congenital heart diseases or A-V malformations in the lungs cause right-to-left shunt. When the deoxygenated blood bypasses the ventilated alveoli and mixes with the oxygenated blood that has perfused the ventilated alveoli, reduction in the arterial content of oxygen occurs, i.e. hypoxaemia (PaO2 level decreases). Such situation

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occurs in conditions such as pneumonia, atelectasis and severe pulmonary oedema of either cardiac or non-cardiac origin. Hypercapnia occurs when the shunt exceeds > 60%. In low V/Q mismatch and intrapulmonary shunting, the decreased PaO2 is always associated with an elevated P (A-a) oxygen gradient. In patients with low V/Q mismatch, the PaO2 has a dramatic rise in response to 100% oxygen, whereas in patients with intrapulmonary shunting, it shows a much smaller response. Differentiating between these causes of hypoxaemia is important clinically (Table 2). Table 2: Physiological Conditions Causing Type 1 Respiratory Failure

Criteria for Diagnosis of Acute Respiratory Distress Syndrome (ARDS) 1. Predisposing factors for ARDS, viz. sepsis, burns, pancreatitis, aspiration, malaria, leptospira, etc. 2. Tachypnoea, breathlessness, tachycardia, crackles on auscultation. 3. Progressive infiltrates in both the lung fields.

Pathophysiology of Hypoxaemia

P (A-a) O2 Gradient

PaCO2

4. Normal pulmonary capillary wedge pressure.

Low partial pressure of inspired oxygen Low ventilation-perfusion mismatch Right-to-left shunt Diffusion impairment

Normal

Normal or decreased

5. Refractory hypoxaemia with PAO2/FiO2 ≤200.

Increased

Normal or decreased

Increased Increased

Normal or decreased Normal or decreased

6. Decreased lung compliance ≤40 mL/cm water.

ARDS is the classic example of severe hypoxaemic respiratory failure. The European American Consensus Conference on ARDS defined ALI and ARDS. ALI is a syndrome of inflammation and increased permeability that is associated with a constellation of clinical, radiologic and physiologic abnormalities that cannot be explained by, but may co-exist with, left atrial or pulmonary capillary hypertension. The clinical criteria for ALI include: (i) acute onset of pulmonary failure, (ii) hypoxia with a PaO2/FiO2 ratio ≤300 mmHg, (iii) bilateral chest infiltrates visible on chest radiograph, and (iv) a pulmonary artery occlusion pressure ≤18 mmHg or no clinical evidence of increased left atrial pressure on the basis of chest radiograph and other clinical data. On the other hand, ARDS is defined as a more severe form of ALI with a PaO2/FiO2 ≤200, regardless of the level of positive end-expiratory pressure (PEEP) used on the ventilator. Clinical Manifestations Manifestations of hypoxaemic respiratory failure are due to a combination of features of arterial hypoxaemia and tissue hypoxia. Arterial hypoxaemia causes hyperventilation due to stimulation of carotid body chemoreceptors, leading to dyspnoea, tachypnoea and hyperpnoea. There may be cyanosis; degree of cyanosis depends on the concentration of the haemoglobin and the patient’s perfusion. Other features include generation of lactic acid due to anaerobic metabolism. Increased blood lactate levels may further stimulate ventilation. Mild hypoxia may also lead to impaired mental performance. With the progression of hypoxia alteration in the sensorium, somnolence, coma, seizures can occur leading to permanent brain damage.

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Chest radiograph may be normal initially but later on (in established cases) may show bilateral infiltration (interstitial, airspace or both). Arterial blood gas analysis is central to diagnosis and reveals hypoxaemia with normal, but usually a low PCO2.

Patient develops tachycardia, diaphoresis, and systemic vasoconstriction leading to hypertension. Severe hypoxia can lead to bradycardia, vasodilation, hypotension, myocardial ischaemia, infarction, arrhythmias and cardiac failure. The manifestations of hypoxia are further amplified in the presence of tissue hypoxia. Symptoms and signs also reflect not just acute hypoxaemia, but also the underlying cause of respiratory failure.

HYPERCAPNIC (TYPE 2) RESPIRATORY FAILURE Aetiology Type 2 respiratory failure can result from abnormalities in any one component of the respiratory system including the brain, spinal cord, neuromuscular system, thorax, pleura and upper airways. Diseases of the lower airways (alveoli) or circulatory system are rare causes of type 2 respiratory failure (Table 3). Table 3: Aetiology of Type 2 Respiratory Failure Brain Drugs: narcotics, barbiturates, sedatives, poisons, general anaesthetics Metabolic: hyponatraemia, hypocalcaemia, hypercapnia, severe alkalosis, myxoedema Infections: meningitis, encephalitis, bulbar polio, cerebral abscess Neoplasms Trauma Central alveolar hypoventilation, obstructive sleep apnoea Occult status epilepticus Spinal Cord Traumatic transection, compressive tumours, poliomyelitis Neuromuscular Drugs: neuromuscular blockers, aminoglycosides Metabolic: hypokalaemia, hypophosphataemia, hypomagnesemia Infections: tetanus, Guillain-Barré syndrome, sepsis Trauma Neoplasm Myasthenia gravis Others: critical illness neuropathy, muscular dystrophies, respiratory muscle fatigue Upper Airways Upper airway mass: adenoid hyperplasia, goiter, polyps, malignant tumours Infections: epiglottitis, laryngotracheitis Trauma Others: bilateral vocal cord palsy, tracheomalacia, laryngeal oedema Chest Wall Trauma: Flail chest Others: kyphoscoliosis, scleroderma and massive pneumothorax or pleural effusion

Reduction in minute ventilation can be affected by processes affecting the central nervous system, peripheral nervous system, neuromuscular junction, respiratory muscles, chest wall abnormalities, metabolic and electrolyte abnormalities, and upper airway obstruction. In these disorders alveolar-arterial oxygen pressure difference (A-aDO2) is usually normal unless lung disease is present. Excessive CO2 production is usually due to fever, burns, sepsis, high carbohydrate diet, burns and hyperthyroidism. Agitation, myoclonus, or other causes of muscle activity can increase VCO2 and contribute to type 2 respiratory failure. Increase in the respiratory quotient, which is normally 0.8-2.0 doubles VCO2. Reduced CO2 elimination also occurs due to decreased alveolar ventilation. Alveolar hypoventilation may result from VA/Q mismatch (high VA/Q, increased physiological dead-space and wasted ventilation) as in pulmonary embolic diseases, intrinsic lung diseases (e.g. emphysema, asthma, cystic fibrosis or pulmonary fibrosis) and in chest wall disorders (e.g., scoliosis). Hypoventilation is characterised by hypercapnia and hypoxaemia. As minute ventilation reduces to less than 4 L/min, the PaCO2 rises dramatically. Usually these patients have normal A-aDO2 gradients. Patients at risk of hypercapnic respiratory failure may also be divided into two major categories: those with normal lungs (e.g., sedative overdose, neuromuscular disorders or chest wall abnormalities) and those with intrinsic lung disease (e.g., emphysema, chronic bronchitis or asthma) where maldistribution of ventilation and perfusion results in an increase in dead space. The final result is inadequate CO 2 clearance despite normal or increased minute ventilation. Clinical Manifestations Patients with acute hypercapnic respiratory failure largely present with central nervous system (CNS) disturbances. Hypercapnia is a CNS depressant leading to lethargy, somnolence, coma, asterixis, restlessness, tremors, slurred speech, headache and papilloedema. Symptoms of hypercapnia may overlap those of hypoxaemia. Basically, hypercapnic patients may have either decreased or increased minute ventilation depending on the primary disorder. As a result these patients have dyspnoea, tachypnoea, hyperpnoea with tachycardia and uncompensated respiratory acidosis. Diagnosis History is most important in diagnosis of ARF. It should aim at eliciting relevant information about possible predisposing factors, co-morbid conditions and identifying processes that affect prognosis. The clinical signs and symptoms of ARF reflect the underlying disease process and the associated hypoxaemia and hypercapnia. Diagnosis of respiratory failure requires

arterial blood gas study, not only to determine the presence and severity of respiratory failure but also to differentiate between type 1 and type 2 respiratory failure. POST-OPERATIVE/PERI-OPERATIVE (TYPE 3) RESPIRATORY FAILURE Post-operative/peri-operative respiratory failure can be defined as the need for intubation and mechanical ventilation (MV) within the 48 hours after surgery. In the post-operative/perioperative period, surgical patients following general anaesthesia often develop reduction in functional residual capacity leading to atelectasis in the dependent lung units. This leads to respiratory failure referred to as post-operative/perioperative respiratory failure (Table 4). To avoid this situation, a proper pre-operative assessment is mandatory to identify the patients who are at increased risk after non-thoracic and thoracic surgery. These subgroup of patients are best managed with frequent change of posture, chest physiotherapy, adequate analgesia for post-operative pain relief. Non-invasive ventilation (NIV) also may be used to tide over the crises. However, evidence-based studies on the usefulness of respiratory physiotherapy, incentive spirometry and NIV to prevent respiratory complications are lacking.

Acute Respiratory Failure

Physiology The hallmark of acute hypercapnic respiratory failure is an elevated PaCO2. Three processes, alone or in combination, can produce acute hypercapnic respiratory failure: a reduction in minute ventilation, an increase in CO2 production and alveolar hypoventilation.

Table 4: Aetiology of Type 3 Respiratory Failure Intra-pulmonary Causes Atelectasis, aspiration, pneumonia Acute lung injury/acute respiratory distress syndrome Volume overload/congestive heart failure Pulmonary embolism Asthma/Chronic obstructive pulmonary disease Pneumothorax Extra-pulmonary Causes Upper airway obstruction Obstructive sleep apnoea syndrome Diaphragmatic dysfunction/phrenic nerve injury

SHOCK-RELATED (TYPE 4) RESPIRATORY FAILURE Respiratory muscles consume less than 5% of the total cardiac output and oxygen delivery. Shock leads to increase in deadspace ventilation and pulmonary inflammation. The increase in dead-space ventilation is an early accompaniment of shock. It leads to hypoperfusion of the respiratory muscles, leading to respiratory muscle fatigue, causing a combined metabolic (lactic acidosis) and respiratory acidosis. Under this situation, more than 40% of the cardiac output is distributed to the respiratory muscles. Intubation and MV help redistribution of the cardiac output to the vital organs while shock is being treated. MANAGEMENT The general principles of support are similar regardless of the type of respiratory failure. The priorities in the management of ARF vary according to the aetiology. However, the primary aim in all the cases are the same: (i) to maintain a patent airway and ensure adequate ventilation and oxygenation; and (ii) to treat, if possible, the primary condition. This includes removal of excessive secretions to maintain clear airway, use of aerosolised bronchodilators, antibiotics, viz. aminoglycoside (tobramycin),

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colistin according to sensitivity pattern and effective systemic antimicrobials for the treatment of infections. Hypoxaemic Respiratory Failure (Type 1) Patients with acute hypoxaemic respiratory failure are best managed in the ICU. The management of these patients involves both supportive and specific strategies that are generally performed simultaneously. Supportive therapy is aimed at stabilising the clinical condition of the patient by improving gas exchange and includes airway management and correction of hypoxaemia. Hypoxaemia is corrected by oxygen administration and use of ventilatory support (non-invasive and invasive mechanical ventilatory support). Measures are also directed towards specific therapy for identifying and reversing the underlying pathophysiologic mechanisms. Specific therapy varies depending on the underlying disease (e.g. use of antibiotics to treat patients with pneumonia and diuretics for pulmonary oedema). Oxygen therapy Oxygen supplementation is the most important therapy for hypoxaemic respiratory failure. After the airway is secured, attention is directed to the management of hypoxaemia. The treatment goal is to provide adequate oxygen delivery to the tissues (SaO2 >90% and PaO 2 ≥60 mmHg). Oxygen can be delivered by different means (nasal cannula for flow rates ≤ 5 L/min, face mask for flow rates ≥6 L/min or use of air entrainment devices, (i.e. venturi masks for higher flow rates). If the patient’s condition does not improve with high-flow oxygen: MV, either invasive or non-invasive, should be considered. Non-invasive ventilation In last few years, substantial data has emerged on the use of NIV in patients with acute hypoxaemic respiratory failure to avoid endotracheal intubation and ventilator-associated pneumonia, thereby reducing mortality. However, despite emerging studies regarding NIV as an adjunct in the management of hypoxaemic respiratory failure, its safety and efficiency remains unanswered. This is mainly due to varied aetiologies in subgroups of patients causing respiratory failure. Recently, a few studies have focused on some of the individual diagnoses within the large category. It has been found to be very effective in cardiogenic pulmonary oedema. NIV may also be useful when some components or degree of cardiac decompensation participates in the clinical feature, even if it is not the main or only cause of episode of respiratory failure.

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It should be noted that patients with hypoxaemic respiratory failure should preferably be ventilated with a full face mask during acute phase and may be shifted to nasal mask, once the condition stabilises. Mechanical ventilation The two major goals of therapy are to maintain alveolar ventilation and correct hypoxaemia. In cases where NIV fails to correct hypoxaemia, invasive MV is used. Patients with severe ARF and a large intrapulmonary shunting may require high FiO2 while on the ventilator. MV increases alveolar ventilation, eliminates CO2 and corrects acidaemia. Due to the danger of oxygen toxicity, patients should be treated with the lowest concentration of oxygen that provides adequate oxygenation.

Hypercapnic Respiratory Failure (Type 2) Oxygen therapy Hypoxaemia secondary to hypoventilation can be easily treated with by supplemental oxygen (increasing FiO2). Failure of PaO2 to improve should alert to the possibility of an unsuspected concomitant lung disease producing a shunt effect (e.g. pneumonia, atelectasis). In many patients with chronic ventilatory failure, especially chronic obstructive pulmonary disease (COPD), oxygen therapy can cause acute worsening of hypercapnia. Three mechanisms have been proposed to explain this phenomenon. These patients may have a ‘blunted’ CO2 drive to breathe and the hypoxaemic drive is suppressed by supplemental oxygen. Oxygen may increase V/Q inequality by inhibition of hypoxic pulmonary vasoconstriction or by changing bronchomotor tone. Finally, haemoglobin affinity for CO2 decreases with increasing oxygen saturation (Haldane effect), which may further contribute to hypercapnia. Therefore, supplemental oxygen therapy for ventilatory failure aims at maintenance of PaO2 in a ‘safe’ range that does not compromise systemic oxygen delivery but minimises the possibility of worsening hypercapnia (SaO2 of 90% to 92%). Air entrainment oxygen masks (venturi masks) can be used to deliver precise doses of oxygen. If venturi masks are unavailable or are not feasible, a nasal cannula at flow rates of 0.5-2.0 L/min may be used to treat hypoxaemia (low-flow oxygen therapy). However, despite therapy, progressive hypercapnia and acidosis may develop in some patients and lead to confusion, stupor or coma, even when the FiO2 is increased only moderately. Such patients may require tracheal intubation and MV. Therapy in patients with asthma or COPD consists of oxygenation, hydration and aggressive treatment of the underlying aggravating factor with bronchodilators (theophyllin, anticholinergics and beta-agonists) and corticosteroids. Infection needs to be treated with appropriate antibiotics and any electrolyte abnormality must be corrected. In patients who progress to respiratory muscle fatigue, elective intubation and MV may be necessary to prevent respiratory arrest. Non-invasive ventilation (NIV) NIV is most commonly applied in acute hypercapnic respiratory failure commonly associated with COPD, where the ventilatory response to raised PaCO2 is decreased. Administration of NIV in patients with COPD with respiratory failure helps to increase the neural output to the diaphragm and other respiratory muscles, and thus, resets the respiratory control centre making it more responsive to an increased PaCO2. These patients are then able to maintain a normal PaCO2 throughout the daylight hours without the need for MV. The use of NIV in patients with acute exacerbations of COPD is considered the ventilatory mode of choice. It helps by reducing the rate of endotracheal intubation. It also improves the vital signs, gas exchange, thereby reducing dyspnoea. There is also reduction in the in-hospital mortality, with reduction in the complications like nosocomial pneumonia. NIV may also be used in patients with acute exacerbations of bronchial asthma. Uncontrolled studies have reported improvements in gas exchange and low rates of intubation after

Although the use of NIV in asthma is inconclusive, a trial of NIV in selected patients is justified, particularly in patients who fail to respond promptly to medical treatment and have no contraindications. It has also been suggested that aerosolised medicines may be delivered more effectively by NIV. However, NIV is not recommended for routine use in patient with asthma exacerbation. Mechanical ventilation Some patients with ventilatory failure may respond to early and aggressive management of the primary disorder. Others, with progressive pathology or whose loads are not rapidly reduced may require MV. Although no PaCO2 absolutely mandates MV, if the pH is < 7.20 and if rapid reversal with therapy is not expected, or failure of NIV occurs or NIV is contraindicated, then prompt MV is initiated. Delayed MV in these patients increases the risk of circulatory collapse and other complications. A common error in MV of a patient with acute on chronic respiratory failure is to reduce the PaCO2 to normal (40 mmHg),

which leads to a compensatory reduction in bicarbonate. On resumption of spontaneous breathing, patients who are chronically hypercapnic will retain CO2 rapidly (to their previous pre-morbid level). As the kidneys require more time (24 to 48 hours) to compensate, an acute respiratory acidosis may ensue and impede liberation from MV. Accordingly, the ventilatory goal in patients with acute on chronic respiratory failure is not a normal PaCO2 but rather a PaCO2 approximating their baseline value when they are not acutely decompensated, at which the pH is normal range.

Acute Respiratory Failure

the initiation of NIV in patients with severe asthma. In another randomised trial, no benefit of NIV in asthma was demonstrated.

RECOMMENDED READINGS 1.

Burns KE, Sinuff T, Adhikari NK, et al. Bilevel non-invasive positive pressure ventilation for acute respiratory failure: survey of Ontario practice. Crit Care Medicine 2005; 33: 1477-83.

2.

Ferreyra G, Ranieri MV. Non-invasive ventilation in hypoxaemic respiratory insufficiency controversies in intensive care medicine. ESICM Year book 2008; pp 3-7.

3.

Hemmila MR, Napolitano LM. Severe respiratory failure: advance treatment options. Crit Care Med 2006; 34 (9 Suppl): S278-90.

4.

Lichtenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure. Chest 2008;134:117-25.

5.

Martin Tobin. Principles and Practice of Mechanical Ventilation; 2nd Ed. New York: McGraw-Hill Professional Publishers;2006: pp 129-54.

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7.7 SEPSIS Sepsis (derived from the Greek word sepo meaning “decay or putrefaction”), severe sepsis (acute organ dysfunction secondary to infection) and septic shock (derived from the French word choquer meaning ‘to collide with’), are major health care problems world over. The incidence of sepsis and related syndromes is increasing and the conditions affect millions of individuals around each year. DEFINITION OF SEPSIS AND RELATED SYNDROMES Though the existence of sepsis and related disorders were known since time immemorial, formal definitions for the same were laid by the American College of Chest Physicians (ACCP) and Society of Critical Care Medicine (SCCM) Consensus Conference in 1991. With advances in the understanding of the pathophysiological aspects of septic shock and the dissatisfaction in several quarters regarding these definitions, a Consensus Sepsis Definitions Conference was convened in 2001 under the auspices of ACCP, SCCM, the European Society of Intensive Care Medicine, and the Surgical Infection Societies to re-visit the definitions of sepsis and related conditions. The key change was regarding the definition of systemic inflammatory response syndrome (SIRS) [manifested by (but not limited to) 2 or more of the following conditions: temperature > 38 °C or, < 36 °C; heart rate > 90 beats/min; respiratory rate > 20/min or (PaCO2) < 32 mmHg; white blood cell count >12.0 × 109/L, < 4:0 × 109/L, or > 10% immature (band) forms] which was expanded to include longer list of possible signs of sepsis (Table 1). As per the new guidelines, sepsis is defined as infection plus systemic manifestations of infection (Table 1). Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion (Table 1). Septic shock is defined as sepsisinduced hypotension persisting despite adequate fluid resuscitation. Staging System for Sepsis Since the definitions of sepsis and related syndromes does not allow for precise characterisation and staging of patients with this condition, staging systems have been proposed to stratify these patients by both their baseline risk of an adverse outcome and their potential to respond to therapy. In line with the tumour, node, metastasis in vogue for cancer, a classification scheme for sepsis that will stratify patients basing on their predisposing conditions, the nature and extent of the infection, the nature and magnitude of the host response, and the degree of concomitant organ dysfunction, termed PIRO staging system has been described (Table 2). Several attempts are underway to apply the PIRO system clinically with promising results.

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Aetiology Gram-negative bacterial infection is the most common cause of sepsis and related syndromes. However, septic shock can be

Sepsis and Acute Respiratory Distress Syndrome Alladi Mohan, Surendra K Sharma caused by Gram-positive bacteria and fungi also. Polymicrobial aetiology of sepsis has also been described. In India, septic shock can occur due to falciparum malaria, enteric fever, dengue fever and other infections. Pathogenesis The pathophysiological hallmark of sepsis and related syndromes is the mismatch of the host response to the intensity of the pathogenic stimuli, ultimately leading to organ injury or Table 1: Diagnostic Criteria for Sepsis in Patients with Documented or Suspected Infection General variables Fever (core temperature >38.3°C) Hypothermia (core temperature 90/min or >2 SD above the normal value for age Tachypnoea Altered mental status Significant oedema or positive fluid balance (>20 mL/kg over 24 hours) Hyperglycaemia (plasma glucose >120 mg/dL) in the absence of diabetes Inflammatory variables Leukocytosis (WBC count >12,000 /mL) Leukopaenia (WBC count 10% immature forms Plasma C-reactive protein >2 SD above the normal value Plasma procalcitonin >2 SD above the normal value Haemodynamic variables Arterial hypotension (SBP 3.5 L/min/m2 Organ dysfunction variables Arterial hypoxaemia (PaO2/FiO2 1.5 or aPTT >60 sec) Ileus (absent bowel sounds) Thrombocytopaenia (platelet count 4 mg/dL) Tissue perfusion variables Hyperlactatemia (>1 mmol/L) Decreased capillary refill or mottling SD = Standard deviation; WBC = White blood cell; SvO2 = Central venous oxygen saturation; INR = International normalisation ratio; MAP = Mean arterial pressure; SBP = Systolic blood pressure; PaO2 = Partial pressure of arterial oxygen; FiO2 = Fraction of inspired oxygen; aPTT = Activated partial thromboplastin time Adapted from: Crit Care Med 2003; 31: 1250-6.

Variable

Clinical Parameters

Laboratory Parameters

Predisposing conditions

Age, co-morbid conditions (e.g. alcoholism, diabetes, cirrhosis of liver), gender, corticosteroid use, immunosuppressive state, religious and cultural beliefs Site of infection (e.g. pneumonia, peritonitis, catheter), Type of infection (hospital acquired versus community acquired) SIRS, other signs of sepsis, shock, CRP

Genetic polymorphisms in components of inflammatory response (e.g. TLR, TNF, IL-1, CD14)

Infection

Response Organ dysfunction

Blood pressure, urine output, Glasgow coma scale, organ dysfunction as number of failing organs or composite score (e.g. MODS, SOFA, LODS)

Virulence of the infecting organism, antimicrobial sensitivity, assay of microbial products (e.g. LPS, bacterial DNA), gene transcript profiles White blood cell count, prothrombin time, APTT, blood lactate levels, biomarkers (e.g. CRP, PCT) PaO2/FiO2, serum creatinine, serum bilirubin, platelet count

TLR = Toll-like receptor; TNF = Tumour necrosis factor; IL-1 = Interleukin-1; LPS = Lipopolysaccharide; DNA = Deoxyribonucleic acid; SIRS = Systemic inflammatory response syndrome; APTT = Augmented partial thormboplastin time; CRP = C-reactive protein; PCT = Procalcitonin; PaO2 = Partial pressure of arterial oxygen; FiO2 = Fraction of inspired oxygen; MODS = Multiple organ dysfunction syndrome; SOFA = Sepsis-related organ failure assessment; LODS = Logistic organ dysfunction system. Adapted from: Crit Care Med 2003; 31: 1250-6.

Sepsis and Acute Respiratory Distress Syndrome

Table 2: Some Clinical and Laboratory Variables Being Evaluated for the PIRO Staging System for Sepsis in Adults

dysfunction with or without hypotension. This results in a predominantly proinflammatory (SIRS), mixed [mixed antagonistic response syndrome (MARS)], or predominantly anti-inflammatory compensatory anti-inflammatory syndrome. The current concepts underlying the molecular pathogenesis of sepsis are shown in Figure 1. The major complications of septic shock are listed in Table 3. Table 3: Major Complications of Sepsis Cardiopulmonary Acute lung injury, acute respiratory distress syndrome Depression of myocardial function Renal Acute kidney injury Drug-induced renal damage Disseminated intravascular coagulation Neurological Critical illness polyneuropathy Multiorgan dysfunction syndrome

Clinical Manifestations The clinical manifestations of sepsis result as a consequence of the complex interplay among the immune, coagulation, and neuroendocrine systems in response to severe infection. These manifestations overlap the signs and symptoms due to the underlying medical conditions and primary site of infection. Septic shock should be suspected whenever, a patient with fever or hypothermia, tachycardia and tachypnoea and evidence of decreased organ perfusion develops hypotension. It is not strictly necessary that tachycardia, tachypnoea or fever be present to make the diagnosis. Generally, there is predisposition to infections such as a patient on cytotoxic or immuno-suppressive drugs, chronic debilitating disease such as diabetes mellitus, cirrhosis of liver, etc. Haemtogenous seeding of the skin or underlying soft tissue can manifest as cellulitis, pustules, bullae, or haemorrhagic lesions. Other features that help in pointing towards a diagnosis of septic shock include evidence of impaired organ perfusion, altered mental status, jaundice, gastrointestinal bleed due to stress ulceration, disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). Acrocyanosis and ischaemic necrosis of

Figure 1: Overview of the molecular pathogenesis of sepsis.

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peripheral tissues, usually digits, may be evident due to hypotension and DIC. Principles of Management The basic principles of initial resuscitation (fluid therapy, vasopressors, inotropic support, infection issues (source identification and control, appropriate antibiotic therapy), blood product administration and haemodynamic support described in the updated Surviving Sepsis Campaign guidelines for the management of severe sepsis and septic shock 2008 must be followed meticulously (Figure 2). Broad-spectrum, site-specific appropriate intravenous antibiotics (monotherapy or combination therapy as appropriate) should be started as early as possible, and always within the first hour of recognising severe sepsis and septic shock. The antimicrobial regimen must be assessed daily to optimise efficacy, prevent resistance, avoid toxicity and minimise costs. The antibiotic therapy must be administered for 7 to 10 days. The duration may be longer if the response is slow, the foci of infection are undrainable, or if immunodeficiency is present. Low doses of corticosteroids and recombinant human activated protein C may be considered as useful adjunctive therapies in selected sub-groups of patients. The optimal timing for initiating these modalities of treatments appears to be 6 to 24 hours from onset of shock. Patients receiving these treatments should systematically be monitored for superinfection and serious bleeding complications. Principles of mechanical ventilation (MV) are described under ARDS. Factors indicating poor prognosis in septic shock are shown in Table 4. Table 4: Factors Indicating Poor Prognosis in Septic Shock Pre-existing factors Old age Nature of co-existing illness (e.g. leukaemia) Number of failed organs Cardiovascular Lack of ventricular dilatation Persistence of tachycardia and raised cardiac output Others Delay in institution of treatment Acute respiratory distress syndrome Disseminated intravascular coagulation Hypothermia Leucopaenia Hyperglycaemia Metabolic acidosis Renal failure Polymicrobial infection

ACUTE RESPIRATORY DISTRESS SYNDROME ARDS is defined as an acute lung injury (ALI) resulting in extensive bilateral pulmonary infiltrates, severe refractory arterial hypoxaemia and stiff lungs. It is a common cause of ICU admission world over.

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Aetiology Bacterial sepsis is the single most important cause of ARDS in hospitalised patients. Other common causes of ARDS are listed in Table 5.

Figure 2: Initial resuscitation with goal-directed therapy in severe sepsis and septic shock. CVP = Central venous pressure; MAP = Mean arterial pressure; SvO2 = Central venous oxygen saturation; SBP = Systolic blood pressure; CI = Cardiac index.

Definition The American-European Consensus Conference definitions of ALI and ARDS are simple to apply in the clinical setting and also recognise that the severity of clinical lung injury varies according to the severity of arterial hypoxaemia. Recently, pulse oximetric saturation (SpO2) to fraction of inspired oxygen (FiO 2) ratio (S/F ratio) has been found to correspond to the arterial oxygen tension (PaO2) to FiO2 ratio (P/F) (Table 6). These non-invasive substitutes for assessing oxygenation can

Common Causes Infections Gram-negative and Gram-positive bacterial sepsis Pneumonia (bacterial, viral, mycoplasma, pneumocystis) Pancreatitis Burns Gastric aspiration Bilateral lung contusion Cardiopulmonary bypass Uncommon Causes Multiple blood transfusions Inhalational injuries (ammonia, chlorine, nitrogen dioxide, phosgene, smoke, sulphur dioxide) Fat embolism Raised intracranial pressure Infections (pulmonary and miliary tuberculosis, falciparum malaria, enteric fever, leptospirosis) Drugs (e.g. thiazides, methadone, barbiturates, narcotics, lidocaine, cytosine arabinoside, phenytoin, salicylates) Heat stroke High altitude pulmonary oedema

Table 6: Definitions of Acute Lung Injury and Acute Respiratory Distress Syndrome Acute lung injury Acute onset PaO2/FiO2 ≤300* SpO2/FiO2 ≤315*† Bilateral infiltrates on the frontal chest radiograph PCWP ≤18 mmHg, or no clinical evidence of left atrial hypertension

Acute respiratory distress syndrome Acute onset PaO2/FiO2 ≤200* SpO2/FiO2 ≤235‡ Bilateral infiltrates on the frontal chest radiograph PCWP ≤18 mmHg, or no clinical evidence of left atrial hypertension

* Irrespective of level of positive end-expiratory pressure; † The sensitivity of 91% and specificity of 56% for identifying acute lung injury; ‡ The sensitivity of 85% and specificity of 85% for identifying acute respiratory distress syndrome. Adapted from: Am J Respir Crit Care Med 1994; 149: 818-24; Chest 2007; 132: 410-7.

be useful in the settings where arterial blood gas (ABG) analysis is not available and facilitate the monitoring of the course of the disease. Clinicopathological Stages of ARDS Irrespective of the precipitating factors ARDS usually evolves along a stereotypic common pathway with characteristic clinical, pathological and radiological changes as exudative phase, proliferative phase, fibrotic phase and phase of healing and repair. These changes are usually described by the term diffuse alveolar damage. Clinical Features ARDS is acute and rapid onset of respiratory failure, dyspnoea, dry cough, disorientation and agitation that usually develops 24 to 72 hours after the precipitating event marking the exudative

phase. Tachypnoea, tachycardia, cyanosis, crepitations and rhonchi may also be present. Arterial hypoxaemia that is refractory to treatment with supplemental oxygen which may eventually warrant tracheal intubation and assisted MV is a characteristic feature of ARDS. Diagnostic Work-up The patient should be carefully evaluated for an underlying cause keeping in mind the possibility of treatable infections, such as sepsis, pneumonia, tuberculosis (TB), malaria among others. Other useful investigations include: Arterial blood gas analysis The ABG analysis usually reveals severe refractory hypoxaemia, hypocapnia and alkalosis if the patient is breathing spontaneously. Hypercapnia usually does not occur unless chronic lung disease co-exists. Chest radiograph In patients with ARDS, the radiographic changes become evident by about 12 hours after the clinical onset of respiratory failure. Initially, patchy, ill-defined opacities may become apparent through out the lungs. They rapidly coalesce and diffuse massive air-space consolidation becomes evident. In contrast to cardiogenic pulmonary oedema of cardiogenic origin, air-bronchogram is frequently visible. After about a week, the lungs remain diffusely abnormal, but the pattern gradually becomes ‘reticular’ or ‘bubbly’ suggestive of a diffuse interstitial and air-space fibrosis.

Sepsis and Acute Respiratory Distress Syndrome

Table 5: Causes of Acute Respiratory Distress Syndrome

Computed tomography Computed tomography (CT) of the chest also facilitates the identification of some causes of ARDS, such as, pneumonia and lung abscess. The CT of the chest reveals diffusely distributed, non-uniform, ground-glass opacification or consolidation which may not conform to the gravity distribution early in the exudative phase. Susbequently in the exudative phase, the consolidation becomes more homogeneous and gravity dependent. As the proliferative and fibrotic stages evolve, there is a decrease in the overall lung density and the appearance of an interstitial reticular pattern. Complications of ARDS, such as pneumothorax, pneumomediastinum and interstitial emphysema may also be evident on CT of the chest. Echocardiography Echocardiography is useful in differentiating ARDS from cardiogenic pulmonary oedema. Swan-Ganz catheterisation Swan-Ganz catheterisation facilitates measurement of pulmonary capillary wedge pressure (PCWP). A PCWP less than 18 mmHg and cardiac index more than 2.1 L/min/m2 is altered in ARDS. Fibreoptic bronchoscopy and bronchoalveolar lavage Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) are employed to exclude infectious causes of ARDS. Most prominent finding on BAL in patients with ARDS (though nonspecific) include increased number of polymorphonuclear leukocytes (making up to nearly 80% of the total cell population; normal value 18 mmHg), and echocardiographic abnormalities may be evident. Once PCWP is brought to normal, infiltrates on the chest radiograph may clear. Diffuse alveolar haemorrhage The initial clinical presentation of diffuse alveolar haemorrhage may resemble ARDS and is accompanied by a dramatic fall in the haematocrit, occurrence of haemoptysis, and the presence of frothy red fluid on bronchoscopy. Haemosiderinladen macrophages may be demonstrable in the BAL fluid. Idiopathic acute eosinophilic pneumonia Patients with idiopathic acute eosinophilic pneumoia may be previously healthy and present with cough, dyspnoea, fever, and occasionally chest pain. Peripheral blood and BAL fluid eosinophilia is present. This condition rapidly responds to corticosteroid treatment, usually within 48 hours. Metastatic malignancy When malignancy presents as ARDS it is uniformly fatal. Cytologic examination of blood drawn from pulmonary circulation through the Swan-Ganz catheter keeping the balloon inflated, or BAL fluid is usually helpful in confirming the diagnosis. More invasive procedures such as transbronchial lung biopsy, open lung biopsy may have to be undertaken at times to ascertain the diagnosis. These procedures are, however, associated with increased risk of complications. Management In the appropriate clinical setting, a high index of clinical suspicion is necessary to diagnose ARDS early. Efforts directed at establishing the cause of ARDS must be actively pursued to facilitate institution of specific treatment. General therapeutic measures Patients with ARDS should be admitted in an ICU equipped with facilities for invasive monitoring and providing assisted MV. Ideally, pulmonary and systemic arterial lines should be inserted for haemodynamic monitoring and rational fluid replacement therapy. SpO2 monitoring by pulse oximetry, periodic ABG analysis must also be done. Adequate nutrition should be ensured; enteral route is preferred to the parenteral route as it does not cause the serious risk of catheter induced sepsis. If sepsis is presumed to be the cause of ARDS, empirical antibiotic treatment may be started in the early phase of the disease as detailed above. Haemodynamic stabilisation The fundamental principles remain same as in Figure 2.

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Ventilatory support While some patients with ARDS can be managed with conservative measures and non-invasive ventilation, tracheal intubation and assisted MV are required in a majority of the

patients. Aim of MV is to maintain gas exchange with minimal complications. Initially, spontaneous ventilation using a face mask with a high flow gas delivery system can be used to deliver a FiO2 of up to 0.5 to 0.6. Continuous positive airway pressure (CPAP) may be added to improve PaO2 without increasing FiO2. If a FiO2 of more than 0.6 and CPAP of more than 10 cm H2O are needed to achieve a PaO2 of more than 60 mmHg, tracheal intubation and MV must be considered. The maximal clinical benefit is likely to occur if MV is initiated early, i.e. within 96 hours of the onset of ARDS, a time when alveolar recruitment potential is the greatest. Recent evidence suggests that, whatever mode of ventilation is used, tidal volume should be set in the region of 6 mL/kg (‘lung protective ventilation’) and the peak pressure should be limited to 30 to 35 cm H2O to prevent lung overdistension. Presently, in the absence of routine static pressure-volume curve measurement, positive end expiratory pressure (PEEP) is set at a relatively high level such as 15 cm H2O in patients with ARDS. It is also a common practice to increase the I:E ratio to 1:1 or 2:1 (inverse ratio ventilation) with close monitoring of intrinsic PEEP and haemodynamics during pressure control ventilation (Table 7). The usefulness of recruitment manoeuvres such as the high function where intermittent breaths of larger tidal volume are administered either via the mechanical ventilators or by hand, sustained inflation or CPAP aimed at increasing alveolar recruitment are also being studied. Other ventilatory strategies Other alternative approaches to conventional MV include prone positioning of the patient, high frequency ventilation (HFV, rate Table 7: Protective Lung Ventilation Protocol from the ‘ARDSNet Study’ Variable

Setting

Ventilator mode Tidal volume (initial)

Volume assist-control 6 mL/kg of predicted body weight* initially < 30 cm H2O 6 – 35 breaths/min

Plateau pressure Rate of respiration Ratio of the duration of inspiration to the duration of expiration Oxygenation target PaO2 SaO2 FiO2 and PEEP†

1:1 – 1:3 7.3 – 10.7 kPa (55 – 80 mmHg) 88 – 95 (%) FiO2 PEEP 0.3 5 0.4 5–8 0.5 8 – 10 0.6 10 0.7 10 – 14 0.8 14 0.9 14 – 18 1.0 18 – 24

* Predicted body weight of male patients = 50 + 0.91 [height (cm) – 152.4]; predicted body weight of female patients = 45.5 + 0.91 [height (cm) – 152.4] † Set according to pre-determined combinations (PEEP range 5 – 24 cm H2O) PEEP = Positive end-expiratory pressure; FiO2 = Fraction of inspired oxygen

Sepsis and Acute Respiratory Distress Syndrome

> 60/min) techniques such as high frequency jet ventilation (HFJV) and high frequency oscillatory ventilation (HFOV), and liquid ventilation, among others. The relative merits of these alternative methods of MV must be critically weighed against the potential side-effects in every setting. Extracorporeal respiratory support In extracorporeal membrane oxygenation (ECMO), venous blood is removed via a cannula in the inferior vena cava or right atrium, passed through a heart/lung machine, and is returned to either the right atrium (veno-venous bypass) or aorta (veno-arterial bypass). Extracorporeal carbon dioxide (CO2) removal (ECCOR) involves use of an extracorporeal venovenous circuit with lower blood flow and oxygenation still occurring via the patient’s lungs. These modalities may be useful in selected patients and, studies with a large sample size are required to clarify their role in the management of ARDS. Pharmacological therapies Though various pharmacological therapies are directed at the pathophysiologic mechanisms of ARDS. These include neuromuscular blockade, inhaled nitric oxide, vasoactive agents (intravenous phenylephrine, inhaled prostacyclins, almitrine, among others. The therapeutic potential of these strategies needs further study. Corticosteroids The role of corticosteroid treatment in the management of ARDS is controversial. The studies published in the 1980s had employed high-dose corticosteroids (1 to 8 doses of 30 mg/kg methylprednisolone) for short durations (< 48 hours). Compared with placebo, corticosteroid treatment resulted in either no difference or increased the incidence of ARDS. In more recent studies, low-to-moderate doses of corticosteroids (methylprednisolone 1 to 2 mg/kg per day to start) for longer duration (mean 25 to 32 days), with gradual tapering has been evaluated. Presently, corticosteroid therapy is not considered to be beneficial before the onset of ARDS or early in its course. A difference of opinion exists among experts regarding the efficacy of corticosteroids for late-stage ARDS. Even though lowdose corticosteroid therapy improves lung function and shortens the duration of MV in persistent ARDS, the impact on long-term mortality is unclear. More data are required from clinical trials before they can be recommended for routine use in patients with unresolved ARDS. Nutritional supplementation Enteral feeding with omega-3 fatty acids, such as, eicosapentanoic acid, γ-linolenic acid, and antioxidants was shown to facilitate improvement in oxygenation and reduction in mortality in earlier trials. However, this benefit has not been replicated in more recent clinical trials. Figure 3 outline algorithm for the management of ARDS. ARDS in the Tropics Infectious causes such as pulmonary and miliary tuberculosis TB, falciparum malaria, enteric fever, and leptospirosis are rare but treatable causes of ARDS. When the cause of ARDS is not clear, especially in endemic areas, these aetiological causes should be kept in mind and active efforts directed at

Figure 3: Treatment algorithm for the management of ARDS. FiO2 = Fraction of inspired oxygen; SaO2 = Arterial oxygen saturation

establishing this diagnosis must be pursued to facilitate early institution of specific therapy. Outcome Interestingly, initial indices of oxygenation and ventilation have not been found to be useful in predicting the outcome in ARDS. Majority of deaths in patients with ARDS are attributable to sepsis or multi-organ dysfunction rather than primary respiratory disease. Certain prognostic factors have been identified to predict risk of death at the time of diagnosis of ARDS (Table 8). Table 8: Predictors of Mortality in Patients with ARDS Advanced age Chronic liver disease Non-pulmonary organ dysfunction Sepsis Organ transplantation Human immunodeficiency virus infection Active malignancy Failure of pulmonary function to improve during the first week of treatment 261

Prevention No form of therapy is known to prevent the occurrence of ARDS. Corticosteroid therapy, routine administration of antibiotics in the absence of evidence of infection, and use of prophylactic PEEP have not been shown to prevent ARDS in patients at risk.

2.

Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Int Care Med 2008; 34:17-60.

3.

Esan A, Hess DR, Raoof S, et al. Severe hypoxemic respiratory failure. Part 1: Ventilatory strategies. Chest 2010; 137: 1203-16.

4.

Levy MM, Fink MP, Marshall JC, et al. SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-6.

5.

Raoof S, Goulet K, Esan A, et al. Severe hypoxemic respiratory failure. Part 2: Nonventilatory strategies. Chest 2010;137:1437-48.

RECOMMENDED READINGS 1.

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Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med 2009; 37: 291-304.

7.8 Mechanical ventilation (MV) of the lungs is defined as assisting or substituting spontaneous respiration of the patient with artificial respiration with a lung ventilator or manual resuscitator bag. Application of positive airway pressure overcomes the increased airway resistance (asthma, chronic obstructive pulmonary disease [COPD]) and inflates less compliant alveoli (acute respiratory distress syndrome [ARDS], pneumonias), improves functional residual capacity (FRC) and improves oxygenation by recruitment of atelactic lung units. Positive pressure counteracts the hydrostatic pressure in capillaries and redistributes (decreases) extracellular lung water. However, MV is associated with a number of complications which are discussed briefly in the following sections. COMMONLY USED TERMS It is important to know the jargon of terms used in context to ventilation for better understanding of this subject. The commonly used terms are as under: Cycling The mechanism used to terminate inspiration and switch over to exhalation is called cycling. It is also used to classify ventilators. Pressure Cycling Inspiration is terminated after desired airway pressure (PAW) is achieved. The tidal volume (VT) is directly proportional to PAW and inversely proportional to airway resistance, e.g. in bronchospasm. Volume Cycling Inspiration stops after delivering the set VT. Airway pressure increases with airway resistance (bronchospasm) or low compliance (pulmonary oedema). Flow Cycling Inspiration is terminated after the flow rate falls to a particular level e.g. 25% of peak flow rate. Time Cycling Inspiration is terminated after the set inspiratory time. Modern ventilators use a combination of these cycling mechanisms. Trigger Trigger is the signal used to start ventilator breaths. Ventilator itself triggers breaths at a set respiratory rate (RR). Alternatively, ventilator senses patient’s inspiratory pressure (pressure trigger) or inspiratory flow (Flow trigger) for triggering breaths. Recently, electrophysiological activity of diaphragm is being used as trigger (see NAVA). Breathing Circuit The arrangement of corrugated tubings designed to deliver gas to the patient is called breathing circuit. It requires periodical and between-patients cleaning and sterilisation. Most

Mechanical Ventilation Surender Kashyap, Surinder Singh components are re-usable, expensive and include corrugated tubings, humidifier or (HME), flow sensor, Y-piece, water traps and exhalation valve. Gas Flow Flow of the air (enriched with oxygen) in the breathing circuit is called gas flow. A number of ventilators use a continuous basal flow of 5 to 10 L which is used for sensing patient’s effort and is called basal flow or bias flow. Diagnostic Functions Newer ventilators can measure changes in compliance, resistance, positive end-expiratory pressure (PEEP) and air trapping, etc. Auto-PEEP is measured by ‘end-exipratory hold’ or occlusion for 5 to 10 seconds whereas similar manoeuvre after end-inspiration ‘inspiratory hold’ depicts plateau/alveolar pressure (PPLAT/ALV). These diagnostic functions are helpful in making rational ventilator adjustments. Nebulisation Some of the ventilators have programmable nebulisers to allow aerosol therapy without interruption, or modification of ventilation. MODES OF VENTILATION Mode of ventilation specifies the method and type of ventilatory assistance being provided by the ventilator. Commonly used modes for ventilating the lungs are as under: Manual Ventilation It refers to the hand delivered ventilation using ambu bag-mask or bag-tracheal tube technique with or without oxygen supplementation. Manual ventilation is quite effective, and controlled or assisted ventilation can be given until a ventilator becomes available. Spontaneous Mode Ventilator does not give breaths, but delivers the set fraction of inspired oxygen (FIO2), continous positive airway pressure (CPAP) and pressure support. Controlled Mechanical Ventilation (CMV) The ventilator is set to deliver fixed breath rate and VT (CMV-V) or inspiratory pressure (CMV-P). Spontaneous respiration is abolished with deep sedation or neuromuscular blocking drugs. CMV is used in initial phase of ventilation. Assist-Control Respiratory rate, VT and trigger sensitivity level are set in this mode and the patient triggered breaths are assisted by the ventilator, otherwise it works CMV mode. Common assisted modes are as follows: Synchronised Intermittent Mandatory Ventilation (SIMV) Ventilator delivers the set breath rate and V T (SIMV-V) or inspiratory pressure (SIMV-P) using patient trigger. SIMV

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improves patient comfort and allows spontaneous breathing between synchronised ventilator breaths. Pressure Support Ventilation (PSV) Inspiratory efforts of the patient trigger the ventilator to augment gas flow to achieve the desired airway pressure. PSV helps the patient to overcome increased airway resistance and decreased compliance and thus it “off loads” the inspiratory muscles. Proportionate Assisted Ventilation (PAV) Proportion of assisted ventilation is directly proportional to the effort of the patient. The proportion to be assisted is set as percentage, but the assistance decreases with decreasing patient’s effort (exhaustion) and hypoventilation can occur. Adaptive Support Ventilation (ASV) The clinician determines minute ventilation and ventilator algorithm manages the RR/VT relationship with changing lung dynamics. If the patient fails to trigger, controlled breaths are delivered automatically to avoid hypoventilation. Neurally Adjusted Ventilatory Assistance (NAVA) This under-investigation mode senses the electrical activity of diaphragm (through oesophageal electrode) to trigger ventilator-assisted breaths and aims at enhanced patient comfort by neuro-ventilatory coupling. The mode is not yet available in most of the available ventilators. Positive End-Expiratory Pressure (PEEP) PEEP is achieved by adding resistance to the exhalation. It prevents complete emptying of alveoli, airway closure and increases the duration for gas exchange. Application of PEEP in ARDS protects the alveoli from shearing stress due to repeated collapse and expansion. However, inap-propriately high PEEP increases the risk of barotrauma and hypotension. Continuous Positive Airway Pressure PEEP during spontaneous respiration is called CPAP. In addition to the effects of PEEP, it decreases the inspiratory work required for opening up of closed airways. Biphasic Positive Airway Pressure (BiPAP) Two distinct phases of positive pressure are applied during inspiration and expiration. Inspiratory PAP (iPAP) resembles PSV whereas expiratory PAP (ePAP) resembles CPAP. Apart from intensive care unit (ICU) ventilators, separate BiPAP machines are also available. S-PAP and DuoPAP are equivalents of BiPAP. Volume Assured Pressure Support; Volume Support; Variable Pressure Support; and Pressure Augmentation In addition to ventilator support, e.g. PSV, these modes ensure delivery of the desired VT in spontaneously breathing patient. Ventilator monitors the inspiratory flow and if the patient is unlikely to inhale desired VT, the ventilator augments the gas flow and delivers the set VT.

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Inverse Ratio Ventilation (IRV) IRV is sometimes used in severe cases of ARDS by setting an inspiration longer than exhalation during CMV. It can improve oxygenation with increased risk of cardiopulmonary complications.

Airway Pressure Release Ventilation (APRV) APRV has been tried in place of IRV with mixed results. The lungs are kept continuously inflated with brief periods of relief for exhalation without formal breath cycles. Spontaneous breathing is possible with considerable effort. Airway pressures and circulatory effects are less pronounced than IRV. Apnoea Back-up Ventilation It is a safeguard CMV mode and starts automatically in case patient stops breathing or triggering breaths. Parameters for back-up ventilation should be adjusted for individual patient while starting the ventilation. TYPES OF VENTILATORS Different types of mechanical ventilators are available for use in the hospitals (ICU ventilators), for transport of the patient (transport ventilators), for use at home (domiciliary ventilators) and (anaesthesia ventilators) for anaesthetic applications. A simple but effective form of multi-purpose ventilator is manual resuscitator bag (Ambu bag). INDICATIONS FOR MECHANICAL VENTILATION Main indications for MV include respiratory failure associated with hypoxia, hypercapnoea or both, compromised circulatory status and pulmonary oedema. Clinical Indications Clinical indications include ARDS, acute severe asthma, COPD with acute exacerbation, Landre Guillain Barré syndrome, poliomyelitis, head injury with diffuse brain oedema, pulmonary oedema and after major surgical operations. Severe tetanus (opisthotonus) and recently bird flu and swine flu have become indications for mechanical ventilation. Only those patients who are likely to recover completely from underlying disease are selected for ventilation. Brain dead patients may require ventilation until organ harvesting. Objective indications for mechanical ventilation are given in Table 1. Table 1: Objective Indications for Mechanical Ventilation Blood gas values

PaO2 50 mmHg HCO3 is also raised and pH 400 mmHg on 100% oxygen

Bedside measurements

Respiration rate >35 breaths/min; Rapid shallow breathing index, i.e. RR/ VT (L) >100

Spirometric values

Tidal volume 10 L/min Vital capacity –25 cm H2O or 0 to 24 cm H2O

PaO2 = Arterial oxygen tension; PaCO2 = Arterial CO2 tension; HCO3 = Plasma bicarbonate Note: All these parameters may not be available in every patient; hence, clinical judgement is important.

PROCESS OF MECHANICAL VENTILATION Initiation of Mechanical Ventilation Initiating MV has inherent risks and requires meticulous preparation, which should be based on ABCDE. A = Airway:

Management of Ventilation Airway is secured with oral or nasal tracheal tube and ventilation of both the lungs is ensured with careful auscultation. Orotracheal tubes require deeper levels of sedation and cause excessive salivation whereas nasotracheal tubes are tolerated better, require less sedation, but there is increased risk of epistaxis, bacteraemia and sinusitis. The VT, RR and airway pressure should be appropriate for the size of the patient and lung pathology. It is safe to use 100% oxygen during first few minutes followed by gradual reduction to a level necessary to maintain pulse oximetric saturation (SpO2) more than 90%. Humidification of inhaled gases is essential for optimal mucociliary function and is achieved with a heated humidifier (e.g. Fischer Paykel humidifier) or a disposable heat and moisture exchanger (HME). Blood gas analysis should be done 1 to 2 hours after starting ventilation make further adjustments in ventilation. Lung physiotherapy with chest wall percussion, postural drainage of lungs and tracheobronchial suctioning is done through tracheal tube intermittently. CARE OF THE PATIENTS ON MECHANICAL VENTILATION General Care The patients on ventilator are totally dependant on nursing staff and meticulous maintenance of hygiene is essential for control of infection and optimal outcome of the patients. General measures include dressing of hair, cleaning of eyes and use of lubricant eye ointment, oral hygiene with brush or small pea-nut gauge soaked in chlorhexidine 2% and oral suctioning, catheterisation of bladder, and diapers for prevention of soiling with faecal matter. Skin is kept clean with daily sponge bath, change of wet clothing or linen, talcum powder and wrinkle free sheets. Use of pneumatic mattresses combined with change of posture every 2 hours reduces the risk of bedsores. These patients are susceptible to stress induced gastrointestinal bleeding and an H2 blocker, proton pump inhibitor or mucosal barrier like sucralfate should be administered regularly. Sedation and Analgesia In the initial phase of ventilation, sedation with narcotics, midazolam or propofol, etc. is required to suppress respiratory efforts of the patient and fighting with ventilator. In postoperative, traumatised and other painful conditions, adequate analgesia is required. Muscle relaxants may cause myopathy, complicate weaning and are avoided, except in neurosurgical patients. Sedatives and muscle relaxants interfere with neurological assessment of the patient. Sedation is reduced

gradually as the patient recovers and weaning from the ventilator is started. The sedatives may be with held in the morning to allow the patients to wake up (daily sedation vacation). Nutrition Maintenance of proper nutrition with sufficient calorie content is mandatory in patients on MV. ESPEN 2004 guidelines state that enternal nutrition should be started within 24 hours in hemodynamically stable patient’s. Enteral feeding is preferred because it is natural, emotionally satisfying and prevents sepsis by maintaining integrity of gut mucosa. Diet should be adequate in calorific value which should be maintained at 2530k cal/kg body weight per day for the patients. These calories are distributed as 50% carbohydrate, protein at 1g/kg per day and rest comprises of fat. Excessive carbohydrates increase carbon dioxide production and respiratory workload which may be harmful in COPD patients. Dietary composition in diabetics and hepatorenal disease requires additional considerations. Patients on ventilator start tolerating Ryle’s nasogastric tube (RT) feed after 24 to 48 hours and require insertion of RT. RT feed is started at 3 to 4 hourly intervals with volumes of 4-5 ml/kg. RT feeds are not available in a number of hospitals in our country (especially, after H1N 1 epidemic, ventilators have been installed in district hospitals), and therefore, relatives may have to be trained to prepare RT feed using common ingredients.

Mechanical Ventilation

Maintenance of patient airway and tracheal intubation is necessary. B = Breathing: Patient requires ventilation with oxygen and bag mask technique during tracheal intubation. C = Cardiovascular instability or even cardiac arrest may occur in sick patients. An intravenous line must be secured with 18G or 16G cannula and normal saline or Ringers’ lactate should be running unless contraindicated. D = A number of drugs are needed; midazolam, or anaesthetic like thiopentone, muscle relaxants usually succinylcholine are used to calm and relax the patient for tracheal intubation. Adrenaline and atropine should be ready for immediate use. E = Equipment must be checked in advance and includes laryngoscopes, oropharyngeal airways, tracheal tubes, manual resuscitator (Ambu bag), ventilator and a patient monitor.

Communication with Patient Most patients undergoing MV are conscious, they should be re-assured and informed about their progress, explained about the procedures to be done on them and taught to co-operate, especially during weaning. Intubated patients cannot speak and often use tapping of bed rails or may sometimes write. Their calls should always be attended with sympathetic and reassuring attitude. Monitoring of Vital Signs Continuous monitoring of vital signs like, electrocardiogram (ECG), SpO2, and non-invasive blood pressure is required. Arterial blood gas analysis and electrolyte status is needed in metabolic disorders, like diabetes. Unstable patients require monitoring of intra-arterial pressure, central venous pressure and cardiac output. Non-invasive technology has largely replaced pulmonary artery catheterisation. Neurological patients may require monitoring of electroencephalogram or intracranial pressure. Urine output is recorded at hourly intervals in case of renal dysfunction otherwise at 3 to 4 hourly intervals. Monitoring of Ventilation Most of the modern ventilators monitor and display parameters like exhaled VT, minute volume, waveforms breath rate and peak airway pressure and display simple pressure/time or volume/ time waveforms on screen (Figure 1). Small variations (± 10%; read user manual of ventilator) from set values are acceptable and, therefore, alarms limits should be set accordingly. Sophisticated ventilators display real time pressure, volume and flow graphics in the form of waveforms or as loops, which are utilised for diagnosing changes in resistance (resistive load, e.g. in asthma), compliance (elastance load, e.g. ARDS, pulmonary oedema), air trapping and auto-PEEP (e.g. COPD). Basic waveforms (open and loop) illustrating important findings are shown in Figures 2A and B.

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Figure 1: Airway pressure waveforms with different modes of ventilation left panel, right panel shows waveforms with 5 cm PEEP/CPAP. VA = Assisted breath; S = Spontaneous breath

Hysteresis The pressure and volume curves are not linear due to variable resistive and elastic properties of the lungs and chest wall. As a result inspiratory curve assumes sigmoid shape and the lung volume is always higher during expiratory phase at any given pressure.

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Upper inflection point (UIP) Over filling of alveoli leads to abrupt rise in pressure and the upper part of inspiratory pressure curve deviates the curve to the right (pressure axis). The upper part of pressure volume curve assumes a ‘duck-bill’ shape. UIP is an abnormal finding and VT needs to be decreased so that the shape of the curve/ loop becomes normal.

Lower inflection point (LIP) Pressure volume curve deviates towards pressure axis due to resistance of closed airways and after opening up of airways the curve becomes steep owing to the compliance of alveoli. This shift creates a distinct point on the axis of airway pressure called LIP or initial point of inflection (iPI). It denotes excessive airway closure and requires application of external PEEP (ePEEP). It has been recommended earlier that ePEEP value should be 2 to 3 cm more than the airway pressure corresponding to LIP, but recognition of air trapping has led to recommendation of lower value of ePEEP based on detection of airway closure or autoPEEP on expiratory curve.

Mechanical Ventilation

Figures 2A and B: (A) Typical flow and pressure waveforms. (B) Loops showing points of inflection. Insp = Inspiration; PIP = Peak inspiratory pressure; LIP = Lower inflection point; PEEP = Positive end-expiratory pressure

Titration of applied PEEP or ePEEP There is no fixed method to determine the value of ‘best PEEP or optimal PEEP’ which would provide maximum gas exchange without side effects, like air trapping and haemodynamic compromise. Airway closure and iPEEP, both occur during expiration and the fact, that lung volume (at corresponding point on expiratory curve) at any given value of pressure on inspiratory curve is much higher. Application of PEEP/ CPAP the basis of LIP may lead to the worsening of air-trapping (iPEEP) particularly in COPD patients. The recent trend is to set ePEEP value up to 7085% of iPEEP. A number of methods like monitoring of oesophageal pressure,monitoring airway pressure and expiratory flow/ volumes, haemodyanamic status, computed tomography and transthoracic-electric impedance and values of PaO2, FiO2/PaO2 ratio etc are being used with reasonable success. Transthoracic impedance is directly proportional to the lung volume and its monitoring is somewhat similar to ECG monitoring. This noninvasive method may become a useful tool for monitoring and real time display of resting lung volume in future. Pressure and flow volume loops Advanced ventilators display these curves in the form of pressure/volume or flow/volume loops, which are very useful in diagnosing various problems. Schedule for Investigations or Tests A bi-weekly or as per protocols of the hospital, schedule for clinical tests like haemogram, cell counts, cultures and

radiography, etc. should be followed. Appearance of new signs and invasive procedures should be appropriately investigated. WEANING FROM MECHANICAL VENTILATION The process of discontinuation of lung ventilation is called ‘weaning from ventilation’ and can take several hours to days. The patient should have substantially recovered from respiratory distress, underlying disease and haemodynamically stable with minimal cardio-respiratory support. Objective assessment of readiness for weaning a patient from ventilator is based on a number of criteria given in Table 2. Common methods used for weaning from ventilation are as under: Table 2: Criteria to Assess Readiness for Weaning a Patient from Mechanical Ventilation Clinical parameters

RR: ≤35 per minute with RSBI: 2 blood cultures in the absence of a primary focus (Staphylococcus aureus, enterococci, Streptococcus viridans, Streptococcus bovis, HACEK)

Predisposition

Definite 2 Major 1 Major and 3 minor 5 Minor Pathologic/histologic findings

Persistently positive blood culture drawn more than 12 hour apart or all ¾ drawn at least 1 hour apart between first and last Evidence of endocardial involvement Positive echocardiogram (TEE) Oscillating intracardiac mass on valve, implanted material or supporting structures in path of regurgitant jets Abscess New partial dehiscence of prosthetic valve New valvular regurgitation

Heart condition Drug abuse Fever >38°C Vascular phenomena Major arterial emboli Janeway’s lesions Septic pulmonary infarcts Immunologic phenomena Osler’s nodes Roth’s spots Rheumatoid factor Glomerulonephritis Microbiologic evidence Positive blood culture Positive serologic finding Echocardiographic evidence consistent with infective endocarditis but not meeting the major criteria

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Possible Findings fell short of the definite but not rejected categories Rejected Alternate diagnosis Resolution of the infection with antibiotic therapy for less than 4 days No pathologic evidence after antibiotic therapy

Major criteria: consider the following as major criteria Staphylococcal bacteraemia (irrespective of community or nosocomially acquired, or with or without a focus) Positive serology for coxiella, chlamydia, bartonella Positive molecular diagnosis for specific gene targets of bacteria and fungi Minor criteria: add the following as minor criteria Raised CRP (>100 mg/L), Raised ESR (>30 for 50 for older) Newly diagnosed clubbing Splinter haemorrhages Microscopic haematuria Splenomegaly Petechiae, or purpura Delete the following from minor criteria Echocardiogram consistent with IE but not meeting major criteria Diagnosis Possible IE can be diagnosed either with one major and one minor, or three minor criteria alone

TREATMENT The treatment of IE entails long course of bactericidal antibiotics intravenously, monitoring for response, decision for surgical treatment if required, attention to portal of entry if possible, and ancillary measures for patients well-being including anticipatory guidance for preventing recurrence. Recommended antibiotic treatment charts are available in all standard texts, the principles of drug therapy are summarised. 1. Therapy has to be of sufficient dose and duration to eradicate bacteria, prevent mortality, and relapse. Usually 4 weeks therapy is required. All patients should be hospitalised for at least 2 weeks initially. 2. Longer-term treatment (6 to 8 weeks) is recommended if the symptoms have been present for >3 months, if IE is complicated by embolism, poor response, likely resistant bacteria, atypical organisms, or for prosthetic valve endocarditis (8 weeks). 3. In penicillin sensitive organism, penicillin is better than vancomycin. The dose of penicillin to be used in a patient (12-24 million units in 4-6 divided doses) depends on the available or perceived sensitivity of the organism, or clinical IE. 4. Intermittent bolus or continuous infusion are probably equally effective, boluses are usually preferred. Attention to planning of veins to be used, changing intravenous lines 48 hourly, use of central lines and aseptic precautions are customary details. 5. Therapy for staphylococcal sp. is based on methicillin sensitivity and not coagulase status. Almost all Staphylococcus are penicillin resistant, methicillin sensitive strain respond better to methicillin congeners. 6. Rifampicin is utilised in patients with prosthetic valves, or foreign materials and staphylococcal IE. 7. Fluoroquinolones can be substituted for Staphylococcus resistant to aminoglycosides as additional therapy. 8. Aminoglycosides are added carefully and therapy is only for few days in Staphylococcus, or for 2 weeks. In some

9.

10. 11. 12.

13. 14.

organism, 4 weeks duration is required with careful attention to renal and vestibular functions. Enterococci do not respond to methicillin, cephalosporin and often have resistance to aminoglycosides as well. Combination therapy is preferred. Linezolid, daptomycin are increasingly used for vancomycin resistant enterococci or Staphylococcus aureus, and others. A consultation from infectious disease specialist should be obtained in difficult circumstances. Culture negative endocarditis can be treated with vancomycin, ceftriaxone and gentamicin pending further insight into the possible organism (some prefer only vancomycin and gentamicin). Ideally trough drug levels should be measured, but is not possible in most circumstances. Surgery should be considered early, rather than late, in some situations.

Infective Endocarditis

Table 4B: Suggested Modifications of Duke‘s Criteria

Treatment of common organisms is shown in the Table 5. Therapy of atypical organisms need special considerations and consultations with infectious disease specialists. Therapy for brucella include doxycycline with streptomycin, (with or without rifampicin), and in children trimethoprim-sulphamethoxazole and rifampicin, Q fever needs doxycycline with hydroxychloroquine (possibly with fluoroquinolones), bartonella can be treated with amoxicillin with gentamicin or tetracyclines/macrolides antibiotics. These are not detailed here. Surgery for Infective Endocarditis Surgical treatment during IE may be required because of (1) severe congestive heart failure from mechanical complications, (2) uncontrolled infection, and (3) repeated embolism. While complications of surgery is higher during IE than without IE, but the mortality without surgery in such patients is very high and surgery is preferred and should be done early without waiting for infection to subside. Although, mortality despite operation in these circumstances may be as high as 20% to 40%, mortality without operation is in the range of 60% to 90%. The chances of postoperative IE in the replaced valves are not higher than 2% to 3%. Early prosthetic valve endocarditis, paravalvular leak, annular abscesses, fungal endocarditis, persistent fever >2 weeks despite antibiotics in the absence of other causes, and embolisms are typical indications for consideration of operative treatment. Various types of operative procedures may be required. Thorough debridement, patch repairs, vegetectomy and valve repair may be done, usually valve replacement is needed. The choice of valve is individual preference and outcomes are not different between mechanical or biological valves. Some may prefer homografts. If the patient has suffered a CNS event, it is better to postpone surgery, if possible. Open heart surgery should be postponed by 3 to 4 weeks after a haemorrhage in the brain and at least a few days to weeks after an infarct because of the use of anticoagulation during open heart surgery and the risks of adverse neurological outcomes. Anticoagulation in Infective Endocarditis Anticoagulation increase the chances of CNS bleed and should be avoided. In a patient with mechanical prosthetic valve, careful titration of minimal possible anticoagulation should be used. It is preferable to stop oral anticoagulant and rely on heparin for the duration of therapy.

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Table 5: Treatment of Infective Endocarditis (Common Organisms) Microorganism

Antibiotics

Streptococcus viridans Penicillin G Streptococcus bovis Amoxicillin or Ceftriaxone If penicillin allergy-vancomycin Enterococcus Amoxicillin or ampicillin with gentamicin If penicillin allergic vancomycin with gentamicin3 Staphylococcus Flucloxacillin or oxacillin If penicillin – allergic vancomycin Optional gentamicin Prosthetic valve IE Vancomycin with Or MRSA rifampicin with gentamicin Fungal endocarditis Amphotericin Flucytosine or fluconazole (second line only) Culture negative

IE HACEK

Vancomycin with Gentamicin and Ceftrioxone5 Ceftriaxone or Ampicillin-sulbactam If allergic, ciprofloxacillin

Dose (Per Day)

Duration 1

12 to 24 MU/6 doses 100 to 200 mg/kg 2g in (100 mg/Kg) single dose 30 mg/kg in 2 doses 200 mg/kg in 4 to 6 dosage 3 mg/kg in 2 to 3 doses 30 mg/kg in 2 to 3 doses 12 g/d in 4 to 6 doses 30 mg/kg in 2 doses 3 mg/kg 30 mg/kg in 2 dose 1,200 mg in 2 dose 3 mg/kg in 2 dose 1 to 1.5 mg/kg4 100 to 150 mg/kg in 4 doses 600 to 800 mg or 10 to 12 mg/kg oral or IV in 2 doses 30 mg/kg in 2 dose 3 mg/kg in 2 dose 2 g in single dose 2g single dose 12 gm (2 g Ampicillin and 1 g Sulbactam) in 4 doses or 300 mg/kg ampicillin 6 hourly, 800 mg IV or 1,000 mg oral in 2 doses

4 weeks2 4 weeks2 4 weeks2 4 weeks2 4 to 6 weeks

4 to 6 weeks 4 to 6 weeks 5 days ≥ 6 weeks ≥ 6 weeks 2 weeks 6 to 8 week or more

4 to 6 weeks

4 to 6 weeks

1 = Dose of penicillin depends on the MIC for the organism, in the absence of that data, empirically decided; 2 = The duration of therapy should be 6 weeks if the symptoms have lasted for more than 3 months. For uncomplicated and responsive endocarditis, some authors have reported cure with 2 weeks therapy of ceftriaxone; 3 = for uncommon vancomycin resistant or multidrug resistant enterococci, Linezolid 600 mg IV or oral BD has been used; 4 = Amphotericin has to be built up slowly to this dose after initial test dosages, lipid soluble formulations may be better tolerated. Newer antifungals like caspofungin and newer azoles are being tried; 5 = Treatment of culture negative endocarditis varies with the clinical background. Some authors recommend adding ceftriaxone to cover Gram-negative organisms.

Monitoring During Therapy Monitoring the patient during long course of treatment is vitally important. Most patients start showing clinical improvement and become afebrile within a week. Some may respond slowly. The diagnosis is doubted if the patient becomes afebrile in less than 4 days of therapy. Appetite, body weight, sense of well

being should be evaluated routinely and thorough physical examination daily is mandatory. Echocardiography should be repeated weekly. Blood cultures, haemogram, ESR, chest radiographs, renal parameters, are monitored frequently. Recurrence of fever after initial response may occur (Table 6) due to several reasons. Drug fever may occur without rash and

Table 6: Fever During the Treatment Cause

Indicators

Treatment

Uncontrolled infection Annular abscess

Continuing ill-health, metastatic foci, extension of infection in heart Conduction disturbance on ECG, pericarditis suggest the diagnosis, often missed, TEE useful Renal, pulmonary or spleen, may become infected Splenic common, ultrasound/CT required Common in CNS, may cause cerebral haemorrhage, not routinely searched Minor phlebitis more often incriminated as cause than actual, may miss more serious cause Common with penicillin after 3rd week, rash, eosinophilia may not be present Patient appear less toxic despite high fever May be nosocomial fungal or Gram-negative infection

Review choice or dosages of antibiotics Consider change in antibiotics, surgery

Organ infarcts Mycotic aneurysms Thrombophlebitis Drug fever

Super infection

Immunologic phenomenon Wrong diagnosis or double disease 658

Reflects poor hospital practices, broad index of suspicious required For example, a patient with glomerulonephritis, or immune mediated phenomena in otherwise responding patient SLE, lymphoma, tuberculosis may masquerade, double disease diagnosis is against the law parsimony (i.e. diagnose one condition in a patient), but very rarely does occur

Splenic abscess may need precutaneous drainage or splenectomy Aneurysm can decrease with antibiotics, surgery may be required Change IV lines frequently, if peripheral Require to change antibiotics, total duration of treatment should count Addition of appropriate therapy required Glomerulonephritis may remit after surgical removal of infection Treat according to the diagnosis

Infective Endocarditis

can be high grade. Other investigations like abdominal ultrasound and CT are utilised as required. Splenic infarct or abscess can be diagnosed with both. Mycotic aneurysms are not routinely searched in the absence of symptoms. MR angiography can detect CNS aneurysms if suspected. SPECIAL SITUATIONS Prosthetic Valve Endocarditis IE in patients with prosthetic valve occurs nearly in 1% in the first year and 0.5% per year afterwards. Early prosthetic valve endocarditis (PVE) occurring within 2 months of operation results from contamination in the operative or post-operative period and carry very high mortality. Organisms like coagulase negative Staphylococcus or S. aureus, Pseudomonas, Candida predominate. Some authors consider early PVE till 1 year period. Surgical treatment is the rule for early PVE and antibiotics are required for 6 to 8 weeks. IE later is due to the usual organisms but carries a higher-risk. PVE is essentially an annular infection, and therefore, chances of annular abscess are higher.

Figure 2: Echocardiogram in four chamber view showing vegetations (arrow) on tricuspid valve in a patient of small ventricle septal defect (not seen). LV = Left ventricle; RV = Right ventricle.

Culture Negative Endocarditis Culture negative endocarditis, although thought of as a group, actually encompass different entities. Culture could be negative because of (1) prior antibiotic therapy in otherwise a usual endocarditis, the commonest cause, (2) poor culture techniques, inadequate sample, media, transport, etc., (3) fastidious organisms needing special media like abiotrophia, HACEK, etc., and (4) organism that do not grow in blood culture like aspergillus, tropheryma whipplei, coxiella. The approach to these groups should be different. As discussed above, serological tests are useful in the diagnosis of brucella, Q fever, etc., and PCR is being utilised for many bacteria and improves the positive yield. In the absence of any clinical clues, suggested broad-spectrum cover include vancomycin with gentamicin and ampicillin or ceftriaxone. Infective Endocarditis in Children IE is uncommon before 2 years of age, except as nosocomial infection in neonates in presence of intravenous cannula and central lines. Staphylococcus aureus and candida dominate. Tricuspid valve endocarditis may present with unexplained dyspnoea due to unanticipated pulmonary embolism. Most other IE in children occur in the presence of a CHD or RHD. IE in the VSD or tetralogy of Fallot patients occurs as right-sided endocarditis (Figures 2 and 3). Systemic embolism does not occur unless there is a right to left shunt or IE occur in the leftsided structures also. Pulmonary complications like infiltrate, infarct, abscess, pulmonary artery pseudo-aneurysm occur. Response to therapy can be satisfactory. Surgery might have to be resorted to in the presence of active infection in unsatisfactory responders. Ligation of ductus arteriosus is frequently followed by response to therapy in patients with ductus arteriosus and pulmonary valve endocarditis. Infective Endocarditis in Drug Addicts IE in drug addicts usually affects normal tricuspid valve, but may also occur on aortic, and mitral valves. Right-sided IE responds well to therapy. Some may have HIV, but IE in them also responds well, unless CD4 counts drop low. Polymicrobial IE or IE due to unusual organisms like bartonella may occur. Addicts using

Figure 3: Chest radiograph of a patient of tetralogy of Fallot having right-sided infective endocarditis. Note the shadow in right lower chest from a pulmonary infarct.

pentazocine have high chances of pseudomonas, and heroine addicts injecting brown heroine in lemon juice frequently have candida. In Elderly IE in elderly is increasingly seen and is more common in males.The underlying predisposing lesion often is mitral valve prolapse with mitral regurgitation or degenerative valvular aortic stenosis. Co-morbidities decide the clinical course. Drug therapy will need extra care and dose adjustments with attention to renal and hepatic functions. MORTALITY Without treatment IE is invariably fatal. Rare case reports of recovery in the pre-antibiotic era may be misdiagnosis. Antibiotics reduced the mortality but IE has a mortality of 20%

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Table 7: Prevention of Infective Endocarditis Underlying Lesions

Procedures

Antibiotics

Rheumatic heart disease Dental procedure Prosthetic valves Involving periapical region of Previous infective endocarditis teeth or perforation of the oral Congenital heart disease mucosa or gingival tissues Unrepaired cyanotic CHD including Respiratory procedures palliative shunts and conduits Respiratory tract that involves incision Within 6 months of repair, devices or biopsy of the respiratory mucosa, such Residual lesions near patches, or prosthesis as tonsillectomy and adenoidectomy, Valve disease after cardiac transplant (none for bronchoscopy) Skin and soft tissue Surgical procedure that involves infected skin, skin structure, or musculoskeletal tissue Genitourinary or Gastrointestinal procedures None

to 40% even in current era. Further reduction in mortality is expected with more frequent surgical treatment. Mortality rates depend on several factors, but large size vegetations, heart failure portends poorer prognosis. Some subsets have particularly high mortality. Prosthetic valve IE has a mortality of 30% to 55% with surgery and 60% to 90% without surgery. The mortality in fungal IE is 60% to 90% despite treatment. With concerted efforts, protocol driven management and teamwork of cardiologist, microbiologists, surgeons and infectious disease specialist, the mortality of Streptococcus viridans IE can be as low as 7% to 10%, but enterococci and Staphylococcus mortality remains about 10% and 10% to 20% respectively. Right sided IE in drug addicts have a better response and lower mortality. PREVENTION In experimental settings, antibiotics administration before inoculating bacteria prevented colonisation and IE, and hence for years, elaborate recommendations were made for drugs to be given before procedures expected to cause bacteraemia. With time, it became clear that bacteraemia occur in daily living activities (like brushing, chewing, etc.) far more frequently than procedure induced, and that very few episodes of IE, if at all, could be prevented by such administration as previously advised. Further, costs and adverse effects of antibiotics use (including development of resistance) are not negligible. Therefore, it is prudent to advise all patients on maintaining good oral health and routine dental visits. Such is not the routine in India, but that can help reducing IE burden more than any antibiotic prophylaxis. Antibiotics before procedures are recommended only to patients in whom risks of occurrence and consequences of IE (if it occurs) are considered high (Table 7). No IE prophylaxis is recommended for gastrointestinal or genitourinary procedures in the American Heart Association recommendations. Dental procedures which may cause gum bleeding or apical tissue handling would cause bacteraemia are specified. Only single dose 2 gm amoxicillin is recommended where required.

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There have been no new data about RHD, and these patients could have poor oral hygiene. Individual judgement should still be used in advising prophylaxis. No prophylaxis is required for vaginal delivery, tattooing, ear piercing, or TEE.

Oral amoxicillin 2 g (50 mg/kg), or Intravenous/intramuscularly ampicillin 2 g, cefazolin, ceftriaxone 1 g (50 mg/kg) In allergic to penicillin: Oral cephalexin 2 g (50 mg/kg), or azithromycin/clarithromycin 500 mg (15 mg/kg), or intravenous clindamycin 600 mg

CONCLUSIONS The following parameters recapitulate important aspects of management of infective endocarditis. Do’s and Don‘ts of Infective Endocarditis 1. Prevent IE by anticipatory guidance on oral hygiene in RHD, CHD and other at risk patients. 2. Think of IE in all susceptible patients with fever, anaemia, weight loss, or heart failure. 3. Do not rely overly on any test including echocardiogram as false positive and false negatives are not uncommon. 4. Think of plausible portal of entry/organism before deciding on therapy. 5. Do not jump to the latest antibiotics, nor slavishly follow the regimens, think critically. 6. Monitor trends carefully, anticipate the complications but do not change antibiotics frequently with any minor alterations including 1 to 2 days fever. 7. Keep the surgeon in the loop for decision regarding early surgery, if required. 8. Prevent recurrence, relapse by appropriate advice and management. RECOMMENDED READINGS 1.

Anderson JL, Sande MA, Kartalija M, et al. Infective endocarditis. In: Fuster V, et al, editors, Hurst‘s the Heart; 11th Ed. McGraw Hill Publication; 2004: pp 2001-36.

2.

Mylonakis EM, Calderwood SB. Infective endocarditis in adults. N Engl J Med 2001;345:1318-30.

3.

Prevention of infective endocarditis. Guidelines from the American Heart Association: A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:1736-54.

4.

The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009); Eur Heart J 2009; 30: 2369-413.

5.

Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK micro-organisms. American Heart Association. JAMA 1995; 274: 1706-13.

12.16

Atherosclerosis KK Sethi, S Lahiri

INTRODUCTION Atherosclerosis is multi-focal, multi-factorial smouldering inflammatory disease that affects the intima of medium sized and large arteries, resulting in intimal thickening that may lead to luminal narrowing and inadequate blood supply. Atherosclerosis derives its name from the Greek word ‘adhere’—means gruel or porridge, and ‘sclerosis’ means hardening, i.e. hardening of gruel-like material inside the blood vessels. According to the original concept, atherosclerosis was thought to be just a bland proliferative process. The advent of cell biology era of atherosclerosis modified the earlier view and implicated inflammatory mechanism in disease development. According to that concept, endothelial denudation resulted in platelet aggregation and release of platelet-derived growth factor (PDGF) which led to the proliferation of smooth muscle cells in the arterial intima. Current evidence integrates inflammation as a key regulatory process with multiple other risk factors in atherosclerosis. PATHOGENESIS Early Atherosclerotic Lesions The earliest lesions of atherosclerosis, i.e. fatty streaks, are present in the aorta from early childhood and may even begin to develop early in foetal life.They are highly cellular inflammatory lesions consisting of macrophage foam cells (intracellular lipid) and T-lymphocytes (immune reaction). Fatty streaks do not protrude into the lumen and hence are not symptomatic. Fatty streaks develop under an intact but activated, dysfunctioning endothelium particularly atherosclerosis prone areas with preexisting intimal thickening. Hypercholesterolaemia is associated with increased endothelial permeability, increased transcytosis and intimal retention of lipoproteins and endothelial activation with focal expression of vascular cell adhesion molecule 1 (VCAM-1) leading to monocyte and T-lymphocyte adhesion. It is thought that inflammatory cells are recruited by adhesion molecules and chemokines such as monocyte chemoattractant protein-1 (M-CSF) and activated in the intima by factors such as oxidised lipids and cytokines. Within the intima, the monocyte-derived macrophages engulf the blood derived low-density lipoprotein (LDL), possibly through their scavenger receptors after oxidative modification and become lipid-filled foam cells. These inflammatory cells constitute the major part of the early fatty streak lesions (Figure 1). Fate of Fatty Streaks Fatty streaks can progress to more advanced lesions because they occur at the same anatomic sites. A smaller fraction of fatty streaks appears to progress to more advanced symptomatic lesions. Advanced Atherosclerotic Lesions When lipids begin to accumulate, extracellular atherogenesis has passed beyond the fatty streak stage.Two different processes

Figure 1: Formation of fatty streak. Source: Weissberg, Heart 2000; 83: 247-52.

are responsible for the extracellular accumulation of lipids. Blood-derived atherogenic lipoprotein particles may be trapped directly within the proteoglycan-rich extracellular matrix and/or lipid may be released from the macrophage foam cells after their death by apoptosis. Within a lipid-rich core, erythrocytes and their lipid-rich membranes may contribute to the expansion of the core (plaque rupture and haemorrhage). There is accumulation of smooth muscle cells which gives rise to a heterogeneous spectrum of plaques ranging from fibro-fatty plaques (abundant smooth muscle cells) to thincap fibroatheroma (scanty smooth muscle cells with rich lipid core). With the passage of time endothelial denudation takes place and adherent platelets can be seen over mature plaques. Growth factors released from the adherent platelets and micro thrombi may stimulate the smooth muscle cells within the plaque to produce more connective tissue matrix. Neovascularisation Neovascularisation is frequently present at the base of advanced atherosclerotic plaques and is thought to be derived from vasa vasorum derived new vessels. Vasa vasorum developing from the adventitial layer of vessel wall also serve the purpose of transit of leukocytes and other growth factors inside the plaque. Vulnerable Plaque and Plaque Instability Pathological studies indicate that certain plaques are more prone to develop acute myocardial infarction (MI) than others. These are called vulnerable plaques, i.e. plaques which are at high risk of for disruption or thrombosis leading to symptomatic cascade of acute coronary events. Vulnerable plaques are characterised by the following:  A thin fibrous cap (thin cap fibroatheroma or TCFA),  A large lipid pool of cholesterol esters,  Heightened inflammation,  Positive remodelling of the vessel (outward expansion of the opposite wall of the vessel), and  Extensive neovascularisation.

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Vulnerable plaque ruptures due to uneven thinning of the fibrous cap. Rupture usually occurs often at the shoulders of the lesion where macrophages enter, accumulate and are activated. Degradation of the fibrous cap results from elaboration of matrix metalloproteinases such as collagenases, elastases and stromelysins. The metalloproteinases are stimulated by activated T-cells which promote plaque instability and rupture (Figure 2).

Figure 2: Vulnerable (instable) plaque formation. VSMC = Vascular smooth muscle cell; INF-γ = Interferon-gamma. Source: Weissberg, Heart 2000; 83: 247-52.

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Role of Innate and Adaptive Immunity Innate immunity is the primitive arm of inflammation and constitutes immune response that is elicited without ‘education’ of the immune system. This response is very rapid and combats perceived foreign invaders. Natural antibodies, certain complement proteins and families of cell surface receptors recognise microbial products and provide primordial host defence responses. These receptors include scavenger receptors which cause uptake of modified lipoproteins, and are toll-like receptors (TLR) that recognise microbial structures and products. These receptors trigger a complex intracellular signalling cascade that stimulates the production of pro-inflammatory cytokines and other inflammatory mediators. The cellular recruitment seen very early in atherosclerosis is an example of innate immunity. The mononuclear phagocytes get attached to activated endothelial cells by leucocyte adhesion molecules. Maturation of monocytes into macrophages, their multiplication and production of mediators ensues. Recent evidence suggests that mononuclear recruitment is a continuous process which is also seen in established lesions and could be a therapeutic target for targeting monocytes for treatment. In the presence of hyperlipidaemia, there is an enrichment of proinflammatory subset of monocytes. Apart from monocytes, there is now firm evidence that mast cells release vasoactive small molecules such as histamine and leukotrienes, serine proteinases and heparin — a cofactor in growth factor action and angiogenesis. Certain pharmacological agents can modulate mast cell function and this can have therapeutic implications. There are links between lipoproteins and innate immunity. Modified lipoproteins such as oxidised lipoproteins and oxidised phospholipids may drive inflammation. A lipoprotein-associated phospholipase-A2 (Lp-PLA2) currently targeted in clinical trials may generate proinflammatory derivatives of oxidatively modified lipoproteins (apolipoproteins).

Recent data suggest that CIII, a constituent of certain triglyceriderich lipoproteins incites inflammation by binding to TLR2. The activation of platelets results in secretions of proinflammatory cytokines such as CD40-ligand and also myeloid-related protein (MRP) 8/14. The MRP serves as a biomarker for adverse cardiovascular events and can promote endothelial cell apoptosis, a process thought to be vital in plaque thrombosis. Adaptive immunity requires antigen presenting cells, such as dendritic cells. The dendritic cells populate atherosclerotic plaques and present antigens to T-lymphocytes, thus forming the key limb of adaptive immunity. These antigens in relation to atherosclerosis are heat shock proteins (HSP), components of plasma proteins and some microbial structures. T-cells proliferate and produce cytokines that amplify inflammation. There are several types of T-cells. Helper T-cells (Th1) response appears to aggravate atherosclerosis as it amplifies proinflammatory pathway by gamma interferon production. The Th2 cells produce cytokines that modulate inflammation. These cytokines such as interleukin (IL)-4 can promote humoral immunity. Regulatory T-cells can, however, dampen atherosclerotic response. There is also a role of CD8 marker T-cells or cytotoxic T-cells or CD8 cells. CD8 T-cells are capable of killing smooth muscle cells and macrophages and cause lesion growth and complications. Humoral immunity is mediated by B-lymphocytes. B-lymphocytes secrete antibodies which attenuate rather than aggravate atherosclerosis. Splenectomy aggravates athero-sclerosis by eliminating some population of B-cells. Humoral immunity against oxidised LDL might protect against atherosclerosis and may be a potential target of vaccine therapy. RISK FACTORS FOR ATHEROSCLEROSIS Classic risk factors of atherosclerosis are also known as traditional risk factors.These risk factors can predict atherosclerotic coronary events to a certain extent.The NCEP ATP- III is based on traditional (old) risk factors of age, sex, total cholesterol, HDL cholesterol, systolic BP and smoking. In a more recent scoring system (PROCAM), eight risk variables are identified: age, LDL cholesterol, diabetes, smoking, HDL cholesterol, triglycerides (TG), systolic BP, family history of premature coronary artery disease. Table 1 presents risk factors for atherosclerosis. Hypertension Hypertension is considered to be one of the traditional risk factors of atherosclerosis. Concentrations of angiotensin-II, the principal product of renin-angiotensin system are often elevated in patients with hypertension. Angiotensin-II is a potent vasoconstrictor. In addition to cause hypertension, it can contribute to atherogenesis by stimulating the growth of smooth muscle cells. Angiotensin binds to specific receptors in smooth muscle cells resulting in activation of phospholipase C, which can lead to increase in intracellular calcium and smooth muscle contractions, increased protein synthesis and smooth muscle hypertrophy. It also increases smooth muscle lipooxygenase activity which can increase inflammation and oxidation of LDL. Hypertension also has proinflammatory actions such as increasing the formation of hydrogen peroxides and free radicals such as superoxide anions and hydroxyl radicals in plasma. These substances reduce the formation of nitric oxide (NO) by endothelium, increase leucocyte adhesion and increase peripheral resistance.

Old

Old/New

New

Sex (men > women)

High-normal blood pressure

Apolipoprotein B; Apolipoprotein A-1

Age

Metabolic syndrome

Triglycerides; triglyceride-rich lipoprotein remnants

Family history of Diabetes premature cardiovas- mellitus; cular disease impaired glucose tolerance; impaired fasting glucose

Small, dense LDL; oxidised LDL; antibodies against oxidised LDL

Total cholesterol; LDL cholesterol; HDL cholesterol (negative risk factor)

Lipoprotein(a)

Hypertension Smoking

Homocysteine High-sensitivity C-reactive protein

Overweight/obesity LDL = Low-density lipoprotein; HDL = High-density lipoprotein.

Smoking Smoking increases the risk of atherosclerosis by several mechanisms. Cigarette smoking is associated with increased levels of lipoproteins and the effects of oxidants in cigarette smoke renders LDL more susceptible to peroxidative modification by cellular elements such as macrophages and vascular smooth muscle cells. The inflammatory cells recruited in the atherosclerotic plaques are increased in smokers. Nicotine activates the complement system as well, which causes increased inflammation in the vessel wall. Certain chemicals in tobacco smoke tend to activate factor XII and favour thrombus formation. The risk associated with smoking diminishes slowly after smoking cessation and equals to non-smokers after 3 years of cessation. Diabetes Mellitus In the first 20 years of the Framingham Heart Study, the incidence of cardiovascular disease among men with diabetes mellitus was twice than that among men without diabetes. Among women with diabetes, the incidence of cardiovascular disease was three times than that among women without diabetes. Microalbuminuria and silent myocardial ischaemia at baseline has predictive value for future coronary heart disease (CHD) in asymptomatic patients with type II diabetes. Subjects with impaired glucose tolerance and those with insulin resistance are more likely to have subclinical atherosclerosis (Framingham Offspring Study) and it is no wonder that NCEP considers diabetes as a CHD risk equivalent. Type II diabetes is associated with insulin resistance. Insulin resistance reduces the ability of adipose tissue to clear/store circulating lipids, in part because of reduced lipoprotein lipase activity. This results in paradoxical elevation in serum TG and free fatty acids (FFA). There is also elevation in the apoB due to increased lipogenesis by the liver. Insulin resistance is characterised by the formation of more atherogenic (small dense) LDL. It can also stimulate inflammation. The secretion of proinflammatory mediators initiated by systemic insulin resistance stimulates several intracellular cascades of nuclear factor kappa beta pathway.

Metabolic Syndrome Metabolic syndrome encompasses a range of cardiovascular risk factors such as elevated TG (> 150 mg/dL), low HDL cholesterol (men < 40 mg/dL; women < 50 mg/dL), impaired fasting glucose (≥ 110 mg/dL), high blood pressure (≥ 130/85 mm Hg) and increased waist circumference (men > 90 cm, women > 80 cm in Asians) is believed to increase the risk for CHD at any level of LDL cholesterol. Further, the presence of metabolic syndrome has a greater impact on the incidence of CHD in women than men. Leptin is a protein that plays a role in fat metabolism and closely correlates with insulin resistance and is an independent risk factor for CHD.

Atherosclerosis

Table 1: Old, Old/New, and New Risk Factors for Atherosclerosis

Lipid Risk Factors Triglycerides and triglyceride-rich remnant lipoproteins Though there was some initial debate on the role of hypertriglyceridaemia as an independent CHD risk factor, data from the PROCAM study showed a significant relation between hypertriglyceridaemia and CHD risk independent of LDL cholesterol and/or HDL cholesterol. Triglyceride-rich lipoproteins comprise a great variety of nascent and metabolically modified lipoprotein particles. The capacity to enter the subintimal area of the vasculature is inversely related to the size of the lipid particles. Whereas chylomicrons and large very low-density lipoprotein (VLDL) particles are unable to pass through the endothelial layers, smaller VLDL, IDL and LDL particles can enter the suboptimal space. In the Framingham Offspring Study, both remnant lipoprotein (RLP)-cholesterol and RLP-TG were significantly increased in diabetic men and women compared to non-diabetes. Remnant lipoproteins were independent risk factors for atherosclerosis. Lipoprotein (a) [Lp (a)] is formed by joining a lipoprotein that is structurally similar to LDL in protein and lipid composition to a carbohydrate-rich hydrophilic protein Apo (a). The Lp (a) particles contain Apo (a) and Apo (B) in a 1: 1 molar ratio. Most of the data on Lp (a) comes from retrospective studies. Prospective studies, however, have mixed results. However, plasma Lp (a) is indeed an independent risk factor for CHD in both men and women. The Lp (a) levels above 33 mg/dL and high LDL cholesterol (>163 mg/dL was associated with increased cardiovascular risk compared with Lp (a) levels below 33 mg/dL. Homocysteine Homocysteine is formed during demethylation of methionine, whereas its degradation takes place via remethylation and/or trans-sulphuration). Impaired homocysteine metabolism has been implicated as a risk factor in atherosclerosis, cerebrovascular disease and peripheral vascular disease. Hyperhomocysteinaemia results from genetic cause (enzyme deficiencies), vitamin deficiency (folic acid, B12, B6), use of certain medications and impaired renal function. Direct relations between homocysteine, cigarette smoking, diabetes, obesity and hypertension have been suggested. The exact mechanism by which hyperhomocysteinaemia may translate into increased CHD and/or thrombotic risk remains speculative. Both direct toxic effects on endothelial cells, in part due to oxidative stress as well as more indirect mechanisms have been postulated. However, treating hyerhomocysteinaemia with vitamins has not shown to be beneficial in large studies both in terms of stroke and cardiovascular event reduction.

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Thrombogenic/Haemostatic Factors Elevated plasma fibrinogen and factor VII are potential risk factors for CHD. Other thrombogenic/haemostatic factors that have been investigated in their potential role in atherogenesis and/or thrombosis include von Willebrand factor and plasminogen activator inhibitor-1. High-Sensitivity C-Reactive Protein and Other Inflammatory Markers Since atherosclerosis represents a chronic inflammatory state, inflammatory parameters (e.g. IL-6, tumour necrosis factor-alpha) have predictive value for future cardiovascular events. Data shows that CRP has additive value for predicting CHD risk on top of traditional risk factors. hs-CRP is associated with subclinical pericardial coronary calcification in men and women and is significantly elevated in patients suddenly dying of severe coronary artery disease. Elevated hs-CRP constitutes an independent predictor of advanced plaques in dyslipidaemic subjects and early onset carotid atherosclerosis with increased intima-media thickness and elevated serum levels of inflammatory markers. Matrix-metalloproteinase 9 concentration has been identified as a novel predictor of cardiovascular mortality in patients with coronary artery disease. Elevated IL-10 has a more favourable prognosis in patients with acute coronary syndrome (ACS) and elevated CRP levels. Though there is no definite hard evidence of a causal relation between infection and atherosclerosis, studies are accumulating that indicate a possible role of infection. Viral agents such as cytomegalovirus (CMV), enterovirus, influenza virus, human parvovirus B19, herpes simplex viruses and bacterial agents such as Chlamydia have been studied extensively. Other potential agents such as Helicobacter pylori and periodontitis have been implicated. In a recent meta-analysis, it has been shown that influenza vaccination in patients with CHD can lower the risk of acute myocardial infarction. Periodontitis is associated with atherosclerotic cardiovascular disease, though direct causal relation is not yet established. The incidence of atherosclerotic cardiovascular events increase in patients with chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and psoriasis.

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Biomarkers such as hs-CRP, IL- 6, IL- 8, soluble CD40 ligand are all markers of widespread inflammatory process in the vessel wall and can be identified by laboratory assays to detect subclinical atherosclerosis. There was an association between CRP and carotid atherosclerosis as assessed by ultrasono-graphy among 3,173 men and women enrolled in the Framingham Offspring Study. Overall, they found that increasing levels of CRP were predictive of carotid artery disease. Elevated levels of CRP may reflect the presence of vulnerable plaque that is at highrisk of rupture, as opposed to solely reflecting the burden of atherosclerosis. Emerging data, however, suggest that CRP may be a mediator as well as marker of atherosclerosis. CRP induces expression of cellular adhesion molecules, IL-6 and endothelin1 by endothelial cells. Recently, interest has focused on the measurement of a circulating soluble form CD40 L (sCD40) for risk stratification of patients with or at risk of developing coronary artery disease. However, in a large multiethnic population-based sample, sCD40L was not associated with most atherosclerotic risk factors or subclinical atherosclerosis.

Technology has now made it possible to image atherosclerosis and the day is not far when it will be routinely used in identifying vulnerable plaques which are prone to rupture. It is yet unproven that therapies directed at sealing such plaques are beneficial. Techniques to image “vulnerable” plaque is given in Table 2. Table 2: Techniques to Image “Vulnerable Plaque” Angioscopy Intravascular ultrasound Palpography Virtual histology Near-infrared/Raman spectroscopy Ocular coherence tomography/ocular frequency domain imaging Thermography Vasa vasorum imaging Magnetic resonance imaging (invasive and non-invasive) Positron emission tomography/computed tomography Molecular imaging

TREATMENT/PREVENTION Systemic pharmacotherapy is the cornerstone of plaque stabilisation, with reductions in lipid content, inflammation and vasa vasorum neovascularisation. Statin therapy in high-dose has been documented to be beneficial in atherosclerotic plaque regression. In the A study to evaluate the effect of Ultrasound rosuvastatin an Intravascular derived coronary Atheroma Burden trial, rosuvastatin 40 mg per day led to an absolute regression in atheroma volume. Increasing HDL levels have been found to be antiatherogenic. However, even with the best combination consisting of high dose statins, ACE-inhibitors and aspirin, there is still a 22% recurrent coronary event rate in 2 years. Regional therapy such as photodynamic therapy and cryotherapy as intravascular treatment of coronary segments may be beneficial in near future. Plaque sealing with balloon expandable stents may tackle the vulnerable plaque. Vaccine development for atherosclerosis Historically, vaccines have been proven to be safe and efficient for protection against infectious diseases. Several antigen targets have been proposed for vaccine design, implementation and efficacy for atherosclerosis. Ideal vaccines for atherosclerosis should provide protective immunity against infection-derived pro-atherogenic antigens and also immune tolerance for auto-immunogenic selfantigens. LDL was the earliest target for vaccine therapy as it is a major mediator of atherosclerosis. Studies focusing on a knockdown of Ox-LDL showed a decrease in atherosclerotic lesion size. Immunisation with phosphatidylcholine (PC) containing Streptococcus pneumoniae generated vaccine which showed reduced atherosclerosis. However, the major problem with Ox-LDL is the chance of cross-reactivity. For greater OX-LDL specificity, more recent studies have targeted ApoB-100 peptide fragments. Studies to target the potential antigenicity of heat shock protein (HSP) mycobacterial HSP 65 elicit a pro-atherogenic response. Immunisation of patients with HSP 70 also showed decreased atherosclerosis. Following the idea that molecular mimicry is the mechanism responsible for cross-reactivity with foreign HSP, vaccination against infectious agents like influenza virus has been examined in the context of atherosclerosis. Vaccines

RECOMMENDED READINGS 1.

Fruchart JC, Niermann MC, Stroes ESG, et al. New risk factors for atherosclerosis and patient risk assessment. Circulation 2004;109: 15-9.

2.

Fuster V, Topol EJ, Nabel EJ. Atherothrombosis and Coronary Artery Disease. 2005; 2: 15-1575.

3.

Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med 2005; 352: 1685-95.

4.

Libby P, Ridker MP, Hansson GK. Inflammation in atherosclerosis: From physiology to practice. J Am Coll Cardiol 2009; 54: 2129-38.

5.

McGill HC, McMahon CA, Gidding SS. Preventing heart disease in the 21st century: Implications of the pathological determinants of atherosclerosis in the youth (PDAY) study. Circulation 2008; 117: 1216-27.

6.

Moreno PR. Vulnerable plaque: Definition, diagnosis and treatment. Cardiol Clin 2010; 28:1-30.

Atherosclerosis

against more risk factors and proteins like nicotine, angiotensin1, gherkin and periodontitis have also been examined with some interesting results. Thus, vaccine development for atherosclerosis is already underway and showing promising results.

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12.17

Ischaemic Heart Disease Inder S Anand, Shibba Takkar Chhabra

Ischaemic heart disease (IHD) is characterised by myocardial impairment due to imbalance between coronary blood flow and myocardial requirement. The commonest cause of IHD is atherosclerotic coronary artery disease (CAD). Nonatherosclerotic causes of myocardial ischaemia are rare and include coronary spasm (Prinzmetal’s angina), coronary artery embolism, coronary arteritis (polyarteritis nodosa, Takayasu’s disease, systemic lupus erythematosus), cocaine abuse or spontaneous dissection of coronary arteries. CORONARY CIRCULATION The left main and right coronary arteries arise from the left and right coronary sinuses of the aortic root, distal to the aortic valve. Within 2.5 cm of its origin, the left main coronary artery divides into the left anterior descending artery (LAD), which runs in the anterior interventricular groove, and the left circumflex artery (LCX), which runs in the atrioventricular groove. The LAD gives branches to supply the anterior part of the septum (septal perforators) and the anterior, lateral and apical walls of the left ventricle (diagonals). The LCX gives obtuse marginal branches that supply the lateral, posterior and inferior segments of the left ventricular (LV). The right coronary artery (RCA), runs in the right atrioventricular groove, giving acute marginal branches that supply the RA, RV and inferoposterior aspects of the LV. The posterior descending artery runs in the posterior interventricular groove and supplies the inferior part of the interventricular septum. It arises from the RCA in approximately 85% of people (dominant right system) and from the LCX in the remainder (dominant left system). The coronary anatomy varies greatly from person to person and there are many normal variants. The RCA supplies the sino-atrial (SA) node in about 60% of individuals and in the remaining 40% SA node is supplied by LCX. The AV node is supplied by a small AV nodal artery which arises from the dominant coronary artery (RCA in 85%) (Figure 1). Proximal occlusion of the RCA, therefore, often results in sinus bradycardia and may also cause AV nodal block. Abrupt occlusions in the RCA, due to coronary thrombosis, result in infarction of the inferior part of the LV and often the RV. Abrupt occlusion of the LAD leads to anterior wall or anteroseptal myocardial infarction (MI). LCX causes infarction in the anterolateral territory of the LV. Acute occlusion of the left main coronary artery is usually fatal.

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PHYSIOLOGY The myocardium relies almost exclusively on oxidative metabolism for its energy needs. Even at rest the transmyocardial oxygen extraction is near maximal with a coronary venous O 2 saturation that is lowest in the body (25% to 35%). Any increase in myocardial O2 demand can only be met by proportional increase in myocardial blood flow, chiefly

Figure 1: The coronary arteries of the heart. Diagram of the anterior view.

mediated by reduction in coronary arteriolar resistance. The left coronary artery fills only in diastole while the RCA shows both systolic and diastolic coronary flow. MAGNITUDE OF THE PROBLEM Cardiovascular disease accounts for approximately 12 million deaths annually and is the commonest cause of death globally. Previously considered a disease of the affluent, the past three decades have seen considerable decline in the incidence and prevalence of atherosclerotic CAD in the industrialised western world; whereas at the same time, this problem is assuming epidemic proportions in the developing world. Asian Indians, whether living in their own country or elsewhere, have much higher incidence of CAD as compared to all other ethnic groups. While the incidence of coronary artery disease has reduced by 50% in the west, in India it has doubled in the last 25 years. The prevalence of coronary artery disease in the years 1960, 1980, 1990 and 2000 progressively increased (2%, 4% to 6%, 9.5% and 10% to 15% respectively). In the rural India, the CAD prevalence increased two-fold from 2% to 4%. In urban India, the increase was three-fold from 3.45% to 9.45%. In 1990, 25% deaths in India were attributable to cardiovascular disease compared to 9% due to diarrhoeal disease, 12% due to respiratory infections and 5% due to tuberculosis. RISK FACTORS The National Heart Lung and Blood Institute of USA initiated the Framingham Heart Study in 1949 and by 1961, the concept of risk factors for CHD was established with hypertension and hypercholesterolaemia being identified for intervention.

Table 1: Risk Factors for Clinical Atherosclerosis Non-Modifiable

Modifiable

Age Male gender Family history of CHD Presence of CHD Menopause Physical inactivity

Dyslipidaemia Hypertension Diabetes Abdominal obesity Smoking Diet

Asian Indians have the highest ethnic risk of CAD despite lower rates of smoking, hypertension, obesity and higher vegetarianism. The insulin resistance syndrome (metabolic syndrome X), lipoprotein(a), atherogenic dyslipidaemic phenotype and some newer emerging risk factors [homocysteine, tissue plasminogen activaetor (tPA), plasminogen activator inhibitor (PAI-1), fibrinogen, infections and inflammation] may be more relevant as underlying genetic susceptibility associated with a modest abnormality in lipid and lifestyle factors makes CAD assume an aggressive course in Asian Indians. Important risk factors in Asian Indians have been listed in Table 2.The INTERHEART study (2004) on 25,000 myocardial infarction patients confirmed nine risk factors attributing to CAD—ApoB/ApoA-1, smoking, diabetes, hypertension, abdominal obesity, psychosocial, fruits and vegetable intake, exercise and alcohol. Of these ApoB/ ApoA-1 and smoking were especially associated with increased incidence of myocardial infarction in younger patients. Table 2: Coronary Risk Factors for Asian Indians Fixed Male age >35 years Female age >45 years Family history of premature CAD (at age 23 Homocysteine >10 mmol/L High PAI – 1

sudden cardiac death (Table 3). The understanding of the conversion of a stable atherosclerotic lesion to a plaque rupture with thrombosis has provoked a unifying hypothesis for the aetiology of acute coronary syndromes. Table 3: Nomenclature of Myocardial Ischaemia Old

Present

Asymptomatic Stable effort angina Unstable angina

Asymptomatic Stable effort angina Acute coronary syndromes, unstable angina without necrosis Non-ST elevation MI (NSTEMI) (evidence of myocardial necrosis) ST elevation MI (STEMI) Sudden death Ischaemic cardiomyopathy

Non-Q wave MI Q wave MI Sudden death Silent ischaemia

Ischaemic Heart Disease

The classically defined eight risk factors for CAD are hypertension, dyslipidaemia, diabetes, physical in activity and sedentary lifestyle, central obesity, stress and type A personality, family history of CAD and smoking. Of these, smoking, diabetes, hypertension and family history of premature CAD are particularly important. Table 1 enlists the modifiable and non-modifiable risk factors for CAD.

CLINICAL PRESENTATION Symptoms The typical clinical presentation of angina refers to poorly localised retrosternal discomfort with radiation to neck, shoulders, arms, jaws, epigastrium or back; usually, not above the jaw and not below the umbilicus. Angina is typically triggered by physical activity, emotional stress, exposure to cold, consuming a heavy meal or smoking. Pain is poorly localised, vague chest discomfort which may be described as squeezing, burning, tightness, choking, heaviness, hot or cold sensation, dyspnoea, fatigue, weakness, lightheadedness, nausea, diaphoresis, altered sensorium and syncope. These symptoms have been called angina equivalents. Pain lasts for 2 to 8 minutes. Ischaemia seldom lasts more than 30 minutes without causing acute myocardial infarction (AMI). Pain is relieved with rest or sublingual nitroglycerine in 2 to 5 minutes. It is less likely to be angina if it is localised (finger pointing), less than 30 s, or more than 30 min without AMI, exclusively at rest (except unstable/Prinzmetal), pricking or jabbing and changing sites of pain (Figure 2).

Modifiable: Lipid Total cholesterol >150 mg/dL Triglycerides >150 mg/dL LDL cholesterol >100 mg/dL ApoA lipoproteins 10 mm Hg in systolic pressure during inspiration.

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Investigations for Pericardial Effusion and Cardiac Tamponade General investigations for pericardial effusion and cardiac tamponade include routine blood counts and ESR. There may be leucocytosis and neutrophilia and the sedimentation rate may be high. Electrocardiography ECG can be normal or non-specific ST-T-wave changes are seen, total electrical alternans is seen in large effusions and tamponade (Figure 3). Bradycardia and electromechanical dissociation are diagnostic of end-stage tamponades.

seen posteriorly. Pericardial effusions large enough to produce cardiac tamponade are almost always circumferential (both anteriorly and posteriorly). Echocardiography reveals the size of effusions: 1. Small (echo-free space in diastole 10 mm posteriorly) 3. Large (>20 mm) 4. Very large (>20 mm with compression of the heart) In cases of gross effusion, the heart assumes a ‘swinging’ effect, wherein the heart seems to oscillate within the pericardial sac. Echocardiography also provides information on the significance of the pericardial effusion. In the presence of cardiac tamponade, there is diastolic collapse of the free walls of the right atrium and/or right ventricle (Figures 5 and 6). The collapse is exaggerated during expiration when right heart filling is reduced. Right atrial collapse is more sensitive for tamponade, but right ventricular collapse lasting more than one-third of diastole is a more specific finding for cardiac tamponade. On echo Doppler study, there can be marked reciprocal respiratory variation in mitral and tricuspid flow velocities reflecting the enhanced ventricular interdependence that is the mechanism of the paradoxical pulse.

Figure 3: Total electrical alternans seen in large pericardial effusion and cardiac tamponade.

X-ray In pericardial effusion, the cardiac silhouette will be increased in size. Enlarged cardiac silhouette with clear lungs on chest radiograph is very characteristic of large pericardial effusion (Money Bag appearance) (Figure 4). The individual chamber and blood vessel contours are lost. Echocardiography Echocardiography is an important part of the evaluation in patients with pericardial effusion and cardiac tamponade. The most important finding is the separation of the two pericardial layers by an ‘echo-free’ space. Small pericardial effusions are only

Figure 5: Echocardiography showing circumferential pericardial effusion with RA collapse (White or red arrow).

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Figure 4: Enlarged cardiac silhouette with clear lung field in large pericardial effusion.

Diagnostic and Therapeutic Pericardiocentesis Aspiration of the pericardial fluid will not only confirm the diagnosis but also help in detection of the aetiology. The aspirated fluid should be analysed and sent for bacteriological culture and sensitivity tests. If there is no haemodynamic compromise and the diagnosis can be established by other means, pericardiocentesis may not be necessary but it is generally advisable in patients with very large pericardial effusions (>20 mm on echocardiography), even in the absence of tamponade. It must be recognised that pericardiocentesis will not yield a diagnosis in most patients and, therefore, the reason for draining large effusions is to avoid potential progression to tamponade.

The feasibility of pericardiocentesis is high (>93%) in patients with anterior effusion more than 10 mm, while the rate of success is only 58% with small, posteriorly located effusions. The most serious, but rare, complications are lacerations/ perforations of the myocardium and the coronary vessels. In addition, patients can experience air embolism, pneumothorax, arrhythmias (usually bradycardia), and puncture of the peritoneal cavity or abdominal viscera.

Diseases of the Pericardium

mammary arteries. It is prudent to drain the fluid in stepped amounts of less than 1 litre at a time to avoid acute right ventricular dilatation.

If the fluid withdrawn is found to be purulent or there is large effusion then an indwelling pigtail catheter is left in pericardial cavity for drainage of residual or reoccurring effusion later on. Along with this, appropriate antibiotic therapy should be instituted.

Figure 6: Echocardiography showing large posterior pericardial effusion (Red arrow).

Other Investigative Procedures Computerised axial tomography and magnetic resonance imaging also help, especially when echocardiography does not reveal good images due to pulmonary disease. Prognosis This depends on the aetiological factor. Tuberculous pericardial effusion very often results in chronic constrictive pericarditis. Pericardial effusion in uraemia and neoplasms are harbingers of death. Purulent pericardial effusion, if not treated vigorously, may prove fatal.

SPECIAL FORMS OF PERICARDITIS 1. Idiopathic Pericarditis As the name suggests, the cause of this type of pericarditis is not known, though it is presumed to be viral. It affects all age groups and presents with fever, bodyache and chest pain. Pericardial effusion develops in about 75% of the cases. Treatment consists essentially of rest and analgesics. If pain is very severe and the effusion does not subside, then corticosteroids may be given. Very rarely, constrictive pericarditis may ensue. 2. Rheumatic Pericarditis This is seen in cases of acute rheumatic fever and is characterised by tachycardia, chest pain and fleeting joint pains. Usually, it is dry pericarditis (‘bread and butter’ pericarditis) but pericardial effusion may occur. There is complete regression with treatment and no sequelae are seen.

Treatment The treatment of pericardial effusion is two-fold; treatment of the aetiological factor and treatment of the effusion.

3. Uraemic Pericarditis Two forms of pericarditis have been described in renal failure:

The treatment of cardiac tamponade is drainage of the pericardial effusion. Medical management is usually ineffective and should be used only while arrangements are being made for pericardial drainage. Fluid resuscitation may be of transient benefit if the patient is volume depleted. The use of inotropic agents is usually ineffective because there is already intense endogenous adrenergic stimulation.

(a) Uraemic pericarditis Fibrinous inflammation with adhesions between the thickened pericardial membranes (‘bread and butter’ appearance) caused by the high degree of azotemia in advanced renal failure before dialysis is started or shortly, thereafter. This is seen usually in the terminal stages of uraemia. The pericarditis is of the dry type.

PERICARDIOCENTESIS Pericardiocentesis is the aspiration of the pericardial fluid for therapeutic as well as for diagnostic purposes. Indications for pericardiocentesis are: cardiac tamponade, diagnosis of the aetiology of pericardial effusion and introduction of drugs into the pericardial cavity (when indicated). Procedure Pericardiocentesis can be performed either using fluoroscopic (cardiac catheterisation laboratory) or preferably in the intensive care unit, under echocardiographic guidance. There are various sites for aspiration but the two commonest sites used are the subxiphoid and the left fifth intercostal space. The subxiphoid approach is the much preferred route, as one can aspirate fluid even in the case of small effusions. This route is extrapleural and avoids the coronary, pericardial, and internal

(b) Dialysis-associated pericarditis Patients on maintenance haemodialysis, and occasionally with chronic peritoneal dialysis caused by inadequate dialysis and/or fluid overload. Most patients with uraemic pericarditis respond within 1 to 2 weeks to haemo or peritoneal dialysis, with resolution of chest pain and reduction of the pericardial effusion. To avoid intrapericardial haemorrhage, heparin-free haemodialysis should be used. 4. Post-Infarction Pericarditis Pericarditis may occur ‘early’ or be ‘delayed’ (Dressler’s syndrome) after myocardial infarction. Early pericarditis occurs in the first few days of a transmural myocardial infarction, although early thrombolytic treatment has decreased its incidence. Dressler’s syndrome occurs from

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one week to several months after myocardial infarction and is considered to be an autoimmune phenomenon. Aspirin, up to 650 mg every four hours for 2 to 5 days, has been successfully used to treat post-infarction pericarditis. Other nonsteroidal agents risk thinning the infarction zone. Corticosteroid treatment is used for refractory symptoms but can delay infarction healing. 5. Tuberculous Pericarditis This is possibly the commonest cause of pericarditis and pericardial effusion in India. It is even more common after the advent of HIV infection and AIDS. Infection occurs through neighbouring structures, e.g. lungs, bronchi, lymph nodes or by blood-borne infection. The patient may have vague complaints of fever, malaise, evening rise in temperature, loss of weight, etc. There may be no cardiac manifestations initially but later on, chest pain, cough and dyspnoea may appear due to an increase in the size of the effusion. Aspiration of the fluid reveals either straw-coloured or bloodtinged exudative fluid. A systematic, multiple diagnostic approach is essential, e.g. sputum cultures, analyses of pericardial effusion by acid-fast staining, mycobacterial culture or radiometric growth detection (BACTEC-460), adenosine deaminase (ADA), pericardial lysozyme, and PCR for Mycobacterium tuberculosis. High ADA (>40 U/L) in pericardial effusion is diagnostic for tuberculous pericarditis (93% sensitivity, 97% specificity). The absolute criteria for diagnosis are the identification of Mycobacterium tuberculosis in the pericardial fluid or tissue, and/or the presence of caseous granulomas in the pericardium. However, pericarditis in proven extracardiac tuberculosis is strongly suggestive of a tuberculous aetiology. PCR is as sensitive (75% vs. 83%), but more specific (100% vs. 78%) for tuberculous pericarditis than ADA. Very often, even on a very close search, no evidence of tuberculosis may be found anywhere in the body. Tuberculous pericarditis should be promptly treated with a combination of antitubercular drugs according to standard protocols. Prednisone should be administered along with antituberculous drugs as it reduces the host reaction to mycobacterial infections, minimises exudation, fibrin deposition, and proliferation of tuberculomas and may decrease symptoms and signs. However, despite combination therapy, many patients develop constriction and if untreated, it is one of the commonest causes of constrictive pericarditis in India.

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6. Purulent Pericarditis This is due to infection of the pericardium by organisms like the Staphylococcus, Streptococcus, Pneumococcus, Meningococcus and Haemophilus, etc. The infection may be either blood-borne, extension of an intrathoracic infection or from outside as in cases of stab wounds. Patient presents with high-grade fever and appears very toxic. If the effusion accumulates very rapidly it may result in cardiac tamponade. Pericardial fluid aspirate should undergo urgent Gram’s, acid-fast, and fungal staining followed by cultures for aerobes and anaerobes. Purulent effusions have significantly lower fluid glucose concentrations than non-infectious effusions.

Purulent pericarditis is an absolute indication for pericardial drainage and rinsing of the pericardial cavity, combined with high doses of systemic antibiotic treatment. A combination of antistaphylococcal antibiotic and aminoglycoside, followed by tailored antibiotic treatment according to the results of pericardial fluid and blood cultures, is mandatory. 7. Viral Pericarditis This is a common cause of pericarditis and is clinically difficult to differentiate from idiopathic pericarditis. Viral pericarditis can be caused by direct viral attack (enterovirus, adenovirus, cytomegalovirus (CMV), Ebstein-Barr virus, herpes simplex virus, influenza virus, parvo B19, hepatitis C virus, HIV, etc.), the immune response or both. Initial presentation is the syndrome of acute pericarditis, often resolving within two weeks but may progress to pericardial effusion which may be serous, suppurative, or haemorrhagic. The diagnosis depends on the demonstration of rising titers of specific antibodies in the serum. A four-fold rise in serum antiviral antibodies is suggestive but not diagnostic per se. In most patients, pericardial viral infection is self-limiting and no specific treatment is necessary. 8. Neoplastic pericarditis Neoplastic pericarditis is also an important specific diagnosis to rule out in patients with pericarditis. It is responsible for about 5% of unselected cases of acute pericarditis and may metastasise to the pericardium, with the most common being lung and breast cancer and lymphomas. Lung cancer is the commonest malignancy giving early invasion of lymph nodes and thus being easily responsible for pericardial effusion. Primary tumours of the pericardium are less common. 9. Haemopericardium Accumulation of blood in the pericardial cavity usually occurs after rupture of a cardiac chamber (after myocardial infarction), coronary artery or a dissecting aneurysm. Rarer causes include scurvy, neoplasms and leukaemia. Pericardial tamponade may occur and need drainage. 10. Pneumopericardium Air in the pericardial cavity may result from stab wounds, perforation of an air-containing organ into the pericardium, by gas-forming organism or by introduction of air into the pericardial cavity. An X-ray of the chest reveals the presence of gas in the pericardial cavity. This usually does not require treatment, but the underlying cause requires treatment. CHRONIC CONSTRICTIVE PERICARDITIS Chronic constrictive pericarditis (CCP) is defined as a dense and rigid thickening of one or both layers of the pericardium with adhesions resulting in compression of the heart with impairment in the diastolic filling. Aetiology The most common causes include:  Tuberculosis  Idiopathic and viral pericarditis  Chest irradiation  Collagen vascular disease



Post-cardiotomy Malignancy

In developing countries with high prevalence of tuberculosis, it is most common cause of CCP. In India, tuberculosis is responsible for nearly two-third of the cases of CCP. The aetiology of CCP in the western world has undergone a significant change, with tuberculosis reported in only 0% to 1% of cases. However, with emergence of the AIDS pandemic these numbers are likely to increase again. The leading identifiable causes of CCP in western world are following cardiac surgery and radiation therapy, besides viral pericarditis, but such cases are possibly missed in India. Pathophysiology The pericardium undergoes thickening and calcification (normal thickness of the pericardium is 3 to 5 mm). The thickened peri-

cardium forms an encasement of the heart and is unable to stretch during diastole. The unyielding pericardium impairs the diastolic relaxation of the heart and thereby diminishes venous filling of the right ventricle. However, there is no interference with systole. The pathophysiological hallmark of pericardial constriction is equalisation of the end-diastolic pressures in all four cardiac chambers. This occurs because the filling is determined by the limited pericardial volume, not the compliance of the chambers themselves. Initial ventricular filling occurs rapidly in early diastole as blood moves from the atria to the ventricles without much change in the total cardiac volume. However, once the pericardial constraining volume is reached, diastolic filling stops abruptly. This results in the characteristic dip and plateau of ventricular diastolic pressures. The stiff pericardium also isolates the cardiac chambers from respiratory changes in intrathoracic pressures, resulting in Kussmaul’s sign (Figures 7 and Figures 8A and B).

Diseases of the Pericardium



Figure 7: Schematic representation of transvalvular and central venous flow velocities in constrictive pericarditis. During inspiration, the decrease in left ventricular filling results in a leftward septal shift, allowing augmented flow into the right ventricle. The opposite occurs during expiration. EA = Mitral inflow; LA = Left atrium; LV = Left ventricle; RA = Right atrium; RV = Right ventricle.

Figures 8A and B: Pressure recordings in a patient with constrictive pericarditis. (A) Simultaneous right ventricular (RV) and left ventricular (LV) pressure tracings with equalisation of diastolic pressure, as well as ‘dip and plateau’ morphology. (B) Simultaneous right atrial (RA) and LV pressure with equalisation of RA and LV diastolic pressure. The y-descent is prominent.

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Due to the reduction in venous filling, the stroke output falls and to compensate for decreased cardiac output the heart rate rises. The systemic pressure rises because of the limited cardiac filling. The liver and spleen are enlarged and the capsule is thickened as a consequence of chronic congestion. Haemodynamics in cardiac tamponade and constrictive pericarditis are compared in Table 4.

calcification of the pericardium.This is best seen in the left lateral or oblique views and is present in about two-thirds of the cases. In the lateral view, if the calcification is seen in the entire pericardium (i.e. anteriorly, inferiorly and posteriorly) the appearance is termed as ‘egg-shell pericardial calcification’ (Figure 9). The lung fields remain clear. Severe venous engorgement may lead to pleural effusions.

Symptoms and Signs The commonest complaint is the distension of the abdomen due to ascites and swelling of the feet. The next common complaint is dyspnoea and fatigue. On inspection, the neck veins are engorged, even in the standing position. A deep ‘y’ descent (Frederick’s sign) is seen. JVP is raised and increases/fails to decrease during deep inspiration (Kussmaul’s sign).The arterial pulse is of a low volume and the rhythm may be irregular indicating the presence of atrial fibrillation. Table 4: Haemodynamics in Cardiac Tamponade and Constrictive Pericarditis Tamponade Paradoxical pulse Equal left/right filling pressures Systemic venous wave morphology

Usually present Present Absent y descent

Inspiratory change in systemic venous pressure

Decrease (normal)

‘Square root’ sign in ventricular pressure

Absent

Constriction Present in ≈ 1/3 Present Prominent ‘y’ descent (M or W shape) Increase or no change (Kussmaul’s sign) Present

Inspection of the praecordium reveals a ‘quiet’ heart and prominent veins may be observed all over the chest. A systolic retraction at the apex may be observed. On palpation, a diastolic ‘tap’ or ‘shock’ may be palpated. It is due to the rapid filling of the right ventricle. The characteristic finding on auscultation is the ‘pericardial knock’.This is a sound due to rapid filling of the ventricle in the early rapid filling phase. It occurs about 0.08 to 0.12 second after the second sound in contrast to the normal third sound, which occurs a little later (0.13 to 0.16 s). The heart sounds are normal and usually no murmur is heard. Examination of the abdomen reveals an enlarged, smooth and tender liver. The chief finding in the abdomen, however, is the presence of ascites which is massive and out of proportion to the oedema on the legs (which may be minimal). It tends to refill very rapidly after aspiration. Investigations Electrocardiography The ECG findings are not characteristic but include low voltage of the QRS complexes, flattening or inversion of the T-waves and occasionally atrial fibrillation. X-ray 744

The heart size is usually normal or slightly smaller. The characteristic finding of constrictive pericarditis, however, is the

Figure 9: Chest radiograph showing marked pericardial calcifications in a patient with constrictive pericarditis.

Echocardiography This is perhaps the most useful investigation to diagnose constrictive pericarditis. The presence of thickened and/or calcified pericardium clinches the diagnosis. However, increased pericardial thickness can be missed on a transthoracic echocardiogram. Transoesophageal echocardiography is more sensitive and accurate in determining pericardial thickness. Doppler echocardiography is important in the evaluation of patients with suspected pericardial constriction. Doppler echocardiography frequently demonstrates restricted filling of both ventricles with a rapid deceleration of the early diastolic mitral inflow velocity (E wave) and small or absent a wave. In addition, there is substantial (>25%) respiratory variation of the mitral inflow velocity (Figure 10). There are signs of systemic venous congestion such as dilation of hepatic veins and distension of the inferior vena cava with lack of inspiratory collapse (Figure 11). CT/MRI CT and MRI allow accurate measurement of pericardial thickness and some assessment of diastolic filling patterns. Ancillary diagnostic findings include conical narrowing of the ventricles, atrial dilation, and enlargement of the inferior vena cava, hepatomegaly, and ascites. Excellent overall sensitivity (88%), specificity (100%), and accuracy (93%) have been reported for MRI. Increased pericardial thickening may not always imply

Diagnosis The combination of pulsus paradoxus, neck vein signs, ascites and pericardial ‘knock’ should pose no difficulty in the diagnosis. However, similar clinical pictures may be seen in tricuspid valvular diseases, restrictive cardiomyopathies and cirrhosis of the liver. Tricuspid valvular defects have their characteristic murmurs, which increase in intensity on deep inspiration. Cardiomyopathies may be diagnosed on echocardiograms.

Figure 10: Doppler echocardiography showing respiratory variation of the mitral valve inflow velocity in a case of constrictive pericarditis.

Diseases of the Pericardium

relaxation of the ventricle during diastole and is usually more than one-third of the systolic pressure. The right atrial tracings show a ‘M’ or ‘W’ shaped pattern corresponding to the right ventricular pressures. It has been observed that the pulmonary wedge pressure, pulmonary artery diastolic pressure, right ventricular end-diastolic pressure, mean right atrial pressure and superior vena cava pressures tend to be equal or near-equal in constrictive pericarditis.

Prognosis Without surgery the prognosis is poor. Long-standing cases of constrictive pericarditis develop hypoproteinaemia due to a protein-losing enteropathy. They also develop a myocardial failure (probably due to fibrosis) which does not respond to digoxin, even after pericardiectomy. Treatment Medical management of constrictive pericarditis, especially in less severe cases, is aimed at relief of fluid overload with careful administration of diuretics and is at best, palliative. Surgical pericardiectomy remains the only definitive management and should be done before calcification and myocardial involvement progresses. However, if the cause is thought to be tuberculosis, then a few weeks on antituberculous drugs should precede the surgery. The results of surgery are very gratifying. Other aetiological causes should get their respective treatments.

Figure 11: M mode showing dilated IVC with minimal respiratory variation in a case of constrictive pericarditis.

constriction, and conversely, constrictive pericarditis can present with normal pericardial thickness on non-invasive imaging, histology, or a combination of these. Cardiac catheterisation Though a very valuable tool in the diagnosis of constrictive pericarditis in the past, it is no longer used routinely after the advent of echocardiography. Catheterisation reveals an elevation of the right ventricular end-diastolic pressure, characterised by an early diastolic ‘dip’ and a late diastolic ‘plateau’. The end-diastolic pressure is high due to incomplete

CONCLUSION Pericarditis remains a common disorder, particularly as a complication of modern treatments such as cardiac surgery, percutaneous interventions, and radiation therapy. Pericardial effusion and constrictive pericarditis are infrequent sequelae that can be diagnosed accurately in most cases by use of modern imaging methods. Cardiac tamponade, a medical emergency should be promptly diagnosed and managed with urgent pericardiocentesis. Management of uncomplicated pericarditis rests largely on NSAIDs with the addition of colchicine for relapses. Pericardial effusion can be managed percutaneously in most cases, whereas definitive treatment for constriction remains surgery. RECOMMENDED READINGS 1.

Bernhard Maisch, Arsen D. Ristic. Practical aspects of the management of pericardial disease. Heart 2003; 89: 1096-1103.

2.

Hoit BD. Management of effusive and constrictive pericardial heart disease. Circulation 2002; 105 (25): 2939-42.

3.

Imazio M, Spodick DH, Brucato A, et al. Controversial issues in the management of pericardial diseases . Circulation 2010; 121: 916-28.

4.

LeWinter MM, Kabbani S. Pericardial diseases. In: Braunwald E, et al. editors, Heart Disease: A Textbook of Cardiovascular Medicine, 7th Ed. Philadelphia: Saunders; 2004: pp. 1757-79.

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12.30

Surgical Management of Heart Disease

INTRODUCTION The era of cardiac surgery was ushered more than a century ago when Ludwig Rehn of Frankfurt operated to relieve cardiac tamponade and sutured a stab wound to the right ventricle in September 1896. However, ‘open-heart surgery’ as we know it today began a little over fifty years ago with the development of an artificial ‘heart-lung machine’ by John H. Gibbon, Jr. On May 6, 1953, the Gibbons-IBM oxygenator was successfully used for total substitution of the heart and lungs for 26 minutes, enabling correction of an atrial septal defect, and thereby the world’s first successful open heart surgery. Since then, technological advances and myocardial protection techniques evolving continuously over the last six decades have enabled routine conduction of successful and complex cardiac surgery, totally bypassing the vital function of lungs and heart for hours to days. Cardiac surgery broadly encompasses: surgery for congenital heart disease; surgery for valvular heart disease; surgery for ischaemic heart disease and cardiac transplantation and related heart failure surgery. SURGERY FOR CONGENITAL HEART DISEASE Congenital heart disease (CHD) has an overall incidence of 0.8%. The patient population is diverse. Defects, presentation, diagnosis, treatment and outcome differ widely according to age of presentation and complexity of lesions. These can be broadly classified into acyanotic and cyanotic heart defects. A. Acyanotic 

Increased pulmonary blood flow (Left to Right shunt) Atrial septal defect Ventricular septal defect Patent ductus arteriosus Partial anomalous pulmonary venous connection

All these patients must be operated upon before schoolgoing age, unless progressive pulmonary arterial hypertension supervenes, in which case, early surgery is indicated to prevent the development of Eisenmenger complex. 

Normal pulmonary blood flow Aortic stenosis/bicuspid aortic valve Mitral regurgitation Coarctation of aorta Mitral stenosis

B. Cyanotic (Right to Left shunt) 

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Increased pulmonary blood flow Truncus arteriosus Single ventricle Transposition of great arteries Total anomalous pulmonary venous connection Hypoplastic left ventricle

Muhammad Abid Geelani, Nikhil Prakash Patil 

Decreased pulmonary blood flow Tetralogy of Fallot Pulmonary atresia Tricuspid atresia with pulmonary stenosis Total transposition of great arteries with pulmonary stenosis Ebstein malformation

All blue babies must be closely observed for cyanotic spells. Severe and frequent spells constitute an indication for urgent operation. Early surgery is preferred as there is always a risk of paradoxical embolism with its complications. Surgery may be classified into: 



Palliative, e.g. Blalock-Taussig shunt (BT shunt), cavopulmonary shunt (Bi-directional Glenn shunt), pulmonary artery banding. Corrective, e.g. atrial/ventricular septal defect repair, ligation of patent ductus arteriosus, arterial switch for simple transposition of great arteries.

Conditions such as patent ductus arteriosus, coarctation of the aorta, atrial septal defect, partial atrioventricular canal and tetralogy of Fallot can now have corrective surgery with hospital mortality ranging from 0% to 5% depending upon the age at surgery and the complexity of the condition. Many complex conditions such as pulmonary atresia, transposition of the great arteries, tricuspid atresia and many other conditions previously considered inoperable are now being successfully treated with acceptable mortality and satisfactory long-term results. SURGERY FOR VALVULAR HEART DISEASE Acquired disease of heart valves can be treated by repair procedures or by replacement with an artificial prosthesis (Figures 1 to 3). The valves commonly affected are the aortic, mitral and tricuspid valves; the commonest pathologies are rheumatic and degenerative disease. Rheumatic heart disease, which has been practically eradicated from Western countries, continues to be a problem in South Asian countries. Rheumatic mitral stenosis (MS) without mitral regurgitation (MR) may initially be treated by balloon mitral valvuloplasty (BMV) or rarely with closed mitral valvotomy when BMV is not possible because of difficulty in percutaneous access to mitral valve, e.g. in inferior vena cava obstruction or inability to puncture the interatrial septum. But when echocardiography suggests unfavourable anatomy (Wilkins score > 8)* or when a left atrial clot is present, it is best to do as an open-heart procedure and * A scoring system exists to grade the morphological changes in the mitral valve during assessment with echocardiography. This takes into account 4 characteristics; leaflet mobility, leaflet thickening, valve calcification and involvement of the subvalvular apparatus. The involvement is graded from 0-4. A total score of more than 8 is predictive of a low success post percutaneous mitral valvuloplasty.

Mitral regurgitation may be caused by degenerative changes in the leaflet, prolapse of the leaflets, rupture of chordae tendineae or due to annular dilatation or tethering of the subvalvular apparatus secondary to ventricular dilatation. In such cases, a repair procedure may be considered. This is usually combined with implantation of a flexible or rigid annuloplasty ring to support the repair. All patients in NYHA class II and above, having orthopnoea, severe pulmonary hypertension, gradually dilating left ventricle and falling ejection fraction (LVEF), must be referred for early surgical procedure for better outcome.

Figure 1: Tilting disc mechanical valve (TTK Chitra valve).

Figure 2: Bileaflet mechanical valve.

Figure 3: Bioprosthetic valve (Pericardial).

repair/replacement of the valve may be indicated. Nowadays, BMV is done even in presence of left atrial appendage clot after giving anticoagulation therapy for 6 weeks. All patients in New York Heart Association (NYHA) functional class II or above, having dyspnoea, orthopnoea, severe pulmonary hypertension,

If a repair is not possible and mitral valve replacement is indicated, there is a wide choice of prosthetic and bioprosthetic valves available. Mechanical heart valves have evolved from a ball and cage design to the tilting disc valve to the bi-leaflet prosthesis. Currently, the bi-leaflet pyrolytic carbon low profile mechanical prosthesis is the most commonly used prosthesis as it has the advantage of central flow and excellent long-term results. The preservation of posterior leaflet with/without anterior chordal apparatus provides better long-term result as it maintains left ventricular geometry. Lifelong anticoagulation is mandatory for all mechanical heart valves to prevent thromboembolic complications. In spite of this, the incidence of thromboembolic complications is 1.5% to 2% per patient year. The alternative to the use of mechanical prosthesis is the use of bioprosthetic valves, which have a biological origin. These are generally stent-mounted porcine valves or pericardium treated with buffered glutaraldehyde to promote cross linkages between the collagen bundles. Anticoagulation is not essential for recipients of bioprosthetic valves after 6 weeks of surgery unless they are in atrial fibrillation. The main disadvantage of bioprosthetic valves is their limited durability; many of them degenerate and even calcify in 10 to 15 years time. The longterm durability of these prostheses have been improved by the use of proprietary anti-calcification treatment and by the development of valves constructed from glutaraldehydetreated bovine pericardium mounted within a specially designed stent. The hospital mortality for mitral valve replacement for primary non-ischaemic mitral valve disease is between 2% and 7%. The survival rate following surgery is 65% to 80% at 5 years, 50% to 60% at 10 years, and 30% to 40% at 15 years from several reported series. Most patients who need replacement of the aortic valve are in the older age group and have calcific aortic stenosis. Aortic regurgitation is either due to rheumatic heart disease causing fibrosis and shrinkage of the leaflets or due to annular dilation as in cystic medial necrosis or in aortic aneurysms and dissections. Aortic valve replacement has better early and late survivals than mitral valve replacement because of afterload reduction and low thrombogenicity in a high flow area. Small aortic root and patient-prosthetic mismatch is still a concern which leads to higher gradient across aortic valve and poor exercise tolerance. It is better to use stentless valves in the aortic position (autografts as in the Ross operation, homografts or xenografts) or root enlargement techniques in such situations. Enlarging left ventricle, syncope or angina in aortic valve disease warrant early surgery.

Surgical Management of Heart Disease

left atrial clot, must be referred for percutaneous/surgical intervention.

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The tricuspid valve is generally treated with repair procedures and the implantation of annuloplasty rings rather than valve replacement as prosthetic valves do not function well in this relatively low pressure area. If the patients are offered surgery during late stages of the disease, the results of valve replacement are adversely affected because of left ventricular dilatation, pulmonary hypertension and congestive heart failure with hepatic and renal dysfunction. Surgery for valvular heart disease is now standardised in Indian centres but problems of late referrals, cost, maintenance of optimal anticoagulation and proper follow-up are the limiting factors. SURGERY FOR ISCHAEMIC HEART DISEASE Coronary artery bypass grafting (CABG) is one of the procedures with the highest impact in the history of medicine. CABG is based on the underlying principle that the symptoms and clinical events of coronary artery disease (CAD) are related to stenotic coronary lesions that can be identified by angiography, and if those lesions are bypassed, then those symptoms and clinical events become less common. Surgical attempts at increasing blood flow to the ischaemic myocardium originated a century ago when Alexis Carrel anastomosed a carotid artery segment between the descending aorta and the left coronary artery in a dog, for which he was later awarded the Nobel prize. Three decades later, Arthur Vineberg started implanting the left internal mammary artery (LIMA) into the anterior myocardial territory of patients with CAD in order to increase arterial inflow and relieve angina, with some experiencing prolonged symptomatic improvement. Surgery on the coronary arteries was introduced clinically in 1958 by William Longmire, who reported on the use of endarterectomy in five patients operated without cardiopulmonary bypass (CPB). The first reported successful CABG operation took place in 1964 in Leningrad, where Vasilii Kolesov grafted a LIMA to the left anterior descending (LAD) artery without CPB. The world’s first CABG program started 3 years later in Cleveland, as Favaloro began to routinely use reversed saphenous veins for aortocoronary grafting. CABG today constitutes the keystone of adult cardiac surgery, but novel surgical, percutaneous, and medical alternatives loom large on the horizon. Yet CABG is constantly evolving and remains the most durable means of revascularisation for patients with CAD. Although CAD is largely diagnosed by conventional coronary angiography, evolving less invasive techniques like cardiac CT angiography may become the diagnostic modality of choice in the future.

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or two-vessel disease not involving the proximal LAD and with only a small area of viable myocardium or no objective evidence of ischaemia on non-invasive testing. Several studies have shown that emergent surgery for relentless unstable angina or non-Q wave MI in the context of failed or unfeasible percutaneous coronary intervention (PCI) is associated with an increase in peri-operative mortality compared with semi-urgent CABG, although surgical revascularisation may still be preferable to a conservative strategy. Consequently, an attempt should be made at stabilising these patients with maximal medical therapy (and in some cases the temporary use of an intra-aortic balloon pump) to allow surgery to be performed on a non-emergent basis with a lower operative risk. Intravenous thrombolytic therapy and primary PCI have supplanted CABG as the first line of therapy for patients in the acute period of ST segment elevation MI. As a result, residual ongoing ischaemia and cardiogenic shock despite maximal non-surgical therapy now constitute the main indication for emergent CABG in acute MI patients. Other acute indications include failed thrombolysis and demonstration of a large myocardial territory at risk in combination with an unsuitable anatomy for PCI, a left main coronary stenosis, an LV failure with severe coronary stenosis outside the initial infarct area, significant valve disease, or a mechanical complication of MI. PCI may occasionally result in intractable coronary dissection or plaque haemorrhage, threatened proximal occlusion with a large myocardial area at risk, loss of a foreign body in a crucial anatomical position, or coronary rupture. These complications are indications for immediate surgical intervention, but inhospital mortality is high in these patients (10% to 14%) because of unfavourable selection factors such as haemodynamic compromise and severe impairment of the coagulation system. CABG should NOT be attempted on an emergency basis in stable patients in whom PCI has failed because of unsuitable anatomy or no-reflow state. Conduit Selection The choice of conduit is determined by the quality of available conduit, the suitability of the target vessels and the age and co-morbidity of the patient.

CABG is indicated in patients with chronic stable angina and left main coronary artery stenosis ≥ 50%, left main equivalent (i.e. proximal stenosis of at least 70% of the proximal LAD and circumflex), three-vessel disease [especially if left ventricular ejection fraction (LVEF) is less than 0.50], and one- or two-vessel disease with either a large myocardial area at risk on noninvasive testing or depressed LVEF.

Internal mammary artery grafts The internal mammary artery (IMA) is the best conduit available for CABG and provides short- and long-term survival benefits in all patients subgroups, including those 75 years of age or older. Use of the LIMA to graft the LAD (or a main target vessel on the left coronary circulation if the LAD is free of disease) should be performed except in exceptional circumstances such as pre-existing or iatrogenic damage to the LIMA, poor flow from severe spasm, injury, or dissection, involvement of the LIMA in providing collateral supply to the lower extremity, mediastinal irradiation (if other arterial conduits are available), and emergency CABG with cardiogenic shock.

CABG may also be indicated for symptomatic improvement in low-risk patients with significant CAD who do not fulfil the above criteria but experience disabling myocardial ischaemia or unacceptable lifestyle restrictions on maximal medical therapy. CABG is not preferred over PTCA in patients with one-

The use of bilateral IMAs should be considered over single IMA grafting whenever, possible in young patients, as they may lead to lower reoperation rates, decreased late PCI rates, and longterm survival benefits. Relative contraindications to the use of bilateral IMAs include emergency operation, advanced age,

Radial artery grafts The radial artery likely constitutes, after the left and right IMA, the next best conduit for CABG. Radial artery harvest is contraindicated in the presence of insufficient collateral supply to the hand or Raynaud’s syndrome, in patients with high manual demands such as professional musicians, in the very elderly (who have a high prevalence of radial arteriosclerosis), during emergency operations, and in patients who are likely to require postoperative vasopressors such as those with very poor LV function. Saphenous vein grafts Saphenous veins are known not to be the conduit of choice for CABG due to proven lower short- and long-term patency than IMAs. Nevertheless, the long saphenous veins are still used in the majority of CABG operations by a large number of surgeons for practical reasons. They are also particularly useful for specific situations. They constitute the most readily available CABG conduit, provide immediate and reliable coronary flow with a low propensity for spasm or flow compromise during lowoutput states, and provide a time-honoured means of coronary revascularisation during emergency procedures or in patients with severe co-morbidity and limited life expectancy in whom procedural simplicity, expeditiousness, and reliability are most desirable. Other conduits The gastroepiploic artery, short saphenous vein and inferior epigastric artery constitute additional available conduits that are rarely needed for primary revascularisation, but which may be useful as a last resort in patients with severe conduit shortage, e.g. redo surgeries. Off-pump: CABG versus CPB CABG can be carried out with CPB (on-pump) or without (offpump: OPCABG). Many surgeons elect to perform CABG on pump, until recently, the advantages of a still, clear operating field, myocardial protection and haemodynamic and respiratory control, appeared to outweigh the disadvantages of CPB. However, recent improvements in methods of stabilising the heart have led to some institutions adopting OPCABG expecting to see lower morbidity and mortality. OPCABG appears to offer favourable outcomes, leading to reductions in postoperative atrial fibrillation, transfusion requirements, inotrope requirements, ventilation times, length of hospital and intensive care unit stay, and cost compared to on-pump coronary artery surgery. But, till date, no randomised trial has been sufficiently powered to detect the widely expected difference in death or stroke at 30 days or one year. Nevertheless, OPCABG is a suitable alternative to CPB in experienced centres. It should probably be the technique of choice in patients with porcelain (calcified) aorta, poor LV function, renal dysfunction, pulmonary dysfunction and advanced age or other co-morbidity.

SURGERY FOR HEART FAILURE Heart Transplantation Dr. Christiaan Barnard performed the world’s first human heart transplant operation on 3 December 1967. The patient, Louis Washkansky, was a 54-year-old grocer, suffering from diabetes and incurable heart disease. Washkansky survived the operation and lived for eighteen days. However, he succumbed to pneumonia induced by the immunosuppressive drugs he was taking. Barnard later wrote, ‘For a dying man it is not a difficult decision because he knows he is at the end. If a lion chases you to the bank of a river filled with crocodiles, you will leap into the water, convinced you have a chance to swim to the other side.’ Though the first patient with the heart of another human being survived for only a little more than two weeks, Barnard had passed a milestone in a new field of life-extending surgery. Since then, nearly 60,000 of these operations have been done worldwide, including over a hundred in Indian centres. The main limiting factor is the availability of suitable donors and the logistics of the procedure. The prognosis for heart transplant patients has greatly increased over the past 20 years. With the current immunosuppressive therapy using anti-thymocyte globulin, corticosteroids and azathioprine or mycophenolate survival is now 80% at 1 year, 70% at 5 years and 50% at 10 years. After the 20% mortality during the first year, the yearly mortality is approximately 4% per year. These results can be achieved only if the patients are carefully followed-up and monitored with percutaneous myocardial biopsy at appropriate time depending upon the clinical progress and modification of the immunosuppressive therapy based on the results of myocardial biopsy. Tony Huesman was the world’s longest living heart transplant recipient, having survived for 31 years with a transplanted heart (he died on August 10, 2009 of cancer)— the operation was performed in 1978 at Stanford University by American heart transplant pioneer Dr. Norman Shumway.

Surgical Management of Heart Disease

diabetes mellitus, obesity, and severe COPD for which the patient requires systemic steroid therapy.

In patients with severe pulmonary vascular disease heart-lung transplantation may be indicated but this operation is technically more difficult to perform and to manage post-operatively, and carries significantly lower survival rates. Cardiomyoplasty using latissimus dorsi muscle is not used anymore but Myosplint and its modification, which prevent dilatation of LV, are currently undergoing clinical trials. The artificial heart, which is essentially a ‘bridge to transplantation’, at present holds a very promising future as externally rechargeable energy sources are in the final stages of clinical trials. RECOMMENDED READINGS 1.

David D Yuh, Luca A Vricella, William A Baumgartner. The Johns Hopkins Manual of Cardiothoracic Surgery; 1st Ed. McGraw-Hill Professional; 2007.

2.

Frank W Sellke, Pedro J del Nido, Scott J Swanson. Sabiston and Spencer’s Surgery of the Chest; 7th Ed. Elsevier Saunders; 2004.

3.

Nicholas T Kouchoukos, Eugene H Blackstone, Donald B Doty, et al. Kirklin/ Barratt-Boyes Cardiac Surgery; 3rd Ed. Churchill Livingstone; 2003.

4.

Stephen Westaby, Cecil Bosher. Landmarks in Cardiac Surgery; 1st Ed. Informa Healthcare; 1998.

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Diseases of the Aorta Manotosh Panja

INTRODUCTION The aorta is composed of a thin intima, a thick media and a thin adventitia. The media is composed of laminated but intertwining sheets of elastic tissue in a spiral manner that gives it not only tensile strength but also distensibility and elasticity. The aorta is divided anatomically into thoracic and abdominal segments. The thoracic aorta is further divided into ascending, arch and descending segments, while the abdominal aorta consists of suprarenal and infrarenal segments. Aortic isthmus is the point where aortic arch joins the descending aorta. This is especially vulnerable to trauma as it is the junction of the mobile ascending aorta and arch and relatively fixed descending aorta.This is also the site for coarctation of the aorta. Other aortic anomalies could be right-sided aortic arch, double aortic arches and cystic medial degeneration as in Marfan’s syndrome and acquired degeneration of the aortic wall secondary to ageing, arteriosclerosis, hypertension and specific inflammatory, infectious or autoimmune diseases. AORTIC ANEURYSMS Aortic aneurysm is a localised dilatation of the aorta having a diameter at least 1.5 times that of the expected normal diameter of that given aortic segment. A true aneurysm involves all the three layers of the aortic wall. It is produced by the progressive distension of the aortic wall that is weakened by the degeneration of the tunica media. Sometimes, there may be a pseudoaneurysm or false aneurysm, which is actually a welldefined collection of blood and connective tissue outside the vessel wall as a consequence of a contained rupture of the aortic wall. Morphologically, an aneurysm is either fusiform or saccular. Fusiform aneurysm is more common. It is a symmetrical dilatation of the full circumference of the aortic wall. Saccular aneurysm on the other hand involves more localised dilation appearing as an outpouching of only a portion of the aortic wall. Incidence The post-mortem incidence of aortic aneurysm is 1% to 3%. There has been a gradual decline in the incidence of syphilitic aneurysms, but this has been offset by an increase in the atherosclerotic variety. ABDOMINAL AORTIC ANEURYSMS Abdominal aortic aneurysms (Figure 1) are far more common than thoracic aneurysms. They are 8 to 10 times more frequent in men than in women. Their incidence shows a rapid rise after 55 years in men and 70 years in women.

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Aetiopathogenesis These aneurysms are usually atherosclerotic. Very rarely they may be traumatic, congenital or myxomatous. Most are

Figure 1: Post-mortem specimen of abdominal aortic aneurysm. Bilateral renal artery stenosis with infrarenal aortic involvement.

infrarenal and fusiform, varying in size from a few millimetre to ten centimetre. Only 2% to 5% are suprarenal. Absence of vasa vasorum in the infrarenal aorta coupled with atherosclerotic thickening of intima may jeopardise nutrient and oxygen supply to the media of this segment. This may hasten degeneration of tunica media in genetically predisposed subjects due to increased elastolytic activity and lead to aneurysm formation. Surprisingly, diabetes mellitus patients are not prone to development of abdominal aortic aneurysm. Clinical Features Symptoms Backache, abdominal pain, limb oedema and venous congestion are common. Acute pain and hypotension secondary to rupture may occur. Signs There is palpable pulsatile mass in the abdomen, presence of peripheral vascular disease, signs of distal embolisation, and haemodynamic collapse. Majority of the cases are asymptomatic and are detected on incidental examinations like abdominal X-ray or ultrasound.

The major risk of abdominal aortic aneurysm is its rupture. Expansion or impending rupture are heralded by sudden onset of new or worsening pain that is characteristically constant, severe, localised to back or lower abdomen and sometimes radiating to the groin, buttocks and legs. The pulsatile abdominal mass, if present already, may become tender on palpation. Abrupt onset of back pain and abdominal pain with tenderness, and hypotension characterises actual rupture, but this pathognomonic sign is present in only one-third cases. In 80% of the cases rupture occurs in the left retroperitoneum and is signalled by haematomas in the flanks and groin. Most of the remainder rupture into the peritoneal cavity, causing uncontrolled haemorrhage and result in abdominal distension. Rupture into the duodenum presents as massive gastrointestinal haemorrhage. Rarely, it may rupture into inferior vena cava, iliac or renal vein producing haemodynamic collapse and acute high-output cardiac failure. Rupture is associated with high mortality; 60% die before any medical intervention and 50% of those survive after operative correction. Diagnosis and Size Estimation Aneurysm may be detected and their size estimated by physical examination, routine roentgenography, abdominal crosssectional ultrasonography, digital subtraction angiography, abdominal aortic angiography, CT scan and MRI. In about 70% of cases, plain X-rays show a curvilinear or linear rim corresponding to the aneurysm wall. In fact aneurysm usually presents as a paravertebral soft tissue mass.With rupture, there is distortion of the psoas muscle shadow and absence of gas in the bowel over the aneurysm. Abdominal ultrasound is the most easily available and inexpensive way of detecting an aneurysm and assessing its size, wall thickness and presence of thrombus. Aortography is a risky procedure and is used in selective pre-operative cases to assess suprarenal extent of the aneurysm, any associated iliofemoral disease and for defining renal and mesenteric arterial anatomy. It may underestimate aneurysmal size in the presence of non-opacified mural thrombus lining its wall. CT scan is an extremely accurate method for both diagnosing and sizing the abdominal aortic aneurysms. MR angiography is also a highly effective method in delineating aneurysm anatomy pre-operatively and it is safe alternative to aortography. Pre-operative aortography is largely replaced by CT scan and MRI now-a-days considering their noninvasive nature and high sensitivity and specificity. Treatment Medical therapy with beta-blockers slows the expansion of aneurysm although its efficacy is less in aneurysm of bigger size. Aneurysmectomy and replacement by a synthetic

prosthesis, usually Dacron, is advised for all abdominal aortic aneurysms 6 cm in diameter or wider since three-fourth of them will rupture. Operative mortality is 4% to 6% in elective repair. The benefit of surgery for asymptomatic aneurysms 4 to 5 cm in size is not yet established. Complications of surgery include stenosis or occlusion of the prosthetic graft, false aneurysm formation, infection and rupture. Endovascular treatment in the form of percutaneously implanted expanding endovascular stents are new interventional options for the treatment of abdominal aortic aneurysms not suitable for surgery (older patients, patients at higher risk for surgery). Endoleaks (persistent residual flow in aneurysmal sac) are a major disadvantage with this option.

Diseases of the Aorta

Younger patients (50 years old or less) are more likely to be symptomatic. The most frequent complaint is a steady, gnawing pain in the hypogastrium or lower back, lasting for several hours or days at a time and not affected by movement. A pulsatile mass extending variably from the xiphoid process to the umbilicus may be felt. Stagnation of blood in the aneurysmal sac forms mural thrombus which may embolise to distal arteries leading to absence of femoral and lower limb pulses and bruits over affected arteries. Rarely, an expending aneurysm can compress inferior vena cava or one of the iliac veins to produce lower limb oedema and venous congestion.

THORACIC AORTIC ANEURYSMS Thoracic aortic aneurysms are divided according to anatomical location into ascending arch and descending aortic aneurysms, each differing in aetiology, natural history and therapy. Ascending aorta aneurysms most often result from cystic medial necrosis. Other causes are Marfan’s syndrome, syphilis, mycotic aneurysm secondary to aortic bacterial endarteritis and rarely atherosclerosis. Aortic arch aneurysms may be due to atherosclerosis, cystic degeneration, syphilis or other infections while descending aortic aneurysms are predominantly atherosclerotic. The basic pathogenetic mechanism is progressive dilatation of the aortic wall weakened by tunica media degeneration. Clinical Manifestations Forty per cent of the patients are asymptomatic and are diagnosed on incidental physical examination or X-ray. Symptoms reflect either a vascular consequence of the aneurysm or a local mass effect. Vascular consequences are aortic regurgitation and secondary congestive heart failure due to aortic root dilatation, myocardial ischaemia due to coronary artery compression by enlarged sinuses of Valsalva, rupture of sinus of Valsalva into the right heart producing continuous murmur with congestive heart failure and thromboembolism causing stroke, lower extremity ischaemia, renal infarction or mesenteric ischaemia. Local mass-effects depend on anatomical location. Ascending aortic aneurysm may cause superior vena cava syndrome due to compression of the superior vena cava. Arch aneurysms cause superior vena cava syndrome; tracheal or main stem bronchus obstruction leading to wheeze, cough, dyspnoea (may be positional), haemoptysis and recurrent pneumonitis. Descending aortic aneurysms may cause trachea or main stem bronchus compression, oesophageal compression producing dysphagia or recurrent laryngeal nerve compression producing hoarseness. Steady, deep, boring and sometimes excruciating chest or back pain develop due to compression of intrathoracic structures or due to erosion of adjacent bone. Aneurysms eroding through the chest wall are visible as pulsating masses. The most serious consequence of thoracic aneurysm is rupture that is heralded by sudden increase in the intensity of pain. Rupture most commonly occurs into the left intrapleural space or the intrapericardial space and presents as hypotension. Next common site is the oesophagus that presents as life-threatening haematemesis. Thoracic aneurysm may also develop aortic dissection.

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Diagnosis Many thoracic aneurysms, except for smaller ones, are evident on chest X-ray. Transthoracic Echocardiography (TTE) is useful in the imaging of aortic valve and proximal aortic root. Transoesophageal Echocardiography ( TEE) can help in assessment of aneurysm of ascending and descending aorta but it cannot visualise aneurysm of the arch. Contrast CT-scan and MR angiography are very accurate in detecting and sizing aneurysms. Aortography was a preferred pre-operative modality to define the anatomy of the aneurysm. However, as in the case of abdominal aorta, CT and MR angiogram are now often sufficient in most of the cases to define aortic and branch vessel anatomy. MR angiography is preferable to CT scanning when the aortic root is involved. Treatment Medical therapy is directed towards risk factor reduction and control of blood pressure. Aneurysmectomy and replacement by a prosthetic sleeve or composite graft-valve (in case of ascending aorta) is indicated for aneurysms 6 cm or larger; however, in case of Marfan’s syndrome, bicuspid aortic valve or rapidly growing aneurysms, early surgery is indicated. Propranolol may be used to delay the surgery in smaller aneurysms. Surgical repair of arch aneurysms is particularly challenging with high incidence of stroke. Descending thoracic aneurysmectomy may produce post-operative paraplegia due to interruption of spinal cord blood supply. Transluminally placed endovascular stent grafts is an alternative approach for treating descending aneurysms in patients with higher risk for surgery. DISSECTION OF THE AORTA Aetiopathogenesis Aortic dissection is initiated by entry of blood through an intimal tear into a degenerated tunica media of the thoracic aorta. The medial degeneration may occur due to classical cystic medial necrosis or connective tissue disorders like Marfan’s or EhlersDanlos syndrome. The blood jet divides the media into two producing a false lumen.The inner portion of the dissected wall forms an intimal flap. The intimal flap may be pushed into the true lumen, by the false lumen distended with blood, or it may be torn open by the blood jet producing an exit site. Old age (50 to 70 years), female sex, pregnancy, hypertension, bicuspid or unicuspid aortic valve, giant cell arteritis, Noonan and Turner syndromes and cocaine abuse may predispose to dissection. Aortic dissection occurs at a rate of 5 to 10 cases per million population per year. Classification (Figure 2) DeBakey classification Type I: Begins in the ascending aorta and extends to the descending aorta and arch. Type II: Confined to the ascending aorta. Type III: Originates in the descending aorta and extends distally or rarely, retrograde into arch and ascending aorta.

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Stanford classification Type A: All dissections involving the ascending aorta, regardless of the site of origin. Type B: All dissections not involving the ascending aorta.

Figure 2: Schematic diagram of classification of aortic dissection.

Descriptive classification Proximal: DeBakey types I and II or Stanford type A. Distal: DeBakey type III or Stanford type B. Proximal dissections are twice more common and more lethal than distal dissections. Clinical Picture A tearing, ripping or severe stabbing pain, from its initiation and with a tendency to migrate from its point of origin to other sites following the course of dissection is typically present in majority of cases except for those with chronic dissections. Severe pain from onset differentiates it from myocardial infarction. Anterior chest pain or neck, throat, jaw or face pain usually signifies ascending aorta involvement and interscapular or back, abdomen or lower limb pain that of descending thoracic aorta. Obstruction of the branches by compression of the true lumen by the distended false lumen or by obstruction of the vessels orifices by a mobile intimal flap may produce pulse deficits, pseudohypotension, syncope, cerebrovascular accident, cardiac arrest or sudden cardiac death, ischaemic peripheral neuropathy and paraplegia. Pulse deficits and neurological manifestations are more common in proximal dissection. Hypertension is seen in 80% to 90% of distal dissection and hypotension is more common in proximal dissection. Aortic regurgitation due to dilatation of aortic root and annulus, detachment of aortic leaflet or prolapse of a mobile intimal flap through aortic orifice is the characteristic of proximal dissection and results in congestive cardiac failure. The murmur has a musical quality and radiates along the right sternal border. Syncope without a focal neurological sign heralds rupture of a proximal dissection into pericardial sac producing cardiac tamponade or that of distal dissection into the intrapleural space. Investigations Anaemia may develop from significant haemorrhage or sequestration of blood in the false channel. A mild-tomoderate polymorphonuclear leucocytosis (10,000-14,000/ mm3) is common. Lactate dehydrogenase (LDH) and bilirubin levels are sometimes elevated. Serum glutamic oxaloacetic transaminase (SGOT) and CK-MB are usually normal, unless associated myocardial infarction develops along with

TTE is a useful tool for the diagnosis of ascending aortic dissections. However, it is limited by its inability to show the distal extent. TEE is highly sensitive and specific for evaluating proximal aortic dissection. Development of helical CT with multiplanar and 3D reconstruction and CT angiography has made CT scan a highly sensitive (83% to 94%) and specific (87% to 100%) mode for diagnosis of aortic dissection. It is fast replacing the conventional angiography (Figures 3A and B and Figure 4) as a standard diagnostic test in many centres. MRI although highly sensitive and specific it is used preferably for chronic aortic dissection and post surgical follow-up. Treatment Therapy is aimed at halting the progression of the dissecting haematoma. Without treatment 25% of the patients die within

Figures 3A and B: Aortogram showing aortic dissection. (A) pre-stenting and (B) post-stenting.

24 hours, more than 50% within the first week, 75% within one month, and more than 90% within one year. Early emergency treatment All patients should be admitted immediately to an intensive care unit. Initial therapeutic goals are the elimination of pain and reduction of systolic blood pressure to 100 to 120 mm Hg with a potent vasodilator like sodium nitroprusside. Nitroprusside when used alone can cause increase in the dp/dt so it should be used with a beta-blocker.

Diseases of the Aorta

dissection. ECG abnormalities are particularly common in Stanford type A aortic dissections. ST depression is most common abnormality. Sometimes, patients present with inferior wall MI due to involvement of right coronary sinus. Chest X-ray may reveal widening of the aortic arch in 40% to 50% of cases, change in configuration of the aorta on successive X-ray, obliteration of the aortic knob with displacement of the trachea to the right, localised hump on the aortic arch and an increase in distance from intimal calcification to the outer edge of the aortic shadow of > 1 cm (calcium sign).

Propranolol is used in incremental doses of 1 mg intravenous every five minutes until there is an evidence of satisfactory betablockade, usually indicated by a pulse rate of 60 to 80 beats/ min. Labetalol and esmolol can also be used in this setting. Patients who have contraindication for beta-blocker therapy should be put on cardioselective calcium channel blockers. In chronic stable dissection propranolol is given orally in dose of 20 to 40 mg six hourly. Definitive subsequent therapy Results of surgical therapy is superior to medical therapy in acute (< 2 weeks) proximal dissection and, conversely medical therapy offers a relative advantage over surgery in most cases of uncomplicated acute distal dissection (Table 1). Table 1: Indications for Definitive Therapy in Aortic Dissection Surgical Treatment of choice for acute proximal dissection Treatment of choice for acute distal dissection complicated by progression with vital organ compromise Rupture or impending rupture Aortic regurgitation (rare) Retrograde extension to the ascending aorta Dissection in Marfan’s syndrome Medical Treatment of choice for uncomplicated distal dissection Treatment for stable, isolated arch dissection Treatment of choice for stable chronic dissection (uncomplicated dissection presenting two weeks or later after onset)

Long-term medical therapy to control hypertension and reduce dp/dt is indicated for all patients regardless of whether they have received definitive surgical or medical therapy. Follow-up of patients should include repeated physical examinations, periodic chest X-rays, CT scans or digital substraction angiograms (DSA) for evidence of localised aneurysm formation. MRI also promises to be a valuable tool for follow-up. INTRAMURAL HAEMATOMA It is an acute aortic syndrome which is typically characterised by haemorrhage within medial layer of aortic wall, but unlike classic aortic dissection, there is no evident tear in intimal layer. It is proposed that it results from the rupture of vasa vasorum within aortic wall although some believe that it results from intimal tear which is too small to be visualised. The risk factors, signs and symptoms resemble classic aortic dissection. Among the various available diagnostic modalities CT scan is the most preferred diagnostic tool to visualise the intramural haematomas.

Figure 4: Aortogram showing dissection of aorta.

The natural history of intramural haematoma is debatable but they can proceed in four possible ways absorption of

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haematoma, persistence of haematoma, development of aortic aneurysm, and conversion to classic aortic dissection. Treatment of this aortic syndrome is similar to classic aortic dissection in the sense that proximal aortic intramural haematoma should be operated while distal intramural haematoma should be managed medically. AORTO ARTERITIS (TAKAYASU’S ARTERITIS) Takayasu’s arteritis (TA) is a chronic inflammatory disease of the aorta and its major branches. Though the disease was named after him,Takayasu was not the first to describe this disease entity. ‘Pulseless’ disease was reported by Adams way back in 1827. In 1908, Takayasu described a peculiar ‘wreath-like’ appearance of arteriovenous anastomosis around the optic papilla. The disease has a worldwide distribution, though the majority of cases are seen in Japan, India, South Africa, Mexico and parts of South America. Mongoloid races are affected the most, followed by the Indo-Aryan. The disease predominantly affects young females. The female: male ratio being 7:1 in Japan, 5:1 in Mexico and 3:1 in India. Aetiopathogenesis The specific cause of the disease is not known, though the bulk of evidence favours an autoimmune aetiology. Association with rheumatic fever, streptococcal infection, rheumatoid arthritis, other collagen vascular disease and tuberculosis were described. The disease has two stages. The early active phase, there is non-specific granulomatous panarteritis involving all the layers of the wall of the aorta and its branches but unlike other forms of the aortitis, pulmonary artery may be involved in this disease. The disease progresses variably to a chronic sclerotic phase, characterised by intimal hyperplasia leading to purely stenotic lesion in 85% of the patients, purely dilatative in 2% and mixed lesion in 13% of the patients. Classification Lupi-Herrera et al in 1977, described four varieties of disease based on predominant site of involvement:Type I (Shimizu-Sano) aortic arch and its branches (Figure 5); Type II (Kimoto) thoracoabdominal aorta and its branches; Type III (Inada) combinesfeatures of both Type I and Type II; and Type IV (Oata) pulmonary artery (Figure 6). Another variety of arteritis is proposed as Type V aorto-arteritis associated coronary artery (Panja et al) (Figure 7). Criteria of American College of Rheumatology for the Classification of Takayasu Arteritis (1990) are given in Table 2.

Figure 5: Aortogram showing involvement of aortic arch with both common carotid arteries with aorto-arteritis.

Figure 6: Pulmonary artery involvement in a patient with aorto-arteritis.

Clinical Manifestations The disease affects teenagers in three-fourths of cases, though no age is immune to this disease. More than half of the patients present with features of active disease viz. fever, anorexia, malaise, weight loss, night sweats, arthralgias, pleuritic pain and fatigue. Localised pain and tenderness may be noted over the affected arteries. Occasionally, it may present as fever of unknown origin. In the sclerotic phase, the manifestations include diminished or absent pulses in 96%, bruits in 94%, hypertension in 74% and heart failure in 28% patients. Retinopathy leading to retinal detachment and loss of vision is seen in 25% of the cases. 754

Patients with types I and III disease present as ‘reverse coarctation’ manifested by absent or diminished pulse and

Figure 7: Severe coronary artery involvement in a patient of aorto-arteritis.

Hypertension, a major complication of this disease, arises due to renal artery stenosis (35.85%) (Figure 8), involvement of baroreceptors by aortitis, loss of elasticity of aorta and coarctation like lesion. Congestive heart failure occurs due to hypertension, dilated cardiomyopathy or more rarely aortic regurgitation. Coronary artery involvement may cause angina, myocardial infarction. Pulmonary artery involvement may result in a clinical picture similar to primary pulmonary hypertension. Investigations During the systemic phase, elevated ESR, low-grade leucocytosis and mild anaemia of chronic disease are frequent. IgG or IgM values are elevated in more than half of the patients. C-reactive protein may be elevated with increased anti-streptolysin titre, rheumatoid factor, anti-endothelial antibodies and elevated fibrogen levels. Chest X-ray is usually unrevealing although a rim of calcification is sometimes seen in the walls of the affected arteries. Arteriography reveals irregular intimal surface with stenosis of the aorta or its branches, post-stenotic dilatation, saccular aneurysm and even complete occlusion of vessels. The affected thoracic aorta has been described as having a rat-tail appearance. Arterial biopsy may be positive in 20% to 35% of the cases. Gallium-67 radionuclide scan may demonstrate uptake in aorta and its branches. High resolution ultrasono-graphy is useful in monitoring disease of common carotid and subclavian arteries. MRI, MR angiography and CT scan are useful for serial examination and diagnosis in early phase of Takayasu arteritis.

Use of contrast may reveal inflammatory lesion prior to development of stenosis. Ishikawa and American College of Rheumatology have proposed criteria for the diagnosis of Takayasu arteritis (Table 2). Table 2: 1990 Criteria of American College of Rheumatology for the Classification of Takayasu Arteritis Criteria

Definition

Diseases of the Aorta

blood pressure in the upper limbs, bruits over diseased arteries and syncope. Type II disease is manifested by abdominal angina, claudication of limbs and hypertension due to renal artery involvement.

Age of onset

Development of symptoms or findings related to Takayasu arteritis at age 10 mm Hg in systolic pressure between arms Bruit Bruit audible on auscultation over one or both subclavian arteries or abdominal aorta Arteriogram Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibro-muscular dysplasia, or similar causes: changes usually focal or segmental

For purposes of classification, a patient shall be said to have Takayasu’s arteritis if at least three of these six criteria are present. The presence of any three or more criteria yields a sensitivity of 90.5% and a specificity of 97.8%. Natural History The disease is basically progressive, though the rate of progression varies considerably. The cause of death is usually heart failure, encephalopathy, renal failure, rupture of aneurysms and cerebral haemorrhage.

Figure 8: Bilateral renal artery involvement with left common iliac artery involvement in patient with aorto-arteritis.

Treatment Medical treatment is recommended for those suffering from active and early lesions, those in whom surgery is not possible or considered too risky because of extensive and multifocal involvement of the arterial tree and where surgery is contraindicated due to uncontrollable congestive cardiac failure or progressive renal failure. Steroids are often effective in relieving the constitutional symptoms. Cyclophosphamide, cyclosporine, mycophenolate mofetil and methotrexate can be tried in cases which fail to respond to steroids. Etanercept and infliximab may be used for inducing clinical remission in steroid-dependent patients. Anticoagulant anti-platelet and drugs like warfarin, aspirin and dipyridamole are recommended to treat transient ischaemic symptoms and to prevent progression. Aggressive treatment of hypertension is important. Surgical treatment for late complications includes endarterectomy, bypass of obstructed arteries especially renal arteries, resection of localised coarctation, excision of saccular aneurysms and rarely aortic valve replacement.

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Percutaneous transluminal coronary angioplasty (PTCA) with or without stenting has emerged as a useful effective and less invasive therapeutic option for Takayasu’s disease. This option is especially effective for discrete lesions. CARDIOVASCULAR SYPHILIS It is very rare as a result of aggressive antibiotic treatment of syphilis in its early stages. Cardiovascular complications occur in approximately 10% of cases of untreated syphilis. The latent period may extend from 5 to 40 years, with a usual time of 10 to 25 years. During the secondary phase of the disease the bacteria directly invade the aortic media. The direct infection and subsequent inflammatory response cause destruction of muscular and elastic media followed by its fibrosis. Clinical Manifestation In the absence of’ aortic regurgitation an aneurysm may undergo significant enlargement without producing symptoms. Eventually it may expand to compress and erode contiguous structure, particularly the sternum and the anterior right thoracic cage. This causes pain at the point of involvement. Ascending aortic aneurysms and those involving the arch may cause a tracheal tug, stridor and dysphagia. There may be hoarseness due to compression of the left recurrent laryngeal nerve and cough from pressure against the left main stem bronchus. Patients may have anginal symptoms due to associated stenosis of the coronary ostia. Diagnosis There is a history of syphilis and other manifestations of tertiary syphilis in 10% to 30% of cases. About 15% to 30% of patients have negative routine serological tests for syphilis (Wassermann, Kahn and VDRL). Serological tests directed against a specific treponemal antigen are almost invariably positive. The chest Xray may show calcification in the ascending aorta proximal to the brachiocephalic vessels. Angiography may delineate the aneurysm and help to quantify the severity of aortic regurgitation. In patients suspected to have coronary ostial stenosis and in patients where surgical correction is contemplated, the coronary artery anatomy, and particularly the ostia, should be visualised by coronary angiography. CT and MRI are quite helpful in evaluating the aneurysm. Treatment All patients who are seen one year or more after the initial contact should be given a course of antibiotic therapy, i.e. injection benzathine penicillin 2.4 million units IM weekly for three weeks. For patients allergic to penicillin, tetracycline 500 mg four times daily for 30 days is recommended. GIANT CELL ARTERITIS This disease is found predominantly in elderly people and characteristically involves medium-sized arteries. The aorta and its branches are affected in about 15% cases. The aetiology of giant cell arteritis is unknown. However, the possibility of an

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autoimmune or infectious origin has been considered. The typical pathological lesion is granulomatous inflammation of the media of small-to-medium calibre arteries about the size of the temporal artery, with a special predilection for the vessels of the head and the neck. Clinical Manifestations It typically affects patients over the age of 50 years and occurs predominantly in females. The typical presentation consists of fever, malaise and headache. Other constitutional symptoms include anorexia, weight loss, myalgias, night sweats and lassitude. Headaches are often intense and unbearable and occur over the involved arteries, usually the temporal arteries, but occasionally over the occipital region. Blindness may occur due to involvement of the ophthalmic artery. The syndrome of polymyalgia rheumatica is seen in nearly 40% of these patients. Physical examination reveals the patient to be febrile. The involved vessels are thickened and tender, pulse may be lost and bruits may be heard over the sites of arterial occlusion. Investigations A high erythrocyte sedimentation rate (ESR) is virtually inevitable, normocytic, normochromic anaemia may be present. Antinuclear antibody and rheumatoid factor are not found. The diagnosis is usually confirmed by biopsy of the temporal artery (TA). Colour duplex ultrasonography of TA is a promising alternative for temporal artery biopsy. Angiography may help to confirm the diagnosis in cases of larger vessel and aortic involvement. CT, MRI are used as second-line diagnostic procedure. Treatment Treatment consists of prednisolone 60 to 80 mg per day for 1 to 2 years. With ESR as guide, steroid may be tapered to a maintenance dose of 5 to 15 mg per day for 1 to 2 years. Cyclosporine and azathioprine or cyclosporine and methotrexate are used in steroid-resistant cases. The overall prognosis with treatment is good. OTHER ARTERITIS SYNDROMES These may be seen in association with ankylosing spondylitis, psoriatic arthritis, ulcerative colitis, and Reiter’s syndrome. AORTIC TRAUMA Aortic injuries may occur with severe blunt trauma as in motor vehicle accident, blast injuries, crush injuries and severe falls. The most common site of tear is the aortic isthmus just distal to the origin of the left subclavian artery. Other sites include the supravalvular portion of the ascending aorta, the aortic arch, the innominate artery, abdominal aorta and combinations of these. RECOMMENDED READINGS 1.

Jonathen L Halperin, Jeffery W Olin. Diseases of Aorta. In: Valentine F, Alexander WR, Robert A; editors. Hurst’s The Heart 11th Ed. McGraw Hill Publication House; 2004; 230:1-22.

2.

Isselbacher ME. Diseases of Aorta. In: Zipes DR, Libby P, Bonow 0R, Braunwald E; editors. Braunwald’s Heart Disease. 7th Ed. Elsevier Saunders; 2005: 1403-36.

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Vascular Disorders of the Extremities

INTRODUCTION Vascular disorders of the extremities can involve the arterial, venous or the lymphatic systems. These are generally more common in the lower limbs than in the upper limbs. These disorders can have an acute onset or may develop chronically. The diagnosis is made in most cases by a thorough clinical, ultrasonographic and Doppler evaluation. These abnormalities can be primary in origin or they may be manifestations of a systemic disorder. ARTERIAL DISORDERS Vascular occlusion, acute or chronic, is the major arterial disorder of the extremities. Table 1 outlines the arterial disorders. Table 1: Classification of Arterial Disorders Occlusive Acute occlusion (embolic, thrombotic, traumatic) Chronic occlusion (Atherosclerotic, Takayasu’s arteritis) Gangrene Wet (due to acute occlusion) Dry (due to chronic occlusion) Aneurysm Arteriovenous fistula Thromboangiitis obliterans (Buerger’s disease) Vasospastic disorders Raynaud’s disease Livedo reticularis Acrocyanosis

Chronic Arterial Occlusion It presents less dramatically than acute occlusion and is much more common. Atherosclerotic peripheral arterial disease (PAD) affects the leg eight times more often than the arm. The pathophysiology of PAD is similar to coronary artery disease. The most important risk factors are smoking, diabetes, hyperlipidaemia and hypertension. The clinical manifestations depend on the anatomical site, the presence or absence of collateral supply, the rapidity of onset and the occurrence of external trauma. Takayasu’s arteritis (pulseless disease) is another common cause of chronic PAD involving the aorta and its major arteries. Most commonly upper limb vessels are affected. Its prevalence is high in young women of Indian, Japanese and Mexican descent. There is a panarteritis in the acute stage, culminating in fibrotic occlusion in the chronic stage. No definitive therapy is available for this disease. However, in acute stage steroids are of some use. Vascular interventions (balloon angioplasty and metallic stents) are often used with variable results. In Indian subcontinent, diabetics form the largest group of patients with atherosclerotic PAD. The occlusive disease in diabetics is more extensive and complicated due to associated

Gurpreet Singh Wander, Bishav Mohan neuropathy and increased risk of infection. Most patients with chronic PAD have bad prognosis due to associated coronary and cerebral atherosclerosis. Diabetic foot is one of the dreaded complication with high rate of amputation. This can be managed with combined approach of preventive measures (education, foot care, special shoes) and treatment strategies (angioplasty ± stents). These have reduced the below knee amputation rate. Patients often present with intermittent claudication when the limb ischaemia is less critical. This is a cramp-like pain felt in the calf muscles, brought on by walking and relieved on standing still. The distance walked is called ‘claudication distance’ and is relatively constant for a patient. Patients with critical limb ischaemia (CLI) are defined as those with rest pain that is felt in the foot at rest and made worse by lying down or elevation of the foot. Characteristically, the pain is worse at night and relieved by hanging the foot out of the bed. Other changes include coldness, numbness, paraesthesias and colour change (ischaemic limbs become blanched on elevation and develop a purple discolouration on dependence). Severe arterial insufficiency can result in painful superficial erosions between the toes, on the dorsum of feet and around the malleoli. Later, this can progress to ulceration and frank gangrene (Figure 1). A severely ischaemic foot is frequently paralysed and cold but may feel warmer as it takes on the temperature of its surroundings. In the upper limb, atheromatous occlusive disease can involve subclavian artery and may cause claudication and rarely frank ischaemia of an arm.The subclavian lesion may also cause distal embolisation and consequent loss of digits. Subclavian steal syndrome may occur if the first part of the subclavian artery is obstructed and the vertebral artery provides a collateral circulation into the arm by reversing its direction of blood flow. The classic syndrome of syncopal attack and visual disturbance associated with arm exercise and a diminished blood pressure in the affected limb is rare. Asymptomatic reversal of flow in the vertebral artery recognised by duplex scanning or angiography is much more common. Relevant investigations include tests for diabetes mellitus, lipid abnormalities and anaemia. Doppler ultrasound is a very sensitive type of stethoscope that can be used in conjunction with a sphygmomanometer to assess the systolic pressure in relatively small vessels. Ankle: brachial pressure index (ABPI) is the ratio of systolic pressure in the ankle to that in the arm. Values under 0.9 indicate mild ischaemia whereas < 0.5 indicate severe ischaemia. Duplex imaging combines B-mode ultrasound with Doppler ultrasound to give detailed knowledge about vessel-wall thickness, blood flow and turbulence. The ‘gold standard’ for arterial occlusive disease is angiography, which involves the injection of radio-opaque dye in the vessels

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performed by inserting a balloon catheter into an artery and inflating it within a narrowed or blocked area. In certain cases, a metallic stent may need to be inserted to keep the lumen patent (Figures 2Ato C, and Figures 3A and B). In feasible cases, a surgical vascular bypass may be performed around the occluded part of the vessel to permit distal perfusion.The long-term results of reconstructive aortoiliac surgery are good and they are usually only marred by a progressive disease producing femoro-popliteal occlusions at a later stage. Stem cell therapy (therapeutic angiogenesis) has generated a lot of interest. However, the results need to be documented in large randomised control trials.

Figures 2A to C: (A) Bilateral common iliac stenosis, (B) Stents placed in both common iliac arteries, (C) Post-stenting angiogram showing normal flow.

Figure 1: Patient with chronic arterial occlusion of left lower limb showing discolouration of left foot, thinning of ankle and foot, and dry gangrene of distal digits.

and then using a real time or single shot X-ray to detect the status of the vessels. Digital subtraction angiography (DSA) helps in better delineation of the vessels by subtracting the images of overlying tissues. More recently, ultra fast CTangiography done by injection of intravenous contrast helps in studying the arterial tree without the need for arterial injection as in conventional angiography. Renal function test should be done before sending the patient for contrast imaging. Magnetic resonance angiography (MRA) provides multiplanar imaging without the need of ionising radiation.

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Arterial occlusive disorders can be managed conservatively in most cases. Encouraging exercise within the limits of disability is a good way of increasing exercise capacity. Spontaneous improvement occurs after a few months due to formation of collaterals. Drugs that have a role in occlusive arterial disorders include those for underlying diabetes, hypertension and lipid abnormalities. Antiplatelet agents like aspirin (75 to150 mg od) or clopidogrel can be used. Cilostazol, a phosphodiesterase inhibitor with vasodilator and antiplatelet properties has been shown to improve claudication distance. Naftidrofuryl oxalate may alter tissue metabolism, thus increasing claudication distance. Pentoxifylline improves RBC rheology (flexibility) and has some blood thinning capacity, thus helping to improve circulation. Prostacyclins may have some minor role in the management of the critically ischaemic limb. Lumbar sympathectomy has been used for pain relief. In vessels with localised blocks, transluminal angioplasty and stenting may be

Figures 3A and B: (A) Angiogram showing stenosis in the peroneal artery, (B) Post-angioplasty angiogram showing normal flow.

Acute Arterial Occlusion Sudden occlusion of an artery may be due to emboli from a remote site, thrombus formation on a pre-existing atheroma or trauma (Figures 4A and B). The emboli can arise from an atrial source as in atrial fibrillation or left ventricular mural thrombus following myocardial infarction. These tend to lodge at vessel bifurcation. Acute occlusion is an emergency and threatens limb viability. It needs immediate diagnosis and early management since delay can compromise limb viability.

Figures 4A and B: This patient presented with a tibial fracture and absent distal pulses: (A) Angiogram showing sudden cut-off of arterial blood flow at the level of the fracture; (B) After stabilisation of the fracture, injection of local vasodilators and ballooning of the blocked segment, flow is restored.

Vascular Disorders of the Extremities

The classical signs in the lower limb are the 6 P’s – pain, pallor, paresis, pulselessness, paraesthesia and poikilothermia. The limb is cold and, almost immediately, the toes cannot be moved. Sensation to touch is soon lost and distal pulses become impalpable. B-mode ultrasound imaging shows lack of pulsation in arteries and Doppler confirms the diagnosis by showing lack of blood flow. Appropriate treatment is the immediate intravenous administration of heparin. This can halt the extension of the thrombus and maintain patency in the surrounding vessels. Pain relief is essential because pain is severe and constant. Surgical embolectomy for larger vessels till the popliteal artery is the treatment of choice when done within 12 hours of ischaemia. Thrombolysis using streptokinase or urokinase is preferred for distal vessels. This has to be done within 6 to 12 hours to preserve limb viability. Patients presenting late often go on to develop gangrene of the distal toes and the feet. Gangrene The combination of rest pain, colour changes and hyperaesthesias with or without ischaemic ulceration is frequently referred to as pre-gangrene. Gangrene implies death of macroscopic portions of tissue. It is commonly seen affecting the distal part of the limb. A gangrenous part lacks arterial pulsation, venous return, capillary response to pressure (colour return), sensation, warmth and function. The colour changes from pale through dusky-gray to mottled until finally taking on the characteristic dark brown, green-black or black appearance. Dry gangrene This occurs when the tissues are desiccated by gradual occlusion of the vessels. It is typically due to atheromatous occlusion of the arteries. The affected part becomes dry and wrinkled, discoloured and greasy to touch. Wet gangrene This occurs when the artery is suddenly occluded and there is venous obstruction as well. Infection and putrefaction are present and the affected part becomes swollen and discoloured and the epidermis may be raised in blebs. Crepitus may also be palpated (Figure 5). Treatment includes general measures like hydration, pain control and control of infection. Once gangrene has set in, the reestablishment of blood flow by percutaneous intervention or surgery does not help. Unviable portions of tissue need to be amputated to relieve pain and prevent the spread of infection and gangrene. Aneurysm An aneurysm is a localised dilatation of a segment of the arterial system. Aneurysms can be true (involving the vascular intima, media and adventitia) or false (with a fibrous wall). In appearance, they may be fusiform, saccular or dissecting. Aetiology can be atheromatous, traumatic, syphilitic or due to collagen disease. These can present due to expansion, thrombosis or embolisation. Intrinsically, a pulsatile swelling is present along the course of an artery, which diminishes on application of proximal pressure. The sac is usually compressible unless thrombosed. A thrill may be felt and a systemic bruit auscultated.

Figure 5: Wet gangrene of both lower limbs due to acute arterial occlusion with blebs, denuded skin and blackish discolouration of both feet.

Extrinsically, pressure on veins or nerves may cause distal oedema or altered sensation. Arteriovenous Fistula This is a communication between an artery and vein. This may be congenital or acquired due to surgical trauma and catheter access. AV fistulas may also be created in the upper limb to facilitate haemodialysis. Haemodynamically significant fistulas may lead to a wide pulse pressure and a thrill is present. A continuous bruit can be heard over the fistula. Pressure on the artery proximal to the fistula may cause the swelling to diminish, the thrill and bruit to cease and the pulse rate to fall (Nicoladoni’s or Branham’s sign) and the pulse pressure to return to normal. Embolisation by autologous material (fat/muscle) or gelatine sponges, silicon spheres can obliterate the fistula. Large, painful or bleeding AV fistula can be managed surgically or with endovascular grafts/stents. Thromboangiitis Obliterans This involves occlusive disease of the small and medium sized arteries, thrombophlebitis of superficial and deep veins, and Raynaud’s phenomenon. It is also known as Buerger’s disease. It is most common in Asian males under the age of 30, generally smokers. Treatment is primarily cessation of smoking. This helps halt the progression of the disease but does not lead to reversal of the established occlusion. Sympathectomy for pain relief is also done. Stem cell therapy has also been tried. Vasospastic Disorders Raynaud’s disease It predominantly affects the upper limbs in young women. The peripheral pulses are normal. Due to an abnormal response to

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cold temperature, the vessels constrict and then dilate. This produces a classic triphasic colour change; pallor, cyanosis followed by redness of the digits. This is often accompanied by pain. Raynaud’s syndrome shares the clinical features of Raynaud’s disease but is much more severe. It is generally a manifestation of collagen vascular disease. It may also follow the use of vibrating tools and is then known as ‘vibration white finger’. Treatment is primarily directed at the underlying condition. Calcium channel blockers may have a role in management. Livedo reticularis This involves purplish mottling of the skin due to spasm of dermal arterioles in lower extremities, especially on cold exposure. Acrocyanosis It is an uncommon condition seen in females and is characterised by bluish discolouration in hands and fingers. No specific therapy is required. VENOUS DISORDERS Blood returns from the limbs via the deep and superficial veins. In the upper limb, the superficial veins are more important. The superficial veins in the leg are the long and short saphenous veins, and they carry only 10% of the blood from the lower limbs. There is a foot-pump that ejects blood from the plantar veins as pressure is placed on the foot during walking. On exercise, the thigh and calf muscles contract compressing the veins and ejecting blood towards the heart. Venous valves control the direction of flow of blood in the veins. During muscle relaxation phase, the pressure within the calf falls to a low level and blood from superficial veins flows through the perforating veins into the deep veins. Venous diseases are of two main types; venous thrombosis and venous incompetence.

thrombosis in young patients. Common acquired thrombophilic states are previous surgery (especially orthopaedic like joint replacement), trauma, pregnancy, certain malignancies, stroke, heart failure, prolonged immobilisation and drugs such as oral contraceptives and hormone replacement therapy (Table 2). Long haul air travel has been associated with an increased incidence of DVT due to the immobilisation. Table 2: Predisposing Causes for Venous Thrombosis Hypercoagulable states Mutations of factor V (Leiden), prothrombin gene Deficiency of protein C, protein S, antithrombin III Antiphospholipid antibody Disseminated intravascular coagulation Surgery Orthopaedic, thoracic, abdominal Neoplasia Pancreas, lung, ovary, testes, breast Trauma Fractures, spinal injuries Immobilisation (any cause) Hormonal Pregnancy, oral contraceptives

The most significant clinical findings are tenderness in the calf and ankle oedema. Pain in the calf on dorsiflexion of the ankle (Homan’s sign) is rare and often misleading. Other signs and symptoms are swelling, pain, redness, dilated superficial veins and low-grade pyrexia (Figure 6). Some

Venous Thrombosis Venous thrombosis of the deep veins involves the lower limbs more frequently than the upper limbs. In most cases, deep vein thrombosis (DVT) is asymptomatic and resolves without sequelae. However, often patients are left with a postthrombotic limb that is persistently swollen, often complicated by venous ulceration. During the acute phase, DVT needs to be taken seriously since the thrombi can dislodge and embolise to the pulmonary circulation. A clot from the lower limb veins detaches from its site and passes via the inferior vena cava and right heart to the pulmonary arteries. It may totally occlude the perfusion to a part or all of one or both lungs. In 10% patients who die in the hospital, the cause of death is pulmonary embolism following a DVT.

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The main causative factors are part of the Virchow’s triad; stasis (slowing of the blood flow), hypercoagulability (increased tendency to clot) and vessel wall damage (which releases thrombogenic substances). The term ‘thrombophilia’ implies an increased tendency for clotting, often for prolonged periods of time. This can be inherited or acquired. The common genetic causes responsible for venous thromboembolism are mutations involving factor V Leiden (20% to 40%) and prothrombin (6%) genes. Inherited deficiency of protein C (3%), protein S (3%) and antithrombin III (1%) have also been shown to lead to venous

Figure 6: Superficial and deep vein thrombosis of right leg showing oedema and calf swelling due to DVT. There is an accompanying superficial vein thrombosis as evidenced by the linear redness and swelling.

For diagnosis, a quantitative D-dimer analysis is done to measure the levels of fibrin degradation products. It is recommended to rule-out DVT in clinically suspicious patients. It is, however, not very specific and hence the value of a positive test is limited. The best method for diagnosis is B-mode and Doppler ultrasound in which we look for flow in the veins and augmentation on calf compression. Ascending phlebography is rarely done. Immobilisation is usually needed only for first 24 hours. Treatment involves anticoagulation after the diagnosis is made. Standard treatment involves unfractionated intravenous heparin (UFH) with dose adjusted according to activated partial thromboplastin time (aPTT). The onset of action is rapid and it is given for about 5 days. The aim is to minimise the risk of pulmonary embolism and to encourage the resolution of the thrombus. Subcutaneous injections of low molecular weight heparin (LMWH) are an alternative method and have been found to produce reliable anticoagulation.These are given twice daily and are easier to administer. They also do not require aPTT monitoring. Many LMWHs are now commercially available and are preferred over UFH nowadays. At the same time, the patient should be started on oral anticoagulants (e.g. warfarin, acenocoumarol) to reduce risk of recurrence of DVT. Duration of treatment is usually for 6 to 12 months. Patients who have inherited thrombophilia require lifelong anticoagulation. The effect of warfarin is monitored by measuring the international normalised ratio (INR), which should be prolonged to 2.0 to 3.0 times the control values. Inferior vena cava (IVC) filters are implanted in patients with contraindication to oral anti-coagulants (GI bleed), recurrent DVT and high risk DVT. Retrievable filters are preferred over permanent ones. Prevention of DVT can be done by both mechanical and pharmacological methods. Graduated elastic compression stockings have been shown to reduce the incidence of deep vein thrombosis. Intermittent pneumatic compression devices are used only peri-operatively. Pharmacological methods include UFH and LMWH. LMWHs are generally preferred. These are considered in all immobilised patients especially those with orthopaedic surgery, congestive cardiac failure and occlusive strokes. Prevention of thrombosis during long distance air travel requires the use of graduated compression stockings, exercise during the flight and avoidance of alcohol and sleeping tablets. Superficial Vein Thrombosis This is a frequent complication of varicose veins and may also follow cannulation of a vein for intravenous infusion. Spontaneous superficial thrombophlebitis may occur in the presence of polycythaemia, polyarteritis and Buerger’s disease and may also herald the presence of a visceral cancer. This condition does not carry the risks of deep vein thrombosis and is normally treated symptomatically with simple analgesics and anti-inflammatory drugs.

Axillary Vein Thrombosis This may occur following excessive exercise or as a complication of thoracic outlet syndrome. It is occasionally associated with a cervical rib. The arm becomes swollen and the superficial veins become distended. Early treatment with anticoagulants may result in rapid resolution. In severe cases, the use of fibrinolytic therapy, streptokinase or TPA may be considered. Definite treatment of thoracic outlet syndrome by surgical decompression of the subclavian may be needed, e.g. by resection of the first rib. Venous Incompetence Unidirectional venous flow requires the competence of the valves in the superficial and deep veins as well as the venous perforators. Dysfunction of these valves leads to venous incompetence and varicose veins. The incidence of varicose veins in developing countries is lower than in the western nations due to genetic, lifestyle and dietary differences. Varicose veins develop more frequently in people who stand during their work and during pregnancy under the influence of oestrogen and progesterone.

Vascular Disorders of the Extremities

patients with DVT may have no symptoms in the leg but initially present with sudden onset dyspnoea due to pulmonary embolism.

Symptoms include tiredness, aching, tingling, ankle swelling and a cramping sensation in the legs, which progressively worsen towards the end of the day and are relieved by elevating the leg. Patients with more severe venous disease may notice skin changes. Some patients may be asymptomatic and may present for cosmetic reasons. On examination, there is an increase in size of the calf muscles, ankle oedema, and skin complications like brown pigmentation, eczema and severe ulcerations. Later on, lipodermatosclerosis may develop. Contraction of the skin and subcutaneous tissue is seen and the ankle becomes narrow. A combination of narrow ankle and prominent calf is often referred to as a champagne bottle leg. Venous ulceration may also develop in these areas. Diagnosis can be made by a thorough clinical examination and Doppler ultrasound evaluation. The treatment depends on the size of the varices, their extent and the symptoms they produce. Compression stockings are used in early stages of disease. Injection sclerotherapy involves the injection of an irritant solution, sodium tetradecyl. Surgical treatment involves the ligation of the source of reflux (usually the saphenopopliteal or saphenofemoral junction) and removal of the incompetent saphenous trunks and the associated varices. Endovenous radio frequency and laser ablation have been used in patients with persistent symptoms and/or who develop ulceration. LYMPHATICS DISORDERS Lymphatic system is composed of interstitial fluid that bathes tissues of the body, lymphatic capillaries that collect interstitial fluid, transporting vessels and the lymph nodes. The lymphatic capillaries absorb interstitial fluid and empty into transporting vessels, which traverse the extremities and join with the visceral channels to form the cisterna chyli adjacent to the upper abdominal aorta.These pass through the diaphragm to become the thoracic duct. The thoracic duct empties into the left 761

subclavian vein. A separate smaller right lymphatic duct drains the right upper extremity and neck, and enters the right subclavian vein. Normally between 2 litres and 4 litres of interstitial fluid is filtered each day and returned to the vascular system by the lymphatic system. Diseases of the lymphatics include lymphoedema due to lymphatic obstruction, lymphangiomas and tumours. Lymphoedema Lymphoedema is caused by excessive accumulation of interstitial fluid in the extravascular, extracellular fluid compartment due to defects in the lymphatic transport system. Inadequate removal of the interstitial fluid by the lymphatic system may be the result of absent hypoplastic or obstructed lymphatic vessels. In the limb, interstitial fluid accumulates mainly in the cutaneous tissues and presents as a swollen extremity. In the early stages, the oedema is pitting but later it typically becomes non-pitting. The skin becomes thickened, hypertrophic and hyperkeratotic. It should be distinguished from other causes of unilateral leg swelling such as DVT (Table 3). Lymphoedema may be primary or secondary (Table 4).

‘Lymphoedema precox’ presents at about the time of puberty and is the most common form of primary lymphoedema accounting for >80% of the cases. ‘Lymphoedema tarda’ refers to lymphoedema that appears at about the third or fourth decade of life. Secondary lymphoedema It is usually due to acquired lymphatic obstruction. The causes of obstructive lymphoedema are infiltration of regional lymph nodes by tumour, surgical excision of regional lymph nodes in the treatment of malignancy, repeated infections, inflammatory processes causing fibrosis and irradiation. In tropical and subtropical countries infestation by filarial parasites is the most frequent cause of secondary lymph-oedema. Eight filarial species infect humans out of which only two; Wuchereria bancrofti and Brugia malayi are found in India and South-East Asia. W. bancrofti is the most widely distributed human filarial parasite. In India, the disease is rampant in Uttar Pradesh, Bihar, Andhra Pradesh, Orissa,Tamil Nadu, coastal Kerala and Gujarat.Tuberculous lymphangitis may also cause lymphoedema. In Western countries lymphoedema occurs most commonly in the arm after surgical excision of lymph nodes for carcinoma of the breast.

Table 3: Differences Between Swelling of the Extremity Due to Lymphatic and Venous Obstruction Lymphatic Obstruction

Venous Obstruction

Swelling typically involves the distal aspect of the extremity and characteristically involves the dorsum of the feet and toes

Swelling is present distal to the site of obstruction and uniformly involves the extremity uniformly

Swelling is usually painless. Pain and redness occur only if there is associated cellulitis

There is pain, redness and dilated superficial veins in the affected extremity

Oedema is pitting in nature and responds to limb elevation, however later on it characteristically becomes non-pitting and does not respond to limb elevation

Oedema is pitting in nature in the initial phase and responds to limb elevation

Due to lymphoedema, skin becomes thickened, hypertrophic and then hyper-keratotic

Due to increase in foot vein pressure, skin around the ankle becomes pigmented due to leakage of blood and fibrin into the surrounding tissues. With passage of time, the skin becomes eczematous and ulcerated

Table 4: Types of Lymphoedema Primary Lymphoedema congenita Lymphoedema precox Lymphoedema tarda Secondary Filariasis Tuberculosis Neoplasia Recurrent lymphangitis Surgery Radiotherapy

Primary lymphoedema This is relatively uncommon and often associated with inherited disorders like Turner’s and Klinefelter’s syndromes. ‘Lymphoedema congenita’ is a severe form of lymphoedema that is usually apparent at birth or during early infancy. Familial cases are termed as Milroy’s disease. These patients have associated lymphatic abnormalities such as intestinal and pulmonary lymphangiectasia. 762

Lymphangiography is used to diagnose lymphoedema and to demonstrate the nature of lymphatic abnormality. However, as this procedure is invasive and because of the risk of oil embolism, it is being replaced by isotope lymphangiography. MRI imaging has also been employed to investigate the lymphatic system. Treatment includes prolonged bed rest, limb elevation, elastic stockings, meticulous skin hygiene, avoidance of local injury and prompt treatment with antibiotics if cellulitis occurs. Surgery is reserved for those with severe disabling lymphoedema. It includes the excision of hypertrophic tissue, pedicle transfer of normal lymphatic bearing tissue and microvascular bypass. Lymphangiomas Lymphangiomas are benign overgrowths of lymphatic vessels. It is not certain whether these are congenital malformations, hamartomas or true neoplasms. Capillary lymphangiomas are small, circumscribed, pale-white to pink lesions composed of network of endotheliumlined, thin-walled lymphatic spaces separated by lymphoid

Cavernous lymphangiomas are more common than the capillary variety. They are slow growing, congenital lesions and are composed of numerous dilated lymphatic channels filled with lymph and often surrounded by a fibrous capsule. Lymphangiosarcoma It is a rare malignant lesion that develops in a lymphoedematous/ extremity. Malignant transformation is more frequent in cases of secondary lymphoedema. It appears as purple-red nodules in the skin. It is an aggressive and rapidly fatal tumour.

RECOMMENDED READINGS 1.

Creager MA, et al (eds): Vascular Medicine. Philadelphia, Saunders Elsevier, 2006.

2.

Faxon DP, et al. Atherosclerotic Vascular Disease Conference: Executive summary: Atherosclerotic Vascular Disease Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2004; 109:p2595.

3.

Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Eng J Med 2001; 344:p1608.

4.

Parakh R, Kakkar VV, Kakkar AK. For Venous Thromboembolism (VTE) Core Group. Management of Venous Thromboembolism. JAPI 2000; 55: 49-70.

5.

Rockson SG. Lymphoedema. Current Treat Options Cardiovasc Med 2006; 8: p129.

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aggregates. These mainly involve skin or mucous membranes of the head and neck.

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12.33 INTRODUCTION Management of pregnancy in patients with heart disease continues to pose a challenge to the clinicians. Heart disease is the third leading cause of death in 25 to 44-year-old women. Because it is relatively common in women of childbearing age, heart disease of varying severity complicates about one per cent of pregnancies. Rheumatic heart disease accounts for most of the cases and mitral stenosis being the commonest lesion, in India. NORMAL PHYSIOLOGIC CHANGES IN PREGNANCY There is an increase in blood volume, by about 50%, and relatively haemoglobin concentration falls, causing the physiological anaemia of pregnancy. Cardiac output increases as early as 5 weeks after the last menstrual period and rises to 45% above baseline at 24 weeks’ gestation. Increased cardiac output is achieved by an increase in heart rate, which rises progressively until 32 weeks’ gestation, and in stroke volume, which begins to increase by 8 weeks and peaks as early as 20 weeks. Twin pregnancies result in an additional 15% rise in cardiac output in mothers. The cardiovascular system is taxed further by stage one of labour, which is associated with an additional 12% increase in demand for cardiac output. This demand increases to a mean of 34% above the already increased baseline value as labour progresses to its final stages. After delivery stroke volume decreases by 2 weeks post-partum, but a small further reduction occurs up to 6 months after delivery. The stroke volume remains at pregnancy levels for the first 2 days post-partum and then falls dramatically. Heart rate remains elevated for 2 days post-partum and returns to the baseline by 10 days after delivery. Cardiac output similarly decreases from pregnancy levels to normal levels between 24 hours and 10 days post-partum. Systemic vascular resistance and diastolic blood pressure decrease as a result of changes in aortic compliance and arterial venous shunting in the uterus.

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Pregnancy and Heart Disease Amal Kumar Banerjee

Table 1: Physical Findings During Normal Pregnancy Mild jugular venous distension Lower-extremity oedema Decreased breath sounds at bases Upward and leftward deviation of point of maximal impulse Volume-loaded ventricle (active praecordium) Increased valve closure sounds ‘Flow’ murmurs (pulmonic and aortic) Mammary soufflé (left sternal border) Wide pulse pressure Increased heart rate Table 2: Some Clinical Indicators of Heart Disease During Pregnancy Symptoms Progressive dyspnoea or orthopnoea Nocturnal cough Haemoptysis Syncope Chest pain Clinical Findings Cyanosis Clubbing of fingers Persistent neck vein distension Systolic murmur grade 3/6 or greater Diastolic murmur Cardiomegaly Persistent arrhythmia Persistent split-second sound Criteria for pulmonary hypertension Table 3: Changes in Non-invasive Test Results That Occur During Pregnancy

DIAGNOSIS OF HEART DISEASE Many of the physiological changes of normal pregnancy tend to make the diagnosis of heart disease more difficult due to alterations in the physical examination of the pregnant patient (Table 1). Symptoms and clinical findings that may indicate heart disease (Table 2), should be carefully recognised. Pregnant women who have none of these findings, rarely have serious heart disease.

Test

Changes

Electrocardiography

Leftward axis deviation Increased ventricular voltage Increased rate Repolarisation changes

Chest X-ray film

Upward diaphragm displacement Horizontal heart placement Enlarged pulmonary silhouette

Diagnostic Studies The physiologic changes associated with pregnancy may also alter the results of non-invasive evaluations of the heart (Table 3).

Echocardiography

Increased left ventricular diastolic dimension Increased left ventricular wall thickness Mild increase in contractility

In most cases,conventional testing including electrocardiography, Doppler echocardiography and chest radiography will provide necessary data. If indicated, right-heart catheterisation can be performed with limited X-ray fluoroscopy. All X-ray procedures should generally be avoided, particularly early in pregnancy.

GENERAL MANAGEMENT Poor maternal functional class, cyanosis, myocardial dysfunction, left-heart obstructive lesions, prior arrhythmia, and prior cardiac events are prognostic of complications during pregnancy. The

A three tiered risk classification of maternal mortality (Table 4), has been developed. This will help in counselling the woman regarding advisability of conception or continuation of pregnancy. Most current management recommendations have been based on expert opinion and/or retrospective series. To date, there has been only one large multicenter study to prospectively ascertain maternal and foetal outcomes in women with cardiac disease. This Canadian study also derived and validated a risk index for the prediction of maternal cardiac complications during pregnancy (Table 5). Women with heart disease who are at intermediate or highrisk for complications should be managed in a high-risk pregnancy unit by a multidisciplinary team from obstetrics, cardiology, anaesthesia, and paediatrics. Table 4: Risks for Maternal Mortality Caused by Various Heart Disease Cardiac Disorder

Mortality (%)

Group 1 – Minimal Risk Atrial septal defect Ventricular septal defect Patent ductus arteriosus Pulmonary or tricuspid disease Tetralogy of Fallot, corrected Bioprosthetic valve Mitral stenosis, NYHA classes I and II

0 to 1

Group 2 – Moderate Risk 5 to 15 2A: Mitral stenosis, NYHA classes III and IV Aortic stenosis Aortic coarctation without valvular involvement Tetralogy of Fallot, uncorrected Previous myocardial infarction Marfan’s syndrome, normal aorta 2B: Mitral stenosis with atrial fibrillation Artificial valve Group 3 – Major Risk Pulmonary hypertension Aortic coarctation with valvular involvement Marfan’s syndrome with aortic involvement

25 to 30

NYHA = New York Heart Association.

Table 5: Risk Factors for Maternal Cardiac Adverse Events During Pregnancy Adverse Maternal Cardiac Event

Risk Factor

Pulmonary oedema Arrhythmia Stroke Death

General NYHA functional class III or IV or cyanosis Systemic ventricular EF < 40% Mitral valve area < 2 sq cm, aortic valve area < 1.5 sq cm, peak left ventricular outflow gradient > 30 mmHg Cardiac event ( arrhythmia, stroke, pulmonary oedema ) prior to pregnancy

The general risk factors can be used to create a maternal risk index for adverse cardiac events related to pregnancy: 0 risk factors < 5% risk, 1 risk factor = 27% risk, ≥ 2 risk factors = 75% risk.

Congestive Heart Failure Management of congestive heart failure (CHF) during pregnancy, is not much different from that at other times. Salt restriction and limitation of activity to a level below that, which causes symptoms are appropriate. In a woman with significant symptoms or pulmonary oedema, standard therapy can be used with the exception of ACE-inhibitors. Congestive heart failure is one situation, where maintaining a woman in supine position may be beneficial by causing preload reduction with obstruction of return of blood from the inferior vena cava to the heart. Low-Cardiac-Output Syndrome A low cardiac output is an ominous sign in pregnancy with heart disease. Although potentially treatable causes such as tamponade or severe valvular stenosis should be considered, it is most often due to intravascular volume depletion. This should be prevented when possible and corrected when recognised.

Pregnancy and Heart Disease

likelihood of cardiac complications during pregnancy is 3%, 30% and 66% when none, one or more than one of these are present.

Thromboembolic Complications The risk of venous thromboemboli increases five-fold during and immediately after pregnancy, and there is an increase in arterial emboli as well. Prevention is optimal, and prophylactic full-dose heparin or low-molecular-weight heparin is indicated in those at high-risk of a thromboembolic complication. If a thrombus or embolus is identified, 5 to 10 days of intravenous heparin therapy followed by full-dose subcutaneous heparin is recommended. If a thromboembolus is life-threatening, like a massive pulmonary embolus or a thrombosed prosthetic valve, thrombolytic therapy can be used. Pulmonary Hypertension Pulmonary hypertension, whether primary or secondary, is associated with 30% to 70% maternal mortality and even with maternal survival, foetal loss exceeds 40%. The mother is most vulnerable during labour and in the first post-partum week. If detected early in pregnancy, interruption is advised. When detected late in pregnancy, close follow-up is necessary. Intravascular volume depletion should be promptly corrected, since it puts these patients at greatest risk. Systemic vascular resistance and pressure must be maintained in patients with pulmonary hypertension who have a right-to-left shunt, and meticulous attention is necessary to avoid air or thrombus emboli from intravenous catheters, which may lead to systemic emboli. At the time of labour and delivery, a central venous line allows adequate fluid administration, and a radial artery catheter makes determinations of blood pressure and oxygen saturation easier. These lines should be continued for 48 to 72 hours post-delivery. Arrhythmias The rules for the treatment are the same as in the non-pregnant patient, with the possible exception that a rhythm causing haemodynamic instability should be treated more promptly and aggressively because of the concern about diversion of blood flow away from the uterus. Complete heart block, which in this age group is most likely to be of congenital origin, is consistent with a successful pregnancy. If required, a permanent pacemaker can be implanted. Endocarditis Infective endocarditis is uncommon during pregnancy and the puerperium. The clinical presentation and management of endocarditis during pregnancy is the same as at other times.

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SPECIFIC FORMS OF HEART DISEASE Rheumatic Heart Disease Rheumatic mitral valve disease continues to be the most prevalent heart disease encountered in pregnant women in India. Women with rheumatic valvular heart disease (VHD), have high rate of clinical deterioration and a marked increase in morbid events during pregnancy, including CHF, arrhythmias and need to either initiate or increase cardiovascular drug therapy or to hospitalise patients during pregnancy. Pregnancy with VHD, may be associated with an increased incidence of intrauterine growth restriction (IUGR), preterm deliveries, and lower birth weight, especially in cases with moderate and severe stenosis of the mitral or aortic valve. Acute Rheumatic Fever This disease occurs only rarely during pregnancy and management is similar to that of non-pregnant patients. Mitral Stenosis This is the commonest VHD in pregnancy and represents a common health problem in our country. The increased preload of normal pregnancy, as well as other factors that require increased cardiac output, may cause ventricular failure with pulmonary oedema in these women with relatively fixed cardiac output. About 25% of women with mitral stenosis experience cardiac failure for the first time during pregnancy. In some cases, this may be confused with idiopathic peripartum cardiomyopathy. The most prominent complaint is dyspnoea due to pulmonary venous hypertension and pulmonary oedema. Other common symptoms are fatigue, palpitations, cough and haemoptysis. The therapeutic approach is to reduce the heart rate and decrease blood volume. Limited physical activity is generally recommended. Prophylactically beta-blocking agents can be used and digoxin may be considered in patients with AF. For chronic AF, anticoagulation with heparin is also indicated. If symptoms of pulmonary congestion develop, activity is restricted even more, dietary sodium is restricted and diuretic therapy is started. Labour and delivery are particularly stressful for women with tight stenosis. Epidural analgesia for labour, with strict attention to avoid intravenous fluid overload, is ideal. Vaginal delivery is preferable. In symptomatic patients with moderateto-severe stenosis (mitral valve area < 1.5 cm2), haemodynamic monitoring is indicated during labour and delivery with haemodynamic optimisation by diuretics, beta-blockers, digoxin or nitroglycerin. Intrapartum endocarditis prophylaxis is required. Closed mitral commissurotomy is associated with only minimal risk to the foetus and therefore, preferable to the open technique. It should be recommended only in centres where it is done routinely.

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The safety and efficacy of percutaneous balloon mitral valvuloplasty (PBMV) has been reported by several investigators. Now, PBMV during pregnancy has been reported without foetal loss and should be the preferred modality of treatment in this subset of patients. Mitral valve repair or replacement during pregnancy should be considered only in cases with severe stenosis (mitral valve area < 1.0 cm2), refractory to optimal medical therapy, PBMV is not feasible or when close follow-up during pregnancy, labour and delivery is not possible. When valve replacement is indicated, selection of the type of

prosthesis should be based on its haemodynamic profile and durability and the need for anticoagulation. Mitral Regurgitation This condition is well tolerated in pregnancy. In symptomatic patients, diuretics are indicated, and digoxin may be beneficial in cases with impaired left ventricular systolic function. Aortic Stenosis Rheumatic aortic stenosis is unusual finding in pregnancy and may occur in conjunction with mitral valve disease in about 5% of pregnant patients with rheumatic valvular disease. Most patients with aortic stenosis (Valve area > 1.0 cm2), tolerate pregnancy well. But patients with more severe stenosis may experience clinical deterioration with exertional dyspnoea, near-syncope or syncope and pulmonary oedema. Serious symptoms during pregnancy, if resistant to medical treatment, may necessitate termination of pregnancy or repair of the valve either surgically (valve replacement) or by percutaneous balloon valvuloplasty. For women with critical aortic stenosis, intensive monitoring during labour is necessary and epidural analgesia seems ideal, thus avoiding potentially hazardous hypotension. Aortic Regurgitation This condition is well tolerated in pregnancy. Symptoms necessitate salt restriction, diuretics and digoxin. Prosthetic Valve Disease A prosthetic valve is a relative contraindication to pregnancy. Maternal mortality is 3% to 4% with mechanical valves and foetal, loss is common. The critical issue is anticoagulation in cases with mechanical prosthesis. Full anticoagulation throughout pregnancy is recommended with subcutaneous heparin, maintaining anticoagulation at the high therapeutic level by following levels of factor Xa. Just before delivery, heparin is stopped. Protamine sulphate may be used to counter excessive bleeding. Anticoagulant therapy with warfarin or heparin may be restarted 6 hours following vaginal delivery. But anticoagulation should be withheld for at least 24 hours, following caesarean delivery. Antibiotic prophylaxis is necessary during labour. Mitral Valve Prolapse Pregnant women with mitral valve prolapse, rarely have cardiac complications. For women who are symptomatic, beta-blockers are used. Antibiotic prophylaxis for labour and delivery in patients with mitral valve prolapse, accompanied by valve thickening and/or regurgitation, seems warranted. Congenital Heart Disease A good maternal outcome can be expected in most cases with acyanotic congenital heart disease. Maternal functional capacity and cyanosis determine foetal outcome. Foetal wastage is about 45% in cyanotic mothers compared with 20% in acyanotic mothers with congenital heart disease. Prematurity and IUGR are common in cyanotic mothers. Risk of congenital heart disease is increased for the offspring of mothers with congenital heart disease with a reported incidence of 4% to 8%. Elective induction of labour, when foetal maturity is confirmed, may be used in high-risk patients for better planning of haemodynamic monitoring. Vaginal delivery is preferred for

Antibiotic prophylaxis for vaginal delivery in all patients with congenital heart disease (except secundum type of ASD, 6 months or more after repair of septal defects or surgical ligation and division of patent ductus arteriosus), is necessary. Atrial Septal Defect Atrial septal defect is well tolerated in pregnancy. Pulmonary hypertension and atrial arrhythmias occur rarely and antibiotic prophylaxis is not indicated. Ventricular Septal Defect Isolated ventricular septal defect is usually well tolerated in pregnancy. The occasional congestive heart failure or arrhythmias, developing during pregnancy, can be managed in the usual manner. The incidence of ventricular septal defect in the offspring has been reported to be 4% to 11%. Volume depletion during or after delivery, may lead to shunt reversal, in patients with pulmonary hypertension. Prompt volume replacement is necessary to prevent further complications. Patent Ductus Arteriosus A patent ductus arteriosus is tolerated well during pregnancy. On occasion, congestive heart failure can occur, but standard treatment is effective. Antibiotic prophylaxis is recommended. Peripartum decrease in systemic blood pressure should be promptly corrected. Congenital Aortic Valve Disease Most patients with mild aortic stenosis have favourable outcome of pregnancy, provided that they are diagnosed early. Appropriate care, including haemodynamic monitoring during labour and delivery and appropriate anaesthesia are associated with favourable outcomes. Moderate and severe aortic stenosis may be associated with symptomatic deterioration during pregnancy and may lead to maternal morbidity and even mortality. Exertional dyspnoea, chest pain, light headedness, and syncope may develop in the second or third trimester. Increased incidence of cardiac defects has been reported in live born infants of mothers with left ventricular outflow obstruction. Optimal management strategies of a pregnant woman with severe aortic stenosis include early abortion followed by valve replacement and repeat pregnancy, and continuation of pregnancy and plan for percutaneous balloon valvuloplasty or surgical intervention who show clinical deterioration not controlled by medical therapy. These procedures have been performed successfully in pregnant women but are not free from complications. So, these interventions should be reserved for patients with severe disease, not manageable by medical therapy and should be avoided during first trimester. Coarctation of Aorta Both maternal and foetal outcome is usually favourable. In case of severe hypertension, congestive heart failure and aortic dissection may occur. To prevent aortic dissection and rupture of cerebral aneurysm, physical activity should be limited and

blood pressure must be adequately lowered. Surgical correction can be performed successfully in patients with severe, uncontrolled systolic hypertension or heart failure. Pulmonic Stenosis Isolated pulmonic stenosis is usually well tolerated in pregnancy. Occasionally, progressive right ventricular failure, symptoms related to stenotic valve or intracardiac shunt at either the atrial or ventricular level with cyanosis may develop. Percutaneous balloon valvotomy should be considered in such situations. Tetralogy of Fallot

Pregnancy and Heart Disease

most patients, and caesarean section is indicated in stable patients only for obstetric reasons. Oxygen should be given to hypoxaemic mother during labour. Haemodynamic and blood gas monitoring is necessary in patients with impaired functional capacity, cardiac dysfunction, pulmonary hypertension, and cyanotic malformations. Blood loss should be treated promptly.

Successful pregnancy can be achieved, but maternal mortality is high and foetal loss can exceed 50%. During labour and delivery, right to left shunt may increase. Maternal haematocrit above 60%, arterial oxygen saturation below 80% and syncopal episodes are poor prognostic signs. In cyanotic women, the rate of spontaneous abortion, premature deliveries and IUGR is high. Close monitoring of systemic blood pressure and blood gases during labour is necessary for cyanotic or symptomatic patients. Incidence of cardiac defects reported born to such mothers infants ranges between 3 and 17%. Patients who have significant residual defects after repair, such as residual ventricular septal defect, pulmonic stenosis or regurgitation, and ventricular dysfunction, are still at higher risk during pregnancy. Patients who had undergone shunt procedures to improve cyanosis, may develop pulmonary hypertension, which increases the risk of pregnancy. After surgical repair, maternal and foetal outcomes improve markedly. Eisenmenger’s Syndrome This condition leads to poor foetal outcome, with high incidence of foetal loss, prematurity, IUGR and perinatal death. Since there is a high-risk of maternal mortality, patients with Eisenmenger’s syndrome should be advised against pregnancy, and early abortion should be recommended for those who are already pregnant. In an overview of 125 pregnancies in patients with Eisenmenger’s syndrome, primary and secondary pulmonary hypertension, maternal mortality was uniformly high at 36%, 30% and 56% respectively. The overall neonatal mortality was 13%. Management of a patient who decides to proceed to term, must include close follow-up for early recognition of clinical deterioration. Anticoagulation is necessary in the third trimester and 4 weeks post-partum, to prevent peripartum thromboembolism. Since premature delivery is common, patients should be hospitalised for any sign of premature uterine activity. Early hospitalisation ensures restricted activity and close follow-up. Spontaneous delivery is preferred to induction, and should lower the chance of prematurity or the need for caesarean section. Blood pressure, ECG and blood gas monitoring are essential during labour and delivery to ensure early detection and correction of problems. High concentration of oxygen may be beneficial. Most patients with stable condition, tolerate vaginal delivery, but an attempt is to be made to shorten the second stage of labour by the use of forceps. A planned caesarean section is often preferred, to avoid risk of foetal distress during vaginal delivery and potential need for emergency caesarean section. Swan-Ganz catheter should be avoided.

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Ebstein’s Anomaly Pregnancy with acyanotic Ebstein’s anomaly is well tolerated. But in cyanotic cases, pregnancy is associated with increased risk of maternal heart failure, prematurity and foetal loss. The management during labour and delivery in symptomatic or cyanotic cases, includes antibiotic prophylaxis, oxygen inhalation, haemodynamic and blood gas monitoring, and measures to prevent a fall in systemic blood pressure due to peripheral vasodilatation or blood loss. Complex Cyanotic Congenital Heart Disease In India, very few successful pregnancies have been reported in patients with partially corrected and uncorrected cyanotic heart disease, like pulmonary and tricuspid atresia, transposition of great vessels, truncus arteriosus, single ventricle, doubleoutlet right ventricle and double-inlet left ventricle. A report (outside India) has demonstrated complications like, heart failure, thromboembolic events, supraventricular tachycardia, peri-partum infective endocarditis, high incidence of foetal wastage, premature deliveries, IUGR and both cardiac and noncardiac congenital malformations, in such situations. Marfan’s Syndrome In this condition, pregnancy may be associated with cardiovascular complications and a high-risk of having a child who will inherit the condition. Cardiovascular complications include dilatation of ascending aorta, leading to aortic regurgitation and congestive heart failure, and proximal and distal dissections of aorta with occasional involvement of the iliac and coronary arteries. Patients with aortic diameter less than 40 mm, usually tolerate pregnancy well. Marfan’s syndrome may be associated with cervical incompetence, abnormal placental site and post-partum haemorrhagic complications. Women with Marfan’s syndrome should be advised to avoid pregnancy and if already pregnant, interruption is recommended. Preconception echocardiographic assessment of the aorta and periodic followup during pregnancy are necessary and transoesophageal echocardiography is preferred. During pregnancy, physical activity should be restricted and beta-blockers should be administered. Substantial dilatation of aorta, necessitates therapeutic abortion or surgical intervention. Caesarean section should be preferred to minimise, haemodynamic stresses of vaginal delivery. Hypertrophic Cardiomyopathy In this condition, pregnancy is associated with a favourable outcome in most cases but there may be increased morbidity and even mortality. If congestive heart failure or abnormal rhythms occur, standard therapy is appropriate. Hypovolaemia should be avoided. Beta-blockers or calcium channel blockers may be used if necessary. Vaginal delivery is safe and second stage of labour may be shortened by the use of forceps. Antibiotic prophylaxis is necessary during labour and delivery.

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Peripartum Cardiomyopathy Symptoms usually occur during last trimester and is detected in the early peripartum period. The clinical presentation and haemodynamic changes are same as in other forms of dilated cardiomyopathy. The incidence is greater in elderly multiparous women with pre-eclampsia and twin pregnancies. There is relatively rapid recovery of cardiac size and function in large number of patients with recurrence of left ventricular

dysfunction in subsequent pregnancies. About 50% to 60% of the patients show complete or near complete recovery of clinical status and cardiac function, usually within first 6 months post-partum. Rest of the patients demonstrate either further clinical deterioration, leading to early death or persistent left ventricular dysfunction and chronic heart failure. Acute heart failure necessitates prompt treatment with oxygen, diuretics, digoxin and vasodilator agents. Anticoagulant therapy is necessary. The temporary use of an intra aortic balloon pump or left ventricular assist device may help stabilise the patient’s conditions pending improvement. Intravenous immune globulin use, has shown a favourable effect on recovery of left ventricular dysfunction. Subsequent pregnancies should be discouraged. CONCLUSION With important exceptions, most women with cardiac disease can be expected to do well during pregnancy with appropriate management based on systematic risk stratification. Pregnancies deemed to be at intermediate or high-risk should be managed and delivered in a tertiary care setting. More thorough pre-pregnancy cardiovascular evaluations, is likely to better identify patients who are capable of proceeding safely with pregnancy and delivery. Best outcome is based on the strong relationships between physicians in cardiology and in high-risk obstetrics. RECOMMENDED READINGS 1.

Bozkurt B, Villaneuva FS, Halubkov R, et al. Intravenous immune globulin in the therapy of peripartum cardiomyopathy. J Am Coll Cardiol 1999; 34: 177-80.

2.

Caulin-Glaser T, Setaro JF. Pregnancy and cardiovascular disease. In: Burrow GN, Duffy TP editors: Medical Complications During Pregnancy, 5th Ed. Philadelphia: Saunders; 1999:p111.

3.

Gupta A, Lokhandwala YY, Satoskar PR, et al. J Am Coll Surg 1998; 187: 409-15.

4.

Jose AM, de Souza MD, Eulogio E, Martinez, Jr MD, et al. Percutaneous Balloon Mitral Valvuloplasty in Comparison with Open Mitral Valve Commissurotomy for Mitral Stenosis During Pregnancy. J Am Coll Cardial 2001; 37: 900-3.

5.

Lock JE, Khalilullah M, Shrivastava S, et al. Percutaneous catheter commissurotomy in rheumatic mitral stenosis. N Engl J Med 1985; 313: 1515-8.

6.

Mangione JA, Zuliani MF, Del Castilho JM, et al. Percutaneous double balloon mitral valvuloplasty in pregnant women. Am J Cardiol 1989; 64: 99-102.

7.

Mishra S, Narang R, Sharma M, et al. Percutaneous Transseptal Mitral Commissurotomy in Pregnant Women with Critical Mitral Stenosis. Indian Heart J 2001; 53: 192-6.

8.

Presbitero P, Somerville J, Stone S, et al. Pregnancy in cyanotic congenital heart disease: Outcome of mother and foetus. Circulation 1994; 89: 2673-6.

9.

Rossiter JP, Repke JT, Marales AJ, et al. A prospective longitudinal evaluation of pregnancy in the Marfan’s syndrome. Am J Obstet Gynecol 1995; 173: 1599-606.

10. Siu SC, Sermer M, Colman JM,et al.Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001; 104: 515-21. 11. Siu SC, Colman JM, Sorensen S, et al. Adverse neonatal and cardiac outcomes are more common in pregnant women with cardiac disease. Circulation 2002; 105: 2179-84. 12. Weiss BM, Hess OM. Pulmonary vascular disease and pregnancy: Current controversies, management strategies, and perspectives. Eur Heart J 2000; 21: 104-15. 13. Warnes CA, Elkayam U. Congenital heart disease and pregnancy. In Elkayam U, Gleicher N, editors. Cardiac Problems in Pregnancy. 3rd Ed. New York: Wiley-Liss; 1998: pp 39-53. 14. Whittemore R, Wells JA, Castellsague X. A second-generation study of 427 probands with congenital heart defects and their 837 children. J Am Coll Cardiol 1994; 23: 1459-67.

Section

13

Gastroenterology Section Editor: Rakesh Tandon 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 13.9 13.10 13.11 13.12 13.13 13.14

Clinical Approach—Gastrointestinal Disorders A.C. Anand Investigations—Gastrointestinal Disorders Ashok Chacko Endoscopy—Diagnostic and Therapeutic Utility Gourdas Choudhuri Diarrhoea and Malabsorption B.S. Ramakrishna Constipation—Diagnosis and Management Uday Chand Ghoshal Gastrointestinal Bleeding Rakesh Kochhar, Mohd. Talha Noor Oesophageal Disorders Shobna J. Bhatia, Praveen Mathew Diseases of the Stomach and Duodenum Pankaj Dhawan Diseases of the Pancreas V. Balakrishnan, G. Rajesh Functional Gastrointestinal Disorders Philip Abraham Abdominal Tuberculosis Govind K. Makharia Inflammatory Bowel Disease Ajit Sood, Vandana Midha Ischaemic Bowel Disorders Deepak Kumar Bhasin Gastrointestinal Symptoms in Systemic Diseases Rakesh Tandon, Sudeep Khanna

770 774 777 782 787 791 799 806 813 819 823 829 834 837

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13.1

Clinical Approach—Gastrointestinal Disorders

Patients with gastrointestinal diseases can have varied presentations. Symptoms like dysphagia, heartburn, abdominal pain, nausea, vomiting and haematemesis point to diseases of the upper gastrointestinal tract, while constipation, diarrhoea and haematochezia are commonly due to disease of the lower gastrointestinal tract. Diagnosis from individual gastrointestinal symptom may however be difficult at times as symptoms may overlap in a variety of diseases. For example, even the classic symptoms of peptic ulcer such as relief of pain by antacids or food and nocturnal pain are commonly seen in functional dyspepsia. DYSPHAGIA, ODYNOPHAGIA AND HEARTBURN Dysphagia, odynophagia and heartburn point towards oesophageal diseases as a cause of the symptoms. Dysphagia is difficulty in passage of solids or liquids from the mouth to the stomach. It should be distinguished from odynophagia, which is pain on swallowing. Heartburn is a burning sensation behind the sternum. It is important to differentiate dysphagia into causes that mostly affect the pharynx or proximal oesophagus (high/

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Figure 1: Approach to a case with dysphagia. * May be intermittent dysphagia in an oesophageal ring.

AC Anand oropharyngeal dysphagia) and low oesophageal dysphagia. Oropharyngeal (transfer) dysphagia is due to diseases of the neuromuscular mechanism of the pharynx and cricopharyngeus. The patient is unable to initiate and execute the swallow mechanism. There may be coughing or regurgitation of fluids from the nose while swallowing besides associated features of cranial nerve palsies in the form of dysarthria and hoarseness of voice. Low oesophageal dysphagia is due to diseases involving the body of the oesophagus and gastrooesophageal junction. The common causes of dysphagia are given in Table 1 and the approach to a patient with dysphagia is summarised in Figure 1. The diagnosis can be confirmed by barium swallow, upper GI endoscopy and oesophageal motility study as indicated. NAUSEA, RETCHING AND VOMITING Nausea is an unpleasant feeling of wanting to vomit; this may be associated with autonomic features like increased salivation and sweating. Retching is a strong involuntary effort at vomiting. Vomiting is associated with bringing out of gastric contents through the mouth.

Associated symptoms like abdominal pain and constipation point to a gastrointestinal aetiology. Vomitus may be projectile in raised intra-cranial tension. There may be stale food in vomitus in gastric outlet obstruction. The vomitus is bilious in obstruction distal to the duodenum. Vomiting of psychogenic aetiology occurs during or soon after a meal. Table 1: Causes of Dysphagia Oropharyngeal or high dysphagia

Neurological

Anatomical or muscular

Low oesophageal dysphagia

Motility disorder

Mechanical obstruction

Cerebrovascular accident Motor neurone disease Parkinson’s disease Multiple sclerosis Myasthenia gravis Oropharyngeal malignancy (uncommon) Zenker’s diverticulum Retropharyngeal abscess Cervical osteophyte Achalasia Scleroderma Chagas disease Diffuse oesophageal spasms Webs Schatzki ring Neoplasm Strictures Dysphagia lusoria (due to aberrant subclavian artery)

DYSPEPSIA Dyspepsia comprises of a group of upper abdominal symptoms including bloating, pain, postprandial fullness, heartburn and belching. Dyspepsia is defined as chronic or recurrent pain or discomfort centred in the upper abdomen. The first step in assessment is to select patients who will require early endoscopy and/or investigations to rule out serious diseases such as malignancy. The warning signs and symptoms that should alert the physician to a possibility of malignant disease are shown in Table 2.

both sides of the spinal cord. Pain location corresponds to those dermatomes that match the innervation of the diseased organ. Generally, visceral pain from abdominal organs proximal to the ligament of Treitz is felt in the epigastrium; pain from organs between the ligament of Treitz and the hepatic flexure of the colon is felt in the periumbilical region; and that from organs beyond the hepatic flexure is perceived in the lower abdomen midline. Pain arising in hollow organs may wax and wane due to peristaltic waves. Parietal Pain Parietal pain is well localised and sharp and is due to peritoneal irritation by the inflamed organ, e.g. appendicitis. Referred Pain Referred pain may be seen, for example, as shoulder pain due to liver abscess causing diaphragmatic irritation. Assessment of cause of abdominal pain includes a careful history of onset, duration, progress, location, radiation, character and aggravating and relieving factors. Clinical examination starts with inspection, which may show scars, hernias, splinting of abdominal movements, and visible peristalsis. A patient with peritonitis would lie still and the abdomen would be tender and would appear rigid. In contrast, a patient with ureteric colic may be rolling in bed due to pain. Visible peristalsis may be seen in bowel obstruction. Palpation may show a lump or tenderness. Guarding or rebound tenderness may be seen in peritonitis. Percussion may show ascites or obliteration of hepatic dullness in bowel perforation. Auscultation may reveal hyperactive or absent bowel sounds, besides bruits. Rectal examination can reveal a rectal growth or a pelvic abscess. GASTROINTESTINAL BLEEDING Bleeding from the GI tract can present as melaena, haematochezia or haematemesis; patients with occult bleed may present only with anaemia. Melaena is black, tarry foul-smelling stool and usually signifies the presence of >50 mL of blood. It usually implies a proximal GI source. It takes about 12 hours of transit time for melaena to develop. It can rarely develop as a result of bleeding from right colonic sources.

Table 2: Alarm Symptoms in a Patient with Dyspepsia that Indicate High Risk for Serious Underlying Disease

Haematochezia (maroon bloody stools) can come from a proximal GI source if intestinal transit is rapid but usually signifies a lower GI source. Fresh red blood is commonly due to rectal or left colonic disease.

Anaemia Weight loss Gastrointestinal bleed Recent onset of progressive symptoms Age >45 years Dysphagia

Haematemesis is blood in vomitus. It may be fresh bright-red or older coffee-ground material and signifies an upper GI bleed. The presence of haematemesis or melaena signifies an upper GI source but patients with rapid upper GI bleed may present with haematochezia.

ABDOMINAL PAIN Abdominal pain can have three broad patterns: visceral, parietal, and referred. Visceral Pain Visceral pain is dull crampy and poorly localised. It is often in the midline because abdominal organs transmit afferents to

Clinical Approach—Gastrointestinal Disorders

Gastrointestinal disorders causing vomiting include infections, bowel obstruction, cholecystitis, pancreatitis, infectious hepatitis, appendicitis and peptic ulcer. Vomiting may also be due to drugs, motion sickness, raised intracranial tension, meningitis, azotaemia, pregnancy, systemic illness and psychogenic causes.

Preliminary clues to the site of haemorrhage include the presence of haematemesis, hyperactive bowel sounds, and increased blood urea nitrogen out of proportion to creatinine (upper GI), or fresh rectal bleeding (colonic). Insertion of a nasogastric tube and aspiration may help in localisation of bleeding. However, it may be negative in some cases of upper GI bleed.

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In upper GI bleeding, from a management point of view, it is important to differentiate between variceal and non-variceal aetiology. The clinical evaluation of upper GI bleed is shown in Table 3. Gastrointestinal endoscopy is usually required to make a definitive diagnosis. In obscure GI bleeding, one may need an isotope scan, angiography, or capsule or doubleballoon enteroscopy to determine the source of bleeding. Table 3: Differentiating Variceal from Non-Variceal Bleed Variceal source suspected if GI bleeding is associated with Jaundice Ascites Splenomegaly Past history of treatment for liver disease Clinical stigmata of chronic liver disease (spider naevi, palmar erythema, testicular atrophy, gynaecomastia, etc.) Non-variceal source is suspected if bleeding is associated with Absence of the above History of epigastric pain Past history of peptic ulcer Recent NSAID intake Recurrent vomiting/retching (Mallory-Weiss tear)

CONSTIPATION Patients usually define constipation not only by infrequent stools (typically fewer than three per week), but also by associated symptoms which are equally important, and probably more important, such as: hard stools, the need for excessive straining, a sense of incomplete bowel evacuation, and excessive time spent on the toilet or in unsuccessful defaecation. Constipation is a common symptom, more so in the elderly. A number of commonly used drugs in the elderly often aggravate constipation, including calcium supplements, iron supplements, diuretics, calcium-channel blockers, etc. A history of recent onset of constipation and/or blood mixed with stool raises the possibility of a malignant colonic lesion. A thorough physical examination should be performed to exclude systemic or neurological illnesses that may cause constipation. Abdominal examination may reveal abdominal mass or palpable stools. Anorectal examination may reveal fissures, haemorrhoids, lack of anal sphincter tone or a rectal stricture. Stool for occult blood is a useful screening test, while colonoscopic examination would be required to rule out local diseases. DIARRHOEA Diarrhoea is defined as increase of volume, frequency or fluidity of stool. It could be acute or chronic. Acute diarrhoea (< 4 weeks) is usually due to infections and is often self-limited. It may be associated with fever, pain in abdomen or dehydration. Chronic diarrhoea (>4 weeks) may be associated with malabsorption and weight loss.

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Evaluation of a case of chronic diarrhoea requires detailed clinical history. Malabsorption will be associated with semisolid (occasionally watery) stools that are bulky, float on water, and stick to the pan. The stools may be explosive in character and be associated with flatulence and borborygmi. It may contain undigested food particles, increase with lactose intake, and decrease on fasting. There may be mild periumbilical pain relieved by passage of flatus or stools. Small volume stools associated with blood, mucous and tenesmus are suggestive of large bowel diarrhoea. The clinical clues to aetiology of chronic diarrhoea are given in Table 4. The approach to chronic diarrhoea (>4 weeks) should follow the following steps: Table 4: Chronic Diarrhoea: Clinical Clues Clubbing: Immunoproliferative small intestinal disease, Crohn’s disease, coeliac disease Fever: Tuberculosis, lymphoma, Whipple’s disease, Crohn’s disease/ulcerative colitis Response to antibiotics: Bacterial overgrowth, giardiasis, tropical sprue, Whipple’s disease Response to steroids: Inflammatory bowel disease (IBD), microscopic colitis, eosinophilic gastroenteritis, Addison’s disease Arthritis: IBD, coeliac disease, Whipple’s disease, collagen disorder Lymphadenopathy: HIV,Whipple’s disease, tuberculosis, lymphoma Dermatitis herpetiformis: Coeliac disease Pyoderma gangrenosum: IBD Abdominal mass: Crohn’s disease, lymphoma, tuberculosis

Step 1: Rule-Out Irritable Bowel Syndrome Red flag symptoms that are against the diagnosis of irritable bowel syndrome are shown in Table 5. Table 5: Red Flag Symptoms that make the Diagnosis of Irritable Bowel Syndrome Unlikely Fever Weight loss Nocturnal diarrhoea Blood in stools ↓ Haemoglobin, ↓ albumin, ↑ ESR Recent symptoms in middle age/elderly

Step 2: Large Bowel versus Small Bowel (Table 6) Table 6: Large Bowel Diarrhoea versus Small Bowel Diarrhoea Large bowel diarrhoea

Small bowel diarrhoea

Presence of blood and mucous

Malodorous, floating, greasy, containing undigested food particles Large-volume stools

Rectal/anal symptoms such as tenesmus/dyschezia Small-volume jelly-like stools Associated hypogastric cramps

Mid-abdominal cramps with borborygmi

Features of carbohydrate malabsorption with lactose intolerance causing explosive stool with flatulence are suggestive of mucosal malabsorption. This can be confirmed by an abnormal d-xylose test. In chronic pancreatitis, classical history of pancreatic pain with radiation to back and imaging evidence of chronic pancreatitis are often clearly evident. The d-xylose test would be normal in chronic pancreatitis and faecal fat excretion is often more than 14 gm/day, much more than that seen in mucosal malabsorption. A clinical approach to chronic diarrhoea is shown in Figure 2. RECOMMENDED READINGS

Figure 2: Approach to chronic diarrhoea: Basic clinical segregation of patient into small bowel diarrhoea and large bowel diarrhoea is usually adequate in directing evaluation. A small subgroup of patients with watery diarrhoea, in whom evaluation for the above have been negative, require advanced evaluation.

1.

Flasar MH, Goldberg E. Acute abdominal pain. Med Clin N Am 2006; 90: 481503.

2.

Owen W. ABC of the upper gastrointestinal tract-dysphagia. Br Med J 2001; 323: 850-3.

3.

Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005; 129:1756-80.

4.

Thomas PD, Forbes A, Green J, et al. Guidelines for the investigation of chronic diarrhoea; 2nd Ed. Gut 2003; 52 (Suppl V): v1-v15.

Clinical Approach—Gastrointestinal Disorders

Step 3: Chronic Pancreatitis versus Mucosal Malabsorption

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13.2

Investigations—Gastrointestinal Disorders Ashok Chacko

INTRODUCTION The gastrointestinal (GI) tract can be evaluated by examination of luminal contents, upper and lower GI endoscopy and various laboratory tests which may help in establishing diagnosis. In this chapter, author discusses about tests for luminal contents and laboratory tests while the endoscopy of GI tract has been covered in next chapter (see Chapter 3 Endoscopy—Diagnostic and Therapeutic Utility). STOOL EXAMINATION Stool examination must be performed in all patients with abdominal symptoms, especially diarrhoea. Stool inspection, often neglected, is important as it gives information regarding volume, consistency and presence of blood and mucous. Stool microscopy helps in detection of RBC and pus cells— suggesting bacillary dysentery and inflammatory bowel disease, parasitic ova/cysts, and fat in stools (Sudan stain) suggesting malabsorption. In immunocompromised patients with diarrhoea, stool evaluation for parasites like Cryptosporidium, Microsporidium, Isospora belli and Cyclospora should be performed. Stool culture is not done routinely except in persistent diarrhoea. Stool positive for occult blood suggests GI blood loss and warrants further evaluation. Acidic stools (pH 50 mOsm/kg is characteristic of osmotic diarrhoea whereas secretory diarrhoea has osmotic gap 15 mmol per hour suggest ZES (normal BAO 0.55 mmol/L false positive results Urine >20% of ingested xylose

Fat

72 h faecal fat

Quantification of stool fat while patient ingests 50 g fat/d Normal: 10% with equal ratio of both isotopes after antibiotics

Gastric disease: Free vitamin B12 absorption decreased Ileal disease: Free vitamin B12 and vitamin B12 - IF factor complex absorption decreased Bacterial overgrowth: vitamin B12 normal

Lactose

Breath hydrogen

Measurement of breath hydrogen every 30 min for 2 hours after 50 g of lactose Hypolactasia >20 ppm

Early rise of breath H2 in small bowel bacterial overgrowth

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Isotopic quantification of 7 days whole body retention of oral dose 75SeHCAT

Accurate and specific

Bile acids

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SeHCAT test

Comments

Normal: >15%

Involves radiation

Abnormal: 12 ppm rise over baseline within 120 min. Time to first sustained response within 3-5 hours 20 ppm rise over baseline within 3 h. 14 CO2 > 0.3% at 2-3 h

Hypolactasia

Bacterial overgrowth 14 Bacterial CO2 > 0.3% overgrowth at 2-3 h Fat malabsorption Breath 14CO2 < 0.0005% 13/14 Confirm H. pylori CO2 > 5-fold eradication baseline at 20 min.

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RADIOISOTOPE TESTS Radioisotope tests are shown in Table 4. Table 4: Radioisotope Tests Test

Isotope

Indication

Gastric emptying

99m

Gastroparesis

Tc pertechnetate In-DTPA 14 C/13C Urea

TUMOUR MARKERS CA 19:9 Pancreatic and biliary malignancy CEA Colonic malignancy Chromogranin Neuroendocrine tumour Molecular Tests

111

Urea breath test Meckel’s scan

99m

Tc-pertechnetate

51 Cr labelled Labelled red cell scan erythrocytes Labelled leucocyte 111In or 99mTc HMPAO scan labelled leucocytes

Albumin tagged scan

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125 51

I-Albumin, Cr-Albumin

Confirm H. pylori eradication Meckel’s diverticulum in obscure GI bleed Obscure GI bleed Distribution of activity (extent) in inflammatory bowel disease Protein losing enteropathy

Disorder

Gene Affected

Familial adenomatous polyposis Multiple endocrine neoplasia Hereditary non-polyposis colon cancer Peutz-Jegher syndrome

APC Menin hMSH 2, hMLH1 LKB1

RECOMMENDED READING 1.

Feldman M, Friedman LS, Sleisenger MH. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease; 8th Ed. Philadelphia: WB Saunders and Co; 2009: pp 81-2.

13.3

Endoscopy—Diagnostic and Therapeutic Utility

INTRODUCTION Advancement in endoscopy has revolutionised our approach to diagnosis and management of various gastrointestinal disorders. The word endoscopy is derived from Greek, ‘end’ meaning within and ‘skopein’ meaning to view or observe. In this chapter upper gastrointestinal endoscopy, colonoscopy and endoscopic retrograde cholangio-pancreatography (ERCP) will be discussed in brief.

Gourdas Choudhuri

Table 1: Indications for Upper Gastrointestinal Endoscopy Diagnostic

HISTORY The first attempt at looking into the body cavity was made by Adolf Kussmaul who devised the first gastroscope in 1868, made up of a rigid metal tube. Subsequently Rudolf Schindler (18881968) improved this instrument but it was Basil Hirschowitz who pioneered the use of fibre optics (glass fibre that conduct light) that greatly improved the flexibility and manoeuvrability of the instrument. In 1957 he himself swallowed the first fibre optic gastroscope. The use of electronic chips (charge couple devices or CCD) to transmit the image from the tip of the endoscope to a video screen resulted in the present generation of video endoscopes since the 1980s. UPPER GASTROINTESTINAL ENDOSCOPY (UGIE) Indications This largely depends on the suspected diagnosis, availability of facilities and expertise, and patient’s choice. The common diagnostic and therapeutic indications for UGIE are given in Table 1 and shown in Figures 1 to 6. Contraindications The absolute contraindications are given in Table 2. Apart from these conditions special precautions should be taken in patients with Zenker’s diverticulum, compromised cardiovascular and pulmonary reserve and coagulopathy. Taking biopsy should be avoided in patients with coagulopathy. Pregnancy is not a contraindication for UGIE, but should only be performed for pressing indications.

Figure 1: Upper gastrointestinal endoscopy showing large oesophageal varices with red colour signs.

Therapeutic

Upper gastrointestinal bleeding: past or present Patients with splenomegaly or suspected chronic liver disease: for presence and grading of oesophago-gastric varices Upper abdominal distress that persists despite an appropriate trial of therapy Upper abdominal distress associated with symptoms or signs that suggest serious organic disease. Dysphagia or odynophagia Oesophageal reflux symptoms that are persistent or recurrent despite appropriate therapy Persistent nausea and vomiting of unknown cause Surveillance for malignancy Gastric or oesophageal ulcers Familial adenomatous polyposis Adenomatous gastric polyps Barrett’s oesophagus Occult gastrointestinal bleeding Small bowel biopsy Cirrhotic patients in whom prophylactic therapy is considered After caustic ingestion to assess for acute injury Treatment of bleeding lesions Sclerotherapy or banding of varices Removal of foreign bodies Removal of selected polypoid lesions or superficial neoplasms Placement of feeding or drainage tubes Dilation of stenotic lesions Palliative treatment of stenosing neoplasms Drainage of pancreatic pseudocysts

Table 2: Contraindications for Upper Gastrointestinal Endoscopy The risks to patient health or life are judged to outweigh the most favourable benefit of the procedure. Adequate patient cooperation cannot be obtained. A perforated viscus is known or suspected.

Figure 2: Upper gastrointestinal endoscopy showing polypoidal, ulcerated growth suggestive of oesophageal cancer.

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Figure 3: Upper gastrointestinal endoscopy showing a benign gastric ulcer.

Figure 4: Oesophageal variceal sclerotherapy. Note the blue scleropathy needle.

Figure 5: Glue injection being done in a patient with large, bleeding fundal varices.

Figure 6: Oesophageal variceal band ligation. Note the blue ‘O’ ring on one of the varix.

Preparation and the Procedure The procedure is performed after anaesthetising the pharynx with lignocaine spray or gel. Tense and apprehensive patients may need intravenous sedation with midazolam or propofol. The procedure is performed with the patient lying in the left lateral position. The endoscope is inserted through the mouth, pharynx, oesophagus, stomach and then further down to the second part of the duodenum under vision.

as the most useful test for evaluation of the colon and terminal ileum.

Complications of UGIE Endoscopic examination of the upper gastrointestinal tract is a fairly safe procedure with overall complications being less than 1% and mortality rate 10 mmHg usually indicates a 20% or greater reduction in blood volume (Table 1). Concomitantly, the patient may have symptoms like light-headedness, syncope, nausea, diaphoresis and thirst. Shock frequently results when the blood loss is more than 25% of the blood volume. Patients may occasionally experience a vasovagal reaction with bradycardia during bleeding episodes. Haematocrit is used to assess the degree of blood loss. However, it does not fall immediately with haemorrhage because of proportionate reduction of plasma and red cell volumes and it reflects the true magnitude of bleed only after a period of 24 to 48 hours. Hence, during this

Patient’s haemodynamic status Resting hypotension Postural hypotension Normal

Blood loss % >26 10-20 3,000 mL). Fresh frozen plasma (FFP) or platelets may be required in patients with coagulopathy or severe thrombocytopaenia, and in patients who require ten or more units of blood. Differentiating Upper from Lower GI Bleeding After resuscitation, the source of bleeding must be localised to direct further management. A nasogastric lavage must be performed irrespective of the probable site of the bleed. A bloody or a coffee ground aspirate confirms an upper GI source but their absence does not rule it out. A clear aspirate may be seen in up to 10% to 20% of patients with bleeding from a duodenal source. However, the presence of bile in the clear aspirate rules out a duodenal source. Other clues to upper GI bleeding include hyperactive bowel sounds and an elevation in blood urea nitrogen (BUN); the latter results from volume depletion and breakdown of blood proteins in the gut. Patients with lower GI bleed are less likely to present with shock or orthostatic symptoms as compared to patients with upper GI bleed. They have higher haemoglobin levels at presentation and also lower transfusion requirements.

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DIAGNOSTIC EVALUATION OF PATIENTS WITH GI BLEEDING Acute Upper Gastrointestinal Bleeding History and physical examination A history of prior episodes of bleeding, illnesses such as ulcers, cirrhosis, cancer or bleeding disorders, prior surgery (such as for peptic ulcer), consumption of excess of alcohol, and medications like nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-coagulants should be elicited. Oesophago-gastric variceal bleed is painless and massive. A bleeding episode preceded by abdominal pain usually indicates underlying peptic ulcer disease. A history of retching and vomiting prior to haematemesis may indicate Mallory-Weiss syndrome. Examination of the skin may reveal cutaneous stigmata of cirrhosis. Rarely, evidence of underlying cancer (e.g. acanthosis nigricans), tumours (e.g. neurofibromatosis, blue rubber bleb nevus). Henoch-Schönlein purpura or vascular anomalies may be found. Skin and musculoskeletal abnormalities of pseudoxanthoma elasticum or Ehlers-Danlos syndrome may be diagnostic. Further clues on systemic examination include lymphadenopathy or abdominal masses, malignancy, abdominal tenderness (peptic ulcers, pancreatitis) and splenomegaly with or without prominent abdominal wall veins (cirrhosis, portal/splenic vein thrombosis). INVESTIGATIONS Endoscopy plays a major role in diagnosing the cause of GI blood loss. Other tests that may help include USG abdomen, CT scan of the abdomen and angiography. Endoscopy Endoscopy should be performed only after the patient has been haemodynamically stabilised. However, if the patient is bleeding massively and responding to resuscitative measures, endoscopy can be performed at the bedside provided adequate support personnel and with resuscitative facilities. Repeated gastric lavage prior to urgent endoscopy helps in clearing the stomach of blood clots, thereby providing a better field of view. Intravenous erythromycin can help clear the stomach if given half an hour before endoscopy. There is no role of cold saline lavage in controlling gastrointestinal bleeding. At endoscopy, detailed evaluation of the oesophagus, stomach and duodenum is carried out.

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A majority of the bleeds occur from peptic ulcers, varices and erosions (Table 2). If there is no evidence of any of these, other uncommon lesions, especially vascular malformations should be carefully looked for. Endoscopy is superior to barium studies as it detects more lesions, it permits mucosal biopsy of suspicious lesions; it may act as a therapeutic modality; presence of active bleeding or stigmata or recent haemorrhage can provide prognostic information; and results of endoscopy guides the decision on the level of hospital care, on when to resume feeding and on length of hospitalisation. Endoscopic Forrest classification of peptic ulcer is useful for stratifying patients into high and low risk of rebleeding. Patient with Forrest 1a (active bleeding) and Forrest 1b (oozing vessel) at the time of endoscopy have high risk of rebleeding. Patients with Forrest 2a (visible vessel), Forrest 2b (adherent clot) and Forrest 2c (pigmented base) have moderate risk of rebleeding. Patients with Forrest 3 (clean base) have low risk of rebleeding. Patients in Forrest class 1, 2a and 2b benefit from endotherapy.

Other Diagnostic Tests Ultrasound of the abdomen can provide evidence of portal hypertension in the form of coarsened liver echotexture, dilated splenoportal axis, presence of collaterals and splenomegaly, it should be carried out in all patients. Computed tomography (CT) of the abdomen is useful to look for any evidence of pancreatitis, tumour or haemosuccus pancreaticus, CT angiography is useful in the diagnosis of visceral aneurysms. AETIOLOGY AND MANAGEMENT OF UPPER GI BLEED The various causes of upper GI bleed and management are given in Table 2 and Figure 1. In India, most common aetiology is oesophageal variceal bleeding, other common causes are duodenal ulcer, gastric ulcer and gastritis. Table 2: Causes of Upper Gastrointestinal Bleeding Common causes Peptic ulcer disease Oesophageal and gastric varices Oesophagitis Gastric erosions Duodenitis Mallory-Weiss tear Gastrointestinal malignancies Uncommon causes Angiodysplasia Dieulafoy lesion Cameron ulcers Gastric antral vascular ectasia Portal hypertensive gastropathy Gastric polyps Aortoenteric fistula Haemobilia Haemosuccus pancreaticus Foreign bodies Iatrogenic-nasogastric tube erosions, endoscopic polypectomy, sphincterotomy

Acute Variceal Haemorrhage In India, non-cirrhotic portal hypertension (NCPF) account for up to 25% of portal hypertension, and they have a better prognosis than cirrhosis. Oesophageal varices are the site of bleeding in most patients. Bleeding from gastric varices can occur in patients with active as well as thrombosed oesophageal varices. Some patients may bleed from portal hypertensive gastropathy and gastric antral vascular ectasia. Treatment options for bleeding oesophageal varices include pharmacotherapy, balloon tamponade, endoscopic, transjugular intrahepatic portosystemic shunt and surgery. In the emergency room, if clinical suspicion of bleed being variceal is high, patients can be started on intravenous terlipressin 1 mg every 4 to 6 hourly or octreotide 50 to 100 µg bolus, followed by infusion at 50 µg/hour. Continuation of these drugs for 3 to 5 days after endoscopic treatment reduces chances of rebleeding. If the patient is bleeding actively and immediate endotherapy is not possible, an alternative of endoscopic therapy is balloon tamponade with Sengstaken Blakemore tube. It has two balloons, oesophageal and gastric, control of haemorrhage requires inflation of gastric balloon with 250 mL of air, oesophageal balloon is usually not inflated as it is associated with risk of oesophageal rupture. It is very effective in immediate controlling of bleeding in over 80%

Gastrointestinal Bleeding

Figure 1: Algorithm for managing acute upper GI bleeding. TIPSS = Transjugular intrahepatic porto-systemic shunt; APC = Argon plasma coagulation.

of patients. It is associated with 50% rebleeding after deflation of balloon. It is also associated with risk of oesophageal rupture, ulceration and aspiration pneumonia. Though associated with significant complications, balloon tamponade can be instituted even by primary physicians. Endoscopic treatment options for bleeding oesophageal varices are endoscopic variceal ligation (EVL) and endoscopic sclerotherapy (ES). Both have an efficacy of about 90%. Endoscopic sclerotherapy involves visualisation of the varix during endoscopy, followed by injection of a sclerosing agent into the varix or into the adjacent tissue. Various sclerosing agents include sodium tetradecyl sulphate, polidocanol, sodium morrhuate and ethanol. Variceal obliteration is usually achieved after 3 to 6 sclerotherapy sessions at periodic intervals. Complications associated with ES include retrosternal pain, oesophageal ulcers and oesophageal stricture. EVL was first reported in 1989. The technique involves the placement of rubber bands around a portion of the varix containing oesophageal mucosa. The varix is sucked into a hollow, clear plastic cylinder attached to the tip of the endoscope. Once suctioned into the sheath, a trigger device allows deployment of the band around the varix. The blood flow is completely interrupted, producing ischaemic necrosis of the mucosa and submucosa. Later granulation takes place with sloughing of the

rubber rings and necrotic tissue, leaving shallow mucosal ulcerations that heal in 14 to 21 days. Application of the bands is started at the gastroesophageal junction and progresses cephalad in a helical fashion. EVL sessions are repeated at approximately 2-week intervals until varices are obliterated, usually requiring 2 to 4 ligation sessions. Complications are less frequent than with endoscopic sclerotherapy. Transjugular intrahepatic porto-systemic shunt (TIPSS) is a procedure in which a self-expanding metal stent is placed radiologically between the portal and hepatic veins. It is highly effective in reducing portal pressures and rebleeding and in controlling acute variceal haemorrhage. TIPSS is, however, associated with a risk of encephalopathy and shunt stenosis, although the latter risk is reduced with the use of the newer polytetrafluoroethylene covered stents. Recently a removable self-expanding oesophageal metal stent has also been used effectively in patients with variceal bleeding refractory to other treatment modalities. Nowadays surgery is rarely needed for variceal bleeding. Surgical options include shunt and non-shunt procedures. The shunts are either total or selective. Total shunts include portacaval, mesocaval and central splenorenal, selective shunt include distal splenorenal shunt. Non-shunt operations are gastroesophageal devascularisation or disconnection procedures.

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For bleeding gastric varices, injection of N-butyl-cyanoacrylate can be made into the varices with good results. This modality can be used in actively bleeding gastric varices as well as to prevent rebleeding; 1 to 2 mL of cyanoacrylate is injected into the varix using a 21 gauge sclerotherapy needle. In refractory cases TIPSS is an effective treatment modality; it controls acute gastric variceal bleeding in over 90% patients. Balloon-occluded retrograde transvenous obliteration (B-RTO) is a new technique; it is highly effective in controlling acute gastric variceal bleeding. Bleeding from portal hypertensive gastropathy and gastric antral vascular ectasia is not massive but difficult to treat. Treatment of portal hypertensive gastropathy is directed towards underlying portal hypertension. First line therapy for gastric antral vascular ectasia (GAVE) is argon plasma coagulation. Recently, endoscopic variceal ligation has also been used for its treatment successfully. Apart from the treatment mentioned above, broad spectrum of antibiotics for a week have been shown to improve survival of these patients. After control of initial haemorrhage, prevention of variceal rebleeding is an important aspect of the management of portal hypertension. Non-selective beta-blockers reduce cardiac output and cause splanchnic vasoconstriction, reducing portal venous pressure. Several randomised controlled trials comparing propranolol or nadolol with placebo have shown a reduction in rebleeding and mortality with beta blockers. Addition of isosorbide mono nitrate to beta-blockers enhances the efficacy of therapy but offers no survival advantage and reduces tolerance to therapy. Peptic Ulcer Disease (PUD) Most ulcer bleeds are from duodenal ulcers, though in patients on NSAIDs, bleeding from gastric ulcers is more common. An ulcer bleeds when it erodes into the lateral wall of a blood vessel. Ulcers located high on the lesser curve of stomach or on the posteroinferior wall of the duodenal bulb are most likely to bleed. Helicobacter pylori infection, NSAID use, and stress due to critical illness contribute to the development of ulcers. Up to 80% of duodenal ulcers are caused by Helicobacter pylori, whereas about 50% of gastric ulcers are associated with this infection. NSAIDs constitute the most important cause of PUD after H. pylori infection, all patients who have PUD should be carefully questioned about NSAIDs use. NSAIDs induced ulcers may be painless because analgesic properties of NSAIDs can mask the pain of ulcers. Concurrent aspirin and oral anti-coagulant use increase the risk of bleeding. Other risk factors are cardiovascular or cerebrovascular disease and hospitalisation. Bleeding stops spontaneously in 80% of instances. Patients with ongoing bleed, haemodynamic compromise, and high transfusion requirements mandate urgent endoscopic therapy, which can achieve haemostasis in more than 90% of cases. Surgical intervention is indicated in patients whose bleeding is refractory to endoscopic therapy.

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Proton pump inhibitors (PPI) are the mainstay of pharmacological treatment. Proton pump inhibitors elevate the pH, thus, enhancing clot formation and platelet aggregation. PPI should preferably be given intravenously, though oral administration is also shown to be effective. High dose intravenous (IV) omeprazole or pantoprazole (80 mg IV bolus followed by 8 mg per hour for 72 hours) has been shown to

reduce rebleeding rate and the need for surgery. Lansoprazole and esomeprazole are the other PPIs available for intravenous use. After the patient’s condition stabilises, intravenous PPI therapy may be switched to oral PPI therapy. Endoscopic therapy is accepted as the most effective method for controlling acute ulcer bleeding and for preventing rebleeding. Depending on the endoscopic appearance of the ulcer, different endoscopic modalities are applied. High risk ulcers are those that are bleeding actively and those with a non-bleeding visible vessel. These patients are shown to benefit the most from endoscopic therapy. Management of ulcers with adherent clots was controversial earlier, but now it has been shown that endoscopic therapy is superior to medical therapy for preventing recurrent haemorrhage in patients with bleeding peptic ulcers with adherent clots. Ulcers with flat pigmented spots or those with clean base have no additional benefit from endotherapy. The most popular endoscopic therapy is injection therapy using epinephrine (1:10,000). Other injection therapies include use of sclerosants, including sodium tetradecyl sulphate, polidocanol or ethanol. Biologic agents like thrombin, fibrin sealant and cynoacrylate glue can also be utilised. The assistant projects the needle, originally designed for injection sclerotherapy, about 5 mm beyond the plastic sheath, injects the solution, multiple injections are given around the ulcer to provide tamponade effect. Thermal methods for controlling bleeding include laser, electrocoagulation and heater probe. These can be combined with injection therapy. Newer techniques include application of metal clips, band ligation, argon plasma coagulation and endoloops. In patients with rebleeding, repeat endoscopy appears to be useful. Presence of hypotension at admission and an ulcer size larger than 2 cm are independent predictors of failure of endoscopic therapy. Eradication of H. pylori and stopping NSAIDS are two factors shown to prevent recurrent bleeding. Relook endoscopy with retreatment in peptic ulcer bleeding significantly reduces the risk of recurrent bleeding, although it does not substantially reduce the need for subsequent surgery or mortality. In summary management of bleeding peptic ulcer include initial resuscitation, pharmacotherapy with proton pump inhibitors, endoscopic therapy and in refractory cases, surgery should be considered. Indications for surgery include failure of endoscopic therapy, large ulcer (>2 cm), massive bleeding and development of complications like perforation. Transcatheter arterial embolisation is reserved for patients who have exceptionally high risks for surgery (e.g. acute myocardial infarction). Erosive Gastropathy Erosive gastropathy refers to endoscopically visualised subepithelial haemorrhages and erosions that may account for upper GI bleeding in 15% to 25% of cases. Antacids, H2 receptor blockers, proton pump inhibitors and sucralfate decrease bleeding from gastric erosions. Endoscopic, argon plasma coagulation has been found to be useful in the treatment of severe bleeding. Mallory-Weiss Syndrome Recurrent vomiting or retching can lead to mucosal tears at the gastro-oesophageal junction causing haematemesis. Bleeding

Dieulafoy’s Lesion Dieulafoy’s lesions are prominent submucosal vessels, usually found in the proximal stomach with no surrounding ulceration. These lesions are difficult to identify if they are not bleeding actively during endoscopy. Standard endoscopic injection, thermocoagulation, haemoclip, argon plasma coagulation or band ligation can successfully achieve haemostasis. Gastrointestinal Malignancies Endoscopy is used for diagnosis and for taking biopsies but it is usually ineffective in controlling the bleed. ACUTE LOWER GASTROINTESTINAL BLEEDING History and Physical Examination Passage of drops of blood either separately or coating the stool may indicate bleeding from an anorectal source, especially haemorrhoids. Bloody diarrhoea with or without pain occurs in infective colitis or inflammatory bowel disease. Associated weight loss or recent change in bowel habits suggests colorectal cancer. A history of radiation therapy suggests radiation proctitis. The abdomen should be carefully examined to detect tenderness, organomegaly or a mass. A per rectal examination should always be performed to look for prolapsed haemorrhoids, mass polyp or ulcer.

AETIOLOGY AND MANAGEMENT OF SPECIFIC CAUSES OF LOWER GI BLEED The various causes and management of lower GI bleed are given in Table 3 and Figure 2. Table 3: Causes of Lower Gastrointestinal Bleeding Common causes

Relative frequency in India

Colonic sources Haemorrhoids Inflammatory bowel disease Neoplasms Arteriovenous malformation, angiodysplasia Diverticula Small bowel source Meckel’s diverticulum or other diverticula Vasculitis Ulcers, e.g. typhoid

70% to 90% 30% to 40% 30% to 40% 15% to 20% 2% to 5%

Less common causes Solitary rectal ulcer syndrome (SRUS) Infectious enterocolitis Ischaemic colitis Aortoenteric fistula Colonic varices in portal hypertension Radiation proctitis Lesions associated with use of NSAIDs

2% to 5%

Gastrointestinal Bleeding

is usually not massive and stops spontaneously. Occasionally injection therapy or haemoclips may be required to control the bleeding.

2% to 5% 10% to 20%

Proctoscopy and Sigmoidoscopy Patients with presumed lower GI bleeding must undergo early proctoscopy and sigmoidoscopy for the detection of obvious, low-lying lesions such as bleeding haemorrhoids, anal fissure, rectal ulcer, proctitis or rectal cancer. Colonoscopy If procto-sigmoidoscopy is not informative, colonoscopy is the next logical investigation. It is superior to barium enema since it can detect vascular lesions and allows biopsies to be taken. As 5% to 10% patients with upper GI lesions present with haematochezia, it is prudent to perform upper GI endoscopy before undertaking extensive investigations. Urgent colonoscopy in lower GI bleeding is safe with high likelihood of making a specific diagnosis (75% to 100%). Performance of colonoscopy requires preparation of the patient with purgatives, polyethylene glycol and sodium phosphate are the commonly used purgatives. Angiography Angiography is helpful in detecting the site of bleed in actively bleeding patients. Angiodysplasias are the commonest lesions detected by angiography. It may also show vascular malformations or tumours, even if extravasation of contrast material is not noted. Radionuclide Scanning It involves intravenous administration of 99mTechnetium tagged sulphur colloid or RBCs followed by imaging with an external gamma camera to detect intestinal extravasation of the substrate. It can detect bleeding even at a slower rate than that detected by angiography.

Figure 2: Algorithm for managing acute lower GI bleeding.

Anorectal Lesions Haemorrhoids are the most common cause of lower GI bleed. Treatment may be in the form of sclerotherapy, banding, and cryotherapy. Surgery is required for large and prolapsed haemorrhoids. Solitary rectal ulcer syndrome (SRUS) is a benign condition in young individuals, which presents as rectal

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bleeding, tenesmus and mucous discharge. Sigmoidoscopy with biopsy is essential for diagnosis. Treatment consists of avoiding digital rectal manipulation, laxatives and sucralfate enemas. Inflammatory Bowel Disease (IBD) Patients with IBD have a history of recurrent episodes of bloody diarrhoea. Colonoscopy with biopsy is required to differentiate IBD from other forms of colitis. Steroids and 5-aminosalicylic acid usually control the disease. Colectomy is required for massive bleeding not responding to medical management. Polyps Adenomatous colonic polyps can present with occult or overt rectal bleeding (if they are larger than 1 cm). Juvenile polyps are hamartomas occurring in the first two decades of life. Colonoscopic polypectomy is the treatment of choice. Bleeding from malignant colonic polyps requires colectomy. Infectious Enterocolitis Various invasive organisms viz. Shigella, Salmonella, Campylobacter, enteroinvasive E. Coli,Clostridium difficile and Entamoeba histolytica present with bloody diarrhoea.Diagnosis is usually made by routine examinations and culture of the stool.Treatment is with antibiotics. Colonic Diverticula Colonic diverticula are less frequent in the Indian population as compared to the West. However, in elderly patients especially those with complications, diverticular disease should be considered and looked for. Bleeding is abrupt in onset, usually painless and often massive, but ceases spontaneously in 80% of patients. Colonoscopy is required for diagnosis. Vasopressin infusion controls bleed temporarily. Segmental surgical resection is indicated for ongoing bleed. Angiodysplasia Angiodysplasia or arteriovenous malformations are also less frequent in Indians as compared to Western population. Bleeding from angiodysplasia is painless, trivial to massive in amount, recurrent and usually resolves spontaneously. Colonoscopic diagnosis and treatment by endoscopic electrocoagulation are generally successful in identification and definitive management of these lesions. Ischaemic Colitis Ischaemic colitis usually occurs in the elderly due to occlusion of a major vessel or low cardiac output. It usually presents with sudden, crampy, left lower abdominal pain and passage of bright red or maroon blood mixed with the stool. Bleeding is usually moderate. The splenic flexure, descending colon and sigmoid colon are most commonly affected. Colonoscopy shows segmental haemorrhagic mucosa with or without ulcerations. CT angiography is a non-invasive test which helps in diagnosis. Colectomy is required only if there are signs of bowel infarction. Radiation Colitis Symptoms of radiation colitis may occur few months to many years after abdominopelvic radiation usually for cancer of the cervix or prostate. Treatment using laser, argon plasma coagulation or sucralfate enema is effective.

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Rectal Varices Rectal varices are an uncommon cause of lower gastrointestinal bleeding, seen in patients with portal hypertension particularly

extrahepatic portal venous obstruction. They can be successfully treated by endoscopic variceal ligation. Postpolypectomy Bleeding Postpolypectomy bleeding is the most frequent complication of colonoscopy and is seen in 0.2% to 1.8% cases of colonoscopic polypectomy. Delayed bleeding may occur up to 14 days after polypectomy. Endoscopic clipping is an effective treatment modality. SMALL INTESTINAL BLEED Only 3% to 5% of all GI bleeding arises between the second portion of the duodenum and the ileocaecal valve. Bleeding from this site is difficult to diagnose, since the small bowel is relatively inaccessible. Patients present either with chronic occult blood loss or with recurrent episodes of melaena. Repeated endoscopies and barium studies are often negative. Various causes of small intestinal bleed are given in Table 4. Vascular ectasias are the commonest cause of small intestinal bleed. Benign small bowel tumours (usually leiomyomas) are the second most common cause. Meckel’s diverticulum is the cause of bleeding in two-third of males younger than 30 years presenting with small bowel bleeding. Bleeding is almost always brisk, resulting from ulceration within the diverticulum or the adjoining ileal mucosa. Table 4: Differential Diagnosis of Occult-GI Bleeding Mass lesions in colon or small intestine Carcinoma Adenoma Inflammation Erosive oesophagitis/gastritis Ulcer (any site) Coeliac disease Inflammatory bowel disease Colitis (non-specific) Worm infestation (hookworm, whipworm, strongyloidiasis, ascariasis) Tuberculous enterocolitis Amoebiasis Other causes Drug intake Haemosuccus pancreatitis Haemobilia Vascular disorders (haemangioma, Dieulafoy’s lesion)

GASTROINTESTINAL BLEEDING OF OBSCURE ORIGIN Obscure bleeding is defined as recurrent bouts of acute or chronic GI bleeding for which no definite source has been discovered by routine endoscopic and barium contrast studies. Obscure gastrointestinal bleeding can be overt or occult, depending upon the presence or absence of clinically evident bleeding. Causes of gastrointestinal bleeding that are commonly missed on upper gastrointestinal endoscopy are Cameron’s erosion, gastric varices, Dieulafoy’s lesion, angiodysplasia, oesophagitis, portal hypertensive gastropathy and gastric antral vascular ectasia. Therefore, upper gastrointestinal endoscopy should be repeated, if it is negative then a cause in the small bowel should be looked

Figure 3: Algorithm for managing obscure gastrointestinal bleeding.

Angiography is performed only if bleeding is likely to be beyond duodenum and is so massive that endoscopy cannot be safely or satisfactorily performed and surgery is contraindicated. Blood loss must be greater than 0.5 mL/min for angiography to detect the site of bleed. Selective mesenteric angiography usually localises the site of bleeding in about 75% of such patients. Radionuclide imaging studies are not useful in the evaluation of upper GI bleeding. Radionuclide scanning is a sensitive method for detecting gastrointestinal bleeding at a rate of 0.1 mL/min. This technique is more sensitive, but less specific than angiography. The major disadvantages are that nuclear imaging localises bleeding only to an area of the abdomen and the intraluminal blood is moved away by intestinal motility leading to false localisation. For proximal small bowel push enteroscopy permits inspection of the entire duodenum and part of the jejunum. Capsule endoscopy (CE) was launched at the beginning of this millennium and since then it has had a very important impact

on managing obscure gastrointestinal bleeding. Before the advent of CE, small bowel was an organ which was very difficult to explore with available endoscopic, radiological and nuclear medicine techniques. Wireless CE is simple, safe, non-invasive, reliable procedure, well accepted and tolerated by the patient. This technique evaluates with high resolution images, the whole small bowel, avoiding surgery or radiation exposure. In this technique a small capsule camera is swallowed by the patient (capsule enteroscopy). It takes up to 50,000 photographs of the entire small intestine and transmits the images to a data recorder externally, enabling visualisation of areas where the endoscope cannot reach.

Gastrointestinal Bleeding

for. The most common cause of obscure GI bleeding is vascular ectasia of the small bowel. Certain lesions are difficult to diagnose because of their rarity or their subtle appearance; and some lesions are detectable only if active bleeding is seen endoscopically (e.g. Dieulafoy’s lesion). Tubercular enteritis/colitis is another cause of obscure GI bleed in our country. Worm infestation, especially with hookworms, is a common cause of anaemia in India. With a heavy parasite load, some patients may have continuous ooze from the small intestine and may have positive stool occult blood. Stool examination is diagnostic. An approach to management of obscure gastrointestinal bleeding is given in Figure 3.

Double-balloon enteroscopy is another new technique that allows access to the whole of the small bowel with the added advantage of therapeutic option, like haemoclip application or polypectomy, etc. As inferred from its name, the two inflatable balloons are the crux of the double balloon system. An overtube is backloaded onto the endoscope before intubation. The distal ends of the overtube and of the endoscope are fitted with inflatable/deflatable air-filled latex balloons. When inflated to 45 mmHg, the balloons grip the intestinal lumen, providing traction against the wall without undue pressure. Exploratory laparotomy with intra-operative endoscopy is indicated in patients with severe recurrent or persistent bleeding in whom all other investigative modalities have proved unsuccessful. Scintigraphy and mesenteric angiography can also be done to guide the surgeon in patients prior to exploratory laparotomy. Faecal Occult Blood Various causes of occult gastrointestinal bleeding are given in Table 4. An important cause of chronic occult bleeding is NSAIDs intake. Other causes are polyps and carcinoma of the colon. Faecal occult blood loss in normal individuals varies from 0.5 to 1.5 mL per day. Faecal occult blood tests are to detect blood not visible overtly. The classic faecal occult blood tests are of guaiac based type. They are based on haemoglobin pseudoperoxidase activity, guaiac turns blue after oxidation by oxidants or peroxidases in the presence of an oxygen donor such as hydrogen peroxide. Various factors influence the result of guaiac test, presence of animal haemoglobin and dietary peroxidases leads to false positivity while presence of vitamin C results in false negativity. Immunological faecal occult blood tests detect human globin epitopes and are highly sensitive for detection of blood. They are more specific than guaiac based tests; their results are not affected by dietary factors. Haem-porphyrin based test relies on spectrofluorometric method to measure porphyrin derived from haem, they provide a highly accurate determination of total stool haemoglobin. Intraluminal degradation of haemoglobin or interfering peroxidase producing substances do not effect the haem-porphyrin assay, although myoglobin, a haem containing protein found in red meats interferes with its result. The initial investigation for evaluation of occult bleeding is colonoscopy which should be followed by an upper GI endoscopy to rule out gastroduodenal pathology. If these tests are unrevealing, small intestinal causes of bleed should be considered. 797

PROGNOSIS OF GASTROINTESTINAL BLEEDING Mortality of each episode of variceal bleed in cirrhotics is 30% to 50%. Variceal bleeding in non-cirrhotic causes of portal hypertension, however, carries a good prognosis. Mortality for ulcer bleed is much lower (3% to 10%). Lower GI bleed is usually less life-threatening than upper GI bleed. Risk factors for increased mortality are presentation with shock, active bleeding at presentation, advanced cirrhosis, old age, co-morbid medical illnesses, occurrence of rebleeding and failure of endoscopic methods to control bleed.

stimulating advancement. Development of endoscopic suturing devices to close gastrointestinal perforations is equally exciting. These techniques will be increasingly adapted to control gastrointestinal bleeding in future. RECOMMENDED READINGS 1.

Anand CS, Tandon BN, Nundy S. The causes, management and outcome of upper gastrointestinal haemorrhage in an Indian hospital. Br J Surg 1983; 70: 209-11.

2.

Ferguson CB, Mitchell RM. Non-variceal upper gastrointestinal bleeding: standard and new treatment. Gastroenterol Clin N Am 2005; 34: 607-21.

3.

Goenka MK, Kochhar R, Mehta SK. Spectrum of lower gastrointestinal haemorrhage: an endoscopic study of 166 patients. Indian J Gastroenterol 1993;12: 129-31.

4.

Gupta R, Reddy DN. Capsule endoscopy: current status in obscure gastrointestinal bleeding. World J Gastroenterol 2007; 13: 4551-3.

5.

Sass DA, Chopra KB. Portal hypertension and variceal haemorrhage. Med Clin North Am 2009; 93: 837-53.

6.

Zaman A, Chalasani N. Bleeding caused by portal hypertension. Gastroenterol Clin N Am 2005; 34: 623-42.

FUTURE PROSPECTS Steady progress in engineering including microelectrical systems will affect the performance of capsule endoscopy. With the advent of robotic capsule in near future, it will be possible to perform drug delivery and tissue sampling, robotic capsule will be equipped with microelectrical system for directed therapy. Natural orifice transendoscopic surgery (NOTES) is a

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13.7 SYMPTOMS Oesophageal disorders are one of the commonest disorder of the GI tract. The description is given in next chapters. The passage of food through the body of the oesophagus is not sensed by an individual in normal circumstances. The major symptoms of oesophageal diseases are heartburn, chest pain, regurgitation and dysphagia. Heartburn (pyrosis) is defined as retrosternal burning pain that travels cephalad. It is exacerbated by bending or lying down, and is worse after meals. It is relieved by upright posture, by swallowing of saliva or water, or more reliably by antacids or acid-inhibiting drugs. Heartburn is a characteristic symptom of gastro-oesophageal reflux (GOR), and may be associated with regurgitation. Regurgitation is described as effortless appearance of acid or a bitter taste in the mouth. It occurs in GOR, and may result in laryngeal aspiration with spells of coughing and choking which awaken the patient from sleep. It may also result in aspiration pneumonia. Regurgitation of bland food suggests that an obstruction exists in the lower oesophagus; in GOR, bland regurgitation occurs when acid secretion has been inhibited by drugs. Dysphagia, or difficulty in swallowing, is a sensation of obstruction to the passage of food through the mouth, pharynx or oesophagus due to a significant problem in the anatomy or motility of these organs. Dysphagia could be oropharyngeal (transfer) or oesophageal. Oropharyngeal dysphagia occurs due to neuromuscular or structural abnormalities of mouth, hypopharynx or upper oesophagus; these patients have difficulty in initiating the swallow. Oesophageal dysphagia is classified as mechanical or motor. Mechanical oesophageal dysphagia is initially to solids only. It could be intermittent (webs or Schatzki ring) or progressive from solid to blenderised food and finally to liquids (stricture, malignancy). The severity of dysphagia in mechanical obstruction varies with the degree of luminal narrowing, type of food bolus, and presence of associated oesophagitis. On the other hand, dysphagia due to motor disorders is equal for solids and liquids, may increase with intake of very cold foods and it could be slowly progressive (achalasia cardia) or intermittent (less specific motility disorder). Nonobstructive dysphagia occurs in patients with reflux disease who have oesophageal inflammation associated with a motility disorder. Odynophagia or painful swallowing is due to mucosal noninfectious inflammation. Causes could be infectious (candidiasis, herpes, cytomegalovirus, Epstein-Barr virus, etc.) or noninfectious like corrosive intake, pill oesophagitis, radiation oesophagitis, severe GOR disease and rarely osesophageal carcinoma.

Oesophageal Disorders Shobna J Bhatia, Praveen Mathew Chest pain of oesophageal origin described as squeezing or burning sensation, is similar to cardiac angina and may not be related to swallowing. Almost 90% of times it is associated with other oesophageal symptoms. More than 50% of cases of non-cardiac chest pain have GOR disease; other causes are oesophageal spasm, achalasia cardia, nutcracker oesophagus and sometimes panic disorders. Water brash is reflex salivary hypersecretion that occurs in response to GOR. It should not be confused with regurgitation. Globus sensation is a feeling of food stuck at the pharyngeal level, but occurs between meal times. MOTILITY DISORDERS Skeletal Muscle Disorders Pharyngeal paralysis may occur following neuromuscular diseases; laryngeal and orofacial muscles also may be involved. It is characterised by transfer dysphagia, laryngeal aspiration and nasal regurgitation. Barium swallow with cineradiography is the investigation of choice, and reveals poor contraction of pharyngeal constrictors, barium in the valleculae and pyriform sinuses, and nasal and tracheal aspiration. Oesophageal motility studies may reveal reduced amplitude of contraction wave in pharynx and proximal oesophagus, reduction in upper oesophageal sphincter (UOS) resting tone, and incoordination between the pharynx and oesophagus during a swallow. Patients who have pharyngeal paralysis due to myasthenia gravis or polymyositis respond to treatment of the primary disease. In other patients, swallowing exercises usually help. In patients with a cerebrovascular accident, the extent of impairment of swallowing and its subsequent recovery depend on the type and extent of lesion. In severe cases, a permanent feeding gastrostomy may be required. In patients with UOS spasm, botulinum toxin injection or cricopharyngeal myotomy may be helpful. Cricopharyngeal achalasia is a disorder of unknown cause, and occurs due to failed relaxation of the UOS and can be associated with Zenker’s diverticulum. Dysphagia and choking are the predominant symptoms. On radiography, a prominent bar representing the contracted UOS may be seen. Cricopharyngeal myotomy may be helpful in selected cases, but should not be done in patients with associated GOR, because of increased risk of pulmonary aspiration post-operatively. Smooth Muscle Disorders Achalasia cardia Achalasia cardia is a motor disorder of the oesophageal smooth muscle in which the oesophageal body is aperistaltic, the lower oesophageal sphincter (LOS) may be hypertensive and does not relax completely with swallowing. In addition, because of the non-relaxing LOS, the intra-oesophageal pressure is higher than the gastric pressure. The underlying abnormality is defective innervation of the smooth muscle portion of the oesophageal body and the LOS.

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Classic achalasia shows a marked reduction in myenteric neurons. Secondary achalasia may be caused by gastric carcinoma infiltrating the oesophagus, lymphoma, Chagas disease, neuropathic chronic intestinal pseudo-obstruction syndrome, irradiation and certain toxins and drugs. Dysphagia, chest pain and regurgitation are the main symptoms of achalasia. Dysphagia occurs with both liquids and solids. Various manoeuvres designed to increase intra-oesophageal pressure, including the Valsalva, may help passage of the bolus into the stomach. Regurgitation and pulmonary aspiration occur because of retention of large volumes of saliva and ingested food in the oesophagus. The overall course is usually chronic over months to years. Chest X-ray may show absence of the gastric air bubble. In advanced cases, an air-fluid level in the mediastinum in the upright position represents retained food in the dilated oesophagus. Barium swallow shows oesophageal dilatation and a persistent beak-like narrowing, representing the non-relaxing LOS, in the lower oesophagus (Figure 1). Oesophageal manometry shows the defining feature of distal body aperistalsis and incomplete or absent swallow induced relaxation of LOS. Other features are hypertensive LOS and low amplitude simultaneous onset oesophageal body contractions. An increased intra-oesophageal basal pressure that exceeds intragastric pressure is commonly seen. High resolution oesophageal manometry with contour plot topographical analysis has found three variants of achalasia (Figures 2A and B), type 1—no significant oesophageal pressurisation; type 2— rapidly progressive compartmentalised pressurisation, either localised to distal oesophagus or throughout the whole oesophagus; and type 3—rapidly progressive pressurisation attributable to spastic contractions. This classification is also helpful in prognosticating outcomes with type 2 responding best to therapy; type 3 achalasia does not respond well, and type 1 has intermediate response to any form of treatment. Endoscopy is helpful in excluding the causes of secondary achalasia, particularly gastric fundal carcinoma.

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Figure 1: Barium swallow showing dilated oesophagus with bird beak appearance at the lower end and fluid level in the oesophagus, suggestive of achalasia cardia.

Figures 2A and B: (A) High resolution manometry shows normal peristaltic wave after a swallow. (B) Manometry shows aperistalsis in oesophageal body after a swallow with elevated lower oesophageal sphincter pressure suggestive of achalasia.

Medical treatment using nitrates is usually unsatisfactory. Calcium-channel antagonists such as nifedipine have been used with some success; these need to be administered sublingually 15 to 30 min prior to a meal. The best available non-surgical therapy involves endoscopy-assisted balloon dilatation of the LOS; this reduces the basal LOS pressure by tearing muscle fibres. Endoscopic injection of botulinum toxin into the LOS is effective in the short term. Heller’s extra-mucosal myotomy of the LOS in which the circular muscle layer is incised, is equally effective. Reflux oesophagitis and peptic stricture may develop after successful treatment of achalasia; this complication is more frequent after surgery than with balloon dilation. Surgery is increasingly being performed laparoscopically; additionally, fundoplication is often done to prevent GOR. Spastic Disorders of Distal Oesophagus Other than Achalasia This section includes a spectrum of disorders ranging from diffuse oesophageal spasm, nutcracker oesophagus, nonspecific spastic disorders and hypertensive LOS. These are differentiated on the basis of manometry findings (Figure 3). They all are present with history of chest pain, occasional dysphagia and rarely regurgitation. Pain is very similar to angina, may occur at rest or after swallowing, and may radiate to the back or neck. These disorders are associated with other functional bowel disorders and have high association with anxiety

Systemic diseases like scleroderma and diabetes mellitus also cause motor disorders of the oesophagus. Scleroderma oesophagus is typically one with a low LOS pressure and aperistalsis. There is atrophy of the smooth muscle. The patient presents with severe gastro-oesophageal reflux disease with complications. Diabetes mellitus, when complicated by autonomic neuropathy, may have associated oesophageal dysmotility. The patients are rarely symptomatic, but may have occasional dysphagia and heartburn. Candidal infection should also be considered; if present, patients may have odynophagia.

Oesophageal Disorders

dilatation of LOS has been found to be beneficial in cases with associated LOS hypertension. In refractory cases, long oesophagomyotomy has been tried with some success.

GASTRO-OESOPHAGEAL REFLUX DISEASE Figure 3: High resolution manometry shows simultaneous and prolonged contraction of oesophageal body suggestive of diffuse oesophageal spasm.

disorders, depression and other psychological abnormalities. The pathogenesis of these disorders is not known, probably functional with no anatomic abnormalities found. Diffuse oesophageal spasm is characterised by non-peristaltic responses of normal amplitude after 30% or more of swallows with a normally relaxing LOS. Barium swallow may reveal intermittent areas of oesophageal spasm that produce an appearance of a corkscrew oesophagus (Figure 4). Treatment includes ruling out the possibility of ischaemic heart disease; smooth muscle relaxants like nitrates and calcium channel blockers are beneficial in a few cases. Anti-depressants like imipramine, trazodone and sertraline have been found to be useful in a number of patients with chest pain. Pneumatic

Gastro-oesophageal reflux (GOR) is defined as backward flow of gastric contents into the oesophagus. A small amount of GOR occurs in normal individuals. GORD (gastro-oesophageal reflux disease) is defined as a condition which develops when stomach contents cause troublesome symptoms or complications, and adversely affects an individual’s quality of life. The typical reflux syndrome is defined by presence of troublesome heartburn and/or regurgitation. GORD is the most common oesophageal disorder, accounting for nearly 75% of all patients with oesophageal disorders. In Western studies, 15% to 20% of the general population suffers from GORD. The prevalence of GORD in Asia is lower (2.3% to 8%), probably due to higher prevalence of Helicobacter pylori, lower body mass index, low fat consumption in diet and genetic diversity. Adenocarcinoma of the oesophagus is on the rise in the Western world. Barrett’s oesophagus, which is a recognised precursor to adenocarcinoma is strongly associated with GORD. Pathophysiology The normal anti-reflux barrier at the gastro-oesophageal junction is a zone whose functional integrity is maintained by the LOS pressure, extrinsic compression of the LOS by the crural diaphragm, the intra-abdominal location of the LOS, integrity of the phreno-oesophageal ligament, and maintenance of the acute angle of His. Transient LOS relaxation is one of the most important causes for GORD; it is not associated with a swallow. It is more harmful because it is longer in duration (>10 seconds) compared with swallow-induced LOS relaxation, accompanied by relaxation of crural diaphragm and not associated with peristalsis. It is usually stimulated by gastric distension due to food or gas, or rarely fat and stress. Small amount of reflux occurs during swallow induced LOS relaxation. The role of hypotensive LOS seems to be present only in patients with severe oesophagitis. Hiatus hernia is seen in 60% to 90% of patients with reflux oesophagitis, especially in patients with peptic stricture or Barrett’s oesophagus. Hiatus hernia breaches the anti-reflux barrier by displacing the LOS from crural diaphragm. Loss of the intra-abdominal segment of LOS increases transient LOS relaxation and impairs oesophageal acid clearance.

Figure 4: Barium swallow showing appearance of a corkscrew oesophagus.

Impaired oesophageal motor function resulting in inadequate volume clearance occurs in oesophagitis; peristaltic dysfunction increases with increasing severity of oesophagitis. The layer of mucous carpeting the mucosa and mucosal bicarbonate also constitute an important line of defence against acid injury.

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If acid injury and cell necrosis occur, the rate of regeneration plays a role in determining the severity of lesions. There is no increase in gastric secretions in GORD patients, but there is a pocket of acid in the distal oesophagus which escapes the buffering action of food; hence the predilection for oesophagitis at this location. Animal and human studies have demonstrated that acid and pepsin are responsible for the mucosal injury. Other factors implicated are duodenogastric reflux, with conjugated bile acids and trypsin as possible culprits. Gastroparesis is found in 6% to 38% of patients with GORD. Helicobacter pylori infection is currently believed to lower the frequency of GORD. This is backed by epidemiological data of low prevalence of GORD in areas with high prevalence of H. pylori and vice versa. Prevalence of more virulent strains of H. pylori in developing countries results in corpus or pangastritis, thus reducing gastric acid secretion and resulting in decreased symptoms of GORD. Pathology Grossly, the spectrum of oesophageal mucosal appearances varies from normal appearing mucosa (40% to 80%) to mucosal injuries of varying severity-erosions to ulcerations. The earliest finding, seen on electron microscopy, is dilated intercellular spaces, at least three times greater than controls; this is reversible on administering proton pump inhibitors. Light microscopy shows papillary height more than half, and basal zone thickness more than 1/6th of total mucosal thickness. Acute inflammation with neutrophils and eosinophils is seen in up to 40% of cases but is not specific for GORD. Development of columnar-lined mucosa, with specialised intestinal metaplasia is the defining feature of Barrett’s oesophagus, visible on endoscopy when normal squamous mucosa is replaced by salmon pink columnar mucosa. This can progress from low grade to high grade dysplasia, and later to adenocarcinoma of the oesophagus. Clinical Features Symptom complex of GORD has been divided into oesophageal and extra-oesophageal syndromes. Oesophageal syndromes include the typical reflux syndrome and reflux chest pain syndromes. Typical reflux symptoms are heartburn, a burning sensation in the retrosternum and regurgitation—a perception of flow of gastric contents into the mouth or hypopharynx.The prevalence of these is 75% to 98% and 48% to 91%, respectively. GORD can be diagnosed by these two symptoms without the need for endoscopy. Reflux chest pain can be indistinguishable from pain of ischaemic heart disease, but is usually associated with other symptoms of GORD. GORD is the most common oesophageal cause of chest pain. Sleep disturbance is often associated with GORD. In patients with minimal symptoms, exercise has been found to worsen symptoms of GORD.

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Dysphagia in a patient with GORD could be a marker of peptic stricture or development of malignancy. Dysphagia may also occur because of reflux oesophagitis and motor functional abnormalities. Barrett’s oesophagus is an endoscopic diagnosis (Figure 5) confirmed on histology showing specialised intestinal

Figure 5: Endoscopy shows evidence of Barrett’s metaplasia in the oesophagus. The normal squamous mucosa of the oesophagus is replaced by columnar gastric mucosa.

metaplasia. There are no symptoms which herald the development of Barrett’s oesophagus. Increasing age, male gender, long duration of GORD symptoms, obesity and smoking are risk factors for Barrett’s oesophagus. Adenocarcinoma may develop in patients with Barrett’s oesophagus especially high grade dysplasia. Extra-oesophageal syndromes are classified as those with established associations and those with proposed associations. Established associations include reflux cough, reflux laryngitis, reflux asthma and reflux dental erosions. These syndromes usually occur with the concomitant manifestation of typical reflux oesophageal symptoms and rarely in their absence. Reflux is rarely the only cause for these extra-oesophageal symptoms. They have been found to respond to treatment of GORD. Other symptoms with proposed associations are sinusitis, pulmonary fibrosis, recurrent otitis media and pharyngitis. The degree of evidence for this last group is minimal, epidemiologically or treatment-response wise. Investigations The diagnosis of GORD is made on the basis of clinical history and confirmed by response to medications. Diagnostic testing is done to avert misdiagnosis, to identify complications of GORD and to evaluate the reason for failure of standard therapy. To avert misdiagnosis and identify reflux complications, the concept of alarm symptoms has been introduced; these include gastrointestinal blood loss, involuntary weight loss, dysphagia and anaemia. In these conditions an endoscopy is warranted. In case any lesion is seen, biopsies should be taken from it. Less than 50% of patients with GORD have endoscopic features of oesophagitis; visible breaks in mucosa is the most reliable marker of reflux oesophagitis.This does not correlate with the frequency or severity of reflux symptoms. Reflux stricture seen in less than 5% of GORD patients is defined by a persistent narrowing in the lumen of the oesophagus and manifests as troublesome mechanical dysphagia. If endoscopy is normal, the patient should be treated empirically as GORD, and further investigated if the symptoms do not resolve. Manometry is useful in detecting severe peristaltic dysfunction which is a contraindication for antireflux surgery. Investigations to demonstrate excessive oesophageal acid exposure are conventional catheter based pHmetry or wireless capsule pH-metry,and impedence-pH monitoring. Therapy Treatment is directed towards decreasing GOR and improving oesophageal clearance. The aim is to alleviate symptoms, heal oesophagitis and prevent complications.

Empirical initial management with acid reduction is the accepted approach currently in patients with uncomplicated heartburn. Evidence suggests that acid reduction helps healing of oesophagitis and relief from symptoms. Meta-analysis of randomised control trials show that proton pump inhibitors (PPIs) are more effective than H2 receptor antagonists (H2RAs) in treating oesophagitis and ameliorating symptoms. PPIs as a class (omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole) are all equally effective in standard doses. There does not appear to be any additional benefit of higher dosage/ twice daily dosing of PPIs or adding a H2RA, except in cases of severe oesophagitis. Patients whose heartburn has not responded to twice daily PPIs are considered treatment failures. Preference of a PPI over another is primarily to ameliorate the side-effects of the PPI need earlier. Patients with reflux chest pain can be given a trial of PPI once ischaemic heart disease has been ruled-out. Patients with extra-oesophageal symptoms require high doses. Maintenance therapy is usually necessary as GORD is a chronic disease, the lowest possible dose of PPI should be titrated for symptom control in patients with definite oesophagitis. PPIs have been shown to reduce the development of reflux strictures, but there is no evidence that they reduce the risk of Barrett’s oesophagus or adenocarcinoma. In patients with extraoesophageal symptoms, maintenance therapy is indicated only to control oesophageal symptoms. Long-term PPI therapy is potentially safe though there is a theoretical risk of hypergastrinaemia, pneumonia, Clostridium difficile colitis and hip fractures. Anti-reflux surgery and PPIs have equal efficacy for control of oesophageal reflux symptoms. Surgery should be offered when an individual is intolerant to PPIs, or when a patient with oesophageal reflux syndrome has troublesome regurgitation. The potential side-effects of anti-reflux surgery include excessive flatulence, inability to belch, dysphagia and recurrence of symptoms post-surgery (30% over 5 years). Patients well controlled on PPIs should not be offered surgery. The surgery recommended is laparoscopic fundoplication. INFECTIOUS OESOPHAGITIS Infectious oesophagitis can be due to viral, bacterial and fungal causes. With an increase in the number of patients with immunocompromised states, there has been an increased frequency of oesophageal infections. Infections of the oesophagus present with acute dysphagia, odynophagia and chest pain. In patients with severe ulceration of the mucosa, bleeding may occur; this is usually self-limiting and small in quantity, but life-threatening haemorrhage may occur. Viral Oesophagitis Herpes simplex virus (HSV) type 1 or 2 may cause oesophagitis in immunocompromised individuals. Systemic manifestations like

nausea, vomiting and fever may be present. On endoscopy, the oesophageal mucosa has 1 to 3 mm vesicles and small, discrete, punched-out lesions, which may proceed to confluent ulcers and diffuse erosive oesophagitis.These lesions may get superinfected by bacteria or fungi. Biopsy or cytology may show ballooning degeneration, ground-glass change in nuclei with eosinophilic inclusions (Cowdry type A) and giant cell formation. Culture may be positive.Treatment consists of acyclovir 250 mg/m2 intravenous 8 hourly. As the patient improves, oral therapy may be started with 200 to 400 mg acyclovir 5 times a day. Symptoms resolve within a week. Ulcers take a longer time to heal.

Oesophageal Disorders

Treatment usually begins with dietary and lifestyle modifications. The patient should be asked to avoid food items that increase reflux (fatty or fried food, caffeinated drinks, chocolate, mint) and decrease intake of acidic foods (citrus fruits, spicy food, carbonated drinks, tomatoes, onions). Lifestyle modifications include weight reduction in those who are obese, elevation of the head end of the bed and avoiding eating within 3 hours of bedtime in those with night time symptoms. Patients with postprandial symptoms are advised to take small frequent meals.

Varicella-zoster virus occasionally produces oesophagitis in children with chicken pox and adults with herpes zoster. The oesophageal lesions are similar to those of HSV, and necrotising oesophagitis may occur in a severely compromised patient. Biopsy from the edge of the ulcer shows findings similar to those of HSV, and differentiation requires culture studies. Acyclovir, in doses higher than for HSV, is required for treatment. Cytomegalovirus infection occurs only in the immunocompromised host. Endoscopy shows serpiginous ulcers which are large and deep with surrounding normal mucosa. In the distal oesophagus the ulcers may coalesce. Biopsy should be taken from the centre of the ulcer and reveals intranuclear and small cytoplasmic inclusions in fibroblasts and endothelial cells of blood vessels. Early diagnosis may be made by immunohistochemistry using monoclonal antibodies to CMV. Ganciclovir is the treatment of choice. Complete healing may take a few weeks to months and treatment should be continued until then. HIV causes oesophagitis during seroconversion and during inversion of T-cell helper: suppressor ratio. The oesophagitis is self-limiting. Steroids may help in this condition. Bacterial oesophagitis is very rare. However, patients with AIDS may develop oesophagitis due to Cryptosporidium or P. carinii. Tuberculosis of the oesophagus is rare and is almost always due to contiguous spread from the lung or mediastinal lymph nodes. Fungal Oesophagitis Candidiasis of the oesophagus occurs in immunodeficiency disorders like diabetes mellitus, chronic renal failure, and AIDS. Individuals receiving steroids or immunosuppressive chemotherapy for malignancy and those with underlying oesophageal diseases that cause stasis of food (achalasia or scleroderma) may also develop candidiasis. Candida is present in the non-pathogenic form in the oral flora in normal individuals. Patients who develop oesophagitis may be asymptomatic, or may have odynophagia and dysphagia. Rarely, bleeding may occur, and the deep ulcers may perforate or may form a stricture. Systemic invasion from oesophageal candidiasis is also reported. Oral candidiasis, if present, suggests the diagnosis by its white flake’s appearance. Endoscopy reveals raised white pseudomembranous plaques with mucosal erythema. In severe cases, confluent linear and nodular plaques with underlying ulcerations may be present. A smear taken from these plaques may reveal hyphae. Treatment in mild cases is with 10 to 20 mL of oral nystatin (100,000 units/mL) 6 hourly, or oral clotrimazole (10 mg 6 hourly), or fluconazole 100 mg per day for 7 days. If symptoms persist, endoscopic biopsy and culture are

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recommended. If anti-fungal resistance is demonstrated, caspofungin may be effective. Narcotics are recommended for patients with severe odynophagia. Corrosive Injury Corrosive is any substance which causes tissue injury upon contact. Caustic injury of the oesophagus occurs following ingestion of strong alkali or acid, most often accidentally or with suicidal intent. Sodium hydroxide is the most frequent cause of alkaline injury. Hydrochloric and sulphuric acids are the common acids causing injury. Most corrosives are available as over-the-counter drain cleaners, dish washing detergents, bleaches, battery fluids, button batteries, nail polish removers, etc. Alkali ingestion provokes liquefaction or saponification necrosis of the oesophageal wall and thrombosis of blood vessels. Acids cause coagulative necrosis. Severity of tissue injury depends upon factors like substance pH, physical state (solids adhere to mucosa and cause more damage), quantity, intention (quantity is usually larger in suicidal cases), tissue contact time and concentration. There is an acute inflammatory response with mucosal necrosis, followed by sloughing of necrotic tissue and ulceration over 4 to 15 days. Risk of perforation is maximum up to 7 days. After 3 to 4 weeks, cicatrisation begins. Significant oesophageal strictures develop when there is circumferential damage. In the oesophagus, corrosives pool at the post-cricoid area, level of aortic arch, tracheal bifurcation, and lower oesophageal sphincter. These are common locations for strictures. In severe cases, there may be perforation into the mediastinum or pleural cavity or development of a tracheo-oesophageal fistula. The damage is mainly in the antrum in the fasting stomach, and in the gastric corpus if the patient has ingested a meal prior to corrosive ingestion. Symptoms include burning pain in the mouth and throat, odynophagia, excessive salivation, stridor, hoarseness, dysphagia and chest pain. Gastric involvement leads to abdominal pain and vomiting, and occasionally symptoms and signs of perforation. There may be oedema and ulceration of the lips, tongue and pharynx. Airway obstruction from severe epiglottic and laryngeal oedema may occur. As the acute inflammatory reaction subsides, odynophagia and dysphagia decrease; with the development of oesophageal stricture, dysphagia gradually returns, usually within 1 to 3 months after the accident. Mortality rate is of 1%, usually due to mediastinitis or peritonitis resulting in multi-organ failure.

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The aim of therapy in the acute phase is resuscitation and supportive care. Assessment of the severity of damage is most important after resuscitation of the patient. Clinical features do not correlate with severity of damage. X-ray films of chest and abdomen are taken to check for perforation, pneumomediastinum or pneumoperitoneum, which if present can be confirmed by CT scan. If there is evidence of perforation, patient should be referred for surgery (oesophagectomy or gastrectomy). Flexible endoscopy should be done at the earliest or up to 96 hours of corrosive ingestion, after ruling out a perforation and is the best way to assess the severity of mucosal damage. Endoscopic grading is helpful in management and prognostication. Patients who have minimal injury can be started on oral liquids by 48 hours and can be discharged early; they also have a low risk of complications. In patients with advanced damage, a nasojejunal tube can be placed over a

guide wire during endoscopy; this serves as a route for maintaining nutrition and also provides a lumen for dilatation in future as these patients are prone to develop strictures. Measures which have shown to be of no use or are harmful are administration of activated charcoal, pH neutralisation or dilution, by inducing emesis, and intravenous steroids. Antibiotic therapy is required only if secondary infection sets in. Early dilatation of the oesophagus has been associated with a high-risk of perforation, and is therefore not recommended. Stricture of the oesophagus is the major long-term complication. Caustic strictures are often extensive and multiple, involving most of the lower oesophagus. They respond to repeated dilatation, and the frequency of dilatation may decrease over time. Recently, self-expandable plastic stents have been placed at the site of stricture for 6 to 8 weeks, with good results. Oesophageal resection with colon or gastric tube replacement may be necessary in cases where the lumen is too small for dilatation, or in cases of extensive damage. Oesophageal squamous cell carcinoma is a potential long-term complication of corrosive injury. Pill-Induced Oesophageal Injury Pill-induced oesophageal injury results from damage due to ingestion of certain medications which cause injury by either production of caustic solution, hyperosmolar solution or direct drug damage. Drugs commonly implicated are tetracycline, doxycycline, potassium chloride, nonsteroidal antiinflammatory drugs, alendronate, ferrous sulphate, theophylline, quinidine, etc. The injury is more common in individuals with anatomic or motility abnormalities of oesophagus. It could be predisposed by taking inadequate water or assuming recumbent posture immediately after taking the pill. Symptoms include severe chest pain, odynophagia and dysphagia. Endoscopy may reveal an ulcer, diffuse oesophagitis or pseudomembrane at the site of damage. Withdrawal of the offending medication, viscous lignocaine solution, adequate hydration, and use of PPIs to reduce acid exposure results in healing of the lesion. Rarely there can be perforation, oesophago-respiratory fistula or a chronic stricture at the site of the ulcer. The disorder is preventable in most cases. Eosinophilic Oesophagitis Eosinophilic oesophagitis (EO) is a disease characterised by eosinophilic infiltration of the oesophageal mucosa. Identified in 1978, the incidence of EO has been increasing in the Western world. Familial clustering and seasonal variation have been noted in patients with EO. Almost 80% of children and 40% to 60% of adults have history of allergies. It is postulated to be IgE or non-IgE mediated. Sensitisation could be via food or inhaled allergens. EO appears to be a Th2 mediated immune response; IL-5 and IL-13 appear to play a key role in pathogenesis. The pathognomonic feature of EO is eosinophilic infiltration of ≥15 eosinophils/HPF in the oesophageal mucosa; eosinophils should be counted in the most densely inflamed part of the biopsy (X 400). Other features are eosinophilic micro-abscesses, superficial infiltration of eosinophils in the upper half of mucosa, basal zone hyperplasia and papillary lengthening. Most of the patients are men with a male to female ratio of 3:1, in the third or fourth decade of life. Presentation varies from dysphagia (60% to 90%), food impaction (50% to 60%), heartburn

Endoscopic findings include oesophageal rings (felinisation or trachealisation), raised white specks, longitudinal furrows, whitish exudates and a friable mucosa which may tear by passage of endoscope. Normal mucosa can be seen in up to a third of the patients. Strictures could be seen in any part of the oesophagus. Multiple (>5) biopsies from different levels of the oesophagus should be taken. Oesophageal pH monitoring should be done in difficult cases to rule-out GORD, or biopsies should be repeated after 6 weeks of PPI treatment. Barium swallow may reveal strictures, Schatzki’s ring or a diffuse narrowing of the oesophagus. Allergic testing by skin prick, skin patch test or food specific radioallergosorbent testing can be done. Treatment Treatment is to control the inflammation using systemic steroids, prednisolone 1 to 2 mg/kg, tapered over 6 weeks in patients with severe dysphagia, weight loss and refractory oesophageal strictures. Steroids should not be used for maintenance therapy. Other steroids used are swallowed topical fluticasone propionate (440 to 500 μg/day) twice daily for 6 weeks, swallowed budesonide mixed with sucralose and beclomethasone have also been used. Symptoms recur in 50% of patients when treatment is stopped and can be managed with reintroduction of same therapy or, use of steroid-sparing drugs like azathioprine. Leukotriene receptor antagonist montelukast 10 to 40 mg/day has been used with some success. Endoscopic dilatation of strictures should be preferably limited to patients after a trial of medical therapy, because of the risk of perforation. Dietary therapy by eliminating foods like dairy, peanuts, soy, fish, eggs wheat and other foods identified by allergic testing has been found to be successful in 70% of paediatric cases. Because of poor tolerability, dietary therapy should be used in individuals not responding to medical and endoscopic treatment. Studies with targeted therapies to IL-5 are underway. Hiatus Hernia Herniation through the oesophageal hiatus occurs in two forms: axial or sliding type in which both the distal oesophagus and a varying portion of the stomach (i.e. the entire oesophagogastric junction) are situated above the diaphragm, and para-oesophageal or rolling type in which the lower most oesophagus and the oesophago-gastric junction retain their position below the diaphragm, while a portion of the proximal stomach protrudes into the thorax alongside the oesophagus. The size of the sliding hernia alone does not predict the presence or severity of symptoms; larger, long-standing hernias are more likely to be associated with symptomatic GOR. In the less common para-oesophageal or rolling hernia, the less-than-atmospheric intrathoracic pressure is transmitted directly through the pleura to the peritoneal sac. With positive intra-abdominal pressure exerting an upward push, this hernia tends to enlarge progressively. The typical para-oesophageal hernia is rarely associated with GOR; however, it can get incarcerated and strangulation or bleeding may occur. The management of symptomatic sliding hiatus hernia is similar to that of GORD. Para-oesophageal hernia needs surgical correction to avoid complications.

OESOPHAGEAL WEBS, RINGS AND DIVERTICULA Oesophageal webs usually occur in the upper oesophagus, but may occur in the mid or lower oesophagus as well. They are thin horizontal membranes of stratified squamous epithelium, usually protrude from the anterior wall, rarely complete and are best demonstrated on the lateral view in the barium swallow. They are usually acquired, but webs in the upper third may be congenital in origin (Figure 6). A syndrome of cervical oesophageal web, anaemia and platonychia, which occurs mainly in middle-aged women, is called the Patterson-Kelly or Plummer-Vinson syndrome.

Oesophageal Disorders

and regurgitation (24% to 50%), refractory GORD, chest pain, abdominal pain, diarrhoea and weight loss. Children present with poor feeding, vomiting, regurgitation and failure to thrive.

Figure 6: Barium swallow shows a web in upper oesophagus.

Oesophageal rings are found near the lower oesophageal sphincter (LOS). They are of 2 types. Type A is a muscular ring, 4 to 5 mm thick and is the hypertrophied upper portion of LOS. Type B ring, or Schatzki ring, is a mucosal ring at the squamocolumnar junction; its upper surface is squamous epithelium and undersurface is columnar. It is usually associated with GORD or rarely EO. Rings and webs present with intermittent dysphagia to solid food. Rarely, dysphagia progresses to a severe state. Treatment consists of breaking the web or ring by dilatation; webs may rupture even during a diagnostic endoscopy. The underlying disorder like anaemia or GOR needs appropriate treatment. Diverticula are outpouchings of the oesophageal wall from an area of muscular weakness. Zenker’s diverticulum occurs due to weakness in the posterior hypopharynx; patients present with dysphagia and regurgitation. Treatment consists of cricopharyngeal myotomy. Epiphrenic diverticula occur in the distal oesophagus and are associated with oesophageal motility disorders. RECOMMENDED READINGS 1.

Clouse RE, Diamant NE. Esophageal motor and sensory function and motor disorders of the esophagus. In: Feldman M, Freidman LS, Brandt LJ, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease; 8th Ed. Saunders Elsevier; 2006: pp 855-904.

2.

Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133: 1342.

3.

Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological Association Institute Technical Review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:13921413.

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13.8

Diseases of the Stomach and Duodenum

The stomach is a J-shaped organ continuous with the oesophagus proximally and the duodenum distally. It is divided from the proximal to distal end into the cardia, fundus, body or corpus, antrum and pylorus (pyloric channel). The duodenum is the first part of the small intestine and is in continuity with the pylorus of the stomach proximally and the jejunum distally. It forms a C-shaped loop around the head of the pancreas. The arterial blood supply of the stomach is derived from the coeliac artery and its major branches, the common hepatic, splenic and left gastric arteries while the duodenum receives additionally from the superior mesenteric artery. The venous drainage is into the portal vein or its tributaries, the superior mesenteric and splenic veins. The lymphatic drainage of the stomach is to the coeliac lymph nodes. The autonomic innervation stems from both the sympathetic (coeliac plexus) and the parasympathetic (right and left vagus nerves) nervous systems. The latter synapses with ganglion cells in the submucosa (Meissner’s plexus) and myenteric plexuses (Auerbach’s plexus). From these plexuses fibres are distributed to secretory components including cells and glands as well as to the gastric smooth muscle. MOTOR PHYSIOLOGY The motor function of the gastrointestinal (GI) tract is controlled at 3 levels. The first is the extrinsic neural control from the parasympathetic pathways via the vagus nerve and the sympathetic supply through the coeliac ganglion. The second level is provided by the enteric nervous system, which constitutes the complex network of ganglion cells in the layers of the gut wall. The third level of control of GI motility is in the excitable smooth muscle cells. Specific receptors in the cell membrane of the smooth muscle bind to amines, peptides, and other transmitters that reach the smooth muscle membrane via neurocrine, endocrine and paracrine routes. The main transmitters involved in excitation of the gastric muscle are acetylcholine and tachykinins, such as substance P and substance K. The main inhibitory transmitters are nitric oxide and vasoactive intestinal peptide (VIP). GASTRIC SECRETION The human stomach secretes water and electrolytes (H+, Na+, K+, Cl– and HCO3–), enzymes (pepsins and gastric lipase) and glycoproteins (intrinsic factor and mucins). The gastric exocrine secretions have a variety of functions.

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Acid Secretion The most important secretion of the stomach is gastric acid, secreted from parietal cells in the fundus and body of the stomach. Parietal cells have on their basolateral membrane receptors for 3 stimulants: histamine (H2) receptor for histamine released from ECL cells and possible mast cells, a muscarinic

Pankaj Dhawan (M3) type of cholinergic receptor for acetylcholine released from post-ganglionic neurons and a cholecystokinin (CCK) receptor for gastrin released from pyloric and duodenal G cells. Hydrogen ions are generated in the parietal cell from water. The corresponding hydroxyl ions combine with cellular carbon dioxide (CO 2) to form HCO 3. This reaction is catalysed by carbonic anhydrase. HCO 3 ions are exchanged at the basolateral membrane for Cl – ions, which are ultimately secreted by the parietal cells. Hydrogen ions are exchanged for K+ catalysed by the magnesium dependant H+-K+ ATPase pump. The H+-K+ ATPase is inhibited by covalent antagonists such as the substituted benzimidazoles (e.g. omeprazole). The apical membrane of the parietal cell is impermeable to H+ and Cl– and hence, it does not diffuse back from the lumen into the cell. Other Secretions The other important gastric secretion is pepsinogen (PG). This is a proenzyme S which gets activated to pepsin in the gastric lumen by the gastric acid. Two types of pepsinogen are PG I and PG II. The gastric mucosa also secretes bicarbonates through the surface cells that are rich in carbonic anhydrase. Under most conditions, luminal HCO3 is overwhelmed by luminal H+ and is converted to CO2. Therefore, HCO3 is not ordinarily present in gastric juice. The other secretory products are gastric mucin and intrinsic factor. The role of intrinsic factor in vitamin B12 absorption is discussed elsewhere. GASTRITIS Gastritis is acute or chronic inflammation of the stomach and is most often diffuse. It is usually diagnosed on upper GI endoscopy and can be confirmed and classified histologically by performing a gastric biopsy. A detailed system for classification (Sydney system) has been adopted recently. Acute Gastritis This is also called erosive or haemorrhagic gastritis. Of these, the most common cause is use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). These agents cause gastric mucosal damage by inhibiting prostaglandins, gastric bicarbonate and mucous, disrupting epithelial tight junctions and altering gastric mucosal micro-circulation. The mucosal damage can result in either slow upper GI bleeding which can be detected as positive faecal occult blood test or can manifest as massive upper GI bleeding. In some patients, epigastric discomfort, anorexia and nausea may be present. Treatment includes omission of the offending agent, acid-suppressive agents such as H2 receptor antagonists and proton-pump inhibitors, prostaglandin analogues such as misoprostol (more useful for prevention) and cytoprotective agents, such as sucralfate.

Diseases of the Stomach and Duodenum

Chronic Gastritis Chronic gastritis progresses over years in three stages. In chronic superficial gastritis, there is infiltration of lymphocytes and plasma cells in the lamina propria; however, the mucosal thickness is normal. In atrophic gastritis, there is reduction in the gastric glands (parietal and chief cells) along with infiltration of plasma cells and lymphocytes. When there is associated polymorphonuclear cells infiltration, gastritis is termed active. In gastric atrophy, glands are lost, mucosal thickness is reduced, infiltration of lymphocytes and plasma cells is minimal and there may be foci of intestinal metaplasia. The two main types of chronic gastritis are autoimmune (formerly type A) and H. pylori-associated (formerly type B). Autoimmune gastritis involves the gastric body and spares the antrum. Parietal cell and intrinsic factor antibodies are serum markers of autoimmune chronic gastritis. Patients present with pernicious anaemia (megaloblastic anaemia with absolute achlorhydria) and features of vitamin B 12 deficiency. Also, autoimmune chronic gastritis is a pre-malignant condition and can progress to gastric cancer. H. pylori-associated chronic gastritis usually involves the antrum but over a period of time may involve the body as well (see Infection Section).

Figure 2: Duodenal ulcer in first part of duodenum.

An uncommon cause of chronic gastritis is Menetrier’s disease (hypertrophic gastritis). The most common presentation is in middle age with features of protein-losing enteropathy. On upper GI endoscopy, enlarged rugal folds in the fundus and body are evident. Histologically, gastric pits and glands are elongated and tortuous and the parietal and chief cells are replaced by mucous-secreting glands. Treatment with protonpump inhibitors may decrease protein loss. However, in patients who do not respond, gastric resection may become necessary. PEPTIC ULCER DISEASE Peptic ulcers are defects in the GI mucosa that result when injury occurs due to the effects of acid and pepsin in the GI lumen. Although the term ‘peptic ulcer’ is commonly used to describe ulcers in the stomach (Figure 1) and duodenum (Figure 2), peptic ulcers can develop in any portion of the GI tract exposed to acid and pepsin such as the oesophagus, Meckel’s diverticulum or site of gastrojejunostomy (Figure 3). In the early Figure 3: Barium meal showing an anastomotic ulcer at the gastro-jejunostomy site.

part of the 20th Century, stress and diet were thought to be important pathogenetic factors. During the 1980s, it was established that most peptic ulcers were related to either H. pylori infection or due to consumption of NSAIDs. This revolutionised the management of peptic ulcer disease. Pathophysiology Peptic ulcer occurs when the deleterious effects of acid and pepsin overwhelm the ability of the mucosa to resist these effects.

Figure 1: Benign gastric ulcer at incisura.

Defence Mechanisms The mechanisms that normally enable the mucosa to resist acidpeptic attack can be divided into three components: preepithelial, epithelial and post-epithelial defence mechanisms.

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Pre-epithelial defence mechanisms A prominent coat of mucous and a layer of unstirred water rich in bicarbonate constitutes this component. Within the mucous layer glycoprotein form a physical barrier to the diffusion of pepsin. Mucous also contains phospholipids which protect the mucosa by forming a hydrophobic layer.

are asymptomatic, but may cause symptoms as well as complications such as, bleeding, perforation and obstruction. Asymptomatic ulcers can be endoscopically documented in 15% to 45% of patients receiving chronic NSAID therapy. However, 1% to 4% of patients receiving NSAIDs for 1 year will experience serious GI complications.

Epithelial defence mechanisms The apical cell membranes and the tight junctional complexes between the surface cells limit the diffusion of hydrogen. Excess hydrogen ions can be removed actively by ion pumps in the basolateral membrane, such as Na+/H+ exchanger and Cl–/HCO3– exchanger. Mucosal cell restitution regulated by growth factors (epidermal and fibroblast growth factors) also plays a part.

The major mechanism of NSAIDs-induced injury appears to be due to its topical effects leading to ulcers, erosions and sometimes acute haemorrhages. Most NSAIDs are weak organic acids that in acidic gastric juice become unionised, and thus, are freely lipid soluble. These diffuse across the gastric epithelium into the cytoplasm. Uncoupling of oxidative phosphorylation resulting in decreased mitochondrial energy production, reduction in cellular integrity and increase in cellular permeability. Attenuation of the gastric mucous gel layer also occurs. Enteric coated NSAIDs produce considerably less acute topical erosive injury than non-enteric coated formulations over short term (1 to 2 weeks) usage.

Post-epithelial defence mechanisms Mucosal blood flow comprises the post-epithelial defence mechanism. Abnormalities in Gastric Acid Secretion, Acid Homeostasis and Gastroduodenal Motility In 1910, Schwarz proposed his famous dictum ‘no acid, no ulcer’. This followed numerous studies on abnormalities in acid homeostasis in peptic ulcer. After the discovery of H. pylori it has been shown that many of these abnormalities may not be the primary defects but reversible consequences of infection with H. pylori. Abnormalities associated with duodenal ulcer Studies have shown these patients to be hypersecretors of gastric acid with an increase in the number of parietal cells. This may be related to H. pylori induced increases in cytokines such as tumour necrosis factor which stimulates gastrin release from G cells and H. pylori mediated decrease in somatostatin, a peptide which suppresses gastric release. Also an increased rate of liquid gastric emptying with increased acid burden in duodenum has also been described. Abnormalities associated with gastric ulcer Whereas the mucosa of the fundus and body is acid secreting (oxyntic) mucosa with abundant parietal cells, the gastric antrum is normally lined by a columnar epithelium that does not secrete gastric acid. The majority of gastric ulcers occur in the non-acid secreting epithelium at or near its junction with oxyntic mucosa. Long standing gastritis as occurs in H. pylori infection can cause atrophy of oxyntic mucosa with development of intestinal metaplasia and extension of the non-acid secreting epithelium into the proximal stomach. Patients who have gastric ulcers in the proximal stomach have chronic gastritis, substantial gastric atrophy and low gastric acid outputs. Helicobacter pylori H. pylori is associated with more than 80% of duodenal ulcers and more than 60% of gastric ulcers patients. Host factors as well as bacterial virulence factors (such as cagA positive H. pylori) may determine disease predisposition in those who are H. pylori positive.

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Nonsteroidal Anti-Inflammatory Drugs A large number of peptic ulcers not related to H. pylori are related to NSAIDs use. Typically NSAIDs-induced ulcers

Injury also occurs through its systemic effects. Peptic ulcers will develop after intravenous or rectal suppository further supporting a systemic effect. Cyclo-oxygenase (COX) is the rate limiting enzyme for prostaglandin synthesis. Most NSAIDs (excepting the specific COX-2 inhibitors) reduce mucosal prostaglandin. A small dose of 10 mg of oral aspirin can decrease gastric prostaglandin levels by 60% and can cause gastric ulcers. Levels do not recover till 5 to 8 days. Animal experiments indicate that for gastric ulcers to occur both COX-1 and COX-2 must be inhibited. Hence, theoretically, COX-2 specific inhibitors are associated with improved GI toxicity profile. Besides COX inhibition NSAIDs increase gastric acid secretion, decrease gastric mucosal blood flow, decrease mucous production and duodenal bicarbonate. Nitric oxide (NO) protects the GI mucosa from NSAIDs-induced injury. Nitric oxide donating NSAIDs or COX inhibiting nitric oxide donating drugs (CINODs) exhibit reduced GI toxicity in animal and human trials. Other Ulcerogenic Drugs Besides NSAIDs the other ulcerogenic drugs are 5-fluorouracil, potassium chloride, mycophenolate mofetil, and bisphosphonates (alendronate and risedronate). Hypersecretory Conditions These should be considered in any patient who has peptic ulcer not associated with H. pylori or NSAIDs. Other clues include severe complicated disease, ulcers in the post-bulbar duodenum and diarrhoea. Hypersecretory conditions include gastrinoma, systemic mastocytosis and myeloproliferative disorders with basophilia, and antral G cell hyperfunction. Epidemiology It has been observed that there is a declining prevalence of peptic ulcer disease, in part related to falling prevalence of H.pylori. In contrast ulcer related complications as well as hospitalisation is on the rise, particularly in elderly due to increased use of NSAIDs. Cigarette smoking is a risk factor for peptic ulcer disease and its complications. It slows healing and predisposes to relapses. However, if H. pylori is eradicated, smoking does not influence relapses.

Clinical Features of Uncomplicated Peptic Ulcer Disease The main symptom of peptic ulcer disease is abdominal pain. Patients with duodenal ulcer describe burning or gnawing epigastric pain. Pain occurs 2 to 3 hours after a meal and is relieved after food or with antacids. Pain may occur in the night. Anorexia and weight loss are uncommon. Patients with gastric ulcers may have pain indistinguishable from duodenal ulcer. Peptic ulcers may be asymptomatic. Symptoms are neither specific nor sensitive for diagnosing peptic ulcers. If peptic ulcer is suspected, investigations must be carried out. Increase in severity of pain, radiation of pain to the back, pallor, vomiting or bleeding should point to the development of complications. It should be remembered that the symptoms of gastric cancer may be very similar to those of peptic ulcer. Presence of alarm signs like increased severity of pain, pallor, weight loss, vomiting, high ESR and presence of occult blood in stool should prompt investigations. In uncomplicated peptic ulcer the clinical examination will be unremarkable or the only sign will be tenderness in the epigastrium or slightly to the right of the midline in the upper abdomen. Diagnostic Tests Upper GI endoscopy has become the gold standard for diagnosis of peptic ulcer. Barium-meal is a far less sensitive investigation. Also endoscopy allows an opportunity for mucosal biopsy. Studies of acid secretion have little role in the diagnosis of peptic ulcer. However, these are useful in the work up of hypergastrinaemia, and to assess the completeness of vagotomy in recurrent ulcer. In patients with refractory peptic ulcer, serum calcium and fasting serum gastrin are indicated. Treatment The treatment of peptic ulcer has dramatically changed over the years. From bed rest and prescription of ‘bland diets’ came the era of antacids. The discovery of H2 receptor antagonists and later of proton pump inhibitors (PPIs) achieved greater ulcer healing rates. The real revolution occurred, however, with discovery of the link between H. pylori and peptic ulcer.

containing) or constipation (aluminium containing). Antacids must be used cautiously in patients with renal insufficiency. Histamine (H2) receptor antagonits These include cimetidine, ranitidine, famotidine, roxatidine and nizatidine. These agents competitively inhibit histamine stimulated acid secretion. All of them decrease basal as well as meal stimulated acid output. These agents are well absorbed after oral dosing and are not affected by food. All of them are eliminated by a combination of renal excretion and hepatic metabolism. H 2 receptor antagonists are remarkably safe and well tolerated. Overall incidence of sideeffects is less than 4% and serious side effects are very uncommon. A variety of central nervous system symptoms have been rarely reported; these include headache, dizziness, depression. Drug interactions (inhibiting elimination of theophylline, phenytoin, lidocaine, quinidine and warfarin) have been reported due to binding of hepatic cytochrome P450 (CYP) system. Tolerance appears to develop quickly and frequently.

Diseases of the Stomach and Duodenum

As far as alcohol is concerned, wine and beer are potent acid secretagogues but its importance in pathogenesis of peptic ulcer is dubious. There is no study which has clearly demonstrated a link between diet and peptic ulcer disease. Coffee (both caffeinated and decaffeinated), tea and colas are potent acid secretagogues. Amongst the diseases associated with peptic ulcer are alcoholic cirrhosis, chronic pulmonary disease and chronic renal failure. Despite popular belief, there is no role of emotional stress and peptic ulcers. Some studies have suggested that genetics may predispose to peptic ulcer disease.

Proton pump inhibitors These agents decrease gastric acid by inhibiting the H+/K+ ATPase pump of the parietal cell. Currently five PPIs are available; omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole. They are all substituted benzimidazoles and are weak bases. They are prodrugs and are acid labile. PPIs are most effective when administered immediately before meals. If the dose is once daily, it is preferable to administer immediately before breakfast. Single dose may inhibit gastric acid secretion for more than 24 hours. Newer PPIs inhibit H+/ K+ ATPase more rapidly than omeprazole. PPIs are remarkably safe. Common side-effects are headache and diarrhoea. No dose adjustment is required in patients with renal or hepatic impairment. Elevation of gastric pH can interfere with absorption of drugs such as ketoconazole (decrease) and digoxin (increase). Drug interactions are uncommon. Potential interactions may occur since PPIs are metabolised by CYP system. One such example is reduction in the effect of clopidogrel. Although PPIs cause hypergastrinaemia, there is no human report of development of gastric carcinoid tumours. Tolerance to the anti-secretory effects of PPIs is not seen. There is no need for routine H. pylori eradication prior to initiating treatment with PPIs. Mucosa protective agents

Acid lowering drugs These are not routinely required for patients with uncomplicated H. pylori ulcers in whom the bacterium has been successfully eradicated. However, anti-ulcer drugs are important for healing of large ulcers, management of complicated ulcer disease such as bleeding, reducing the risk of ulcer relapse in patients on NSAIDs and treating idiopathic ulcers.

Sucralfate: This is a complex metal salt of sulphated sucrose and aluminium hydroxide. When exposed to gastric acid, the aluminium hydroxide dissociates, leaving sulphate anions that can bind electrostatically to positively charged proteins in damaged tissue. It forms a protective layer over the ulcer craters. Other beneficial effects include increase in mucosal prostaglandins, stimulation of mucous and bicarbonate secretions, binding of bile salts and promotion of angiogenesis. It is effective in promoting healing when given in a dose of 1 g four times a day. Since it is not absorbed, there is no systemic toxicity.

Antacids: Besides increasing the gastric pH, antacids have a variety of cytoprotective effects. At present, they are used mainly for relieving symptoms. Side-effects include diarrhoea (magnesium

Bismuth: The two commonly used preparations are colloidal bismuth subcitrate and bismuth subsalicylate. The bismuth component forms complexes with mucous and coats the ulcer 809

craters. Also bismuth has anti-microbial action against H. pylori. Bismuth is unabsorbed if given over a short duration and systemic toxicity is rare.

compliance, failed H. pylori eradication, ongoing NSAIDs, smoking, hyper-secretory condition and other aetiologies (neoplastic, infective).

Prostaglandin E analogues: Prostaglandin E2 regulates mucosal blood flow, epithelial cell proliferation, epithelial restitution, mucosal immunocyte function, mucous and bicarbonate secretion, and basal acid secretion. Misoprostol, a prostaglandin analogue is used for prevention of NSAIDs-induced ulcer disease. It is well absorbed after oral administration. Dose related diarrhoea is observed in nearly one-third of the patients. It is contraindicated in pregnant women.

Complications The complications of peptic ulcer are penetration, perforation, haemorrhage and obstruction.

Ulcers associated with H. pylori Peptic ulcer management was revolutionised after discovery of H. pylori. It is well established that H. pylori eradication not only heals ulcers but also prevents relapses. H. pylori is associated with 70% to 90% of duodenal ulcers and 40% to 70% of gastric ulcers. For uncomplicated duodenal ulcers, additional antisecretory treatment is not required. For large gastric ulcers additional anti-secretory treatment may promote ulcer healing. For large gastric ulcers, biopsy must be taken to exclude malignancy. After successful eradication, maintenance therapy with anti-secretory agents is not required. Ulcers associated with NSAIDs In this situation NSAIDs should be discontinued, if possible. PPIs are more effective than H2 receptor antagonists or misoprostol for healing of NSAIDs-induced ulcers. There is little role of substituting a selective COX 2 inhibitor in place of conventional NSAIDs once an ulcer develops. H. pylori needs to be eradicated if present in these patients. Prophylaxis of NSAIDs ulcers H2 receptor antagonists reduce the risk of duodenal ulcers but not gastric ulcers. Misoprostol reduces the risk of NSAIDsinduced gastric and duodenal ulcers. Higher dose (800 μg/day) of misoprostol reduced ulcer complications. PPIs are very effective in reducing the risk of NSAID-induced gastric and duodenal ulcers. COX 2 inhibitors induced fewer ulcers than conventional NSAIDs. New data suggest that a combination of non-selective NSAIDs with PPI is as effective or better than using selective COX 2 inhibitors in prevention of NSAIDs-ulcers. Also studies have shown increased serious cardiovascular events with the use of COX 2 inhibitors. If H. pylori is present, it needs to be eradicated. This is also recommended for patients on long-term, low-dose aspirin. In patients with risk factors for ulcer complications (Table 1), co-therapy with a PPI is recommended.

Penetration refers to the extension of the ulcer through the bowel wall into the adjacent structures without producing free perforation into the peritoneal cavity. The ulcer can penetrate into the pancreas, biliary tract, omentum or colon. Perforation into the colon leads to gastro-colic fistula. Symptoms of penetration vary depending on the organ involved. It manifests as increase in severity and duration of pain and failure of pain relief with antacids or food. Bleeding from peptic ulcer is a life-threatening complication.The patient may present with melaena, haematemesis or both. When the bleeding is massive haematochezia will be present. Old age, shock at the time of admission and massive bleeding necessitating transfusion of more than five units of blood indicate poor prognosis, and surgery should be considered in these situations. The first step in the management is resuscitation of the patient by replacing the blood volume and managing haemodynamic instability. Upper GI endoscopy should be done as soon as the patient is stable. This will show the site of bleed. Active bleeding or the presence of high-risk lesions—visible vessel or adherent clot (Figure 4)—call for endoscopic management. Injection of saline or dilute adrenaline (Figure 5), application of heater probe, endoscopic application of clips (Figure 6) can all arrest the bleeding. Anti-secretory treatment (intravenous, continuous infusion of PPI) should be started.

Table 1: Risk Factors for NSAIDs-Induced Ulcer Complications History of peptic ulcer complication Increasing age Use of steroids Use of anti-coagulants Use of combination NSAIDs Co-morbid diseases Smoking

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Refractory Peptic Ulcers Most peptic ulcers heal with 8 to 12 weeks of anti-secretory therapy. If this does not occur, consider the following: lack of

Figure 4: Duodenal ulcer with stigmata of recent bleed (black base).

Perforation of peptic ulcer is an emergency. The patient presents with sudden onset of abdominal pain; peritonitis and free gas in the peritoneum are present. Patients who present late and those who develop perforation while in the hospital have a poor prognosis. Surgical treatment, which involves closure of the perforation with an omental patch is the procedure often employed. Effective treatment of H. pylori infection and strong acid suppressants are available now, and

Diseases of the Stomach and Duodenum

Figure 5: Injection sclerotherapy being done for bleeding duodenal ulcer with stigmata of recent bleed (visible vessel).

Figure 7: Endoscopic balloon dilatation for pyloroduodenal stenosis.

Ulcers in the lower end of the oesophagus may in the long run lead to peptic strictures and dysphagia. Endoscopic balloon dilatation gives symptomatic relief to these patients. Fibrosis during healing of gastric ulcers may result in rare deformities of the stomach like ‘tea-pot stomach’ or the ‘hourglass stomach’. Recurrent ulcer is the term used for recurrence of ulcers after surgical treatment of duodenal ulcer. Incomplete vagotomy and retained antrum are the most common causes. Duodenal ulcer does not turn malignant. H. pylori is implicated as an aetiological agent in carcinoma stomach. In spite of the high prevalence of H. pylori in persons with peptic ulcer, duodenal ulcer is not a risk factor for the cancer of the stomach or of the duodenum. However, persons who had undergone surgery (partial gastrectomy) for duodenal ulcer are at increased risk of developing cancer in the post-operative stomach. Figure 6: Haemoclips applied to base of bleeding ulcer.

hence, a definitive surgical treatment may not be necessary in selected patients; small leaks into peritoneum can be managed conservatively. Obstruction in peptic ulcer may be due to fibrosis, inflammation or spasm. It is the pyloric channel ulcers or ulcers in the first part of duodenum that develop gastric outlet obstruction. Gastric outlet obstruction (pyloric stenosis) (Figure 7) presents with postprandial bloating, fullness and vomiting. Vomiting brings out food consumed several (>6) hours ago. Foul smelling eructations may be present. Examination reveals a visibly dilated stomach, visible peristalsis or succussion splash. Barium meal shows a dilated stomach with delayed emptying. Endoscopy should be performed after thorough cleaning of the stomach. Carcinoma of the stomach should be excluded in every patient with gastric outlet obstruction as malignancy is seen in about half of such cases. Management includes gastric lavage to remove food debris, correction of fluid and electrolyte disturbances and metabolic consequences of prolonged vomiting and loss of gastric acid. Anti-secretory drugs should be administered parenterally since absorption is poor. H. pylori infection and NSAID intake should be looked for and managed. If the symptoms fail to respond, surgery is indicated. Endoscopic balloon dilatation of the narrowed segment has also been used successfully (Figure 7).

GASTRIC VOLVULUS Twisting of the stomach upon itself leads to gastric volvulus which can present clinically either acutely or as chronic volvulus. Three types have been described—organoaxial volvulus is the most common; in this type the stomach twists along its long axis (cardiopyloric line); mesenteroaxial volvulus is one in which the stomach falls on itself along an imaginary line drawn from the mid-point of the lesser curvature to the mid-point of the greater curvature and is the least common of the three; mixed gastric volvulus is a combination of organoaxial and mesenteroaxial types. Anatomical anomalies such as ligamentous laxity, paraoesophageal hiatus hernia, eventration of the diaphragm, extrinsic compression from adjacent organs or submucosal tumours of the stomach can cause gastric volvulus. Patients with acute gastric volvulus present as an acute abdomen with the classical triad of violent retching and little vomiting, severe epigastric pain and inability to advance a nasogastric tube into the stomach. In patients with chronic volvulus the major symptoms are epigastric pain, bloating and eructations. Barium-meal examination usually demonstrates the twisted stomach. Acute volvulus is an emergency and usually requires an emergent laparotomy although endoscopic derotation of the

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volvulus is sometimes successful. Recurrent symptoms in patients with chronic volvulus need surgical treatment wherein the stomach is fixed to the anterior abdominal wall by performing a gastropexy. Recently, percutaneous endoscopic gastrostomy has been found to be an alternative to surgical gastropexy. BEZOARS These have been classified into two main groups: hair or trichobezoar and plant or phytobezoars. Other materials such as chemical concretions, food boluses and foreign bodies may also cause bezoars. For phytobezoars, hypochlorhydria, gastroparesis and incomplete mastication are important predisposing factors. In patients with trichobezoar, underlying neuropsychiatric disturbances may be present. Bezoars present with pain in the upper abdomen, periodic attacks of nausea and vomiting and a lump in the abdomen. Complications such as gastric ulcer, perforation and peritonitis may occur. Plain X-ray abdomen in the standing position occasionally demonstrates a mass invading the gastric air bubble. Barium-meal examination demonstrates a barium shell coating an irregular large filling defect. In most cases upper GI endoscopy is diagnostic. For treating phytobezoars, endoscopic internal fragmentation using forceps and polypectomy snares may be tried. Chemical dissolution using papain, cellulase and acetylcysteine is sometimes successful. If these methods fail, surgical removal needs to be done. In most cases of trichobezoars, surgery is required. DUODENAL DIVERTICULUM It is usually single and present along the medial wall of the duodenum. It is acquired as an outpouching of the duodenal mucosa at the point of maximum weakness. Most often this diverticulum is asymptomatic and incidentally detected during a barium-meal examination or Upper GI endoscopy (Figure 8). Rarely, duodenal diverticulum may perforate retroperitoneally, cause upper GI bleeding or obstruct the bile duct or pancreatic

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Figure 8: Barium-meal examination showing duodenal diverticulum along medial wall.

duct. The treatment of a complicated duodenal diverticulum is surgical. RECOMMENDED READINGS 1.

Chiba N, Hunt RH. Ulcer disease and Helicobacter pylori infection: aetiology and treatment. In: McDonald JWD, Burroughs AK, Feagan BG, editors. Evidence Based Gastroenterology and Hepatology. Bangalore: Panther Publishers; 1999: pp 91-117.

2.

Desai HG. Gastritis: Indian Perspective. Vakils, Feffer and Simons Pvt Ltd 2008.

3.

Spechler JS, Cryer B. Peptic ulcer disease. In: Mark Feldman, Lawrence S. Friedman, Lawrence J. Brandt editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases Pathophysiology/Diagnosis/Management. WB Saunders & Co.; 2006: pp 1089-110.

13.9 ACUTE PANCREATITIS Acute pancreatitis (AP) is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems. Mild acute pancreatitis consists of minimal or no organ dysfunction and an uneventful recovery. Severe pancreatitis manifests as organ failure and/or local complications such as necrosis, abscess, or pseudocyst (Table 1). Overall, about 20% of patients with acute pancreatitis have a severe course, and 10% to 30% of those with severe acute pancreatitis die. Table 1: Criteria of Severe Acute Pancreatitis Organ failure Shock: Systolic blood pressure of 500 mL in 24 hours And/Or local complications Necrosis Abscess Pseudocyst Unfavourable prognostic signs >3 Ranson’s signs >8 APACHE II points

Aetiopathogenesis The gallstone disease and alcohol are the two most common causes for AP (Table 2). The initial step in the pathogenesis of acute pancreatitis is conversion of trypsinogen to trypsin within acinar cells.Trypsin, in turn, catalyses conversion of pro-enzymes, including trypsinogen and inactive precursors of elastase, phospholipase A2, and carboxypeptidase, to active enzymes. Active enzymes autodigest the pancreas and initiate a cycle of releasing more active enzymes. Factors that may initiate gallstone pancreatitis include reflux of bile into the pancreatic duct or obstruction of the pancreatic duct at the ampulla by a stone(s) or oedema resulting from the passage of a stone. The pathophysiology of acute pancreatitis includes microcirculatory injury, leucocyte chemoattraction and release of cytokines, oxidative stress, and bacterial translocation. Clinical Features Abdominal pain is present at the onset, but the timing of abdominal pain is variable. Biliary colic may herald or progress to acute pancreatitis. Alcohol-related acute pancreatitis frequently occurs 1 to 3 days following drinking. The pain radiates to back and is associated with nausea and vomiting. Its onset is rapid and reaches maximal intensity in 10 to 20 minutes. Occasionally, pain takes several hours to reach maximum intensity. It is steady and moderate to very severe in intensity. Physical findings depend on the severity of an attack. Patients with mild pancreatitis may not appear acutely ill and have mild

Diseases of the Pancreas V Balakrishnan, G Rajesh abdominal tenderness. In severe pancreatitis, patients look severely ill and often have abdominal distention, especially epigastric, which is due to gastric ileus or dilatation of the transverse colon. Bowel sounds are reduced and may be absent. Table 2: Aetiology of Acute Pancreatitis Gallstones Biliary sludge and microlithiasis Alcohol Mechanical obstruction of ampulla Metabolic: Hypertriglyceridaemia and hypercalcaemia Infections: Mumps, HIV, CMV, EBV, Clonorchiasis, and Ascariasis Toxins: Scorpion venom, organophosphorous insecticides Trauma Post ERCP Pregnancy Post-operative Hereditary Ischaemia Drugs: Pentamidine, didanosine, salicylates, sulindac, frusemide, thiazides Sulphasalazine, mesalamine, L-asparaginase, azathioprine, valproic acid, ACE-inhibitors

Diagnosis Acute pancreatitis can be diagnosed by the presence of typical clinical features along with corroborative laboratory findings of elevated serum enzymes (amylase/lipase) and/or imaging features. It needs to be differentiated from other abdominal causes which may present as an acute abdomen. Investigations Blood investigations The white blood cell count is usually elevated, markedly so in severe pancreatitis. A raised haematocrit, indicative of haemoconcentration, may indicate severe disease. Serum amylase is the most frequently ordered test. However, hyperamylasemia can also occur in other conditions. In acute pancreatitis, the serum amylase concentration is usually more than three times the upper limit of normal. Measurement of serum lipase is performed less frequently. Amylase levels tend to return to normal faster than lipase levels, so that measurement of the latter is particularly useful in patients who present several days after the onset of pain. An increase in serum alanine aminotransferase (ALT) 3 to 4 times the base-line level suggests gallstone-induced pancreatitis. Imaging There can be localised ileus of a segment of small intestine (‘sentinel loop’) or the colon cut-off sign on a plain radiograph of the abdomen. Thirty per cent of patients with acute pancreatitis have abnormalities in chest radiograph in the form of elevation of a hemi-diaphragm, pleural effusion(s), basal or

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plate-like atelectasis secondary to limited respiratory excursion, and pulmonary infiltrates. Transabdominal ultrasonography is the best initial imaging modality. It is used during the first 24 hours of hospitalisation to search for gallstones, dilatation of the common bile duct due to choledocholithiasis and ascites. Pancreas is usually diffusely enlarged and hypoechoic. A contrast enhanced computed tomography (CECT) scan of the abdomen is the most important imaging test for the diagnosis of acute pancreatitis and its intra-abdominal complications and is also used to assess the severity of the disease. Magnetic resonance imaging (MRI) shows the pancreas as well CT scan. In addition, it has certain advantages over the latter. It does not carry the potential nephrotoxicity of the contrast required to perform CECT, better than it avoids the radiation exposure of CT scan and finally, it shows a greater ability than CT scan to distinguish necrosis from fluid. Endoscopic ultrasound (EUS) helps in timely diagnosis of common bile duct (CBD) or ampullary stones in the setting of acute gallstone pancreatitis; hence it can be used instead of diagnostic endoscopic retrograde cholangio-pancreatography (ERCP) to identify patients who would likely benefit from therapeutic ERCP. Treatment The algorithm for treatment of acute pancreatitis is outlined in Figure 1.

Mild acute pancreatitis The prognosis of mild pancreatitis is good and can be managed in a regular hospital ward with fluid administration, bowel rest and analgesics. Fluid resuscitation is important to replace low intravascular volume due to vomiting, diaphoresis, and third-space losses. Abdominal pain is treated with parenteral analgesics. Most patients require no further therapy and recover within a week. Severe acute pancreatitis Patients with signs of severe acute pancreatitis should be identified early and admitted promptly to an intensive care unit. The goal is to provide supportive care and treatment of complications when they develop. Maintaining adequate intravascular volume may require 5 to 10 litres of fluid daily for the initial few days. Hypoxaemia (oxygen saturation 55 16000 >200 >350 >250

>70 18000 >220 >400 >250

>10 >5 6L

>10 >2 5 >4L

CHRONIC PANCREATITIS Chronic pancreatitis (CP) is characterised by pancreatic inflammation and fibrosis, the end point of which is destruction of pancreatic parenchyma with eventual loss of exocrine and endocrine function. Aetiology The aetiologic risk factors associated with chronic pancreatitis is given in Table 5. Alcohol The most common cause of chronic pancreatitis in the Western world and in Japan is excessive alcohol consumption. In most patients, at least five years of alcohol intake exceeding 80 g/ day is required prior to the development of chronic pancreatitis. Tropical pancreatitis Tropical pancreatitis ( TCP) remains an important form of chronic pancreatitis in certain areas of India. The exact aetiopathogenesis of TCP remains unknown. Nutritional

deficiencies, especially of micronutrients and antioxidants or/ and dietary toxins such as cyanogenic glycosides (cassava or tapioca), have been considered as likely aetiological factors. Hereditary pancreatitis Hereditary pancreatitis is a rare autosomal dominant disorder with approximately 80% penetrance. It presents typically in childhood or early adulthood with abdominal pain and recurrent acute attacks of pancreatitis.

Diseases of the Pancreas

scoring systems like Ranson’s score, Glasgow score, acute physiology and chronic health evaluation (APACHE) II, among others (Tables 3 and 4). A new prognostic scoring system, the bedside index for severity in acute pancreatitis—BISAP (blood urea nitrogen >25 mg/dL, impaired mental status, systemic inflammatory response syndrome (SIRS), age >60 years, and pleural effusions) was comparable to existing scoring systems.

Table 5: Aetiologic Risk Factors Associated with Chronic Pancreatitis: TIGAR-O Classification System Toxic-metabolic Alcohol, tobacco smoking, hypercalcaemia (hyperparathyroidism), chronic renal failure, medications (phenacetin), toxins (organotin compounds, e.g. DBTC) Idiopathic Early onset, late onset Tropical (tropical calcific pancreatitis,fibrocalculous pancreatic diabetes) Genetic Autosomal dominant (Cationic trypsinogen codon 29 and 122 mutations) Autosomal recessive/modifier genes (CFTR mutations,SPINK1 mutations Cationic trypsinogen codon 16, 22, 23 mutations, α1-antitrypsin deficiency) Autoimmune Isolated autoimmune chronic pancreatitis Syndromic autoimmune chronic pancreatitis (Sjögren syndromeassociated chronic pancreatitis, inflammatory bowel disease-associated chronic pancreatitis Primary biliary cirrhosis—associated chronic pancreatitis) Recurrent and severe acute pancreatitis Post-necrotic (severe acute pancreatitis), recurrent acute pancreatitis, vascular diseases/ischaemic, post-irradiation Obstructive Pancreatic divisum, sphincter of Oddi disorders, duct obstruction (e.g. tumour) Pre-ampullary duodenal wall cysts,post-traumatic pancreatic duct scars

Obstructive chronic pancreatitis Obstruction of the main pancreatic duct by tumours, scars, cysts, or stenosis of the papilla of Vater or minor papilla can produce chronic pancreatitis in the parenchyma upstream of the obstruction. Blunt and penetrating trauma to the pancreas can also lead to pancreatic duct strictures. Autoimmune pancreatitis This is characterised by presence of autoantibodies, elevated levels of immunoglobulins especially IgG4, enlargement of the pancreas (diffuse or focal), pancreatic duct strictures, and pathologic features of a dense lymphocytic infiltrate. A common presentation is that of a pancreatic mass mimicking cancer. It is often steroid responsive. Low dose steroids or immunomodulators may be needed to maintain remission. Idiopathic chronic pancreatitis Idiopathic chronic pancreatitis accounts for 10% to 30% of all cases of CP in the West and 40% to 60% in India, and appears to occur in two forms, early onset and late onset type. Pathophysiology The pathophysiology of CP remains incompletely understood. Four major theories include toxic-metabolic, oxidative stress, stone and duct obstruction, and necrosis-fibrosis.

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Pathology In early CP, areas of interlobular fibrosis are seen, with the fibrosis often extending to the ductal structures. Infiltration of the fibrotic area and lobules with lymphocytes, plasma cells, and macrophages is seen. In affected lobules, acinar cells are replaced by fibrosis. As the disease progresses, fibrosis within the lobules and between lobules becomes more widespread. The pancreatic ducts become more abnormal, with progressive fibrosis, stricture formation, and dilation. Protein plugs may calcify and obstruct major pancreatic ducts. Clinical Features The cardinal symptom of CP is abdominal pain. Fat malabsorption leading to steatorrhoea and weight loss is common in CP. Steatorrhoea does not occur until pancreatic lipase secretion is reduced to less than 10% of normal. Diabetes in CP is considered as a secondary form of diabetes mellitus. Weight loss is most commonly due to decreased intake in episodes of acute exacerbation. Weight loss may also occur owing to the development of small bowel bacterial overgrowth, malabsorption, uncontrolled diabetes or pancreatic or extrapancreatic malignancy. Physical examination might show evidence of nutritional deficiencies. Complications of common bile duct obstruction or a pseudocyst may produce physical findings of jaundice, or a palpable swelling in the epigastrium. Ascites may rarely follow a leak from a ruptured pancreatic duct. A palpable spleen may be seen following thrombosis of the splenic vein (Table 6). Diagnosis Serum amylase or lipase may be found to be elevated only during acute exacerbations. A full diabetic work-up should be done for all patients with suspected pancreatitis. A prediabetic stage has been well described.

Imaging The demonstration of pancreatic calcification on imaging is pathognomonic of CP. Diagnosis is difficult in early cases of pancreatitis where the patient may have typical symptoms but lack diagnostic imaging features on ultrasonography (USG)/CT. In such cases, an endoscopic retrograde pancreatography (ERP) or a EUS may be helpful. Pancreatic calcifications are most common in alcoholic, lateonset idiopathic, hereditary and especially in tropical pancreatitis and may be detected on abdominal radiograph. Ultrasonography findings indicative of CP include dilation of the pancreatic duct, pancreatic ductal stones, gland atrophy or enlargement, irregular gland margins, pseudocysts and changes in the parenchymal echotexture. CECT scan of the abdomen is superior to USG. The sensitivity of CT for CP is 75% to 90% and specificity 85% or more. ERCP is considered the most specific and sensitive test of pancreatic structure. The sensitivity of ERCP is between 70% and 90%, with a specificity of 80% to 100%. Magnetic resonance cholangiopancreatography (MRCP) agrees with ERCP in 70% to 80% of findings. MRCP is noninvasive, avoids ionising radiation and contrast administration, and does not routinely require sedation, making it a diagnostic procedure of choice in some groups of patients, particularly children. EUS is the best among currently available tests for the detection of early changes of CP. Typical findings in CP include parenchyma features like hyperechoic strands, hyperechoic foci, lobularity, cysts; and ductal features like stones, main duct irregularity, hyperechoic main duct, visible side branches, main duct dilatation.

Table 6: Complications of Chronic Pancreatitis No.

Complication

Signs and Symptoms

Treatment

1.

Pseudocyst

2.

Biliary obstruction

Increased abdominal pain, nausea, vomiting, jaundice, palpable mass, bleeding, increase in amylase and lipase Jaundice, biliary pain, cholangitis, pruritus

3.

Gastric outlet obstruction Pancreatic adenocarcinoma External pancreatic fistula

Abdominal pain, early satiety, nausea and vomiting Increased pain, weight loss, jaundice, elevated Ca 19-9 Consequence of surgical or percutaneous therapy for chronic pancreatitis or pseudocyst

6.

Pancreatic ascites

7.

Pleural effusion

8.

Splenic vein thrombosis

Increased abdominal girth, high ascitic fluid amylase typically greater than 4000 units/L Shortness of breath, high amylase in pleural fluid typically greater than 4000 units/L Bleeding from gastric varices

Endoscopic drainage (transmural or transpapillary) Surgical drainage (cyst-gastrostomy or cyst-jejunostomy) Percutaneous drainage Drainage of obstructing pseudocyst Endoscopic decompression Surgical decompression Surgical biliary bypass, either with a cholecystojejunostomy or choledochojejunostomy Drainage of pseudocyst Surgical gastrojejunostomy Whipple’s or modified Whipple’s surgery Palliation if advanced disease NPO, parenteral nutrition, octreotide and endoscopic stent placement Surgical treatment includes pancreatic resection (if the fistula is in the tail) or a fistulojejunostomy, in which the fistula tract is ‘capped’ with a defunctionalised limb of jejunum Endoscopic stent placement, total parenteral nutrition

4. 5.

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Therapeutic thoracentesis, endoscopic stent placement, total parenteral nutrition Splenectomy

Relief of pain Analgesics like acetaminophen for mild pain or non-narcotic agents for moderate to severe pain are usually used. If nonnarcotic agents fail, it is useful to begin with the less potent opioid agents like propoxyphene napsylate or tramadol before starting morphine. Pancreatic enzyme preparations, particularly those with high protease content and antioxidants may also help to relieve pain. Failure of medical management necessitates use of interventions like coeliac plexus block, extra-corporeal shock wave lithotripsy (ESWL), endoscopic therapy or surgery. Correction of maldigestion Pancreatic enzymes (~ 30,000 units of lipase) have to be given along with each meal. The enzyme activity tends to be degraded by the gastric acid, especially in case of non-enteric coated preparations; hence it is better to also administer proton pump inhibitors or H2 receptor antagonists. Management of diabetes A few newly detected diabetics in CP can be controlled with diet and regular exercise. The majority can be managed with oral hypoglycaemic agents for varying periods. A large group will require insulin for glycaemic control. Endotherapy The general goal of endoscopic therapy is to improve drainage of the pancreatic duct by relieving obstruction. Patients with a solitary stone or a few small stones in the head region with a dilated proximal duct are the ideal candidates. Sphincterotomy, with pancreatic duct stenting, sometimes undertaken after ESWL to crush the stones, is the usual procedure. Surgery Surgery is indicated for intractable abdominal pain that has failed medical therapy. Other indications for surgery include complications involving adjacent organs (duodenal, splenic vein, or biliary obstruction), pseudocysts failing endoscopic or radiologic management, internal pancreatic fistulas, and suspected or proven malignancy. Surgical options for pain can include pancreatic ductal drainage, resection of all or part of the pancreas, or both. If there is suspicion of a malignancy in the head, a pancreaticoduodenectomy should be undertaken. PANCREATIC CANCER Pancreatic cancer remains a leading cause of death with 5-year survival rates of less than 5%. Despite advances in diagnosis and staging, most cancers are diagnosed in an advanced stage and are suitable only for palliative treatment. Pathophysiology Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15% to 20% occur in the body of the pancreas, and 5% to 10% occur in the tail. It is a very

aggressive neoplasm. At the time of diagnosis, 80% will already have metastasised. Clinical Features The presenting symptoms of pancreatic carcinoma are generally non-specific. Cancer that originates from the head of the pancreas can produce obstructive jaundice, epigastric pain and weight loss. The presence of pain is a late symptom and back pain typically signifies advanced disease. Jaundice is usually progressive and associated with pruritus, which can often be severe. Dyspepsia and early satiety may be present due to delayed gastric emptying (gastroparesis). Vomiting may be present if the tumour has invaded or compressed the second portion of the duodenum, creating a partial or complete intestinal obstruction.

Diseases of the Pancreas

Treatment Continued alcohol abuse hastens the development of pancreatic dysfunction and continued alcohol abuse, along with smoking, increases mortality. Moreover, smoking is one of the risk factors for the progression to pancreatic cancer. There are good reasons, therefore, to encourage patients to stop drinking and smoking.

The patient is usually jaundiced and may be anaemic or cachectic. There may be an epigastric mass or an irregular, enlarged liver because of metastases. There may be a palpable gallbladder secondary to common bile duct obstruction. Other findings include left supraclavicular lymphadenopathy (Virchow’s node) and superficial thrombophlebitis (Trousseau’s sign). Investigations The lesion may have a variable appearance on ultrasonography; it may be hypoechoic, isoechoic, or hyperechoic as compared to normal pancreas. Pancreatic ductal dilatation and biliary ductal dilatation are easily demonstrated in patients with a tumour in the head of pancreas. Lymphadenopathy, relation of the tumour to peripancreatic vessels, and the tumour margins are demonstrated less reliably with sonography. CECT scan of abdomen using a pancreas protocol is the most useful and widely used imaging modality especially when some intervention is planned. Features on CT scan include: alterations in morphology of the gland with abnormalities of CT attenuation values, obliteration of peripancreatic fat, loss of sharp margins with surrounding structures, involvement of adjacent vessels and regional lymph nodes, pancreatic ductal dilatation, pancreatic atrophy, and obstruction of the common bile duct. Tumours less than 1 cm are readily visualised with EUS. ERCP has a sensitivity of 95% and a specificity of 85% for pancreatic malignancy. MRCP is a non-invasive alternative to ERCP. Serum carbohydrate antigen (CA) 19-9 has an overall sensitivity of approximately 80% and specificity of 90%. Treatment Surgery is the mainstay of treatment, but it is of value only if the primary tumour is less than 3 cm, free of major blood vessels and if there is no metastatic spread (Tables 7 and 8). Suitable patients undergo Whipple’s procedure, which involves excision of the head of the pancreas, the distal common bile duct, the gall bladder, the duodenum and distal stomach, followed by anastomosis of the pancreatic duct, the common hepatic duct, and the distal stomach to a loop of jejunum. Perioperative mortality is less than 5% in experienced hands. Modified Whipple’s procedure involves preservation of the distal stomach and pylorus, which may have long-term nutritional benefits. Distal pancreatectomy may be suitable for carcinoma of the body or tail.

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Table 7: American Joint Committee for Cancer (AJCC) Staging of Carcinoma of the Pancreas (2002) T stage TX – Primary tumour cannot be assessed T0 – No evidence of tumour Tis – Carcinoma in situ T1 – Tumour limited to the pancreas,2 cm or less in greatest dimension T2 – Tumour limited to the pancreas, more than 2 cm in greatest dimension T3 – Tumour extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4 – Tumour involves the coeliac axis or the superior mesenteric artery (unresectable primary tumour) N Stage NX – Regional lymph nodes not assessed N0 – No regional lymph node metastasis N1 – Regional lymph nodes involved M stage MX – Distant metastases cannot be assessed M0 – No distant metastases M1 – Distant metastases present

Palliative Treatment Jaundice is palliated by stenting the biliary stricture. Both plastic and self-expandable metal stents (SEMS) have been used for palliation of jaundice. When endoscopic biliary drainage is unsuccessful or contraindicated, percutaneous transhepatic biliary drainage is done. Pain requires graded use of analgesic agents. Coeliac plexus block (percutaneous or EUS guided) and splanchnectomy are useful interventions for palliation of pain. Gemcitabine is the standard chemotherapeutic agent used for pancreatic cancer. Other drugs are capecitabine, 5-fluorouracil, cisplatin and oxaliplatin. RECOMMENDED READINGS 1.

Balakrishnan V, Unnikrishnan AG, Thomas V, et al. Chronic pancreatitis. A prospective nationwide study of 1,086 subjects from India. J Pancreas (Online) 2008; 9 (5): 593-600.

2.

Banks PA, Freeman ML. Practice Parameters Committee of the American College of Gastroenterology. Practice Guidelines in Acute Pancreatitis. Am J Gastroenterol 2006; 101(10): 2379-2400.

3.

Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008; 371(9607): 143-52.

4.

Whitcomb DC, Beger HG. Definitions of pancreatic diseases and their complications. In: Beger H, et al editors. The Pancreas: An integrated Textbook of Basic Science, Medicine, and Surgery. Blackwell; 2008: pp 1-6.

5.

Working Party of the British Society of Gastroenterology; Association of Surgeons of Great Britain and Ireland; Pancreatic Society of Great Britain and Ireland; Association of Upper GI Surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut 2005;54 (suppl 3): iii1-9.

Table 8: TNM Staging of Pancreatic Cancer Stage Classification 0 1A 1B IIA IIB III IV

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Clinical classification

5-year survival rate

Tis, N0, M0 Resectable (7.5%) 15.2% T1, N0, M0 T2, N0, M0 T3, N0, M0 T1-3, N1, M0 Locally advanced (29.3%) 6.3% T4, any N, M0 Any T, any N, M1 Metastatic (47.2%) 1.6%

13.10

Functional Gastrointestinal Disorders

The term ‘functional gastrointestinal disorders’ is used for a group of conditions with clinical manifestations in the absence of obvious organic disease in gastrointestinal (GI) tract. These disorders constitute the most common gastrointestinal cause for consultation. The characterisation and classification of these disorders is based on predominant symptoms (which may suggest region of origin in the GI tract), because no single aetiological factor or investigative pattern has been identified in any subgroup. CLASSIFICATION For the sake of convenience, the disorders have been broadly classified as due to upper or lower GI disturbance. Although each subgroup has distinct features, many subjects have overlapping symptoms, suggesting that the disorder may be more diffuse than implied by the predominant symptom. Thus, patients with the irritable bowel syndrome (IBS), a predominantly lower GI disturbance, often have dyspeptic symptoms in addition. Also, in IBS, what is considered abnormal bowel frequency by the patient may overlap what is considered normal by a segment of the general population, suggesting visceral hypersensitivity in the patient. The Rome III criteria for functional bowel disorders (Table 1) are an attempt to improve on several previous classifications. FUNCTIONAL DYSPEPSIA (Synonyms: Idiopathic, essential or non-ulcer dyspepsia) Functional dyspepsia is a chronic or recurrent heterogeneous symptom complex that has its origin in the upper gastrointestinal tract, is localised to the upper abdomen, and is generally mealrelated. The Rome III criteria identifies two primary symptom groups, namely, epigastric pain or burning (the epigastric pain syndrome) and meal-related early satiety or postprandial fullness (the postprandial distress syndrome). The diagnosis of functional dyspepsia ideally requires that organic conditions with similar symptoms (peptic ulcer disease, gastro-oesophageal reflux disease, giardiasis, pancreatic and biliary diseases) be excluded first. In clinical practice, however, a normal upper gastrointestinal endoscopy is generally taken as adequate evidence, unless the suspicion of pancreatic or biliary disorder is strong enough to merit investigation. The likelihood of endoscopy detecting an organic lesion is low if it is undertaken as a regular practice. Aetiopathogenesis Recent data implicates phenotypic changes in acid secretion; alterations of fundic accommodation, antro-duodenal motility and gastric emptying; gastric hypersensitivity triggered by chemo- or mechanoreceptors; and hormonal disturbances; as the possible causes of dyspepsia, but each of these is present in only a proportion of the patients. A possible role of alphaadrenoceptor gene polymorphism has also been suggested.

Philip Abraham

Table 1: Rome III Diagnostic Criteria for Functional Bowel Disorders Functional Dyspepsia At least 3 months, with onset at least 6 months previously, of one or more of the following: Bothersome postprandial fullness Early satiation Epigastric pain Epigastric burning No evidence of structural disease (including an upper GI endoscopy) that is likely to explain the symptoms This is subclassified into: Epigastric pain syndrome At least 3 months, with onset at least 6 months previously, with all of the following: Pain and burning that is: Intermittent Localised to the epigastrium of at least moderate severity, at least once per week, And not: Generalised or localised to other abdominal or chest regions relieved by defaecation or flatulence Fulfilling criteria for gall bladder or sphincter of Oddi disorders Postprandial distress syndrome At least 3 months, with onset at least 6 months previously, of one or more of the following: Bothersome postprandial fullness occurring after ordinary-sized meals at least several times a week or Early satiation, which prevents finishing a regular meal and occurs at least several times a week Cyclic vomiting syndrome At least 3 months, with onset at least 6 months previously, of: Stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week) Three or more discrete episodes in the prior year Absence of nausea and vomiting between episodes Supportive criteria: History of migraine headaches or a family history of migraine headaches Chronic idiopathic nausea At least 3 months, with onset at least 6 months previously, of: Bothersome nausea, occurring at least several times per week in the last 3 months Not usually associated with vomiting Absence of abnormalities at upper endoscopy or metabolic disease that explains the nausea Irritable Bowel Syndrome At least 3 months, with onset at least 6 months previously, of recurrent abdominal pain or discomfort* associated with two or more of the following: Improvement with defaecation; and/or Onset associated with a change in frequency of stool; and/or Onset associated with a change in form (appearance) of stool * Discomfort means an uncomfortable sensation not described as pain.

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It is generally agreed that Helicobacter pylori has a poor or irrelevant role in the pathophysiology. Gastric acid secretion is normal in most patients although acid-related symptoms may be present. Non-painful dyspeptic symptoms are suggestive of motor disorder. Post-prandial fullness and vomiting have been associated with delayed gastric emptying of solids, and early satiety to postcibal impaired accommodation of the gastric fundus. Many patients with this condition implicate particular articles of diet as cause of symptoms. Higher anxiety and neuroticism scores have also been described.

Idiopathic gastroparesis

Investigations Investigations are mandatory in the following situations (‘alarm’ or ‘red flag’ features): recent onset, late age at onset of symptoms (>40 years), weight loss, no response to adequate standard therapy, and any abnormality on physical examination.

The diagnosis rests on documenting delayed gastric emptying by radionuclide scan or other appropriate techniques. More frequent small meals, liquids or soft solids, and prokinetic drugs are the mainstay of therapy.

The utility of routine laboratory testing is debated. Haematocrit, stool examination (including test for occult blood in the elderly), and liver and renal profiles are used as screening tests. Diagnostic oesophago-gastroduodenoscopy with or without biopsy-based testing for H. pylori should be considered with the slightest suspicion of organic disease. The most common finding is antral gastritis; its relevance in the absence of H. pylori infection is not clear. Ultrasound screening for biliary and pancreatic diseases is done when suspicion exists. Specialised tests (antro-duodenal manometry, electrogastrography, radionuclide evaluation of gastric emptying) are confined to the research setting. Management Simple dietary precautions may go a long way in alleviating symptoms. Regular meal timings; having unhurried meals; not habitually sipping fluids during meals; avoidance of excessively spicy and fatty food; restricting intake of caffeinated and aerated beverages may all be helpful to the patients.‘Avoid what you cannot tolerate’ is a better advice than a blanket ban on food items; this also leaves the patient feeling in charge of himself. Tobacco in any form, and immoderate alcohol consumption, should be avoided. The most common medication used is antacid; since most of the commercial preparations are antacid-antiflatulent combinations, they may alleviate a wide range of symptoms. When this is not effective (its long-term use is also not desirable), a histamine H2-receptor antagonist (ranitidine, famotidine) can be substituted in patients with acid-peptic symptoms. More powerful acid suppressants (proton pump inhibitors) are seldom required. In patients with symptoms of gastroduodenal dysmotility (bloating, early satiety) a prokinetic agent (metoclopramide, domperidone, mosapride, itopride, levosulpiride) may be beneficial; cisapride may be preferred when the patient has additional lower gastrointestinal symptoms (constipation, incomplete evacuation); its use is, however, restricted by fears of cardiotoxicity. There is no evidence to show that treatment for H. pylori is indicated.

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Other distinct functional upper gastrointestinal conditions with features suggesting dysmotility have been described, but these are uncommon in clinical practice. These include:

As the term implies, these patients have defective gastric contraction and emptying. While this may be a consequence of systemic diseases, e.g. diabetes mellitus, acute viral infections, or of drug therapy (beta-adrenergic agonists, dopamine D2 agonists such as bromocriptine, levodopa and opioids), in some cases no cause is identified. These patients may present with dyspepsia-like symptoms (early satiety, bloat, nausea and occasional vomiting) acutely over months or years.

Aerophagia and belching syndrome Aerophagia is the semivoluntary swallowing of abnormal amounts of air while eating or drinking. When this results in increased intragastric air volume, belching occurs. Patients with the syndrome voluntarily aspirate air into the oesophagus, and then expel it loudly. Frequent swallowing is an accompanying feature. Some of them push the air further into the stomach and present with bloat and discomfort. Anxiety may aggravate the condition, which takes on the nature of a compulsive tic. Gastric hypomotility has been documented in such subjects, but whether this is a cause or effect is not known. Management is empirical, and should include a search for psychological factors. Cyclic vomiting syndrome This condition is characterised by stereotypic episodes of vomiting, with absence of nausea and vomiting in between episodes. Sometimes it is confused with other functional gastrointestinal syndromes because abdominal pain is not uncommon when episodes occur. The causes remain unclear, but some investigators have considered it to represent a migraine variant. Antral hypomotility and delayed emptying have been recorded in some patients. Nutritional compromise may occur in the long term. Available evidence suggests poor response to prokinetics. Anti-depressants work in some individuals, suggesting a central origin for the symptoms. Rumination syndrome Rumination is a process by which food from the stomach is brought back into the mouth; some of the food is chewed and re-swallowed, and the process is repeated. Contraction of abdominal muscles and simultaneous relaxation of the lower oesophageal sphincter seem to occur as an effortless, semivoluntary action. A psychological element seems to be underlying. Apart from erosion of tooth enamel and bad breath (halitosis), this condition may also lead to nutritional deficiencies because patients tend to be withdrawn. Psychological support and physical training to overcome the muscle activity may be helpful. IRRITABLE BOWEL SYNDROME (IBS) The terms spastic colon, mucous colitis, irritable colon, among others were used to describe this condition earlier. While each of them reflected the predominant symptom or the

Patients with IBS report with abdominal pain and altered bowel habits. The earlier criteria laid down by Manning et al for its diagnosis have been supplemented by the recent Rome III symptom criteria (Table 1). These identified pain or discomfort as an overwhelming symptom and introduced a time factor for diagnosis. It is accepted now that a positive clinical diagnosis of IBS can be made and the condition need not be a diagnosis established by absence of evidence for structural disease. The presence of certain ‘alarm’ features (Table 2), however, requires that the patient be investigated. Table 2: Features Against Diagnosis of IBS History Late age (>40 years) at onset of symptoms Large-volume diarrhoea or steatorrhoea Frequent nocturnal symptoms Blood in stools (except from anal lesions, e.g. haemorrhoids, fissure) Fever, dehydration Significant weight loss Progression of symptoms or development of new symptoms Physical examination Abdominal mass Signs of malabsorption, bowel obstruction, thyroid dysfunction Extraintestinal manifestations (arthritis, skin lesions) Laboratory findings Occult blood in stools

Epidemiology About 15% of the general population have symptoms that justify a diagnosis of IBS; however, only about 20% of these will seek medical opinion, prompting a suggestion of hypersensitivity in them. IBS is the most common single reason for referral to gastroenterologists. In Western series, female patients predominate; in South Asia and in India, most reporting patients are young men. The reason for this difference is not known. Clinical Features Pain (or discomfort) is an important feature of IBS, and is localised to the periumbilical region or lower abdomen, especially the left side. Altered bowel habit is the other symptom. While Indian patients generally do not have the alternating diarrhoea and constipation pattern described from the West, whether diarrhoea or constipation predominates varies regionally within the country. Abdominal pain and other accompanying features like gas bloat are usually relieved temporarily by defaecation. In patients with constipation, sense of incomplete evacuation is a particularly distressing symptom; since these patients actually have increased attempts at defaecation, they may wrongly be labelled as having diarrhoea and are treated accordingly, with worsening of symptoms. Some of them attempt digital evacuation of the anal canal; these patients often have a profusion of mucous, and may develop ulcers in the anal canal or lower rectum (solitary rectal ulcer syndrome). Many patients with straining at stools as their only complaint may actually have an evacuation disorder.

Stool consistency may vary from small-quantity semisolid or liquid with mucous in those with diarrhoea, to hard, pellet-like with mucous in constipated subjects. Blood in stools may take the form of streaks or fresh drops after defaecation; the former are due usually to anal fissures and the latter to haemorrhoids, two conditions these patients are predisposed to. Though the predominant symptoms arise from the colon, up to one-third of patients have accompanying upper gastrointestinal symptoms like dyspepsia, heartburn and bloat. Extraintestinal symptoms like dysmenorrhoea, dyspareunia, urinary frequency and headache are also common in female patients. Abnormal psychological features have been reported in over 70% of patients; stressful life events are also reported with increased frequency. However, a cause and effect relationship is not certain.

Functional Gastrointestinal Disorders

understanding of the condition at that time, they all reflect the recognition that the symptoms arise primarily in the colon.

Pathophysiology The pathophysiology of IBS is considered to be multifactorial, generated by interplay between genetic, psychosocial and environmental factors. These produce abnormalities in central nervous system processing as well as in the periphery, where they generate abnormal motility and possibly abnormal secretory activity. No consistent anatomic, physiological or microbiological abnormality has, however, been demonstrated; it is unlikely there is a single unifying explanation. Alterations in bowel motility and transit, as a consequence of abnormal myoelectric rhythm, are the most common features identified. In a subgroup of patients the onset of symptoms follows an episode of infective diarrhoea (post-infective IBS). These and other patients with documented bacterial overgrowth may benefit from short courses of antibacterial treatment. This response to drugs, including a nitroimidazole, has often led to a wrong label of ‘chronic amoebiasis’, especially when this is associated with incidental stool detection of amoebae. As stated earlier, a proportion of individuals from the general population have symptoms overlapping those of IBS, but do not consult a physician. Whether this represents a noncomplainant group, or suggests that visceral hypersensitivity plays a role in distinguishing ‘patient’ from ‘normal’, is an open question. Investigations The diagnosis is generally based on history with normal physical examination (at most, tenderness in the lower abdomen, especially on the left side). Finding anal fissures or haemorrhoids on proctoscopic examination confirms the source of local pain and bleeding. Twenty four hours stool weight is recorded to rule out causes of large-volume (small intestinal or pancreatic) diarrhoea; stool weight in normal Indian subjects and those with IBS is less than 350 g/24 hours. Routine stool examination is done for amoebae and giardia. Sigmoidoscopy or colonoscopy is done when features against the diagnosis of IBS exist (Table 2). Recent Western studies suggest that routine investigation of all patients with diarrhoea predominance may identify a small number with unsuspected coeliac disease, bacterial overgrowth syndrome, or inflammatory bowel disease.

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Management

Table 3: Drugs with Potential for Use in Treatment of IBS

The most important component of management is reassurance and psychological support. Cancer phobia is often the reason for medical consultation, and some investigations may become necessary if only to allay this fear. Despite the lasting discomfort and morbidity, patients should be assured that no complications arise out of IBS. Tranquilisers or anxiolytics may be required in the highly apprehensive patients (Table 3). Non-pharmacological relaxation modalities like yoga and biofeedback may also help.

Predominantly centrally acting drugs Selective serotonin-reuptake inhibitors (SSRIs) Centrally and peripherally acting drugs Neurokinin-receptor antagonists Serotonin-receptor (mainly 5-HT3 and 5-HT4) modulators: alosetron, tegaserod, prucalopride Drugs with opioid (mu, kappa, delta) action: diphenoxylate, loperamide Neurotrophins Corticotrophin-releasing factor (CRF) antagonists Somatostatin analogues Predominantly peripherally acting drugs Antibiotics (rifaximin) and probiotics Selective chloride-channel activators: lubiprostone Cholecystokinin (CCK) antagonists Peripheral receptor modulators: guanylate cyclase

Dietary advice should include restriction on items known to aggravate symptoms. Thus, milk and spicy food may need to be restricted in those with diarrhoea; milk, legumes and cabbage in those with gas bloat. Patients often report relief by eliminating meat from the diet. Obviously, advice will have to be individualised. High-fibre diets are most effective in patients with constipation; when adequate fibre is already being consumed in the diet with no relief (as often happens in Indian patients), fibre supplementation may be tried. Commercially available isaphgol husk preparations can be taken with meals; usually 1 to 2 teaspoons of the refined preparations are given with breakfast and dinner, to ensure an additional 15 to 20 g fibre/day. These hydrophilic agents bind water and so prevent stool dehydration and add bulk. They may also help in patients with diarrhoea. One side-effect of fibre supplementation that is particularly distressing to patients with IBS is bloat. Relief can be obtained by combining this with preparations of simethicone or methylpolysiloxane. An alternative is the fibre substitute calcium polycarbophil. Drugs that have the potential for use in the treatment of IBS are listed in Table 3. Tegaserod, a specific serotonin (5-HT4) agonist, can improve symptoms in patients with IBS and constipation. Lactulose, lactitol and oral solutions containing polyethylene glycol (PEG) have been associated with improvement in stool frequency and consistency. Bowel retraining may improve bowel regularity. Patients with diarrhoea may benefit from a morning dose, or if necessary thrice-daily doses, of the anti-diarrhoeal agent loperamide; milder symptoms may be controlled with racecadotril. Abdominal pain may require anti-spasmodics (e.g. mebeverine, dicyclomine).

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FUNCTIONAL ABDOMINAL PAIN SYNDROME Many of these patients are young women with other features to suggest psychological problems, including somatisation. Where suspicion is strong, investigation for the rare metabolic cause, e.g. porphyria, or poisoning (lead) should be done. The more common metabolic causes of abdominal pain (diabetes mellitus, uraemia) usually have other characteristic features present. The diagnosis of functional abdominal pain should be entertained only after organic causes are eliminated with reasonable certainty. Management includes reassurance, psychologic support measures, anxiolytics if necessary, and spasmolytics, antacids, analgesics or other similar drugs depending on the type of pain described by the patient. RECOMMENDED READINGS 1.

Gaman A, Bucur MC, Kuo B. Therapeutic advances in functional gastrointestinal disease: irritable bowel syndrome. Therap Adv Gastroenterol 2009; 2: 169-81.

2.

Ghoshal UC, Abraham P, Bhatt C, Choudhuri G, Bhatia SJ, Shenoy KT, et al. Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol 2008; 27: 22-8.

3.

Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006; 130: 1480-91.

4.

Talley NJ, Vakil N. Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005; 100: 2324-37.

13.11 INTRODUCTION About 20% of patients with tuberculosis (TB) have extrapulmonary TB and 7% to 10% of them have abdominal TB. While abdominal TB continues to be a common problem in the developing countries including India; increasing population migration, epidemic of acquired immunodeficiency syndrome (AIDS) and use of more potent chemotherapeutic agents led to resurgence of this disease in regions where TB had previously been largely controlled. Reliable epidemiologic data on abdominal TB from India is lacking. Of all hospital admissions, nearly 0.8% is reported to be due to intestinal TB. Three per cent to twenty per cent of all intestinal obstruction and 5% to 7% of intestinal perforation are due to intestinal TB in India. In the abdomen, TB infection can involve many organs including gastrointestinal (GI) tract, peritoneum and many others (Table 1). In an analysis of 6 reports including 596 patients, Marshall et al reported that 42%, 50% and 8% had peritoneal, GI and lymph node TB, respectively and only a minority had combined peritoneal and GI TB. Table 1: Classification of Abdominal Tuberculosis Gastrointestinal tuberculosis Intestinal (both small and large) Gastroduodenal tuberculosis Oesophageal tuberculosis Peritoneal tuberculosis Acute tuberculosis peritonitis Chronic peritoneal tuberculosis Ascitic form Encysted (loculated) form Dry type Tuberculosis of the solid viscera Hepatobiliary Spleen Pancreas Tuberculosis of the abdominal lymph nodes Tubercular mesenteric lymphadenitis Tubercular retroperitoneal lymphadenitis Genitourinary tuberculosis

INTESTINAL TUBERCULOSIS Site of Involvement While any part of GI tract may be involved by the TB infection, the most common site of involvement is ileocaecum (ileum, ileocaecal valve and caecum). Other common sites of involvement are the colon (where the frequency decreases segmentally from the ascending colon to the rectum), appendix, jejunum, stomach, duodenum and oesophagus.The preferential location of ileo-caecum is because of a number of reasons including: the abundance of lymphoid tissue, relative physiologic stasis, higher electrolyte and water absorption, and

Abdominal Tuberculosis Govind K Makharia minimal digestive activity, permitting greater contact time of the acid-fast bacilli (AFB) with the mucosal surface. Pathogenesis The mycobacterial infection can develop primarily within the intestinal tract or secondary to a focus elsewhere in the body. There are 4 possible ways by which an infection can reach GI tract: direct invasion by the ingested mycobacteria, transport by the way of infected bile, extension from adjacent diseased organs or tissues and spread through mycobacterial bacteraemia. Animal studies have shown that intestinal TB can result from ingestion of food containing tubercle bacilli, especially milk. With widespread pasteurisation of milk, milk is not a significant cause of TB. Secondary infection of the GI tract may arise from contamination of enteric chyme by bacteria from another site, usually the lungs, through swallowing of infected sputum. Intestinal involvement is probably related to the number and virulence of the ingested organisms and the nutritional status of the patient. Invasion of the intestine does not seem to occur when there is TB involvement of the peritoneum. Generalised tuberculous peritonitis is usually not associated with intestinal TB other than as a consequence of the extension of the infectious process transmurally or from an infected, ulcerating lymph node to the serosal surface. Pathology Traditionally, intestinal TB is described as of three types— ulcerative, hypertrophic and ulcero-hypertrophic.The ulcerative form of the disease is mainly due to deprivation of blood supply, because of endarteritis. In GI TB, ulcerogenesis is relatively slow, and an inflammatory wall develops ahead of the advancing ulcer. Thus, most perforations are confined. There is an accumulation of collagenous tissue during the process of ulcer healing that subsequently contracts and cause circumferential stricture of the intestinal lumen. The diseased segment is moderately indurated and the serosa is studded with nodules. The mesenteric lymph nodes are usually enlarged. The mucosal surface may show single or multiple ulcers, and skip areas may be present with normal appearing mucosa between involved segments. The ulcers are characteristically transverse and circumferential, but may be round, stellate, or longitudinal. The ulcers are deep, these however, generally do not penetrate the muscularis propria. In the acute phase, there may be a functional stenosis of the involved segment because of the spasm. In the more chronic phase, circumferential strictures may develop. The hypertrophic form of the disease, there is a marked inflammatory fibroblastic reaction in the submucosa and subserosa of the involved segment mostly ileocaecum. Caseating granulomas (Figure 1) are the histologic hallmark of TB. The granulomas in intestinal TB are usually larger (>200 μm), multiple in number (>5/section) and confluent (Figure 1). Careful scrutiny should be made of acid-fast stained tissue for

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tubercle bacilli. The ulcers usually do not penetrate beyond the muscularis and are lined by non-specific inflammatory granulation tissue. It must be emphasised that the histologic features of intestinal TB may be altered and may remain undiagnostic in patients who have received anti-tuberculosis drugs earlier or where tissue specimen is small.

obstruction, (c) fistula formation between the small and large intestine, (d) deconjugation of bile salts secondary to bacterial overgrowth, and (e) decreased bile salt pool because of impaired active absorption in the distal ileum. Bleeding per rectum is seen in 10% to 15% of patients with intestinal TB and occasionally massive bleeding. Almost half of patients have constipation. Constitutional symptoms in the form of fever, malaise, night sweats, anorexia, and weight loss are reported by 40% to 70% of patients with intestinal TB. A few patients may have active TB elsewhere especially lungs. On examination, there are no characteristic signs. Most patients appear sick, poorly nourished and febrile. Doughy consistency of abdomen (due to extensive fibro-adhesive inflammation) is infrequent and non-specific. Abdominal tenderness is frequently present in the right lower quadrant. Palpable mass, which is a conglomerate of adhered bowel loops, lymph nodes and sometimes mesentery, may be observed in 10% to 20% patients.

Figure 1: Photomicrograph showing caseating granuloma, multiple submucosal large (> 200 μm diameter) epitheloid cell granuloma with lymphocytic cuffing. Focally, the granuloma show central necrosis and presence of Langhan’s giant cells (Haematoxylin and Eosin x 40).

Clinical Features The most common age of patients with intestinal TB is between 20 to 40 years it, however, can occur in any age. Intestinal TB may have symptoms arising from the (a) intestinal ulceroconstrictive disease (intestinal colic, abdominal distension, nausea, vomiting, constipation, bleeding manifestations); (b) symptoms due to chronic inflammatory process (fever, weakness, weight loss, night sweats); (c) symptoms due to associated adjacent tissue involvement (ascites, lymph node enlargement or tubo-ovarian symptoms); and (d) coincident pulmonary TB (chronic cough, expectoration, haemoptysis).

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The symptoms of GI TB will depend upon the site(s) of involvement of the GI tract and also the type of lesions it produces. As discussed earlier in the pathogenesis, ileocaecal area is the most common site of involvement in patients with intestinal TB, and most of the lesions are ulcerative or ulceroconstrictive. Abdominal pain is the most common manifestation and occurs because of stricture of the lumen, stretch on the surrounding tissue, mesenteric inflammation and peritoneal involvement. While the pain arising from the intestine is mostly colicy in nature, the pain arising from mesentery or peritoneum is diffuse and dull ache. As disease advances with time, the severity and frequency of pain increases. Therefore, the patient may initially present with occasional episodes of intestinal colic only, which may be disregarded by a physician as an episode of GI infection. As the stricture advances, the patient may develop partial intestinal obstruction (abdominal distension, gurgling in the abdomen, partial or complete cessation of flus, vomiting or movement of ball of wind in the abdomen). Diarrhoea is seen in 20% to 30% of patients and can be because of both small and large intestinal involvement. Malabsorption results from: (a) decreased small intestinal mucosal surface, (b) lymphatic

Complications The complications of intestinal TB are partial or complete intestinal obstruction, lower GI bleeding, intra-abdominal abscess, malnutrition and at occasions intestinal perforation. Intestinal obstruction occurs due to contraction of intestine following healing of circumferential tuberculous ulcers, bowel wall thickening, kinking of the intestine by intra-peritoneal adhesions, retraction of the mesentery and obstruction at the ileocaecal junction (due to changing the angle of entrance of the ileum into the colon of 90° to nearly 180°). Malnutrition occurs because of anorexia, inadequate food intake (because of sitophobia and poverty), and malabsorption. Investigations The haemogram in patients with intestinal TB shows a mild-tomoderately severe normochromic, normocytic anaemia, thrombocytosis and a normal white cell count with relative lymphocytosis. The erythrocyte sedimentation rate is almost always raised. Mantoux test is positive in over 70% of patients but high prevalence of Mantoux positivity in developing countries (≈ 60%) limits its usefulness. False-negative result is often seen in the elderly, malnourished, immunosuppressed, or in patients with disseminated disease. Pulmonary lesions on chest radiograph may be noted in a quarter of subjects; recognition of active pulmonary disease reduces the cost and expedites the diagnosis. Plain radiograph abdomen should be done in those who present with intestinal obstruction and may reveal air-fluid level and dilated bowel loops. One should review the radiograph properly to see other suggestive evidences, such as calcified lymph nodes, calcified granuloma in the spleen, liver and pancreas and enteroliths. The aims of the investigations in patients suspected to have intestinal TB are detection of lesion, site and extent of the lesion, type of lesion, detection of any associated complication, histological diagnosis, microbiological confirmation and detection of TB either active or healed elsewhere, most commonly lungs. Intestinal imaging includes: luminal imaging (endoscopic, barium studies), and imaging of the wall and extra-intestinal extent which is detected by cross sectional imaging, such as CT scan and MRI. Both these techniques may be combined in one, such as CT-enteroclysis or MRenteroclysis.

ulcers become confluent. In patients with TB, barium findings in the advanced stage of fibrosis are more definitive. There is a thickening of the ileocaecal valve with narrowing of the terminal ileum (Fleischner or inverted umbrella sign). In further advanced disease, the characteristic deformity include symmetric, annular stenosis with obstruction, and shortening of the intestine and the colon. The caecum classically becomes conical, shrunken, and pulled up from the iliac fossa due to contraction of the mesocolon. There may be a loss of the normal ileocaecal angle (Figure 3). A localised narrowing opposite the ileocaecal valve with a rounded smooth caecum and a dilated terminal ileum is termed as ‘purse string stenosis’. Spasm of the distal ileum and the ascending colon with contraction of the caecum (Stierlin sign) may be seen in association with shrunken ascending colon. The ileocaecal valve classically becomes incompetent, rigid and fixed with an irregular outline.Tubercular strictures are typically short and multiple separated by unaffected segments. Enteroliths may form proximal to the

Abdominal Tuberculosis

Endoscopic Investigation Since ileocaecal area is involved in the majority of the patients with intestinal TB, colonoscopy with retrograde ileoscopy is the investigation of choice. Colonoscopic examination provides an opportunity to visualise the lesion directly and one can obtain biopsies from the lesions at the same time. The morphological appearance of intestinal TB depends upon the stage of the disease. The lesions may vary from mild lesions, such as loss of vascular pattern, erythema, small ulcerations and superficial ulcerations, to more advanced lesions including deep ulcerations, nodularity and strictures. One should realise that the evolution of intestinal TB takes from months to years. The classical morphological features described in the textbooks are seen in advanced cases. Some of the patients may present in early stages of evolution of the disease, thereby one may not find classical lesions and instead finds minute lesions. The wisdom lies in identifying these minute lesions so that the progression of the disease can be prevented. Common colonoscopic features of intestinal TB include deep ulcers (50% to 80%), nodules (30% to 60%) and strictures (Figure 2). One should take multiple biopsies from the lesion for not only histological examination but also for M. tuberculosis culture, PCR and AFB staining. For small intestinal lesions, newer endoscopic techniques such as single and double balloon enteroscopic examination can be done. Capsule endoscopic examination is generally not done for those patients where obstructive lesion such as intestinal TB is suspected.

Figure 2: Colonoscopic picture showing ulceration of the ileocaecal valve in a patient with intestinal tuberculosis.

Radiological Investigations Although there are many suggestive features on radiological investigations, none however is diagnostic of intestinal TB. The radiological features depend upon the stage of the disease, site of involvement and severity of the disease. In the early stage of mucosal invasion and ulceration, barium findings of ileocaecal TB are non-specific and include spasm and hyper-motility of the intestinal segment, oedema of the ileocaecal valve and mucosal thickening. Tubercular ulcers are circumferential or transverse in orientation. With progression of the disease, the

Figure 3: Barium-meal follow through study showing contracted and pulled up caecum with narrowing of the ileocaecal junction and loss of the normal ileocaecal angle. The terminal ileum appears suspended and hanging from the caecum.

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strictures and may vary from a single large lamellated calculus to multiple small stones visible on the radiograph. CECT or CT-enteroclysis/MR-enteroclysis is essential for the evaluation of extra-luminal, peritoneal, nodal and visceral involvement. CT is more accurate than ultrasonography in detecting most of these manifestations including peritoneal and intestinal involvement. CECT/CT enteroclysis may show intestinal wall thickening (unifocal or multifocal), stricture with proximal dilation of the intestine, and regional lymphadenopathy. The pattern of lymphadenopathy in TB may vary widely, including increased number of normal sized nodes, mildly enlarged nodes to large confluent nodal masses. The involved lymph nodes typically show hypodense centre and peripheral enhancement in 40% to 70% cases; which reflects central necrosis (Figure 4).

2. Histological demonstration of typical ATB. 3. Histological evidence of necrotising granuloma. 4. Definite response to ATT in a patient with probable TB based on clinical, endoscopic, histological features (Logan’s modification). Differential Diagnosis Crohn’s disease (CD) and intestinal TB are granulomatous diseases of the intestine. The clinical, morphological and histological features of intestinal TB and Crohn’s disease are so similar that it becomes difficult to differentiate between these two entities. In geographical regions like Asia where both Crohn’s disease and intestinal TB are prevalent, differential diagnosis between the two may be challenging. In Asia, intestinal TB is common, but CD is also being increasingly reported from all over Asia. Natural history of CD is quite different from that of intestinal TB. While intestinal TB gets cured by appropriate ATT, CD has a remitting/relapsing or persistent course and usually stays lifelong. Because of similarity in the clinical presentation and morphology of these two entities, at times such patients are treated empirically with anti-tuberculous drugs. The clinical, endoscopic and histological features which can differentiate these two diseases are summarised in Table 2. Table 2: Clinical, Endoscopic and Histological Differentiation between Intestinal Tuberculosis and Crohn’s Disease Variables

Figure 4: A contrast enhanced computerised tomography showing enlarged mesenteric lymph nodes with central hypodensity and thickening of the caecum (arrow) in a patient with abdominal tuberculosis.

Microbiological Tests Isolation of M.tuberculosis using culture is the most specific method for diagnosis of active TB. It can detect 10-100 bacilli per mL of the sample. The most commonly used solid media is the LowensteinJensen medium, on which it usually takes 4 to 6 weeks to grow. Radiometric (BACTEC) method and MGIT culture system can grow M. tuberculosis in shorter period of time, however, these are expensive. PCR using M. tuberculosis specific primer shows a positivity varying from 20% to 65%. Identification of acid-fast bacilli (AFB) on microscopy is presumptive for TB infection as saprophytic mycobacteria may give false-positive result. Serological Tests Although enzyme-linked immunosorbent assay (ELISA) using semi-purified antigens has sensitivity of 80% in abdominal TB; however, it fails to distinguish active from the past infection and it has high false positive rate. At present, there is no role of commercially available ELISA in making diagnosis of TB. One should not base one’s decision of starting anti-tuberculous treatment (ATT) on ELISA report unless there are enough clinical, endoscopic and histological evidences.

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Diagnostic Criteria for Tuberculosis At least one of the following criteria must be met: 1. Culture of tissue (colonic biopsy, lymph nodes) resulting in growth of M. tuberculosis.

Intestinal Tuberculosis

Crohn’s Disease

Symptoms Chronic diarrhoea Blood in the stools Abdominal pain Constipation Partial intestinal obstruction Peri-anal disease Fever Loss of appetite Weight loss Extra-intestinal manifestations

20 to 40% 10 to 20% 90% 50% 50 to 60% 5% 40 to 70% 40 to 80% 60 to 90% 10%

60 to 80% 50 to 70% 60 to 80% 10 to 30% 20 to 30% 30 to 80% 30% 40 to 60% 50 to 60% 20 to 50%

Involvement of the Intestine Anal canal Rectum Sigmoid colon Descending colon Ascending colon Ileocaecal area Ileum

90/min Present

Normal

>30%

ESR

90% Ileal involvement 1.5, patients with platelet counts less than 80,000/mm3 and inability to tackle complication as a result of the procedure. Liver biopsy carries a small but definite risk of mortality and complications, with rates of approximately 0.01% and 0.1 to 0.3%, respectively. The common complications include pain arising from pleura, peritoneum or diaphragm, intra-peritoneal haemorrhage, intra-hepatic haematoma, haemobilia, bile peritonitis, infection, etc. These complications can be managed using intravenous analgesics, blood transfusions, and radiological or endoscopic interventions. Surgical intervention is rarely required. Transjugular liver biopsy is used in patients with abnormal coagulation, massive ascites or small liver, or those who need measurement of hepatic venous pressures. It does not carry the risk of bleeding complications, but is costly and needs a trained operator. IMAGING STUDIES These are discussed in chapter on “Hepatobiliary Disorders— Imaging”. HAEMODYNAMIC STUDIES A balloon catheter is introduced into the hepatic vein via the femoral or internal jugular veins. Pressure measurements are taken in the hepatic veins by inflating [wedged hepatic venous pressure (WHVP)] and deflating [free hepatic venous pressure (FHVP)] the balloon catheter. The hepatic venous pressure gradient (HVPG) represents the difference between the WHVP and the FHVP, and is a measure of portal hypertension. 853

The normal value for HVPG is less than 5 mm Hg. The HVPG value more than 5 mm Hg signifies “portal hypertension” and more than 10 mm Hg signifies “clinically significant portal hypertension”. Increase in value above 10 mm Hg is required for the development of oesophageal varices and above 12 mm Hg for the appearance of other complications, such as variceal bleeding. Decline of HVPG below 12 mm Hg or through more than 20% of the baseline level is associated with prevention of variceal bleeding, and at times with

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a reduction in size and possibly disappearance of varices. The achievement of these haemodynamic targets also lowers the risk of developing ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome and death. RECOMMENDED READING 1.

Boyer TD, Wright TL, Manns MP, editors: Zakim and Boyer’s Hepatology: A Textbook of Liver Disease; 5th Ed. Philadelphia: Saunders; 2006.

14.4

Hepatobiliary Disorders—Imaging Shrinivas B Desai

Imaging plays a crucial role in the management of hepatobiliary diseases. This topic can be divided into imaging in liver diseases and imaging of the biliary system.

well-defined, non-enhancing and thin walled cystic lesions. On MRI, they are hypointense on T1 WI images and hyperintense on T2 WI images.

IMAGING IN LIVER DISEASES Techniques for studying the liver include plain radiograph, ultrasonography (USG), computed tomography (CT), magnetic resonance imaging (MRI), angiography and radionuclide scanning.

Haemangioma It is the most common benign tumour of the liver. On sonography, these appear as well-defined homogenously hyperechoic lesions (Figure 1). On non-enhanced CT (NECT) (Figure 2), they are seen as hypodense well defined mass lesions. Following contrast administration, there is filling in of the contrast from the periphery. On MRI, haemangiomas show a characteristic very long T2 relaxation time and therefore appear hyperintense on T2 WI images. On labelled RC SPECT scans, they appear as filling defects on early scans with prolonged and persistent radiotracer uptake on delayed scans.

Abdominal Radiograph The liver casts an appreciable soft tissue density shadow, with its borders outlined against fat and gas in adjacent organs. Hepatomegaly can be made out on plain radiographs of the abdomen by noting the displacement of gas in the adjacent gasfilled organs. Riedel’s lobe, a normal variant seen commonly in women, is an inferior tongue-like projection of the right lobe. Focal hepatic lesions may distort one or more hepatic margins or may be seen as diffuse hepatomegaly on the plain radiograph. Calcification within the liver may be localised or diffuse. Hydatid disease is the commonest cause. Other causes include old abscess or granuloma (single or multiple foci), hepatocellular carcinoma (stippled or sunburst type) and metastasis from mucous secreting adenocarcinoma and medullary carcinoma of the thyroid gland (faint fluffy calcification).

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is a developmental hyperplastic lesion comprising of hepatocytes, Kupffer cells, biliary ducts and components of portal triads. It appears as a well-defined mass

Gas is normally not seen in the liver. It may be seen confined to the parenchyma (e.g. abscess), within the biliary tree (e.g. after bilioenteric anastomosis or endoscopic papillotomy) or within the portal vein radicals (e.g. necrotising enterocolitis). Distribution of air helps in differentiation between air in the biliary tree (centrally located) and that in the portal veins (more peripherally distributed). FOCAL HEPATIC LESIONS Simple Liver Cyst A liver cyst is a fluid-filled space with an epithelial lining. On sonography, liver cysts appear as anechoic, thin-walled lesions with posterior acoustic enhancement. On CT, they appear as

Figure 1: Ultrasound showing a hyperechoic lesion in segment 3 of left lobe of liver. Diagnosis: Haemangioma. Courtesy: Dr Raju Sharma, AIIMS.

Figures 2A to C: Triple phase CT of the abdomen. Arterial phase (A) shows peripheral nodular discontinous enhancement with progressive centripetal extension on venous (B) and delayed (C) phase. Retention of contrast in the lesion is seen on the delayed image (C). Diagnosis: Liver haemangioma. Courtesy: Dr Raju Sharma, AIIMS.

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lesion with a central stellate scar that is isoechoic with the liver parenchyma on USG. The central scar appears hyperechoic with significant vascularity on Doppler imaging. On NECT, these lesions are iso- to hypodense to the liver parenchyma with a hypoattenuating central scar. Being highly vascular, these lesions show marked enhancement on arterial phase of contrast-enhanced CT (CECT) with rapid washout of the contrast, whereas the scar shows persistent enhancement. On T1 WI images, FNH appears iso- to slightly hypointense and turns iso- to slightly hyperintense on T2 WI images. The central scar is typically hypointense on T1 and hyperintense on T2 WI images. On administration of gadolinium contrast agents, the enhancement pattern is similar to that seen on CECT. On sulphur colloid scan, 50% of these lesions take up sulphur similar to adjacent normal liver and 10% appear as hot spots. Hepatocellular Adenoma It is a benign neoplasm that contains hepatocytes with dilated sinusoids but lacks bile duct components. The lesions are very heterogeneous on imaging due to the presence of fat, old or fresh blood and necrosis. Majority of adenomas are hyperintense to surrounding liver parenchyma on T1 WI images, and iso- to hyperintense on T2 WI images. They show marked contrast enhancement and are seen as cold spots on sulphur colloid scans.

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Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is a common malignant tumour. It can be solitary, multifocal or a diffusely infiltrating tumour. The sonographic features of HCC are very variable. It can be hypoechoic, echogenic or complex. In smaller tumours, there is seen a hypoechoic halo corresponding to fibrous capsule. Portal vein thrombosis is a frequent feature. The CT appearance is also variable. Most HCC are hypodense to the liver parenchyma on NECT, show enhancement on arterial phase and become isoto hypodense on portal venous phase. As they are vascular tumours supplied by the hepatic artery, hypertrophy of the hepatic artery may be noted. Calcification is seen in 5% to 10% of HCC. Portal and hepatic vein thrombosis and arterioportal shunting may also be seen. On MRI, they are seen to be iso-, hypo- or hyperintense to the liver parenchyma on T1 WI images, and usually hyperintense on T2 WI images. They are heterogeneous with intratumoural septations. Fibrolamellar HCC is a histological subtype that shows no gender predilection and occurs in a younger age group. It arises commonly in noncirrhotic livers. It is a vascular mass with a central scar, which is often calcified. On MRI, it is hypointense on T1 and hyperintense on T2 WI images, whereas the central scar remains hypointense on both sequences and shows no contrast enhancement. Metastatic Tumours They are usually multiple and hypoechoic on USG. Hyperechoic lesions are seen with GIT and urogenital tumours. Occasionally, metastatic disease may be seen as target lesions.They are typically hypodense to the liver parenchyma on NECT and show peripheral rim enhancement on arterial phase in CECT (Figure 3). Hypervascular metastases may become isodense to liver on portal venous phase and may be visualised on arterial phase as hyperdense lesions. Therefore, it is necessary to do dual phase imaging of the liver when looking for metastatic disease. On MRI, they are usually hypointense on T1 and hyperintense on T2 WI images and show an enhancement pattern similar to CT.

Figures 3A to D: Triple phase CT of the abdomen. Non-contrast CT (A) shows no lesion. Arterial phase (B) shows multiple hypodense lesions with thick rim enhancement. Portal venous phase (C) and delayed phase (D) shows washout from these lesions. Diagnosis: Liver metastases. Courtesy: Dr Raju Sharma, AIIMS.

Liver Abscess Liver abscesses may be pyogenic, amoebic (Figure 4) or fungal in nature. They are seen as hypoechoic lesions. As liquefaction sets in, the abscesses become more echo poor. Fungal abscesses show a hyperechoic central punctum, which represents an artery plugged by the fungus. On CT and MRI, they are seen as necrotic lesions with thick enhancing capsule.

Figure 4: CT scan shows a hypodense lesion in segment IV of liver with thick peripheral enhancement and oedema in adjacent liver. Diagnosis: Amoebic liver abscess. Courtesy: Dr Raju Sharma, AIIMS.

Hydatid Disease Liver presents as a hypodense mass with multiple daughter cysts (water lily sign) (Figures 5 to 7). Hydatid cysts can rupture into the peritoneal cavity, biliary tree or pleural cavity with resultant pleural effusion. Calcification can be noted in longstanding hydatid cysts.

Hepatobiliary Disorders—Imaging

deposition show signal drop-out. In focal fatty deposition, focal deposits of fat stand out against the background of normal liver parenchyma; the reverse occurs in focal fatty sparing. None of above the imaging methods can differentiate simple fatty liver from those with steatohepatitis and fibrosis. Ultrasound elastography (Fibroscan) is a new non-invasive method for assessment for hepatic fibrosis. It uses a modified

Figure 5: Ultrasound shows a multiloculated mass with daughter cysts in the periphery. Diagnosis: Hydatid cyst. Courtesy: Dr Raju Sharma, AIIMS.

Figure 8: CECT scan shows liver is markedly hypodense as compared to the spleen suggestive of diffuse fatty change. Courtesy: Dr Raju Sharma, AIIMS.

Figure 6: Hydatid cyst: CT scan shows a multilocular lesion in the left lobe of the liver. Density of daughter cysts is less than the centre of the lesion. Courtesy: Dr Raju Sharma, AIIMS.

ultrasound probe to measure the velocity of a shear wave created by a vibratory source. Estimates of stiffness (fibrosis) of the liver by ultrasound correlate with fibrosis stage, and values above 12.5 kPa are indicative of cirrhosis. This technique is used in fatty liver/chronic hepatitis for separating patients with minimal or no fibrosis from those with significant fibrosis or cirrhosis. A linear correlation with increasing fibrosis has not been demonstrated, and 15% discordance between elastography scores and histologic fibrosis has been observed. Cirrhosis Sonographic features of cirrhosis include coarse echogenic echotexture, nodular surface and regenerating nodules surrounded by fibrous septae. The nodules are seen as iso- to hypoechoic lesions with echogenic borders corresponding to fibrous septae. There may be features of complication of cirrhosis in the form of portal hypertension or HCC. The caudate lobe to right lobe liver ratio of >0.65 is highly specific for cirrhosis.

Figure 7: Hydatid cyst: Ultrasound reveals a right lobe cyst with multiple daughter cysts, pre and post aspiration.

DIFFUSE DISEASE OF THE LIVER Fatty Liver On USG, this is seen as diffuse increase in the echogenicity of the liver with poor visualisation of intrahepatic vessels and diaphragm. On CT (Figure 8), it is seen as a generalised low attenuation of the liver. MRI can confirm the diagnosis by utilising chemical shift imaging. On opposed phase images, areas of fat

CT and MRI show similar features (Figure 9). Regenerating nodules appear iso- to hyperdense to liver on NECT. Better appreciated on MRI, they are seen as hyperintense lesions on T1 and hypointense lesions on T2 WI sequences, and show an enhancement pattern similar to the rest of the liver. These features help in differentiating metastases and hepatomas from regenerating nodules. Of the various imaging techniques, MRI is the most sensitive and specific for this differentiation. Viral Hepatitis Imaging has little role in the diagnosis of viral hepatitis, and may reveal hepatomegaly, diffuse fatty change, periportal oedema and gall bladder (GB) wall thickening in the acute phase.

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Figures 9A to C: Triple phase CT abdomen. Arterial phase (A) shows multiple lesions showing homogeneous arterial enhancement with washout in venous phase; (B) with suggestion of a peripheral capsule around some lesions.; (C) Background changes of cirrhosis in the form of nodular liver and ascites are noted. Diagnosis: Multifocal HCC in cirrhotic liver. Courtesy: Dr Raju Sharma, AIIMS.

VASCULAR DISORDERS Portal Hypertension Ultrasonography may show features of underlying liver disease, collaterals, splenomegaly and ascites. Colour Doppler imaging is a non-invasive modality for studying portal haemodynamics (Figure 10). A portal vein diameter of >13 mm is characteristic of portal hypertension. Portal venous velocity is reduced in portal hypertension. Colour Doppler imaging can demonstrate the direction of flow in the portal vein. When paraumbilical vein is the major decompressive collateral, the flow in portal vein is hepatopetal. When other collateral channels open up, if the resistance to portal venous flow exceeds that in the collateral bed, the flow in portal vein becomes hepatofugal.

portovenography can show the collateral circulation, and the presence of underlying cirrhosis, splenomegaly and ascites. It can also effectively monitor for development of hepatoma in the cirrhotic liver. The currently available 3D CT techniques can provide excellent three-dimensional images of the portal venous system with the entire collateral circulation, and have replaced splenoportograms (Figure 11).

Figure 11: Contrast-enhanced computed tomography in a patient with portal hypertension: Multiple tortuous serpiginous splenic hilar, lienorenal gastric bed and paraoesophageal collateral channels.

Figure 10: Colour Doppler in portal hypertension: Multiple tortuous serpiginous periportal collateral channels.

Portal vein thrombosis can be well evaluated by sonography. A portal cavernoma comprises multiple tubular structures in the porta hepatis. A pulsed Doppler spectral waveform of portal flow from multiple tubular channels at the porta is highly diagnostic of a portal cavernoma. In portal hypertension, variability of calibre of the splenic and superior mesenteric veins with respiration is lost. 858

Colour Doppler imaging can also be used to assess surgical porto-system shunts for patency. CT with angiography and

Budd-Chiari Syndrome Obstruction to the hepatic venous outflow either due to hepatic veno-occlusive disease or due to IVC obstruction can be well evaluated by colour Doppler, CT, MRI and inferior venacavogram. The flow on Doppler imaging in IVC and hepatic veins changes from the normal phasic flow to absent, reversed, turbulent or continuous flow. In long standing disease, changes of cirrhosis and porta hypertension may set in. In the acute stage, NECT shows a large liver with generalised hypoattenuation, due to congestion and ascites. CECT shows patchy parenchymal enhancement and thrombosis of the IVC or the hepatic veins. In chronic stages, caudate lobe hypertrophy and dilated azygous and hemiazygous veins can be seen. MRI is very sensitive in Budd-Chiari syndrome and shows hepatomegaly, reduction in calibre or non-visualisation of hepatic veins, IVC thrombosis and generalised increase in signal intensity on T2 WI images due to congestion in the acute stage. Once the disease becomes chronic, the hepatic signal is low on both T1 and T2 WI images. Caudate lobe hypertrophy, dilated azygous and hemiazygous venous systems, and comma-shaped foci of signal void representing intrahepatic collaterals are seen.

Ultrasonography (USG) The free availability, low cost, lack of ionising radiation and high sensitivity and specificity in detecting biliary diseases make USG a favoured imaging modality. The biliary system can be visualised by subcostal scanning. The normal GB is well distended after a fast of 8 to 12 hours and its wall should not be >3 mm in thickness. The GB should be scanned in two planes and in two patient positions so as not to miss any disease. The intrahepatic biliary ducts are seen as tubular structures accompanying the portal vein. Normally, they are 2 mm or less in diameter. The entire extrahepatic biliary tree can be well visualised on sonography. The normal mean duct diameter of common bile duct (CBD) is 4 mm at age 40, 5 mm at age 50, 6 mm at age 60 years, and so on.

Hepatobiliary Disorders—Imaging

IMAGING OF THE BILIARY SYSTEM The various imaging modalities available today for studying the biliary system include plain radiographs, USG (trans-abdominal and endoscopic), endoscopic retrograde cholangiopancreaticography (ERCP), CT, MRI, MR cholangiopancreaticography (MRCP) (Figure 12), percutaneous transhepatic cholangiography (PTC), T-tube cholangiograms and radionuclide imaging.

Endoscopic Retrograde Cholangiopancreatography (ERCP) It involves cannulation of the major minor duodenal papilla under endoscopic visualisation and injection of iodinated contrast medium into the bile duct and pancreatic duct under fluoroscopic monitoring. Spot films in multiple projections are obtained. ERCP has the advantage of allowing collection of brushings and biopsy for cytological and histopathological examination, respectively, as also therapeutic procedures such as biliary stenting, balloon dilatation of strictures and extraction of stones. CT and MRI Figure 12: MRCP: Rare sequence delineating normal pancreatico-biliary tree.

Oral and IV cholangiography are of historical interest today, and CT cholangiography is hardly used in India. Plain Radiographs Gall stones Approximately 20% to 30% of gallstones are radio-opaque and are seen on plain radiographs. A characteristic feature is the presence of central stellate fissure that contains gas (Mercedes Benz sign). Limey bile On horizontal ray projections, a horizontal level representing layered high-density bile, that contains a mixture of calcium carbonate and calcium phosphate, is seen. Porcelain gall bladder The GB wall shows calcification, as a result of chronic inflammation. Emphysematous cholecystitis Seen particularly in diabetics and following hepatic artery embolisation, this condition is a severe form of cholecystitis with gas-forming organisms. On plain radiographs, air is identified within the GB wall. Air within the biliary tree This will be seen as a centrally-located branching pattern of air confined to the biliary tree. The causes include bilio-enteric fistulae caused by gallstones, perforated peptic ulcer, and malignant diseases. It may also occur following biliary surgery or ERCP, and in elderly persons with physiological laxity of the biliary sphincter (old age).

These are non-invasive and highly sensitive methods of determining the level and nature of biliary obstruction, and the extent of the disease process. They also play a useful role in postoperative evaluation. The normal GB is seen on CT as an oval structure located along the inferior surface of the liver, with a density (0 to 20 HU) similar to that of water. On MRI, it is seen as a bile-filled structure, bile in a non-fasting patient is hypointense on T1WI and hyperintense on T2WI images as compared to liver parenchyma. In fasting patents, bile gets concentrated and appears hyperintense to liver on both T1WI and T2WI sequences. Magnetic Resonance Cholangiopancreatography This is a non-invasive technique for visualisation of the biliary tree and pancreatic ducts which is based on heavily T2WI sequences. It does not require the use of any contrast medium. Magnetic resonance cholangiopancreatography (MRCP) has 95% accuracy in differentiating normal from dilated ducts, 100% accuracy in determining the level of biliary obstruction and 96.4% accuracy in determining the cause of obstruction. Percutaneous Transhepatic Cholangiography Percutaneous transhepatic cholangiography (PTC) is an interventional technique in which the biliary tree is punctured percutaneously using a Chiba needle under fluoroscopic guidance. After ensuring a secure access to the biliary system, iodinated contrast medium is injected and spot films of the opacified biliary stem are taken. It also permits therapeutic procedures like drainage of the obstructed biliary system and stenting of strictures. Biliary Scintigraphy 99mTc-labelled N-substituted iminoacetic acid compounds (99mTc-HIDA) are used for imaging the hepatobiliary tree. After a

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2 hour fast,3 to 10 mCi of 99mTc-HIDA is administered intravenously and sequential images obtained with a gamma camera at 1-minute intervals over the first 1 hour and then at longer intervals over 24 hours. Functional and morphological information about the hepatic parenchyma is obtained over the first 10 minutes and about of the extrahepatic biliary tree over the next 10 minutes; normally, the dye reaches the bowel by 1 hour. Biliary Disorders Biliary atresia Features on sonography include non-visualisation of the GB or a hypoplastic thick GB, non-visualisation of the common hepatic duct and presence of intra- or extra-hepatic cysts.

Gall stones USG is very sensitive in detecting gallstone disease. On sonography, the typical feature is that of a mobile highly reflective echo with posterior acoustic shadowing. CT is less sensitive than USG for this purpose, but is better for detecting calcified gallstones. On MRCP, gallstones produce no signal, and therefore, appear as inclusion defects against the background of bright bile; it is very sensitive in detecting gallstones in the lower CBD (Figure 14). Endoscopic USG also permits good evaluation of the lower CBD, which may be obscured by bowel gas or obesity on a transabdominal USG.

Choledochal cyst Choledochal cyst, or cystic dilatation of extrahepatic bile ducts, is seen on CT as a hypodense (0-20 HU i.e. water density) lesion, which does not enhance on contrast administration. The lesion runs along the course of the CBD, and a separate CBD is not seen. On MRI, it appears as a fluid intensity lesion, which is hypointense on T1 WI images and markedly hyperintense on T2 WI images. In patients without cholangitis, calculi or history of previous surgery, presence of contrast enhancement, or focal or diffuse thickening of the cyst wall should arouse a suspicion of carcinoma. In a large majority of cases, a long common channel with the pancreatic duct is seen which supports the hypothesis of reflux of pancreatic juice into the CBD as a causative factor in the development of choledochal cyst. Based on the cholangiographic features, choledochal cysts are divided into five types (Todani classification; Table 1). Knowledge of the type of choledochal cyst (Figure 13) aids in planning surgery.

Figure 13: MRI of choledochal cyst: fusiform dilatation of the common hepatic duct and the common bile duct.

Table 1: Todani’s Classification of Choledochal Cysts, based on Cholangiographic Features Type 1a Type 1b Type 1c Type 2 Type 3 Type 4a Type 4b Type 5 860

– – – – – – – –

Cystic dilatation of the CBD Focal segmental dilatation of distal CBD Fusiform dilatation of both CHD and CBD True diverticulum arising from the CBD Choledochocoele of the intraduodenal portion of CBD Intra- and extrahepatic cysts Extrahepatic cysts Intrahepatic bile duct cysts

Figure 14: MRCP showing gall bladder calculi.

Cholecystitis USG features of acute cholecystitis include presence of gallstones, oedema of the GB wall (wall thickness > 3 mm with a hypoechoic rim around it), calcific inclusion defect in the GB, probe tenderness over the GB, pericholecystic fluid collection, GB enlargement and gas in the GB wall (emphysematous cholecystitis). In chronic cholecystitis, the GB is contracted and has a thickened wall which may get calcified (porcelain GB). HIDA scan may show obstruction of the cystic duct. CT is more sensitive in picking up features of acute cholecystitis, which include pericholecystic fluid, GB wall thickening, GB enlargement, GB or CBD calculi, pericholecystic abscess, and gas within GB wall. It also helps to exclude other diseases that mimic cholecystitis. GB carcinoma CT and MRI usually show a soft tissue mass within the GB or in the GB fossa with direct extension into the adjacent liver. Lymphadenopathy may be present. Occasionally, there may only be focal or diffuse thickening of the GB wall (Figure 15). These tumours are usually hypodense and show heterogeneous enhancement. On T1 WI images they appear hypointense and hyperintense on T2 WI sequences. Fat-suppressed gadoliniumenhanced images are the best for detecting local invasion. Bile duct tumour They are usually adenocarcinomas of the scirrhous or papillary type. On imaging, there is proximal biliary dilatation with an abrupt cut-off due to a soft tissue mass that may occasionally be entirely intraluminal or may be apparent only as thickening of the bile duct wall. On non-enhanced CT, these tumours are frequently isodense to the liver and show minimal enhancement. On MRI, they are usually low signal on T1 WI and bright on T2 WI sequences. Fat-suppressed, gadolinium-enhanced images are the best for detection of periductal extent of the tumour.

Hepatobiliary Disorders—Imaging

Figure 15: Carcinoma of gall bladder: Enhancing mass arising from GB wall with infiltration of porta hepatis and segment 4B of liver with resultant marked intrahepatic biliary radical dilatation.

Primary sclerosing cholangitis In this condition, bile ducts have multiple strictures with focal areas of ductal dilatation leading to a beaded appearance on cholangiography (Figure 16). There may also be evidence of cirrhosis or portal hypertension. It predisposes to malignancy and there is an association with ulcerative colitis, retroperitoneal and mediastinal fibrosis,Riedel’s thyroiditis and orbital pseudotumour. Biliary parasitic infestations Parasites that commonly infest the biliary tree include Clonorchis sinensis, Ascaris lumbricoides and Echinococcus granulosus. The infestation may be asymptomatic or may present with cholangitis. On MRCP, ascariasis is seen as linear filling defects within the bile duct or GB. Presence of fluid (bile) within the intestine of the round worm appears as a hyperintense line within the linear filing-defect. Clonorchis sinensis infestation may be associated with intrahepatic biliary structures and intraductal calculi (Figure 17).

Figure 16: Colour Doppler in porta hypertension: Mutiple tortuous serpiginous periporta collateral channels.

Figure 17: Contrast-enhanced computed tomography in a patient with portal hypertension: Multiple tortuous serpiginous splenic hiar, lienorenal, gastric bed and paraoesophageal collateral channels.

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14.5 INTRODUCTION Acute viral hepatitis (AVH) was known to mankind since the middle ages. During the second world war, AVH was described to be of two types: (1) infectious hepatitis transmitted through contaminated water, (2) serum hepatitis transmitted by percutaneous exposure. The landmarks in the history of AVH are discoveries of Australia antigen by Barry Bloomberg in 1965, hepatitis A virus (HAV) by Feinstone in 1973, hepatitis C virus (HCV) by Hougton and colleagues in 1989, and hepatitis E virus (HEV) in 1990 by Reys et al. Acute hepatitis is characterised by the parenchymal liver damage by any agent on an underlying normal liver which produces similar clinical and biochemical features. It can be caused by viral infections, non-viral infections, drugs,toxins, alcohol, metabolic diseases and ischaemia. A proper history and serological tests for infectious agents and assays for identifying drugs/poisons are required to diagnose the cause. When viral hepatitis is suspected, special emphasis should be given in history taking on blood transfusion, intravenous drug use, sexual practices, contact with jaundice person, needle stick exposure, working in hospitals in the areas like dialysis, trauma units, shared razors or tooth brushes, body piercing, tattooing, type of domestic water supply, and history of travel to the endemic areas for Hepatitis A and E. Sometimes, acute hepatitis may be first manifestation of underlying occult chronic liver disease e.g. acute exacerbation of chronic liver disease, or acute hepatitis may bring to light underlying chronic liver disease e.g. AVH occurring on underlying undiagnosed Wilsons’ disease. AETIOPATHOGENESIS AVH is a systemic infection mainly affecting liver caused by hepatotropic viruses (hepatitis A to E). Other viruses like cytomegalovirus (CMV), herpes simplex, Coxsackie and adenovirus can also cause hepatitis in certain situations. AVH caused by hepatitis A to E is most common cause of liver disease worldwide and is a major public health problem in India. AVH leads to 1 to 2 million deaths annually worldwide.

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The agents causing AVH are classified into two groups: (1) enterically transmitted (HAV and HEV) and (2) parenterally transmitted (HBV, HCV and HDV). Enterically transmitted viruses are not enveloped viruses, they are shed in faeces, survive intact when exposed to bile, do not cause chronicity and do not have prolonged viremia or carrier state. HAV and HEV are highly endemic in India. HEV is the main cause of most of the epidemics in India and accounts for 30% to 70% cases of acute sporadic hepatitis and a major cause of acute liver failure especially in pregnant women in India. In paediatric population, HAV is predominant cause of AVH. Dual infections with HAV and HEV have been reported in children and adolescents especially in acute liver failure in India.

Acute Viral Hepatitis Deepak Amarapurkar Parenterally transmitted hepatitis viruses are HBV, HDV and HCV which are enveloped viruses which can cause chronicity and be associated with persistent viraemia and carrier state. About 15% to 30% of acute cases in India are due to HBV infection. HDV infection is found in less than 10% patients with HBV infection. HCV is rarely a cause of icteric AVH. Majority of the AVH episodes are anicteric or subclinical; but when symptoms appear they are all similar in different types of AVH. The symptoms are characterised by prodrome of fever, anorexia, nausea, vomiting, mild abdominal pain, dark coloured urine followed by development of scleral icterus. AVH is characterised by 5 to 10 times elevation in serum alanine transaminases (ALT) with or without rise in serum bilirubin. However, the levels of ALT do not reflect the severity of AVH. To determine the severity of AVH estimation of prothrombin time (PT) (expressed as INR) is essential. PT expressed as INR more than 1.5 is considered severe acute hepatitis. Majority of the AVH are self limiting. Chance of fulminant liver failure varies from 0.01% to 1%. HEPATITIS A VIRUS (HAV) Virology and Modes of Transmission HAV is a RNA virus belonging to Picorna virus family which is non enveloped, 27 nano micron size, has 7.5 kb genome. HAV is transmitted faeco orally. In rare instances, parenteral transmission via blood transfusion has been documented. Incubation period for HAV is 15 to 50 days with an average of 30 days. Epidemiology HAV has worldwide distribution and highly endemic in developing countries. India is hyperendemic region for HAV. There are estimated 1.5 million cases of HAV annually worldwide. Most of these cases occur in areas of poor hygiene and poor sanitation. Risk factors for HAV are children living in unhygienic condition, poor sanitation, consumers of high risk food, e.g. raw shell fish, people travelling to endemic areas and those participating in anal sex, intravenous drug abuses. Natural History and Clinical Course Main symptoms of HAV are fatigue, abdominal pain, anorexia, nausea, fever, dark coloured urine, jaundice, and diarrhoea. Rarely, HAV is associated with prolonged cholestasis leading to prolonged icetric illness. HAV never causes chronic infection and produces life long immunity. The risk of fulminant hepatic failure (FHF) is 0.01% to 0.1% which increases with age and patients having pre-existing liver disease (Figure 1). Diagnosis HAV is diagnosed by serological tests. IgM anti-HAV suggests acute infection; IgG anti-HAV suggests previous infection or vaccine acquired immunity. HAV RNA can be detected in blood, stool and liver during early part of the illness, but this test is not used in clinical practice.

Treatment Management of HAV includes symptomatic and supportive measures; no specific antiviral treatment is required. Majority of the patients do not require hospital admission. Patients should be advised rest and given normal hygienic diet. Antiemetics may be given for nausea and vomiting. Patients with severe AVH and patients with HAV super imposed on underlying chronic liver disease require hospitalisation. Patients with HAV should be advised to avoid hepatotoxic agents such as alcohol, oral contraceptive medicines, paracetamol and non-steroidal antiinflammatory drugs. Prevention Provision of clean drinking water, proper sewage disposal, public education about the hygiene are the mainstay for prevention of HAV infection. Infection with HAV provides long term immunity. Highly effective active and passive immunisation are available. Pre-exposure prophylaxis with inactivated vaccines can give protection up to 20 years. Passive immunisation is used for postexposure prophylaxis within two weeks and should be accompanied with active vaccination (Table 1). Table 1: Immunisation for Hepatitis A Indication for active vaccination Travellers to high risk area Homosexual men Injection drug users Children and young adults when there is community outbreak Susceptible patients with chronic liver disease Food handlers Children in the area of high endemicity Schedule for hepatitis A vaccination Children over two years of age, 3 dose regime Inactivated HAV vaccine (360 ELISA units) 0, 1 and 6 to 12 months Two dose regime : Inactivated HAV vaccine (720 ELISA units) 0, 6 to 12 months Adults above 19 years of age Inactivated HAV vaccine (1440 ELISA units) 0–6 to 12 months Combined hepatitis A and B vaccine also can be used containing 20 mu/g HBsAg protein and more than 720 ELISA units of inactivated hepatitis A vaccine scheduled at 0, 1 and 6 months. Post-exposure immunoprophylaxis—0.02 mL/kg body weight immunoglobulin specific to HAV on deltoid as early as possible after the exposure.

Acute Viral Hepatitis

Figure 1: Natural history of hepatitis A virus infection.

HEPATITIS B VIRUS (HBV) Virology and Pathogenesis HBV is a single-stranded DNA virus, with particle size 22 to 42 nano micron with 3.2 kb circular DNA genome. HBV replicates through an RNA intermediate using a virus-encoded reverse transcriptase enzyme. HBV genome has four genes, namely: surface, core, DNA polymerase and X. Four antigens HBsAg, HBcAg, HBeAg and HBxAg that have been identified in relation to HBV. Antibodies against this can be detected in the blood and are useful in diagnosis of various phases of HBV infection. There are at least 7 HBV genotypes (from A to G). Genotype D and A are more common in India. In immunocompetent persons, HBV is not cytopathic, and liver damage in this infection is caused through an immune-mediated mechanism directed against HBV-infected hepatocytes. However, in post-transplant patients, the virus appears to produce liver damage via a cytopathic effect. Modes of Transmission HBV is transmitted by blood-borne route, such as transfusion of infected blood and blood products, intravenous drug use, haemodialysis, sexual contact, percutaneous exposure (like needle-stick injuries, shared razor blades and tooth brushes, tattooing, acupuncture, etc.), and mother-to-newborn (i.e. perinatal) transmission. In India, a majority of chronic HBV infections are acquired horizontally, and less than 20% of chronic HBV infections results from vertical mother-to-child transmission. Epidemiology Acute hepatitis B is generally seen in patients with high risk behaviour for parenteral transmission in the western countries while in endemic region it can be seen in family contacts of patients infected with hepatitis B. More than one million people are infected with hepatitis B annually. In India 15% to 30% of the acute hepatitis cases are due to HBV infection. Natural History and Clinical Presentations Incubation period of HBV varies from 15 to 180 (average 60 to 90) days. In adults, almost 70% of acute infections are silent and subclinical; 30% develop icteric hepatitis. The proportion with clinical illness is smaller when infection occurs in early life. Thus, perinatal or childhood HBV infections are usually asymptomatic. About 1% of patients with acute hepatitis B develop fulminant hepatic failure (Figure 2).

Figure 2: Natural history of hepatitis B virus infection.

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HBV viraemia lasts for weeks to months after infection. Infection persisting beyond 6 months is labelled as chronic HBV. Risk of developing chronic HBV infection after acute exposure is dependent on age at the time of acquisition of infection; thus, nearly 90% of neonates, around 50% of young children aged 1 to 5 years, and 1% to 5% of adults with acute HBV infection develop chronic infection and persistent viraemia. The risk of chronic HBV infection is higher among immunocompromised individuals like HIV-infected, patients under immunosuppressive therapy and haemodialysis patients. Diagnosis Diagnosis of HBV infection is based on detection of various antigens and antibodies in the serum, or of HBV-DNA in serum or liver tissue. Presence of HBsAg in the blood suggests the presence of HBV infection. Presence of HBeAg in blood suggests active viral replication. IgM anti-HBc antibodies indicate recent (acute) infection. Anti-HBc IgG antibodies persist in the blood life-long after exposure to HBV. Anti-HBs antibodies appear with the clearance of HBV infection, and their presence suggests complete recovery. Detecting the presence and quantity of HBV-DNA in blood by polymerase chain reaction is useful in assessing whether virus is actively replicating, judging the need for and response to treatment. More specialised tests are used to detect mutant virus strains. Diagnosis of acute HBV is based on detecting IgM anti HBc in the blood. Treatment Acute HBV infection in adults is mostly a self-limiting disease and hence does not require any specific anti-viral treatment. The patients should be followed up to detect those in whom the infection becomes chronic; this is particularly important for children. Treatment with oral antivirals like Lamivudine, Telbivudine or Entecavir is indicated in patients with fulminant HBV, protracted severe HBV infection in immunosuppressed patients. Prevention HBV infection can be prevented by screening the transfused blood and blood products for HBsAg, using disposable needles and syringes, using safety precautions and practicing safe sex. Both active and passive immunisation are available. HBV vaccines, recombinant as well as plasma-derived, have more than 95% efficacy and are very safe. Hepatitis B immunoglobulin is useful for post-exposure prophylaxis (i.e. within 48 hours) and prevents mother-to-child transmission. HBV vaccination has been shown to reduce chronic HBV infection rate, and the incidence of hepatocellular carcinoma. HBV vaccination should be integrated into routine infant immunisation programme (Table 2).

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HEPATITIS C VIRUS (HCV) Virology and Pathogenesis HCV is a single-stranded, enveloped RNA virus with a single open reading frame and 9.5 kb linear RNA genome. The anti HCV antibody has been used for the diagnostic purposes and does not have a protective value. The viral strains have significant genetic variability and have been grouped into six genotypes. In India, genotype 3 is the commonest; it is characterised by a good response to interferon treatment.

The exact mechanism of hepatocellular injury in HCV infection is unknown. Initially, HCV-induced liver injury was considered to be cytopathic in nature but current data suggest that host immune responses to HCV-infected hepatocytes play a major role in the pathogenesis of chronic hepatitis C. Table 2: Immunisation for Hepatitis B Indication for active vaccination Universal infant immunisation shortly after the birth Catch up vaccination for adolescents if not previously vaccinated High risk groups Household contacts of HBV carriers Health care professionals Injection drug abusers Homosexual men Individual with multiple sex partners Haemodialysis patients Patients with chronic liver disease HBV vaccine schedule Below the age of 19 years 10 mu intramuscularly on deltoid at 0, 1, 6 months Above the age of 19 years 20 mu intramuscularly on deltoid at 0, 1, 6 months Accelerated schedule of 0, 1, 2, 12 also can be used Post exposure prophylaxis 0.04 – 0.07 mL/kg HBIG intramuscularly within 48 hours alongwith the first dose of active vaccine.Further doses of active vaccine at 1 and 6 months should be continued. In neonates born to HBsAg positive mothers should be vaccinated at a dose of 0.5 ml of HBIG within 12 hours of birth along with the first dose of active vaccination. Futher doses of active vaccine at 1 and 6 months should be continued.

Mode of Transmission Similar to HBV infection, HCV is also transmitted by blood-borne routes. Transmissibility of HCV is much lower than that of HBV. Recipients of infected blood and blood products, intravenous drug abusers, and haemodialysis patients form the major HCV risk groups. Sexual and perinatal transmission of HCV is uncommon. More than 80% of Indian patients with chronic HCV infection are either transfusion recipients or undergoing haemodialysis. Epidemiology Worldwide prevalence of HCV infection is around 1% with marked geographical variation. HCV carrier rate in India is around 1% to 2%, thereby meaning that 15 million people in India are infected with this virus. HCV is responsible for 20% to 30% of patients with chronic liver disease in India. Natural History and Clinical Presentation Incubation period of HCV ranges from 15 to 160 days. Prolonged viremia and persistent infection are common. More than 75% of acute HCV infections are silent. Only 25% acute HCV infections manifest as clinical hepatitis. In the stage of acute hepatitis, patients should be monitored for spontaneous viral clearance. Patients with symptomatic acute hepatitis and female gender are more likely to clear the virus. Fulminant hepatic failure due to HCV infection alone is extremely uncommon. Nearly 50% to 85% of patients with HCV infection develop chronic infection;

Diagnosis Diagnosis of HCV infection depends on detection of anti-HCV antibodies, using third generation enzyme immunoassays (EIAs); the current tests for this purpose are highly sensitive and specific. In acute HCV infection serum HCV RNA are detected within 1 to 2 weeks of exposure while elevation in ALT occurs 2 to 8 weeks after exposure. Anti HCV antibody develop 4 to 6 weeks after exposure to hepatitis C. Treatment More than 50% patients with acute HCV infection develop chronicity. Treatment of acute HCV infection after 12 weeks is recommended as spontaneous resolution at this stage is unlikely. The objective of antiviral treatment in acute HCV infection is to prevent chronicity. Interferon alpha, peg interferon alpha and peg interferon alpha + ribavirin have been shown to be highly effective in treatment of acute HCV infection. Prevention Use of blood from voluntary blood donors (as opposed to professional donors) and screening of blood and blood products using an anti-HCV antibody test prior to blood transfusion can bring down HCV transmission dramatically. Use of disposable syringe and needles is also helpful. Currently, no active or passive immunisation is available for preventing HCV infection. HEPATITIS D INFECTION (HDV) HDV is an incomplete enveloped virus with particle size of 3537 nano microns, 1.7 kb circular RNA genome. It uses HBsAg of HBV as its envelope protein, and hence can cause infection only in the presence of HBV infection. Infection with both HDV and HBV may be acquired simultaneously (known as deltacoinfection); alternatively, HDV infection may occur in a person previously having chronic HBV infection (delta-superinfection). HDV is transmitted by parenteral and sexual routes; vertical transmission is extremely rare. HDV infection is prevalent worldwide. However, its frequency has shown a decline globally, as well as in India. HDV coinfection has a good prognosis with 80% to 90% of patients showing complete recovery. Fulminant hepatic failure is seen in 5% to 10% of patients as compared to only 1% of those with isolated acute HBV infection. HDV superinfection in a chronic HBV infected person is associated with increased rates of progression to cirrhosis, decompensation, development of hepatocellular carcinoma and death as compared to isolated chronic HBV infection. Clinical presentation of HDV infection varies from asymptomatic carrier stage, acute hepatitis, fulminant hepatitis, chronic hepatitis, cirrhosis decompensation and HCC. Acute deterioration in chronic stable HBV infection should lead to suspicion of delta superinfection. Diagnosis of HDV infection depends on demonstration of anti-HDV antibodies in the serum and HDV-RNA in serum or liver tissue.

Response of HDV infection to interferon as well as lamivudine is suboptimal. Since HDV depends on HBV for survival and multiplication, it can be prevented using methods to prevent the latter. HEPATITIS E VIRUS (HEV) Virology and Modes of Transmission HEV is a positive stranded 7.6 kb base non enveloped RNA virus and belongs to family of calcivirus. The particle size of HEV virus is 32 to 34 nano microns. HEV antibodies have protective value are also used for the diagnostic and epidemiological purpose. HEV is predominantly transmitted by faeco-oral route with incubation period of 2 to 9 weeks with mean of six weeks. Rarely parenteral transmission, person to person transmission and mother-foetal transmission has been documented.

Acute Viral Hepatitis

of these, 60% to 70% develop chronic hepatitis, 30% develop cirrhosis and 15% develop hepatocellular carcinoma. Average time duration between acquisition of infection and development of chronic hepatitis, cirrhosis and HCC is 10 years, 20 to 30 years and 40 years, respectively.

Epidemiology HEV infection is most common cause of acute sporadic and epidemic viral hepatitis in India. Contamination of drinking water due to sewage has been the important source of majority of these epidemics. Faecal contamination may be due to backflow during the floods, leaking sewers located close to the corroded drinking water pipes and contamination of well water during raining seasons. Natural History and Clinical Course Clinical manifestation of HEV infection ranges from asymptomatic to icteric hepatitis to fulminant hepatic failure (FHF). Prodromal symptoms are similar to other forms of AVH. Cholestatic hepatitis with striking jaundice and itching may last for several months in 20% to 30% patients with acute HEV infection. By and large HEV is a self-limiting acute infection. 1% of the patients with HEV can develop FHF. Pregnant females (especially during 2nd and 3rd trimester) have high attack rates and 10% to 12% chance of FHF (Figure 3).

Figure 3: Natural history of HEV infection.

Diagnosis IgM anti HEV antibodies are available for diagnosing of acute HEV infection. IgG anti HEV antibodies can be used for the sero-epidemiological studies. The virus can be identified in faeces, bile and the liver but this is not used in clinical practice. Treatment Treatment is supportive as described initially. 865

Table 3: Acute Viral Hepatitis in Special Situations Specilist

HAV

Children

Benign course

Infrequently affected

Chance of chronicity is high

Chance of chronicity is high

Adolescents

Benign course Severe disease above the age of 40 years

Common benign course

Need to exclude underlying chronic hepatitis B

Chance of chronicity

Pregnant females

Course similar to non pregnant

Increase attack rate and increased chance of fulminant failure in 3rd trimester Increased foetal loss, possibility of transmission to foetus

Perinatal transmission to foetus likely Active and passive vaccination to child immediately at birth should be given

Chance of transmission to foetus if mother is coinfected with HIV

Course can be severe, can become chronic in post transplant period

High risk of chronicity may need antiviral treatment. Risk of chronicity in post treatment situation

High risk of chronicity, may need antiviral treatment. Risk of chronicity in post treatment situation

Immunosuppressed Course can be severe patients

HEV

HBV

Acute Viral Hepatitis in Special Situation The general clinical features of acute viral hepatitis have to kept in mind while dealing with such group. The clinical features and investigations are delineated in Tables 3 and 4.

Table 4: Diagnostic Tests for Acute Viral Hepatitis Hepatitis

Diagnostic Test For Acute Stage

HAV

IgM Anti HAV

HBV

IgM Anti HBc, HBsAg

HDV

Anti HDV in presence of IgM Anti HBc +ve

HCV

No antibody test to determine acute stage HCVRNA +ve in the absence of Anti HCV +ve in immune competent phase suggestive of acute infection

HEV

IgM anti HEV

Prevention The best way of avoiding HEV infection is using safe drinking water, uncooked shell fish and foods which are contaminated. HEV vaccine has been recently shown to be effective and is awaiting commercial availability. In conclusion, all forms of AVH in immune competent persons are self limiting. They do not require any specific therapy other than stopping hepatotoxic medications, including oral contraceptives and paracetamol. There is no role of vitamin supplementations, hepato-protective medications and dietary restrictions like avoiding proteins, fats and tamarind. Patients can start their routine work as soon as they feel fit to do so. Dietary restrictions and alternative medications may have deleterious course in AVH.

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HCV

RECOMMENDED READINGS 1.

Acharya SK, Madan K, Dattagupta S, et al. Viral Hepatitis In India. Nat Med J India 2006;19:203-17.

2.

Heathcote J, Elewaut A, Fedail S, et al. Management of Acute Viral Hepatitis World Gastroenterology Organization Practice Guidelines.

3.

Viral Hepatitis Report by the Secretariat – World Health Organization – Sixty-third World Health Assembly 25th March 2010-07-14.

14.6

Chronic Viral Hepatitis Rajesh Upadhyay, Nitin Gupta

Chronic hepatitis is defined as hepatic necro-inflammation (detectable by biochemical or histological methods) continuing for more than 6 months. The condition may be self-limiting but usually progresses to fibrosis and subsequent architectural distortion with regenerating nodules leading to cirrhosis. There are many diverse causes of chronic hepatitis which can be broadly categorized into viral and non-viral causes (Table 1). This chapter presents an overview on chronic viral hepatitis. Table 1: Causes of Chronic Hepatitis Viral

Non-Viral

Chronic hepatitis B Chronic hepatitis C Chronic hepatitis D

Alcoholic hepatitis Non-alcoholic steatohepatitis Wilson’s disease Drugs Auto-immune hepatitis Others

AETIOLOGY Chronic viral hepatitis may be caused by hepatitis B, hepatitis C and hepatitis D. Of these, hepatitis B and C are the two most common viruses. In India, deaths from chronic hepatitis B (HBV) and chronic hepatitis C (HCV) infections are increasing over the years. Hepatitis B Virus (HBV) Epidemiology HBV is a ds DNA virus belonging to Hepadnaviridae family of viruses. Hepatitis B is endemic throughout the world (350 million infected worldwide) especially in countries like Bangladesh, Thailand and Myanmar which have HBsAg carrier rates as high as 9 to 12%. In India, the carrier rate has been found to be around 4 to 7% with an estimated 45 million infected individuals. HBV is present in the blood, saliva, semen, vaginal secretions, and menstrual blood and, to a lesser extent, perspiration, breast milk, tears and urine of infected individuals. The virus can survive outside the body and is easily transmitted through contact with infected body fluids. The pattern of infection differs in developed and developing nations. Sexual transmission is common in the western world, whereas in developing countries like India, vertical transmission (mother to child at birth) and early childhood infections predominate. Chronic infection leads to cirrhosis and hepato-cellular carcinoma (HCC) in 15 to 40% patients. Clinical features and outcome The clinical presentation of chronic viral hepatitis is similar for both HBV and HCV. Chronic HBV infection is usually asymptomatic and is commonly detected on routine blood testing or during evaluation of incidental, unexplained elevation in alanine aminotransferase

(ALT) levels. The clinical symptoms, when present, are generally mild and non-specific such as fatigue, mild right upper quadrant pain, nausea, weight loss, weakness, pruritus, etc. Patients with more advanced disease may have jaundice, abdominal swelling, gastrointestinal (GI) bleed or hepatic encephalopathy. Sometimes, the condition is diagnosed when the patient presents with an acute hepatitis illness which is due to reactivation of chronic hepatitis B. Physical examination is usually unremarkable but stigmata of chronic liver disease may be present. Hepatomegaly with or without splenomegaly may be present depending on the stage of disease. The outcome of chronic HBV infection depends on the age of acquisition of infection. Most patients are infected in early childhood and initial infection leads to inactive HBeAg-positive disease with high-level viraemia and minimal liver damage (immune tolerant phase). With advancing age, many patients develop an immune response (immune clearance phase) that leads to liver inflammation with progressive disease (high AST/ ALT levels) and often seroconversion to HBeAg-negative phase of infection with low-level viraemia and normal liver function tests (LFT) (inactive replicative phase). A proportion of patients have reactivation of infection (reactivation phase) and develop HBeAg negative disease with fibrosis progression. The stages of chronic hepatitis B infection are shown in Figure 1. Diagnosis When chronic viral disease is suspected, the next step involves work-up of viral hepatitis using serological or molecular biological methods. Patients with chronic hepatitis B (CHB) are diagnosed when hepatitis B surface antigen (HBsAg) persists in serum for more than 6 months. There are two main forms of chronic hepatitis B: (a) HBeAg-positive form associated with wild-type infection; and (b) HBeAg negative form associated with core promoter and/ or pre-core mutant viruses. Hepatitis B core antibody (Total) is present in CHB infection and presence of HBeAg or high HBV-DNA are markers of replicative virus. The transaminases (AST, ALT ) are typically elevated usually 1 to 5 times the upper limit of normal with ALT> AST, whereas the alkaline phosphatase level is only mildly elevated. The albumin: globulin ratio remains normal except in advanced stages of disease where reversal of A:G ratio may be seen. Abdominal ultrasonography (USG) is the most commonly used imaging modality although it is not useful in making the diagnosis. Its importance, however, lies in distinguishing patients with cirrhosis (small, shrunken nodular liver or atrophy of right lobe with hypertrophy of caudate/left lobe) or those with portal hypertension. It is also a useful screening test for

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Figure 1: Stages of chronic hepatitis B infection.

hepato-cellular carcinoma. (USG) elastography (fibroscan) is a new non-invasive imaging modality used for assessment of fibrosis (stiffness) in chronic hepatitis. It may be useful in detecting patients with advanced fibrosis. Chronic hepatitis is a necro-inflammatory process that may be complicated by fibrosis. A hallmark of chronic hepatitis is portal inflammation (portal hepatitis), predominantly lymphocytic. These changes are common to all aetiologies of chronic hepatitis. Certain changes are characteristic, but not pathognomonic, of chronic HBV. “Ground-glass” hepatocytes are a hallmark of hepatitis B infection which is due to proliferation of smooth endoplasmic reticulum containing HBs antigens. Liver biopsy is not required for diagnosis of chronic viral hepatitis. Its usefulness lies in the histological assessment of liver for severity of necro-inflammation (grading) and degree of fibrosis (staging). Several histological classification systems are used for this purpose, e.g. Knodell-Ishak score, Scheuer score, Metavir score, etc. Such information is often useful for making therapeutic decisions. Treatment Treatment for chronic HBV infection should be restricted to patients with active inflammation and high replicative state (HBeAg positive or high level HBV-DNA). Such patients have higher risk of progressive disease leading to cirrhosis and hepato-cellular carcinoma.

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Inflammation may be assessed indirectly by elevated ALT or directly by assessing liver biopsy specimen. Biopsy is usually not required for patients with ALT more than two times upper limit of normal. It may be considered in patients with borderline elevated ALT levels. Current guidelines advocate treatment in patients with HBV-DNA >20,000µ/ml in HBeAg-positive patients and HBV-DNA >2000µ/ml in HBeAg-negative patients.

The short-term goal of treatment is to convert patients from the high replication phase (HBeAg-positive or high HBV-DNA) to the low replication phase characterized by the appearance of HBeAb (called as seroconversion) or disappearance of HBV-DNA. This end-point is associated with lower or normal ALT levels and histological improvement. The long-term goals are to delay or prevent histological progression to cirrhosis and hepato-cellular carcinoma leading to improved survival. The ideal aim of treatment is HBsAg/HBsAb seroconversion which is difficult to achieve. Treatment options include interferon injections (both standard and pegylated) and anti-viral drugs, such as nucleoside or nucleotide inhibitors. Currently used oral anti-viral drugs include lamivudine, adefovir, emtricitabine, entecavir and tenofovir. Interferon therapy is of finite duration, whereas a long-term therapy should be planned when using nucleoside analogues. The usual regimen for Peg-interferon is a weekly dose for 12 months. Nucleoside treatment should be continued for at least 6 months (preferably 12 months) after seroconversion in HBeAg-positive patients, or after HBV DNA levels have become undetectable in HBeAg-negative patients. Interferons should be avoided in HBeAg-negative patients as the results are disappointing and the end-points of treatment are not well defined. The problem with oral anti-viral drugs is the long duration of treatment and the risk of resistance (albeit low with newer anti-virals). Hepatitis C Virus Epidemiology Hepatitis C virus is an RNA virus belonging to the Flaviviridae family of viruses. It was first identified in 1989. About 3% of the world population is infected with HCV and among them 170 million individuals are chronic carriers, and at risk of developing cirrhosis and liver cancers. In India, the prevalence of HCV

Clinical features Acute infection with hepatitis C leads to chronicity in almost 85% of the patients. Chronic infection leads to a slowly progressive hepatitis that can cause significant liver disease including cirrhosis and sometimes hepato-cellular carcinoma over 15 to 30 years. The disease is usually asymptomatic and detected during routine testing or during evaluation for asymptomatic elevation of transaminases. Sometimes it is present with icteric hepatitis and a few patients may present for the first time with decompensated cirrhosis.

Treatment All anti-HCV positive patients with detectable HCV-RNA are potential candidates for treatment. Patients suspected of having acute or chronic HCV infection should first be tested for anti-HCV. HCV-RNA testing should be performed in patients with a positive anti-HCV test especially in whom, antiviral treatment is being considered. HCV genotyping should be performed in all HCV-infected persons prior to treatment. This helps to plan for the dose and duration of therapy and to estimate the likelihood of response. Treatment decisions should be individualized based on the severity of liver disease (decompensated liver disease is a contraindication to treatment), the potential for serious side effects and the presence of co-morbid conditions (like HIV co-infection).

The differentiation of acute from chronic HCV infection depends on the clinical presentation, namely the presence of symptoms and whether or not there was a prior history of ALT elevation and its duration.

The optimal therapy for chronic HCV infection is the combination of peginterferon alfa and ribavirin. Peginterferon alfa 2a is given as a fixed dose and alfa 2b is given according to body weight. Genotype 1 and 4 patients are treated with 48 weeks of treatment while genotype 2 and 3 patients are treated with 24 weeks of treatment. The finding of undetectable levels of HCV-RNA levels at 24 weeks after completion of treatment (sustained virological response) ensures that the treatment can be considered curative. The expected response rate is lower with genotype 1 and 4 patients (55 to 60%) compared to genotype 2 and 3 (75 to 80%).

The clinical features of chronic hepatitis C are similar to those of CHB infection. However, these patients are less likely to present with a past history of icteric hepatitis compared to patients with chronic hepatitis B.

In view of the poor response rate, especially in genotype 1 and 4, a number of drugs, such as telaprevir, are being currently tried in combination with pegylated interferon and ribavirin with encouraging results.

Diagnosis The diagnosis is based on the presence of both anti-HCV and HCV-RNA.These assays have no role in the assessment of disease severity. After acute exposure, HCV-RNA can be identified as early as 2 weeks following exposure whereas anti-HCV is generally not detectable before 8 to 12 weeks. Careful analysis of both these markers helps in diagnosis of acute or chronic HCV infection or resolved HCV infection (Table 2).

Hepatitis D Virus This is uncommon in India but is more commonly seen in West Africa, Mediterranean and in parts of South America.

Table 2: Serology in the Diagnosis of HCV Infection Anti-HCV HCV-RNA

Analysis

Yes Yes No No

Active infection (acute or chronic) Resolved HCV infection Early acute infection, false positive serology No HCV infection

Yes No Yes No

The pattern of LFT abnormality, use of imaging modalities and assessment of liver histology in chronic hepatitis C is similar to that in chronic hepatitis B (CHB).

Chronic Viral Hepatitis

antibodies has been found to be 2% in voluntary blood donors, and 42% of patients with hepato-cellular cancer. The prevalence of HCV infection is also age-related with children and adolescents exhibiting very low rates (0.4%). The hepatitis C virus is blood borne and in the developed world transmission is common in IV drug abusers sharing contaminated needles or those who received blood or blood products before screening for HCV was introduced. The routes of transmission are diverse and include contaminated medical equipment (used in treatment or immunization) as well as contaminated nonmedical equipment (such as barbers’ razors).

HDV (hepatitis delta virus) is a RNA virus discovered in 1977 and causes infection which requires HBV particles to infect the liver. The viral transmission is similar to HBV (blood borne and sexual). HDV infection may either be co-infection with HBV (simultaneous infection) or superinfection (HDV in chronic HBV carrier). Chronic hepatitis D occurs in less than 5% of co-infected patients and in 80% of superinfected patients. The clinical features are similar to chronic HBV or HCV. The disease is progressive and 60 to 70% develops cirrhosis over 5 to 10 years. HCC also occurs with same frequency as in HBV or HCV infection. The diagnosis is confirmed with a positive test for anti-HDV and HDV-RNA by RT-PCR. No specific treatment is available

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14.7 When hepatic inflammation when continued for more than 6 months duration, the disease process is termed as chronic hepatitis. Progression of chronic hepatitis can lead onto cirrhosis and, less commonly, hepatocellular carcinoma. This section presents an overview of chronic non-viral hepatitis and discusses auto-immune hepatitis (AIH) in detail. CHRONIC NON-VIRAL HEPATITIS Aetiology Hepatitis viruses B, C and D are important causes of chronic hepatitis, which are discussed separately in chapter 6, section 14. The important non-viral causes of chronic hepatitis are Wilson’s disease, AIH, non-alcoholic steatohepatitis (NASH), druginduced hepatitis, iron overload and unexplained/cryptogenic chronic hepatitis. Clinical Features Chronic hepatitis may be asymptomatic, with the disease being detected on routine blood tests. Patients may also present with non-specific symptoms, like fatigue or joint pains. Some patients may present with features of portal hypertension (like oesophageal variceal bleed) or liver cell failure. Physical examination may be normal. Some patients have jaundice, peripheral stigmata of liver cell failure, like spider nevi and splenomegaly. Clinical clues may suggest the aetiology of chronic hepatitis. Acne may be a prominent feature of AIH, however it may also occur in other causes of chronic hepatitis (like Wilson’s disease). Other autoimmune diseases like Hashimoto’s thyroiditis, pernicious anaemia, insulin dependent diabetes mellitus or coeliac disease may be seen in AIH. Kayser-Fleischer rings in eyes, neurological features (extrapyramidal involvement: tremors, drooling of saliva, pseudoParkinsonian features) or psychiatric illness point to a diagnosis of Wilson’s disease. Family history of liver or neurological illness also favours a diagnosis of Wilson’s disease. Being an autosomal recessive disorder, Wilson’s disease is more often seen in children born to parents of consanguineous marriage. Chronic hepatitis in a patient with metabolic syndrome (obesity, diabetes mellitus, hypertension) is likely to be due to NASH. A detailed drug history should be obtained in a patient with chronic hepatitis. Hepatotoxicity is a well recognised side-effect of some drugs, for example, anti-tuberculosis drugs like isoniazid, rifamipicin and pyrazinamide are a common cause of drug-induced hepatitis in India. In patients with drug-induced hepatitis, inadvertent continued use of the drug or repeated exposure to the drug may lead to more severe liver injury. Hepatic iron overload may either be due to genetic haemochromatosis (clinical clues: family history of similar illness, 870

Chronic Non-Viral Hepatitis CE Eapen presence of hyperpigmentation, diabetes mellitus, cardiomyopathy or hypogonadism) or haemosiderosis (example: a patient with thalassaemia who has been multi-transfused). It is also possible that more than one hepatotoxic factor may be operant in an individual with chronic hepatitis (for example, a patient with metabolic syndrome and NASH, who develops alcoholic hepatitis). Investigations Persistent elevation of serum transaminases for more than 6 months raises the possibility of chronic hepatitis. Serum (AST to ALT) ratio is useful to distinguish NASH (AST: ALT ratio < 1) from alcoholic liver disease (ratio >/= 2).Viral markers (serology, molecular tests) are used to rule out hepatitis viral infections. Specific tests are done to look for the different causes of chronic non-viral hepatitis. For example, serum caeruloplasmin, urine copper and slit lamp examination of the eye for Kayser-Fleischer rings are done to look for Wilson’s disease. Liver Biopsy The liver histology shows hepatic necro-inflammation with infiltration of portal tracts by chronic inflammatory cells— lymphocytes, plasma cells and varying degrees of fibrosis. Histological changes in chronic viral hepatitis are scored by ‘grading’ (degree of necro-inflammation) and ‘staging’ (degree of fibrosis). Mallory hyaline bodies can be seen in a variety of conditions (for example, Wilson’s disease, alcoholic hepatitis, NASH). Eosinophilic infiltrate may suggest drug-induced hepatitis. Special stains for copper (Rhodanine stain) and copper associated protein (orcein stain) help diagnose copper overload. Iron deposits are detected on Perl’s Prussian blue stain. Treatment If an aetiological factor for chronic hepatitis is identified, specific treatment can be given. With effective treatment of Wilson’s disease, the affected patients (often children or young adults) can be expected to outlive their doctors! Medications to reduce the copper overload state (for Wilson’s disease), immunosuppressive treatment (for AIH), stopping the offending drug (in drug-induced hepatitis), measures to reduce insulin resistance (for NASH) and iron chelation (in iron overload states) are examples of specific treatment when the cause for chronic non-viral hepatitis is identified. AUTOIMMUNE HEPATITIS This is an uncommon type of chronic hepatitis that improves after treatment with corticosteroids and other immunosuppressive drugs. The other autoimmune liver diseases are primary sclerosing cholangitis, primary biliary cirrhosis and overlap syndrome. In a series of patients with autoimmune liver

Epidemiology AIH comprised 2% to 6% of the causes of acute and chronic liver diseases in reports from North and Western India. The disorder can occur at any age but has a predilection for girls and young women.The mean age of presentation of adults with AIH in India is between 31 and 36 years with female preponderance (male: female ratio is 1:3). Pathogenesis of Autoimmune Hepatitis A young lady on minocycline for treatment of acne who presents with chronic hepatitis could be having AIH. What predisposes an individual to develop AIH? One explanation is an interaction between human leukocyte antigens (HLA), hepatocyte antigens and receptors on T-lymphocytes (Figure 1). Candidate self-antigens are asialoglycoprotein

receptor (located on hepatocyte surface) in AIH type 1 and cytochrome P450 2D6 (in hepatocyte microsomes) in AIH type 2. HLA-DR3 and DR-4 increase the risk of AIH type 1. In Western India, AIH type 1 is associated with HLA DRB1*0301, DRB1*1301, DRB1*14 and DRB1*1501. Molecular mimicry between viruses (hepatitis A, B, C, EpsteinBarr, measles virus) or drugs (minocycline, atorvastatin, methyldopa, nitrofurantoin) and hepatocyte antigens is a possible mechanism of pathogenesis. In genetically predisposed individuals this may result in an inappropriate immune response against the hepatocyte, even after elimination of the virus or cessation of the drug.

Chronic Non-Viral Hepatitis

disease from Delhi, AIH was seen in 78%, primary sclerosing cholangitis (10%), primary biliary cirrhosis (8%) and overlap syndrome (4%).

Clinical Features The majority of patients present insidiously with malaise, anorexia and arthralgia while some may have features similar to acute hepatitis. Some patients may be asymptomatic. Fulminant hepatic failure is an uncommon presentation. In a report from Lucknow, patients with AIH presented with chronic hepatitis (50%), cirrhosis (34%), acute hepatitis (13%) and cholestatic hepatitis (3%). Associated Autoimmune Diseases About 40% of Indian patients with AIH have other autoimmune disorders. It is important to look for these disorders in patients with AIH. Fatigue in a patient with AIH may be attributed to the liver disease, while undiagnosed coeliac disease, hypothyroidism or vitamin B12 deficiency may be the cause of fatigue. In a report of 38 patients with AIH from Lucknow, other autoimmune diseases seen were diabetes mellitus (4 patients), hypothyroidism (3 patients), vitiligo (2 patients), thrombocytopaenia (2 patients), rheumatoid arthritis (2 patients), Sjögren’s syndrome (1 patients) and autoimmune polyglandular syndrome III (1 patients). Diagnosis The diagnosis is based on clinical features and laboratory abnormalities. Elevation of serum transaminases is more than the elevation of alkaline phosphatase. Hyper-globulinaemia, increased serum immunoglobulin (Ig)G levels, positive autoantibodies: anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver kidney microsomal antibody (anti-LKM), or anti-liver cytosol-1 (anti-LC1) and interface hepatitis on biopsy are the key tests to confirm the diagnosis. The levels of elevation of serum transaminases or serum globulins do not reflect severity of changes seen on liver biopsy. Making a confident diagnosis of AIH is difficult at times. A composite score to make the diagnosis of AIH has been proposed and presented in Table 1.

Figure 1: Pathogenesis of autoimmune hepatitis.

Types of Autoimmune Hepatitis Autoantibody profiles are used to classify AIH into two types; however, these antibodies may not be involved in pathogenesis of AIH. Type 1 or classic AIH is characterised by the presence of ANA and/or ASMA. Anti-LKM-1 and anti-LC1 are found in type 2 AIH. Classic (type 1) AIH occurs predominantly in women in all age groups, while type 2 AIH is generally a disease of girls and young women.

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Table 1: International Diagnostic Criteria for Diagnosis of AIH Parameter Female sex Ratio of elevation of serum alkaline phosphatase vs transaminase

Score +2

>3.0 1.5 to 3 2.0 upper limit normal) 1.5 to 2.0 1.0 to 1.5 1:80 1:80 1:40 15 before treatment and >17 after treatment; Probable AIH: total score 10-15 before treatment and 12-17 after treatment. AIH = Autoimmune hepatitis; IgG = Immunoglobulin G; ANA = Anti-nuclear antibody; SMA = Smooth muscle antibody; LKM-1 = Liver kidney microsomal-1; AMA = Anti-mitochondrial antibody; HLA = Human leucocyte antigen.

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Differential Diagnosis The other viral and non-viral causes of chronic hepatitis need to be ruled out before diagnosing AIH. Treatment Appropriate treatment for AIH can improve the quality of life, prolong survival and delay the need for liver transplantation. The benefits of achieving control of disease activity with immunosuppression has to be weighed against the potential side-effects of immunosuppression. Treatment decisions are thus individualised. Asymptomatic patients with minimal disease activity on liver biopsy or inactive cirrhosis may not need immunosuppression. Corticosteroids are the mainstay of treatment. Prednisolone only regimen (1 mg/kg/day or 60 mg once daily) or combination of Prednisolone (0.5 mg/kg/day or 30 mg once daily) along with Azathioprine at 50 mg once daily are standard regimens to start treatment. In patients with uncontrolled disease despite steroids and azathioprine, treatment with cyclosporine, mycophenolate, tacrolimus and methotrexate have been tried. Immunosuppression is tapered down once control of liver disease is achieved and low dose prednisolone and/or azathioprine is given as maintanence treatment for prolonged time periods. The end point of immunosuppressive treatment is sustained remission without need for medications, however this may be possible in only 10% to 40% of patients. Patients with decompensated autoimmune cirrhosis do well after liver transplantation. RECOMMENDED READINGS 1.

Choudhuri G, Somani SK, Baba CS, et al. Autoimmune hepatitis in India: profile of an uncommon disease. BMC Gastroenterol 2005; 5:27.

2.

Eapen CE, Roberts-Thomson I. Autoimmune hepatitis. J Gastroenterol Hepatol 2006; 21:1756-7.

3.

Gupta R, Agarwal SR, Jain M, et al. Autoimmune hepatitis in the Indian subcontinent: 7 years experience. J Gastroenterol Hepatol 2001; 16:1144-8.

4.

Shankarkumar U, Amarapurkar DN, Kankonkar S. Human leukocyte antigen allele associations in type-1 autoimmune hepatitis patients from western India. J Gastroenterol Hepatol 2005; 20:193-7.

14.8

Alcoholic Liver Disease Rajesh Upadhyay

INTRODUCTION World Health Organization (WHO) estimates that about 2 billion people worldwide consume alcoholic beverages and 76.3 million have diagnosable alcohol-use disorders. India has also, unfortunately, witnessed a steadily increasing consumption of alcohol in the last 2 decades, attributable to socio-economic and demographic changes in population. The per capita consumption of alcohol in India has risen to 4 litres per year although it is still less than in US (16.2 litres per year). The National Family Health Survey (NFHS) 2007 reported that 30% of adult Indians have been consuming alcohol and of which 4% to 13% are daily users. Table 1 shows some recent trends in alcohol consumption in India. Table 1: Recent Changes in Alcohol Consumption Patterns Emergence of wine and beer drinking Increased drinking among women Decreasing age of initiation Shift from urban to rural areas More ‘binge drinking’ Greater social acceptability

PREVALENCE AND RISK FACTORS There is a high prevalence of alcoholic liver disease (ALD) in India and about 50% cases of cirrhosis in India may be due to alcohol abuse. The quantity and duration of alcohol intake are the most important risk factors for the development of ALD. Different alcoholic beverages contain varying quantities of alcohol (Table 2) and the quantity is expressed as units (1 unit = 10 g alcohol). A high daily intake of alcohol ( >60 g in males and 20 g in females) taken for more than 6 to 8 years significantly increases risk of ALD. Indians develop cirrhosis with smaller quantity and duration of alcohol intake. Other risk factors also influence the development of ALD in different individuals given the same dose or duration of alcohol intake (Table 3). Table 2: Content and Quantity of Alcohol in Different Alcoholic Beverages Beverage

Alcohol Content (per cent)

Serving Size (in mL)

Quantity of Alcohol (in grams)

Beer Wine Hard liquor

5 12 40

350 120 30

13.85 10.7 10.0

PATHOPHYSIOLOGY A simple model explaining alcohol related hepatic injury is the three hit explanation: 1. lipogenic hit, 2. inflammatory hit and 3. fibrogenic hit. Liver and gastrointestinal (GI) tract are the main sites of alcohol metabolism. Within the liver, there are two main pathways of alcohol metabolism, alcohol dehydrogenase and cytochrome P-450 (CYP) 2E1. Alcohol dehydrogenase is an enzyme that

converts alcohol to acetaldehyde. Acetaldehyde is subsequently metabolised to acetate via the acetaldehyde dehydrogenase. CYP 2E1 also converts alcohol to acetaldehyde. Table 3: Factors Increasing Risk of Alcoholic Liver Disease Quantity of alcohol (>60 g in male and >20 g in female) Duration of intake (High risk cirrhosis with >10 years intake) Sex (Females susceptibility twice as males) Hepatitis C co-infection (in up to 20% case) Genetic factors Malnutrition Obesity Smoking Iron overload

Lipogenic Hit Alcohol dehydrogenase and acetaldehyde dehydrogenase leads to reduction of nicotinamide adenine dinucleotide (NAD) to NADH. The altered ratio of NAD/NADH promotes fatty acid accumulation through the inhibition of gluconeogenesis and fatty acid oxidation. Inflammatory Hit The CYP 2E1, which is up-regulated in chronic alcohol use, generates free radicals through the oxidation of NADPH to NADP. Chronic alcohol exposure also activates hepatic macrophages, which produce tumour necrosis factor-alpha (TNF-α). TNF-α increases the production of reactive oxygen species. This oxidative stress promotes hepatocyte necrosis and apoptosis, which is exaggerated in the alcoholic, who are deficient in antioxidants, such as glutathione and vitamin E. Free radicals initiate lipid peroxidation, which causes inflammation and fibrosis. Inflammation is also incited by acetaldehyde that, when bound covalently to cellular proteins, forms adducts that are antigenic. Alcohol also increases permeability of intestine thereby releasing endotoxins which ignites Kupffer cells to initiate inflammatory cascade. Fibrogenic Hit The stellate cell is the major source of collagen production which leads to fibrosis. It is normally in a quiescent state and serves as a storehouse for vitamin A. The cytokine tumour growth factorbeta (TGF-β) is a major stimulus for stellate cell activation and collagen production. Other cytokines, such as platelet derived growth factor; connective tissue growth factor and oxidative stress also stimulate stellate cells to produce fibrosis. A simplified pathogenic mechanism for ALD is shown in Figure 1. SPECTRUM OF LIVER DISEASE Chronic alcohol abuse leads to a spectrum of liver disease ranging from fatty liver, alcoholic hepatitis to cirrhosis and hepato-cellular carcinoma. Fatty liver is the earliest change and is almost universally present in heavy alcoholics. It is generally

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a benign condition and usually reverses with abstinence. Alcoholic hepatitis (AH) occurs in 10% to 35% of heavy drinkers who develop necro-inflammation with or without fat infiltration and fibrosis. AH is a precursor of cirrhosis (9 times higher than patients with fatty liver alone) and patients with severe AH have extremely high short-term mortality. Cirrhosis

occurs in 8% to 20% of heavy drinkers. It is advanced, irreversible stage of the disease characterised by hepatic fibrosis and regenerating nodules (micro- or macro-nodular). Hepato-cellular carcinoma may develop in this setting. The spectrum of alcoholic liver disease and the inter-relationship is shown in Figure 2.

Figure 1: Pathogenic mechanisms of alcoholic liver disease. ADH = Alcohol dehydrogenase; CYP2EJ = Cytochrome P2EJ; TNF-α = Tumour necrosis factor-α; PDGF = Platelet-derived growth factor; TGF-β = Tumour growth factor-beta.

874

Figure 2: The spectrum and inter-relationship of alcoholic liver disease.

Survival rate at 5 years is as follows: fatty liver – 70% to 80%, AH or cirrhosis – 50% to 75% and cirrhosis with AH – 30% to 50%. Overall one year survival rate is 80% which drops down to 50% at 5 years. Clinical and laboratory features are powerful prognostic indicators for short-term mortality in acute AH. The Maddrey’s score or discriminant, function [DF = 4.6 (patient’s prothrombin time – control time) + serum bilirubin (mg/dL)]. Patients with DF > 32 (severe AH) have a one-month mortality of approximately 50%. AH patients with hepatic encephalopathy and hepato-renal syndrome have a mortality of 50% and 75%, respectively. Other prognostic indicators used to predict outcome are model for end stage liver disease (MELD) and Glasgow alcoholic hepatitis score (GAHS). The MELD score is calculated based on a patient’s prothrombin time, serum creatinine and bilirubin and is equally sensitive and specific as DF but is more difficult to calculate at bedside. The Childs Pugh score and MELD remain the most widely used systems for the assessment of outcome in patients with alcoholic cirrhosis. CLINICAL FEATURES AND DIAGNOSIS The key to diagnosis is a history of excessive alcohol intake along with features of liver disease (symptoms, physical signs, laboratory data and imaging). Patients frequently deny or understate alcohol abuse, and hence, a clinical suspicion should be confirmed by thorough questioning of family members and close friends as well. Patients with fatty liver and most patients with mild/moderate AH are usually asymptomatic. Some patients have vague symptoms such as anorexia, malaise, nausea or right hypochondrial discomfort/pain. Physical examination in these patients is unremarkable although a mild smooth, non-tender hepatomegaly without any signs of chronic liver disease (CLD) may be present. Patients with more severe AH usually present with fever and signs of hepato-cellular failure, such as jaundice, ascites and encephalopathy. Patients with cirrhosis may remain asymptomatic and others have vague symptoms, such as tiredness, malaise or features of hepato-cellular failure, such as jaundice, ascites, peripheral oedema, etc. Physical signs of CLD is usually present in patients with cirrhosis and can broadly be divided into the following: 1. Signs of portal hypertension, i.e. ascites, splenomegaly and prominent abdominal wall veins. 2. Signs of alcoholism and liver disease, such as jaundice, telangiectasia, palmar erythema, parotid enlargement, clubbing, Dupuytren’s contracture, neuropathy, etc. 3. Signs of hormonal dysfunction (feminisation), such as hypogonadism and gynaecomastia. None of these signs are specific for ALD but parotid enlargement, feminisation and Dupuytren’s contracture are

seen more commonly in ALD. Other signs of extra-hepatic involvement in ALD, such as cardiomyopathy, muscular wasting, pancreatic dysfunction and neuropathy may also be present. LABORATORY TEST Liver Function Test (LFT) The ratio of SGOT: SGPT >2:1 or higher is suggestive of ALD (present in >70% of the cases). Characteristically the SGOT is 2 even in the absence of cirrhosis. Elevated gammaglutamyl transferase is suggestive of alcohol abuse. Serum alkaline phosphatase is elevated markedly in patients with biliary cirrhosis or sclerosing cholangitis. Tests for hepatitis B and C viruses; autoantibodies; serum copper and caeruloplasmin and urinary copper; serum iron and transferrin; and alpha-1 antitrypsin levels should be undertaken based on the clinical suspicion of aetiology of the disease. Psychometric tests in early cases, electroencephalography and evoked potentials may be required for the evaluation of hepatic encephalopathy. Tests for serum or cerebrospinal ammonia and glutamate are not routinely done and may be of more relevance when studied sequentially.

880

Imaging techniques useful in the diagnosis and evaluation of cirrhosis include ultrasonography, computed tomography (CT scan), radionuclide scan and MRI. Of these, ultrasonography is the most informative and is the least costly: apart from assessing liver size and shape, it can detect fatty infiltration,

hepato-cellular carcinoma, ascites, portal hypertension and collateral circulation. Radionuclide scan can reliably differentiate cirrhosis from non-cirrhotic portal hypertension. Endoscopy is performed to detect oesophageal varices (a reliable sign of portal hypertension) and other potential sites of bleeding. When indicated, endoscopic therapeutic measures can be instituted. Ascitic fluid paracentesis is done to determine the characteristics of the fluid. In most of the uncomplicated cases, the fluid has low protein concentration (1.1 g/dL is highly specific for ascites due to portal hypertension, even in the presence of complicating factors. Rarely (in 250/mm3) suggests spontaneous bacterial peritonitis, a complication seen more frequently in patients with low fluid protein level (3.5 1 to 4

1 and 2 Slight 2 to 3 2.8 to 3.5 4 to 6

3 and 4 Moderate >3 6

CTP class A B C

RECOMMENDED READINGS 1.

Angulo P. Non-alcoholic fatty liver disease. N Engl J Med 2002; 346: 1221.

2.

Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128: 343.

3.

de Franchis R. Evolving consensus in portal hypertension report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005; 43: 167.

4.

Rodriguez-Roisin R, Krowka MJ, Herve P, et al. On behalf of the ERS Task Force on Pulmonary-Hepatic Vascular Disorders Scientific Committee. Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 2004; 24: 861.

14.10

Extra-Hepatic Portal Venous Obstruction

DEFINITION AND EPIDEMIOLOGY Extra-hepatic portal venous obstruction (EHPVO) is blockage of the portal vein either in the lumen, in the wall or extrinsic compression from outside the portal vein.EHPVO is a form of noncirrhotic portal hypertension (NCPH) characterised by obstruction (acute, chronic or insidious) of the extra-hepatic portal vein, with or without the involvement of intra-hepatic portal veins or splenic or superior mesenteric veins. Most commonly, the blockage occurs at the site of portal vein formation (90%). Isolated occlusion of the splenic vein or superior mesenteric vein does not constitute EHPVO. Portal hypertension in EHPVO is pre-sinusoidal and the hepatic blood flow is normal or decreased. EHPVO is common in India and is responsible for 6% to 40% of all patients with portal hypertension in various series; this proportion is 30 kg/m2] had evidence of steatosis on ultrasound. The prevalence of NASH is even more difficult to determine as large population-based studies are not possible, as liver biopsy is required for diagnosis of NASH. Urbanisation and associated changes, such as sedentary life style and fat rich diet, and a higher inherited tendency for diabetes mellitus makes Indians more prone to metabolic syndrome or insulin resistance and its manifestations, such as NAFLD and NASH. In a more recent, community-based epidemiological study, 1911 inhabitants of a rural area in West Bengal were studied. The prevalence rates of NAFLD, NAFLD with elevated alanine aminotransferase, and cryptogenic cirrhosis were 8.7%, 2.3%, and 0.2%, respectively. The risk of NAFLD was the highest in those with BMI >25 kg/m 2. Both fatty liver and NASH have been reported in all age groups, including children, with highest prevalence in those between 40 and 49 years of age. Recent studies have shown that NASH occurs with equal frequency in males and females.

Yogesh K Chawla, Sunil Taneja AETIOPATHOGENESIS Several mechanisms have been postulated to explain the pathogenesis of NASH.The ‘multiple hit’ hypotheses is currently favoured.The first ‘hit’ is development of hepatic macro-steatosis as a result of increased lipolysis and free fatty acids. Postulated mechanisms leading to hepatic steatosis include increased lipogenesis, decreased lipid export, and a reduction of free fatty acid oxidation with insulin resistance leading to fatty acid dysregulation. Several potential ‘second hits’ include oxidative stress from reactive oxygen species in the mitochondria and cytochrome P450 enzymes. Other second hits include the presence of endotoxins, cytokines, adipokines, and environmental factors. These complex interactions of the various factors lead to insulin resistance, and serum and liver iron overload and oxidative stress that lead to necroinflammation and fibrosis. NAFLD is associated with metabolic syndrome which leads to insulin resistance resulting in fat deposition in hepatocytes by inducing increased lipolysis, increased uptake of fatty acids and reduced export of very low-density lipoprotein (VLDL). Truncal or central obesity is more strongly associated with NAFLD. In severely obese people, the risk of liver disease increases progressively with the number of features of metabolic syndrome present. Family studies suggest that genetic factors may also play a role in the progression of NAFLD. CLINICAL PRESENTATION Most patients with NAFLD are asymptomatic. Diagnosis most often follows incidental detection of raised liver enzymes or of fatty liver on ultrasound. These abnormalities are usually picked up during evaluation for dyspepsia, malaise or fatigability, prior to medical procedures like organ donation, or routine health examination. A smaller fraction of patients experience symptoms indicative of more serious liver disease and may develop pruritus, anorexia, and nausea. The development of ascites, anasarca, variceal hemorrhage, or symptoms of hepatic encephalopathy indicates decompensated cirrhosis. Similarly, jaundice occurs late in the course of NASH and indicates advanced liver disease. No specific symptoms can distinguish NAFLD or NASH from other type of liver diseases. The diagnosis of NAFLD requires the exclusion of other specific etiologies of liver disease and excessive alcohol consumption. The majority of patients have one or more risk factors for metabolic syndrome, such as type 2 diabetes, obesity, hypertension, or hyperlipidaemia. Clinical examination is often unremarkable though nearly half the patients have mild hepatomegaly. Jaundice or signs of liver failure are absent. DIAGNOSIS NAFLD should be suspected as a cause of asymptomatic elevation of aminotransferases. However, it is important to remember that NAFLD can be present with normal or fluctuating aspartate aminotransferases (AST) and alanine aminotransferases (ALT). In general, ALT is higher than AST. The diagnosis of NAFLD is

885

strongly suggested when metabolic syndrome is present and other specific aetiologies for hepatic dysfunction have been excluded. About 30% to 50% of patients with NASH have either diabetes or glucose intolerance. A fasting lipid profile shows hypertriglyceridaemia in 20% to 80% of patients. Ultrasound may show liver steatosis as a hyperechogenic image, that is,‘bright liver’. Radiologic techniques used to evaluate NAFLD include ultrasound, computed tomography (CT),magnetic resonance imaging, and magnetic resonance spectroscopy (MRS). However, these radiologic modalities are accurate in detecting hepatic steatosis only when there is moderate to severe steatosis. Although these modalities can detect hepatic steatosis, none is able to distinguish simple steatosis from NASH or determine the stage of hepatic fibrosis. Fibroscan (tissue elastography) is a new non-invasive modality in detecting liver fibrosis and its role in various liver diseases, including NAFLD, is still evolving. Liver biopsy is diagnostic, but may not be routinely required. It allows semi-quantitative assessment of amount of fat deposition and of associated necro-inflammation and fibrosis. Typical histological features of NAFLD predominate in perivenular regions, i.e. zone 3 of hepatic acinus and include the presence of macrovesicular steatosis, lobular neutrophilic inflammation, presence of Mallory bodies, ballooning degeneration, lipogranuloma and pericellular fibrosis. Non-Alcoholic Fatty Liver Disease (NAFLD) in India NAFLD is an important cause of liver disease in India. Epidemiological studies suggest prevalence of NAFLD in around 9% to 32% of general population in India with higher prevalence in those with overweight/obesity and those with diabetes/ prediabetes. Indian population has a higher body fat content and abdominal adiposity; the latter is particularly associated with insulin resistance and thus NAFLD, even if the BMI is normal. Indians also more often have atherogenic dyslipidaemia

(combination of hyper-triglyceridaemia, low high-density lipoproatein (HDL)-cholesterol and high low-density lipoprotein (LDL)-cholesterol), and diabetes. These factors, along with urbanisation and associated sedentary life-style and fat-rich diet may make Indians particularly prone to metabolic syndrome, insulin resistance, and NAFLD/NASH. In Indian patients with NAFLD, the disease is usually milder, often with either no or mild inflammation and fibrosis on liver biopsy even in those with elevated liver enzymes. Role of NAFLD in Cryptogenic Cirrhosis and Hepato cellular Carcinoma (HCC) NASH is associated with cryptogenic cirrhosis. Patients with NASH and fibrosis can progress to cirrhosis with the risk varying from 0% at 5 years to 12% over 8 years. It has been observed that when patients progressed to cirrhosis, inflammation and fat disappeared from their liver biopsy. A number of epidemiologic studies of cryptogenic cirrhosis have estimated that antecedent NASH constitutes a large proportion of cryptogenic cirrhosis cases. An early asymptomatic phase followed by appearance of decompensated cirrhosis is now a recognised complication of NASH. Once cirrhosis develops, patients are at high-risk of developing HCC. TREATMENT Currently, there are no approved therapies for NAFLD. There are many proposed agents being evaluated currently, each targeting a different step in the pathogenesis of development of hepatic steatosis or progression to steatohepatitis.The proper dosing, duration of treatment, safety, and tolerability of these treatments is still evolving (Table 1). At the present time, the initial approach involves dietary modification based on the metabolic profile (obesity, diabetes, hyperlipidaemia, hypertension) and getting patients to increase

Table 1: Therapy for Non-Alcoholic Fatty Liver Disease Treatment Insulin sensitisers Metformin

Thiazolidinediones Pioglitazone and Rosiglitazone (Not in use) Antioxidants Vitamin C and E Hepatoprotective Agents Betaine Ursodeoxycholic acid Pentoxifylline Lipid lowering Drugs Statins, poly unsaturated fatty acid (PUFA) and Probucol L-Carnitine 886

Effects

Mechanism of Action

Side Effects

Enhance weight loss Improve insulin sensitivity and plasma glucose levels Reduce metabolic syndrome

Decrease production of hepatic glucose and increasing the uptake of peripheral glucose by skeletal muscle and fatty acid oxidation

Gastrointestinal (GI) intolerance

Improve ALT, histological steatosis Stimulate free fatty acid (FFA) oxidation, and inflammation increase adiponectin expression

Weight gain and lower extremity oedema

Improve ALT and steatosis

Decrease oxidative stress

No significant adverse effects

Improves ALT, steatosis and inflammation Marginally significant benefit on various liver enzymes Improves ALT and histology

Increases S-adenosylmethionine levels Bile acid, which has various cytoprotective, GI side effects: diarrhoea,motility anti-apoptotic and immunomodulatory disorders properties It functions by inhibiting TNF-α Minor GI side effects

Improves aminotransferases, steatosis and slows progression of fibrosis

Lowers elevated triglycerides and improves low HDL

Improve steatosis, and aminotransferases

A modulator of mitochondrial FFA transport and oxidation

Risk of hepatotoxicity reduced HDL with probocul, safety concern in patients at high cardiovascular risk Well tolerated

Various other treatment modalities used for NAFLD have included treatment of risk factors like diabetes mellitus and hyperlipidaemia, and use of insulin sensitizing agents such as biguanides (metformin), thiazolidinediones (rosiglitazone, pioglitazone) and antioxidants and various hepatoprotective agents. Weight loss, thiazolidinediones (especially pioglitazone), and antioxidants have been extensively evaluated. Weight loss is safe and improves histological disease activity in NASH, but more than 50% of patients fail to achieve target weight loss. Thiazolidinediones improve steatosis and inflammation, but cause significant weight gain. Studies show conflicting results with antioxidants. Antioxidants are heterogeneous in relation to type and dose of drugs, their duration of action and implementation of life-style intervention. Other agents like pentoxifylline, telmisartan, L-carnitine and vitamin E are being evaluated.

CONCLUSION NAFLD is a major cause of liver-related morbidity in both developed and developing countries. It is frequently associated with the presence of insulin resistance. There is increasing evidence that NAFLD can progress to cirrhosis and liver failure. Physicians should actively check for the presence of NAFLD in those who are overweight and/or diabetic. There is no established treatment for NAFLD. Treatment usually is directed toward optimising body weight and role of pharmacological therapy is under evaluation. RECOMMENDED READINGS 1. 2. 3. 4.

5.

6. 7.

8.

Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221-31. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221-31. Duseja A, Chawla Y. Nonalcoholic fatty liver disease in India: how much? how soon? Trop Gastroenterol 2005; 26:1-3. Duseja A, Sharma BK, Kumar A, et al. Nonalcoholic fatty liver in a developing country is responsible for significant liver disease. Hepatology 2010; 52:2248-9. Farrell GC, Chitturi S, Lau GKK, et al. The Asia-Pacific Working Party on nonalcoholic fatty liver disease (NAFLD). Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: Executive summary. J Gastroenterol Hepatol 2007; 22:775-7. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology 2006; 43:S99-112. Musso G, Gambino R, Cassader M, et al. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010; 52:79-104. Sanyal AJ, American Gastroenterological Association.AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123:1705-25.

Non-Alcoholic Fatty Liver Disease

levels of physical activity. Even small changes in body weight (0.5 to 3 kg) can achieve improvement in hepatic necroinflammatory activity and/or radiologic resolution of hepatic steatosis and/or reversal of insulin resistance. The role of weightreducing pharmacologic regimens, such as phentermine, sibutramine, and orlistat in NAFLD is not established. The most consistent and spectacular evidence for treatment efficacy against NASH comes from literature on obesity surgery in which highly reproducible benefits against steatosis, steatohepatitis, and hepatic fibrosis have been reported. In patients with morbid obesity, bariatric surgery may be considered.

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14.12

Acute Liver Failure SK Acharya , Shalimar

INTRODUCTION The term liver failure is used when the survival of an individual is endangered as a consequence of multiple metabolic and haemodynamic disturbances resulting from severe acute or chronic liver injury. In a clinical setting, hepatic injury is usually recognised by appearance of jaundice and liver failure is recognised by occurrence of encephalopathy, ascites or coagulopathy.

Table 1: Various Causes of Acute Liver Failure

Authors prefer to categorise liver failure into three distinct groups: acute liver failure (ALF), subacute hepatic failure (SHF) and chronic liver failure (CLF). ALF is defined as occurrence of hepatic encephalopathy with or without coagulopathy within 4 weeks of the onset of acute hepatitis. Occurrence of progressive ascites with or without encephalopathy after 4 weeks, but before 6 months of the onset of acute hepatic illness is termed as SHF. Occurrence of progressive ascites or encephalopathy after 6 months of recognisable or unrecognised hepatic illness is considered as CLF.

Drugs

Broad Category

Individual Aetiological Agents

Infections

Hepatotropic viruses (A-E) Cytomegalovirus Herpes simplex virus Wilson’s disease Acute fatty liver of pregnancy Galactosaemia Paracetamol Rifampicin and isoniazid Sodium valproate Halothane Zidovudine Didanosine Amanita phalloides Bacillus cereus Akee fruit (hypoglycin)

Metabolic diseases

Toxins

Table 2: Causes of Acute Liver Failure in India Author Year

DEFINITION AND NOMENCLATURE Trey and Davidson define ALF as occurrence of encephalopathy with or without coagulopathy within 8 weeks of onset of symptoms of acute hepatitis in an individual without any history of pre-existing liver disease. Patients who develop ALF within 7 to 10 days of the onset of icterus have significantly higher survival rates than those who develop encephalopathy later. Therefore, in Western countries, ALF is classified into hyperacute if encephalopathy develops within 10 days of onset of icterus and acute if it occurs between 10 days and 4 weeks of onset of jaundice. Liver failure occurring more than 4 weeks after the onset of acute hepatic illness manifests with progressive ascites. In these patients, encephalopathy as a presenting feature is extremely rare. This condition, named as (SHF), behaves differently than ALF and majority do not survive beyond 6 months. The overall mortality rate is 70%; in addition, 60% of the survivors develop chronic sequelae. AETIOLOGY OF ACUTE LIVER FAILURE

888

The causes of ALF are listed in Table 1. Geographical variations in the occurrence of common causes of ALF are well recognised and probably influence the clinical behaviour of such patients. ALF in the Eastern World, particularly in the developing world, is predominantly caused by various hepatotropic viruses (Table 2). Conditions like paracetamol overdose, metabolic liver diseases like Wilson’s disease, acute fatty liver of pregnancy, amanita poisoning and druginduced liver injury are important causes of ALF in the West, whereas these are extremely infrequent in the Eastern World (Table 3).

No. of Patients

Causes HAV HBV HCV HDV HEV Mixed Non-A, Drugs Non-E

Acharya 1999 458 et al Khuroo 1997 119 et al Jaiswal 1996 95 et al

4%

11% 4%

0%

23% 6%

3%

15% 2.5% 2.5% 38% NR

38.6% 0.8%

4%

27% 2%

15%

5.2% 41% 4%

47%

5%

0%

HAV = Hepatitis A virus; HBV = Hepatitis B virus; HCV = Hepatitis C virus; HDV = Hepatitis D virus; HEV = Hepatitis E virus; NR = Not reported.

Table 3: Differences in Aetiology of Acute Liver Failure (ALF) in Various Geographical Areas

Viral Drugs Other Viruses

Drugs

India

USA

UK

95% 4.5% 0.5% HEV, HBV, Mixed viral infection Anti-tuberculars

60% 30% to 35% 5% Cryptogenic HBV: 15% HAV: 8% to 10% Acetaminophen

30% 50% to 60% 60% 15% to 20% 10% 10% to 15% NANB HBV HBV HAV HAV Acetaminophen Other drugs

France

NANB = Non-A, non-B viral hepatitis.

CLINICAL PRESENTATION AND NATURAL COURSE Demographic and clinical profile of 423 consecutive patients with ALF admitted to AIIMS, New Delhi, during 1987 to 1993 is summarised as follows. Most of the patients (n = 334) were below 40 years of age. Females outnumbered males. Twenty-fiveper cent of females were pregnant in contrast to a 3% pregnancy rate in the general population, indicating that pregnant women who develop acute viral hepatitis are more likely to develop ALF

ALF and Pregnancy Mortality is similar in pregnant and non-pregnant women, and is independent of the cause or trimester Pregnancy per se should not be regarded as a poor prognostic factor COMPLICATIONS Complications encountered in patients with ALF may involve several organ systems, either in isolation or in combination. Neurologic Manifestations Neurologic complications include rather distinct, but overlapping syndrome of cerebral oedema manifesting as increased intracranial pressure (ICP) and encephalopathy. The grading of encephalopathy is depicted in Table 4. Table 4: Grading of Encephalopathy in Acute Liver Failure (ALF) I II III IV

Loss of sleep rhythm, drowsiness, confusion, hepatic flap Features of grade I encephalopathy with loss of sphincter control Unconsciousness, no response to oral commands, but responds to painful stimuli No response to pain, deep unconscious state

In addition to changes in mental status, signs of raised ICP include myoclonus, focal seizures, decerebrate postures, absent pupillary reflexes and hyperventilation. Papilloedema is usually absent. Lowering the ICP in patients with ALF is important because raised ICP decreases cerebral perfusion pressure and oxygenation of the brain tissue. Unlike porto-systemic shunting, which is the major cause of encephalopathy in patients with cirrhosis, encephalopathy in ALF is usually multifactorial. Ammonia, mercaptans, biological amines, short chain fatty acids, pseudo-neurotransmitters from aromatic aminoacids, gamma amino butyric acid (GABA) have been implicated in the causation of encephalopathy. Identification of elevated ICP is important because cerebral oedema resulting in brainstem herniation is the commonest cause of death among patients with ALF. Renal Renal failure occurs in 30% to 70% of patients with ALF in western countries where drugs and toxins are the usual causes of ALF. In contrast, renal failure occurs in only 3% to 5% of Indian patients where hepatotropic viruses are the predominant cause of ALF. Presence of renal failure is considered to be a bad prognostic indicator. Decreased water clearance, electrolyte imbalance, increased ammonia production due to raised blood urea are sequelae of renal failure which aggravate encephalopathy and cerebral oedema in patients with ALF. Pulmonary Pulmonary infection is the commonest form of respiratory problem encountered in ALF. In addition, acute respiratory

distress syndrome, atelectasis, aspiration and pulmonary oedema may occur. Cardiovascular Cardiac arrhythmias may occur due to electrolyte imbalance, hypoxaemia, acidaemia, or during placement of pulmonary artery catheter. Usually patients with ALF have a hyperdynamic circulatory state similar to septic shock. This may be caused by decreased systemic vascular resistance subsequent to a vasodilator substance which under normal conditions is cleared by liver. Candidate vasodilator substances implicated in ALF include endotoxins, nitric oxide, glucagon, substance P, vasoactive intestinal polypeptide, GABA, atrial natriuretic factor and bradykinin.

Acute Liver Failure

than non-pregnant women. Most patients (88%) had a prodrome preceding the icteric illness; mean duration of the prodrome was 4.7 days. The interval between prodrome and onset of encephalopathy was similar in survivors and non-survivors indicating that rapidity of onset of encephalopathy did not influence the outcome. The survival rate using conservative and aggressive supportive therapy was 34%.

Coagulopathy Most proteins that promote or inhibit coagulation are synthesised in the liver. Further, Kupffer’s cells in the liver act as scavengers for the activated coagulation factors in the circulation. With the exception of factor VIII, the levels of all coagulation factors are reduced in patients with ALF. The coagulation test that can be easily performed in most laboratories is prothrombin time. Almost all patients with ALF show a variable degree of prolonged prothrombin time. Prothrombin time is a good indicator for prognosis. Other coagulation problems that may be encountered in patients with ALF are thrombocytopaenia (which may be due either to marrow suppression or hypersplenism), disseminated intravascular coagulation and fibrinolysis. Each of these conditions may cause life-threatening bleeding, such as intracranial haemorrhage and gastrointestinal (GI) bleeding. Sepsis Sepsis occurs in 55% to 80% of patients with ALF. Bacterial infections are the commonest cause (70% to 80%) of sepsis and fungal infection occur in 10% to 20% of these patients. The reasons for this propensity to develop sepsis include abnormal opsonisation due to reduced hepatic synthesis of proteins like fibronectin, impaired Kupffer cell function, decrease in complement synthesis and neutrophil dysfunction. Metabolic Three distinct metabolic complications have been documented in patients with ALF. Hypoglycaemia occurs due to decreased insulin clearance, impaired gluconeogenesis, and loss of glycogen store due to liver damage. Both acidosis and alkalosis can occur in ALF. Respiratory alkalosis can occur due to central neurogenic hyperventilation, whereas depression of respiratory centre due to raised ICP may cause respiratory acidosis. Acidosis can also result from hypoxaemia or hypotension leading to accumulation of lactate, pyruvate, citrate, acetoacetate, and free fatty acids (FFAs). Electrolyte imbalance is common in patients with ALF secondary to renal failure, dehydration, drugs, tissue damage, and acid-base imbalance. PROGNOSIS The assessment of prognosis soon after initial presentation is crucial in order to allow most efficient use of available therapeutic options, particularly orthotopic liver transplant (OLT) which is increasingly becoming available in the developing countries like India. Arterial ammonia concentration higher than 124 µmol/L, associated with severe hepatic encephalopathy, cerebral oedema

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and high mortality. Prognostic markers in Indian patients with ALF are: age >40 years, clinical evidence of cerebral oedema at admission, serum bilirubin >15 mg/dL and prothrombin time >25 seconds more than the normal. More than 90% of the patients with ALF having three or more of these factors die (Tables 5 and 6). Anti-tuberculosis therapy (ATT) induced ALF has a poor prognosis as compared with viral hepatitis.

of respiratory and cardiovascular support particularly in the presence of cerebral oedema is probably responsible for modest improvements in the survival. However, if OLT is available, early referral of such patients may reduce greater posttransplant mortality and morbidity. The essential supportive measures are listed in Table 7. MANAGEMENT OF COMPLICATIONS

Table 5: King’s College Prognostic Criteria in Acute Liver Failure (ALF), Predicting High Mortality Non-Paracetamol-Induced ALF

Paracetamol-Induced ALF

Prothrombin time >100 seconds or Any three of the following Age 40 years Aetiology: non-A, non-B hepatitis Drug-induced hepatitis Icterus-encephalopathyinterval >7 days Prothrombin time >50 seconds (INR >3.5) Serum bilirubin >17.5 mg/dL

Plasma pH 100 seconds (INR >6.5) and serum creatinine >3.4 mg/ dL in patients with grade 3 to 4 encephalopathy

Table 6: Clichy Criteria (France) for Poor Prognosis in Patients with Acute Liver Failure Factor V levels < 20% of normal in patients < 30 years of age Factor V levels < 30% of normal in patients > 30 years of age

Causes of Death Survival rate of patients with ALF is approximately 34%. Twothirds of deaths occur within the first 72 hours of hospitalisation, indicating that any therapeutic intervention for such patients must be instituted soon after hospitalisation, and that early referral of such patients to advanced centres should be encouraged. The median survival time is 4 days. Cerebral oedema, sepsis, renal failure, and GI bleeding are the most important causes of death. TREATMENT All the patients diagnosed to have ALF should ideally be admitted to an intensive care unit. The use of aggressive monitoring, and

Cerebral Oedema Patients with advanced grades of encephalopathy and/or with overt cerebral oedema need measures to prevent further rise in ICP and specific therapeutic intervention to decrease ICP. Measures to prevent rise of ICP include positioning of head and trunk at 35° to 40° angle above horizontal, avoiding unnecessary motions of the head, and avoiding hypoxaemia, hypercapnoea, fluid overload and acid-base imbalance. For treating raised ICP, rapid infusion of mannitol (20%) at a dose of 100 mL is the first step; it can be repeated hourly as long as patient maintains adequate renal function. Usual recommendation is to keep the ICP below 25 mm Hg; however, it is probably more important to maintain the cerebral perfusion pressure (mean arterial pressure minus intracranial pressure) above 50 mm Hg. The placement of intra cranial transducers in patients with ALF may be associated with life-threatening bleeding and sepsis. In patients with advanced encephalopathy without overt features of cerebral oedema and intact renal function, authors use 20% mannitol at a dose of 1 g/kg body weight every 8 hourly. Hyperventilation using a ventilator and administration of corticosteroids has not been found to be useful in the treatment of cerebral oedema. Induction of barbiturate coma may be used as a rescue therapy if mannitol fails. Phenobarbital is used at an initial intravenous dose of 5 mg/kg followed by an infusion rate of 1 to 3 mg/kg per hour. However, hypotension is a major problem during such therapy and intra-arterial pressure monitoring is necessary during such therapy. Seizures might complicate advanced hepatic encephalopathy and worsen prognosis, phenytoin prophylaxis neither improves cerebral oedema nor survival.

Table 7: Supportive Therapy in Acute Liver Failure

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Hospitalisation in intensive care unit Detailed clinical evaluation and assessment of grade of encephalopathy, cerebral oedema and prognostic indicators Laboratory investigations Complete blood counts, platelet count, smear for malarial parasite Blood grouping Electrolytes, blood urea nitrogen, creatinine Serum bilirubin, transaminases, albumin, alkaline phosphatase, amylase Prothrombin time, fibrin degradation products Arterial blood gases, arterial ammonia Urine analysis, urine output Bacteriologic evaluation: blood, endotracheal aspirate in intubated patients and urine culture for bacteria and fungi Serology including HBsAg, IgM anti-HBc, IgM anti-HEV, IgM anti-HAV, anti- HCV, anti-HDV 24-hour urine copper, serum copper, serum caeruloplasmin, anti-nuclear antibody, anti-smooth muscle antibody, anti-liver kidney microsomal antibody Bedside ultrasonography to rule out liver abscess, acute hepatic venous out flow tract obstruction Other measures Central venous line insertion Chest X-ray Assisted ventilation in patients with cerebral oedema and grade IV encephalopathy Intravenous H2 blockers, nasogastric tube placement, blood glucose, monitoring for gastrointestinal bleed, oliguria, sepsis Nutritional supplement through nasogastric tube Optional measures Placement of extradural or subdural transducers to measure ICP Prophylactic broad-spectrum intravenous antibiotic and antifungal therapy Dialysis, if acute renal failure supervenes

Renal Failure In patients with ALF developing oliguria despite maintenance of adequate central venous pressure, low dose dopamine (2 to 2.5 µg/kg/hr) may be beneficial. However, mainstay of management of renal failure in patients with ALF is haemodialysis or continuous arterio-venous haemofiltration or continuous veno-venous haemofiltration. However, these procedures are associated with problems, such as, hypotension, aggravation of cerebral oedema due to fluid overload and increased risk of bleeding. The only satisfactory treatment in patients with ALF associated with renal failure seems to be liver transplant. Coagulopathy Coagulopathy associated with ALF is currently not preventable. Prophylaxis use of fresh frozen plasma (FFP) and vitamin K has not been shown to prevent bleeding. However, once bleeding occurs, FFP and platelet transfusion may help. Other Complications Hypoglycaemia, hypokalaemia and metabolic acidosis should be looked for and treated promptly. SPECIFIC THERAPIES Many therapeutic measures have been tried in an attempt to improve liver function, to reduce hepatocyte necrosis, or to improve encephalopathy. Acetylcysteine N-acetylcysteine (NAC) is useful in patients with paracetamol overdose, probably through an increase in the concentration of hepatic glutathione which converts paracetamol to its non-toxic metabolite. However, it is most effective if given within 8 hours of the drug overdose. Even in non-paracetamol ALF patients, this drug may produce improvement in haemodynamic parameters like cardiac index and mean arterial pressure, leading to improved tissue oxygen delivery. Recent data suggests NAC is well tolerated in this group and is associated with improved non-transplanted survival, but only in those treated early in the course and with Grade I-II encephalopathy. Antivirals Lamivudine for hepatitis B or acyclovir for HSV related ALF, might improve outcomes, but data is scarce. L-Ornithine L-Aspartate (LOLA) LOLA does not improve ammonia concentration, hepatic encephalopathy or survival in ALF. Novel agents like L-ornithine phenylacetate are being investigated. Prostaglandins Intravenous prostaglandin E1 has been used in patients with ALF with conflicting results. Other Forms of Therapy For Amanita phalloides poisoning, infusions of penicillin and silymarin appear to be effective. Penicillin antagonises the effect

of mushroom toxin, amatoxin, and silymarin blocks its hepatocellular uptake. Liver Transplantation (LT) Urgent LT is now the standard therapy for ALF in individuals who, on clinical and laboratory criteria, have a less than 20% chance of survival. Contraindications to LT include irreversible brain damage, uncontrolled bacteraemia, human immuno-deficiency virus infection, concurrent malignant disease and the presence of failure of any organ which would preclude a satisfactory outcome.

Acute Liver Failure

Sepsis Sepsis, as described above, is the second major cause of death among Indian patients with ALF. Gram-negative bacteria are the major cause of sepsis in these patients. Prophylactic parenteral antibiotics using third-generation cephalosporins may reduce the incidence of sepsis.

Auxiliary liver transplantation is another treatment option for ALF. The native liver is left in situ. The procedure aims to provide temporary liver support until the native liver recovers. In one such study, native liver regenerated in 68% of those surviving more than 3 months. At this stage, immunosuppression can be withdrawn in the majority of patients and the donor liver can either be removed surgically or left in place to atrophy. In India, cadaveric LT has not been able to take off due to lack of organisational priority, severe donor shortage and lack of awareness. Living-donor liver transplant (LDLT) programme is being offered in some institutions in India. Other Methods of Liver Support The frequent lack of donor livers for urgent transplantation has necessitated the use of liver support or replacement therapies until a liver becomes available. Several different approaches have been tried. All of these methods involve the use of very expensive and complicated equipment and their role awaits clarification by randomised clinical trials. These include extracorporeal liver assist devices, bioartificial liver, and extracorporeal wholeorgan perfusion. Hepatocyte Transplantation Uncontrolled trials using infusion of human hepatocytes into the splenic artery or portal vein have shown encouraging preliminary results. The mass of hepatocytes required to provide adequate support remains unknown. Therapies Not Useful in Acute Liver Failure 1. Lactulose 2. L-ornithine L-aspartate 3. Branched-chain amino-acids 4. FFP transfusion in absence of bleeding 5. Enteral decontamination 6. Prophylactic phenytoin 7. Prophylactic hyperventilation for raised intracranial hypertension PREVENTION Public health measures like availability of safe drinking water; screening of blood in blood banks; vaccination for hepatitis B and use of disposable syringes will reduce the incidence of hepatitis A, B and E viral infections, which are the major causes of ALF in our country. Empirical use of ATT should be avoided, whenever possible. RECOMMENDED READINGS 1.

2.

Kumar R, Shalimar, Bhatia V, et al. Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome. Hepatology 2010; 51: 1665-74. Riegler JL, Lake JR. Fulminant hepatic failure. Med Clin North Am 1993; 77: 1057-83.

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14.13

Inherited Metabolic Disorders of the Liver

INTRODUCTION Inborn errors of metabolism include a variety of disorders with varied presentations and pathophysiology. These may present as an acute life-threatening illness in the neonatal period or may manifest as chronic liver disease during adolescence and progress to liver failure, cirrhosis or hepato-cellular carcinoma. In the United States of America, 5% of liver transplants are performed for metabolic liver diseases. Although liver transplantation is lifesaving for these patients, new non-transplant treatment options have become available for some of these conditions. The presenting features of metabolic liver diseases are diverse and can range from hypoglycaemia, hyperammonaemia, psychomotor retardation, elevation of aminotransferase levels, hepatosplenomegaly, acidosis, ascites, jaundice, bleeding diathesis, coma, short stature or failure to thrive. An infant presenting with cholestasis should undergo evaluation for metabolic liver disease; as should an infant with progressive neuromuscular disease; developmental delays or regression of developmental milestones. A history of consanguinity in parents, multiple miscarriages or early infant death may suggest metabolic derangement. History of undiagnosed liver disease, progressive neurological or muscular disease or undiagnosed developmental delay in family members should raise suspicion. Introduction of certain foods may correlate with the onset of symptoms, as in urea cycle defects, galactosaemia or fructosaemia. Since patients with metabolic liver disease often present with recurrent symptoms, it is important to investigate the patient early. Apart from screening tests (Table 1), liver biopsy can be a useful diagnostic tool. Serum and urine samples should always be saved and frozen for definitive studies. Table 1: Screening Laboratory Tests for Metabolic Liver Disease Serum electrolytes Anion gap Serum glucose Serum ammonia Serum organic and amino acid Urine organic acid Hepatic enzymes Coagulation profile Serum lactate Urine for reducing substance Peripheral blood smear Evaluation for haemolysis Serum alpha-1 antitrypsin levels Alpha-1 antitrypsin phenotype

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WILSON’S DISEASE AND HAEMOCHROMATOSIS Refer to chapter on Wilson’s disease and Haemochromatosis in Metabolism Section.

P Advaitham ALPHA-1 ANTITRYPSIN DEFICIENCY Alpha-1 antitrypsin deficiency is inherited as an autosomalrecessive disorder. The gene responsible is located on chromosome 14q31. Alpha-1 antitrypsin is synthesised and secreted predominantly by the liver. It is present in tears, duodenal fluid and saliva. Homozygous protease inhibitor phenotype ZZ (PiZZ) alpha-1 antitrypsin deficiency is the most common genetic cause of liver disease in children. In adults, it is associated with chronic liver disease and hepato-cellular carcinoma. Currently, there is no evidence that heterozygous forms, such as PiMZ, PiMS, PiSZ cause liver disease in children; their role in adults remains unclear. The hypothesis to explain liver damage include: proteolytic imbalance, abnormal immune response and inefficient over-accumulation of the mutant alpha-1 antitrypsin Z protein in liver cells. Clinical Features Neonatal jaundice occurs between 2 and 3 weeks of age but this may occur any time within the first 4 months of life. Jaundice usually lasts for 2 to 3 months, but may persist for up to one year. Hepatosplenomegaly is seen in 50% of symptomatic infants. Biochemical analysis shows both cholestasis and hepato-cellular damage. Liver disease may also occur in late childhood or adolescence. The affected children may present with signs of decompensated liver disease with portal hypertension. In adults, this disorder manifests clinically at some point during their lifetime in two-thirds of subjects with homoz ygous form of the deficiency and the rest are asymptomatic. This will present in about 40% of adult cases as cirrhosis of liver with portal hypertension including ascites and variceal bleeding. Hepato-cellular carcinoma occurs in up to 40% of cirrhotics due to this disorder. Diagnosis Liver biopsy shows characteristic periodic acid-Schiff (PAS) positive, diastase-resistant globules in the endoplasmic reticulum of hepatocytes. Alpha-1 antitrypsin phenotyping and serum alpha-1 antitrypsin levels are diagnostic. Treatment In the absence of cirrhosis of liver, alpha-1 antitrypsin deficiency is managed by supportive therapy. Avoidance of smoking and hepatotoxic agents (including alcohol) is recommended to prevent lung and liver disease, respectively. In advanced liver disease, liver transplant is the treatment of choice. Other therapies that have been tried include synthetic androgens, such as danazol to raise the alpha-1 antitrypsin level, inhalational alpha-1 antitrypsin in cases with pulmonary disease and gene replacement therapy. GLYCOGEN STORAGE DISEASES In glycogen storage diseases (GSDs), enzyme deficiencies cause impaired glucose production and accumulation of abnormal

GSD type I (Von Gierke’s) is due to deficiency of glucose-6phosphatase which is the most common type of GSD seen clinically. It manifests as profound hypoglycaemia, hepatomegaly due to adenomas, retarded growth, hyperlipidaemia, lactic acidosis and hyperuricaemia. Liver biopsy and direct measurement of glucose-6-phosphatase activity in the liver tissue are confirmatory. Carbohydrate challenge will demonstrate the absence of any rise in blood sugar level. Treatment is aimed at maintaining normal blood glucose, by high carbohydrate meals taken at frequent intervals. In children, frequent feeding during the day and nocturnal feedings through nasogastric tube may be required. In adults, daytime frequent feeding alone is advised. Corn starch undergoes slow degradation to glucose and steadily releases glucose into the system, hence should be the major ingredient in the diet. GSD type III (debranching enzyme deficiency) is due to deficiency of amylo-1,6-glucosidase (debranching enzyme). The development of hepatic fibrosis and, rarely, progression into end-stage liver disease due to the direct toxic effects of abnormal form of glycogen in the liver are distinguishing features of this disorder; in addition, hypoglycaemia, growth failure, progressive muscle weakness and enlarged liver are seen. The diagnosis is made by liver histology and confirmed by direct measurement of debranching enzyme activity using 14 C-labelled glucose. The treatment of choice is liver transplant apart from nutritional support in the form of high-protein, low carbohydrate diet and corn starch therapy for refractory hypoglycaemia. GSD type IV (amylopectinosis) is caused by the absence of branching enzyme β-1,4-glycosyl transferase, which results in the formation of amylopectin-like polysaccharides. Its deposition in the liver leads to hepatic fibrosis and early cirrhosis. This rare disorder presents clinically as hepatosplenomegaly, signs of liver dysfunction; failure to thrive and muscular hypotonia. The diagnosis is confirmed by demonstrating pale, basophilic deposits within the liver cells and micronodular cirrhosis with broad bands of fibrous tissue. Liver transplant is curative; however, providing nutritional support in the form of high-protein and low carbohydrate diet can control the disease. TYROSINAEMIA Tyrosinaemia is an autosomal recessive disorder that affects numerous organ systems, including liver, kidneys and peripheral nerves. The underlying defect is a deficiency of fumaryl-acetoacetate hydrolase, leading to accumulation of toxic metabolites. The acute form of this disorder presents as hypoglycaemia, ascites, bleeding diathesis, anorexia, irritability and jaundice in the first 6 months of age. Serum tyrosine, methionine and alphafoetoprotein levels are elevated. Chronic forms usually present after one year of age with hepatomegaly, enlargement of kidneys, rickets, growth retardation, cirrhosis and hepatocellular carcinoma. Diagnosis can be confirmed by estimation of fumaryl-aceto-acetate hydrolase enzyme in the liver tissue.

Dietary restriction of tyrosine and phenylalanine. NTBC [2-nitro4-(trifluoromethyl benzoyl)-cyclohexane-1,3-dione], a potent inhibitor of hydroxyphenylpyruvate dehydrogenase, which reduces the production of toxic intermediates that damage the liver and the kidney has been shown to be useful. Liver transplantation normalises the enzyme activity and liver function. CYSTIC FIBROSIS Cystic fibrosis (CF) is an autosomal recessive, multiorgan disorder. The responsible gene is located on the long-arm of chromosome 7. Liver disease may manifest in the newborn period, and neonatal cholestasis has been identified in up to 30% of patients. Liver disease is becoming more common since the mean duration of survival of patients with CF has increased with improvements in treatment. Up to 30% of patients may have clinical or symptomatic liver disease after neonatal period. Focal biliary cirrhosis is the pathognomonic lesion; however, 5% of patients have multilobular biliary cirrhosis.

Inherited Metabolic Disorders of the Liver

glycogen in the liver causing organ damage, leading to formation of hepatic adenomas and rarely progressing into hepato-cellular carcinoma. Clinically, three types of GSDs are common (type I, III and IV).

Ursodeoxycholic acid (20 to 30 mg/kg body weight) has shown improvement in cholestasis and nutritional status. Orthotopic liver transplantation (OLT) has been successfully performed for patients with portal hypertension and stable pulmonary function. PORPHYRIA This diverse group of metabolic derangements are due to errors in haeme synthesis. For some of these conditions, liver is the primary site of expression. Haeme synthesis occurs both in liver (15% to 20%) and bone marrow (70% to 85%). The term acute porphyria refers to the occurrence of acute neurological attacks, which are often recurrent and life-threatening. A majority of porphyrias manifest with neurological or cutaneous symptoms. Hepatic involvement is variable. In general, acute porphyrias may be associated with elevated serum levels of aminotransferases and bile acids; this abnormality worsens during acute attacks. Liver biopsy may show fatty change and iron deposition. Although the changes are minor, these patients are at an increased risk of developing hepato-cellular carcinoma. Porphyria cutanea tarda and hepatoerythropoietic porphyria are most commonly associated with hepatic complications like enlarged liver due to fatty changes, inflammatory and granulomatous changes. Siderosis and fibrosis may lead to cirrhosis and liver failure. In porphyria cutanea tarda, the liver damage may be due to the metabolic abnormality or to additional factors, such as alcoholism and hepatitis C virus infection. In protoporphyria, protoporphyrin may have a direct toxic effect on the liver. Increased urine porphobilinogen may suggest the diagnosis. To differentiate between different types of porphyria, urine and stool samples should be sent for porphyrin studies. UREA CYCLE DEFECTS Although these syndromes are not associated with liver disease, the basic genetic defect is located in the liver, and their manifestation may mimic other metabolic liver diseases. The most common defect identified is ornithine transcarbamylase deficiency.

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These defects, with the exception of arginase deficiency, present as acute life-threatening events in the neonatal period. Infants are usually normal in the first 24 to 72 hours, since feeding during this period provides the initial protein load for ammonia production. Symptoms are irritability, seizures, coma, vomiting, hypertonia, lethargy and respiratory distress. Plasma ammonia reaches >3,400 µg/dL. Blood urea nitrogen level is low. Allopurinol loading test (300 mg orally) leads to excretion of orotic acid 10 to 20 fold greater than normal. Serum ammonia level should be restored to normal. Haemodialysis is more effective than exchange transfusions. On stabilisation, introduction of low-level dietary protein (0.5 to 1g/kg) may be started. Arginase deficiency usually presents with spastic diplegia, quadriplegia or seizures. HEREDITARY FRUCTOSAEMIA This disorder, caused by fructose aldolase deficiency, presents clinically as chronic hepatitis or steatohepatitis. Diagnosis is made on enzyme analysis on liver biopsy. Treatment consists of removal of all fructose, sucrose, and maltose from the diet. Water-soluble vitamins should be given. GALACTOSAEMIA This disorder, caused by a defect of galactose-1-phosphate uridyl transferase synthesis, presents as vomiting, hepatitis, liver failure and disseminated intravascular coagulation, usually with sepsis, when the infant is first exposed to milk feeds. Diagnosis is made by measurement of enzyme levels in the infant’s red blood cells. Early management consists of removal of galactose from the diet and standard treatment for liver failure and sepsis. INHERITED DISORDERS OF BILIRUBIN METABOLISM See chapter 2, section 14 on Clinical Approach to a Patient with Liver Disease. NIEMANN-PICK A, B AND C DISEASES These rare conditions are considered together because of their clinical similarities. Types A and B are associated with deficiency of sphingomyelinase in leukocytes or fibroblasts and type C with an enzymatic defect of cholesterol esterification. The genetic defect is linked to a locus on chromosome 18. All these diseases can present with neonatal hepatitis, portal hypertension and neurological disorders like ataxia. Liver disease with liver failure occurs in about 10% of cases. The overall mortality is about 67%. Demonstration of cells that stain with periodic acid-Schiff in the bone marrow aspirate helps confirm the diagnosis. The treatment is symptomatic; combined liver and bone marrow transplantation may be tried. GAUCHER’S DISEASE It is the common lysosomal storage disorder due to deficiency of acid β-glucosidase. The clinical presentation is massive hepatosplenomegaly but cirrhosis and portal hypertension is

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uncommon. Demonstration of Gaucher cells in the liver is difficult and bone marrow aspirate shows the characteristic diastase-resistant, periodic acid-Schiff positive histiocytes. The diagnosis is confirmed by estimation of enzyme levels in leukocytes. Regular infusions of the deficient enzymes have been tried with some benefit, but long-term results are not unknown. For patients with bone marrow infiltration with pancytopenia, combined liver and bone marrow transplantation has been tried. MITOCHONDRIAL RESPIRATORY CHAIN DISORDERS Mitochondrial respiratory chain disorders (MRCDs) as a cause of liver diseases are seen mostly in children. There is no ‘gold standard’ for the diagnosis of these conditions. Primary liver disease in MRCDs may present as acute liver failure, steatohepatitis, or cirrhosis of liver. Management is not specific but only supportive. Since other organ systems are also involved, the prognosis is poor. INBORN ERRORS OF BILE ACID NUCLEUS SYNTHESIS It may occur in conditions like 3β-hydroxy-C27-steroid dehydrogenase/isomerase and δ-4-3-oxosteroid 5β deficiencies. Patients may present with neonatal liver failure, haemo-chromatosis or neonatal cholestasis. Diagnosis is made by analysis of plasma and urine bile acid profiles on fast atom bombardment mass spectroscopy. Ursodeoxycholic acid along with fat-soluble vitamins may be useful in treating these conditions. PROPIONIC ACIDAEMIA In this condition, there is a deficiency of mitochondrial propionyl coenzyme, a carboxylase enzyme, involving all the tissues. It presents soon after birth with episodic vomiting, coma, hypoglycaemia and acidosis, which are precipitated by protein intake or infection and can be corrected by liver transplantation. PRIMARY OXALURIA TYPE I This condition is due to the deficiency of alanine glyoxylate aminotransferase, which is found only in liver peroxisomes. This enzyme is used for the catabolism of oxalate, which has been either produced by the liver or consumed as food constituents (particularly leafy vegetables, rhubarb and strawberries). Oxalate can precipitate in the kidneys and is nephrotoxic. The typical presentation of primary oxaluria is with nephrolithiasis in adults. Occasionally, it may be diagnosed in infants, based on elevated plasma oxalate level and measurement in liver biopsy material of the deficient enzyme. The ideal treatment is liver transplantation before the development of renal damage. If renal impairment has already set in, combined liver and kidney transplanstation from the same donor is useful. RECOMMENDED READING 1.

Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol 2003; 38: 107-17. A thorough review.

14.14

Parasitic Diseases of the Liver Samir R Shah

INTRODUCTION Parasites are organisms, which live on or inside, and derive nourishment from another living organism. Several parasites are known to produce liver disease (Table 1). Table 1: Parasitic Diseases of the Liver Protozoal Infections

Helminthiasis

Amoebiasis Malaria Visceral leishmaniasis Cryptosporidiasis

Ascariasis Echinococcosis Blood and liver flukes Visceral larva migrans Strongyloidosis Capillariasis

AMOEBIC LIVER ABSCESS Amoebic liver abscess (ALA) is an inflammatory spaceoccupying lesion of the liver caused by Entamoeba histolytica. This disease is endemic in India and is the most common form of extra-intestinal or invasive amoebiasis. The amoebiasis is extensively discussed in section 17 chapter 53. LIVER INVOLVEMENT IN MALARIA All the four Plasmodium species, viz. P. falciparum, P. vivax, P. malariae, and P. ovale, multiply in hepatocytes during their lifecycle. P. vivax and P. ovale can persist in a dormant phase in the liver for long periods extending up to years, capable of causing recrudescence of the disease. Pathophysiology In the exoerythrocytic phase, the malarial parasites are confined to the hepatocytes. In uncomplicated malaria, significant hepatocyte damage is conspicuous by its absence. A persistent exoerythrocytic cycle of P. vivax and P. ovale is also not thought to produce pathological changes in the hepatocyte, except for the presence of hypnozoites. In all forms of malaria, pathological findings are similar and include sinusoidal dilatation and congestion, Kupffer cell hyperplasia, parasitised red cells and fine pigment in red cells and Kupffer cells. In severe falciparum infection, cytoadherence and sequestration of the infected erythrocytes leads to microcirculatory disturbances, which in turn lead to end-organ damage in the kidney, brain, intestines, retina and bone marrow.The resultant tissue hypoxia, lactate production and release of cytokines, such as tumour necrosis factor (TNF) and interleukin-1 is responsible for the characteristic clinical picture of the multiorgan failure.Loss of microvilli of bile canaliculi has been observed on electron microscopy; this may explain the cholestasis and conjugated hyperbilirubinaemia noted in some patients with severe falciparum malaria. Clinical Presentation Fever is the presenting complaint. Similar clinical presentation may occur in other common causes of community-acquired

infections like viral fever, enteric fever and viral hepatitis. Mild jaundice during uncomplicated malaria is usually due to haemolysis. Complicated falciparum malaria may present with rapidly progressive jaundice, fever, altered sensorium, oliguria and shock. Coma in these patients is believed to be due to the involvement of the brain and not due to liver cell failure. Diagnosis Detection of malarial parasites on peripheral blood smear is the mainstay of diagnosis. However, multiple smears may need to be examined. In uncomplicated malaria, hyperbilirubinaemia is predominantly unconjugated in nature. Elevation of liver enzymes (AST/ALT) is mild, and much lower than the range seen in acute viral hepatitis. Enteric fever may have a similar clinical presentation, with fever, normal leucocyte count and hepatosplenomegaly; however, jaundice is uncommon. In complicated falciparum malaria, hyperbilirubinaemia is especially marked and may be predominantly conjugated. Treatment No specific treatment related to the liver is required either in uncomplicated or in falciparum malaria. Unconjugated hyperbilirubinaemia improves with clearance of the malarial parasites and regression of hepatosplenomegaly. In complicated falciparum malaria, treatment is directed towards the multiorgan failure with haemodynamic and respiratory support, treatment of metabolic acidosis, renal failure and hypoglycaemia; specific hepatic support is not needed. Conjugated hyperbilirubinaemia rapidly declines on clearance of parasites and improvement in renal failure. TROPICAL SPLENOMEGALY SYNDROME Tropical splenomegaly syndrome, also known as hyper-reactive malarial splenomegaly, is a condition that occurs in residents of areas endemic for malaria. It is postulated to be caused by repeated immunologic stimulation, and is characterised by high titres of total IgM and specific anti-malarial antibodies, hepatic sinusoidal lymphocytosis and splenomegaly. Clinical presentation is with dragging abdominal pain due to an enlarged spleen (which is often enormous in size) and symptoms related to anaemia. Due to a prominent immunological response, malarial parasites may not be detected in the peripheral blood smear. However, most patients respond well to anti-malarial treatment with a reduction in IgM levels and splenomegaly. If untreated, the condition has a high mortality, primarily due to overwhelming sepsis. HYDATID DISEASE OF THE LIVER Hydatid disease is a zoonotic infection caused by larval stage of tapeworms of genus Echinococcus. It is characterised by the presence of medium-to-large sized cysts in the liver and other body organs. It is a public health problem in areas in Europe, Asia,

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South America, Kenya and the Mediterranean region, where sheep are raised (See chapter 59 of section Infectious Diseases). Clinical Presentation Although the infection is usually acquired during childhood, most cysts are detected in third to fifth decades of life. The cysts may be asymptomatic and detected incidentally at imaging done for another reason. Symptoms are usually related to the presence of an expanding mass, pressure on surrounding structures, infection in the cyst or rupture of the cyst. Examination reveals an enlarged liver with or without palpable soft to firm masses. A thrill may be elicited over the mass. A calcified cyst may feel hard, and thus, needs to be differentiated from a liver tumour. Compression of the hepatic veins and inferior vena cava by the cyst can cause Budd-Chiari syndrome. A large cyst in the hilar area may compress the common bile duct and lead to obstructive jaundice. The cysts can rupture into the biliary tree, leading to biliary colic and cholestasis, with cholangitis; blockade of the ampulla by cyst contents can lead to acute pancreatitis. Cyst rupture into the peritoneal cavity can lead to anaphylactic shock; should the patient survive this acute catastrophe, implant of scolices on the peritoneal surface can cause extensive peritoneal cyst formation. Diagnosis Diagnosis can be made by detection of specific antibodies or circulating antigen. Enzyme-linked immunosorbent assay (ELISA) for IgG anti-echinococcus antibodies has a specificity of 88% to 96% with a sensitivity of 80% to 100% in patients with hepatic cysts. False positive tests can occur in persons living in endemic areas and in those with other parasitic infections. Positive tests require confirmation by arc-5 immuno-electrophoretic test, which detects antibodies against an antigen specific to the cestodes. Cross-reactions with Taenia solium do occur and need to be considered in regions where both the infections are a problem. A plain radiograph of abdomen may show curvilinear calcification in the liver cyst. Endocyst calcification is spotty in nature and appears as speckled calcification. Liver cysts are well seen at ultra-sonography. Cysts may appear uni- or multi-vesicular with clear fluid. Some cysts may have a hyperechoic solid pattern or may have reflective wall suggestive of calcification. Rupture of liver cyst into bile duct can be suspected on ultrasonography. Chest radiography and computed tomography (CT) can be used to concomitant cysts in other parts of the body.

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Treatment Surgery with the potential to cure patient was the standard modality of treatment till recently. It is the treatment of choice for patients with a large liver cyst, subcapsular cyst, pedunculated cysts and infected cysts. Surgery may not be possible in patients with multiple cysts, cysts that are difficult to access and in patients at extremes of age, or those with comorbid conditions. Mebendazole (40 to 50 mg/kg/day), albendazole (10 to 15 mg/kg/day) and praziquantel have welldocumented scolicidal activity. Administration of drugs in three cyclic one-month courses interspersed with drug-free intervals of 14 days each have been widely used. Recent data favour the use of uninterrupted drug therapy for 3 to 6 months. Addition of praziquantel (40 mg/kg once a week) increases the efficacy

of benzimidazoles. Drug therapy is effective in small cysts (10%

Rifampicin Indomethacin Halothane Methotrexate Amiodarone Colchicine Griseofulvin

SPECTRUM The spectrum of drug-induced liver injury can be quite varied. The liver injury may be biochemical in nature, i.e. asymptomatic elevation of alanine aminotransferase (ALT ) or aspartate aminotransferase (AST) [AST; 1.1-6.0 times the upper limit of normal (x ULN)] or alkaline phosphatase [(ALP); (1.1-1.7 x ULN)]. Other patients may have acute hepatitis-like picture, which includes symptomatic acute hepatitis or marked elevation of transaminases (>6.0 x ULN) or alkaline phosphatase (>1.7 x ULN). Less frequent manifestations are listed in Table 2. Table 2: Spectrum of Drug-Induced Liver Injury Manifestation

Definition

Biochemical, ALT/AST Acute

1.1-6.0 x upper limit of normal (ULN) Symptoms like acute hepatitis and AST/ALT >6.0 x (ULN)

Acute cytolytic Acute cholestatic Fulminant hepatitis Granulomatous hepatitis Chronic hepatitis Steatosis Vascular Benign tumour Malignant tumour

Defined histologically or biochemically Defined histologically Elevation of transaminases for > 6 months

Defined histologically

DIAGNOSIS There is no reliable test for the diagnosis of drug-induced liver injury. All drugs taken during the 2-week period preceding the onset of liver injury should be suspected as the cause of liver injury. Therefore, the diagnosis depends on following the temporal relation of suspected drug intake to both the onset ( 95%; specificity 99%). Gallstones are seen as areas of echogenicity in the gall bladder with posterior acoustic shadowing (Figure 2A). Even stones in the common bile duct (CBD) can be seen (Figure 2B); CBD is identified as lying above the portal vein on ultrasound (USG) doppler. The timehonoured oral cholecystography can also be done to visualise radiolucent stones in the gall bladder. Opacification of gall bladder following oral contrast administration also indicates patency of cystic duct, an important pre-requisite for treating gallstones with oral bile acids or lithotripsy. Computed tomography (CT) helps further in knowing the density of the stones but does not detect any stones missed by other tests. For demonstrating stones in the CBD, endoscopic retrograde cholangio-pancreatography (ERCP) is the gold standard but magnetic resonance cholangiopancreatiography (MRCP) is a good non-invasive alternative. Endoscopic ultrasonography, however, appears to be the most sensitive technique for detection of these stones, and can pick up small calculi in the gall bladder as well as the bile duct .

Figure 2B: Stone seen in dilated common bile duct (CBD). Below and parallel to CBD it is seen portal vein.

However, for those who are averse to surgery or those who carry a high surgical risk because of associated coronary artery disease or advanced lung disease, several non-surgical treatment options are available. Both surgical and non-surgical modes of therapy are briefly discussed below. Surgical treatment Cholecystectomy is curative and is relatively safe with an overall mortality of 0.1% to 0.6% and a morbidity of 10% to 30%. Both these proportions increase with age, presence of concomitant disease or when the procedure is accompanied by CBD exploration because of a suspected stone in the bile duct. Conventional cholecystectomy through laparotomy has been almost universally replaced by laparoscopic cholecystectomy. The latter has advantages of reduced postoperative pain and shorter hospital stay, as compared with conventional cholecystectomy. In patients with a history of obstructive jaundice or with a demonstrated CBD stone, the prevailing treatment approach is to clear the CBD by performing an endoscopic sphincterotomy and basket removal of stones, and to then perform the laparoscopic cholecystectomy rather than doing a conventional surgery for both the gall bladder and CBD stones.

Figure 2A: A single calculus in the gall bladder seen with acoutic shadowing.

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Treatment Asymptomatic gallstones are best left alone and treated expectantly except in special circumstances such as in the case of astronauts or people residing in places that lack medical facilities. The symptomatic patients (10% to 15%) should, on the other hand, be treated effectively as they tend to have recurrence of symptoms or may develop acute cholecystitis, acute pancreatitis or other complications. Surgical removal of the diseased gall bladder (cholecystectomy) appears to be the best treatment option at present, since it provides protection against reformation of gallstones as well as development of carcinoma of the gall bladder.

Non-surgical treatment Non-surgical treatment modalities include oral bile acid therapy (OBT), extra-corporeal shock wave lithotripsy (ESWL) and contact dissolution with methyl-1-tert-butyl-1-ether (MTBE). The most popular of these and the one with which substantial experience is available is OBT with chenodeoxycholic acid (CDCA) or its 3-beta epimer ursodeoxycholic acid (UDCA). For bile acid therapy as well as ESWL, it is essential that the cystic duct is patent as established by visualisation of gall bladder on oral cholecystography. Cystic duct patency is required to allow drugs like UDCA to enter and concentrate in the gall bladder as also to let stone fragments pass out of the gall bladder. For OBT, the gallstones should not be >1.5 cm in size, should be radiolucent and preferably have a density of 12 mm, delayed drainage of the CBD >45 minutes and abnormalities in serum liver function tests (LFT). Definitive diagnosis of SOD requires tests of biliary tract motility. Manometric findings in SOD include one or more of

the following: elevated basal pressure >40 mmHg, more than 7 contractions per minute, retrograde progression in >50% of the contractions, and contractions of the sphincter as a response to cholecystokinin. The management of SOD is based on the Geenen-Hogan classification (Table 1). Group I patients mainly have sphincter of Oddi stenosis and can safely undergo endoscopic sphincterotomy without first performing SOD manometry, thus avoiding the risk of pancreatitis due to manometry. Group II patients may have stenosis or dyskinesia, and manometric findings should guide further management. Patients with elevated basal pressure may be treated with endoscopic sphincterotomy or a trial of long-acting nitrates or calcium channel blockers. Group III patients may have a nonbiliary cause for pain, and therefore, common causes of abdominal pain must be ruled out.

Diseases of Gall Bladder and Biliary Tract

the stones fairly fast. There are three methods of shockwave generation: underwater electrostatic spark-gap discharge, electromagnetic generation and piezo-electric generation; of these, the spark-gap lithotripsy is still the most popular and effective.

Table 1: Geenen-Hogan Classification of Sphincter of Oddi Dysfunction Group 1

Group 2

Group 3

Biliary pain + Biliary pain + Biliary pain + All of the following 1 or 2 of the following None of the following criteria criteria criteria Delayed drainage of the common bile duct (>45 min.) Dilatation of the common bile duct (>12 mm) on USG Elevation of serum aspartate aminotransferase or alkaline phosphates to >2 times normal on 2 or more occasions

BILIARY TRACT MALIGNANCIES Biliary tract carcinomas are locally invasive adenocarcinomas which usually manifest as painless jaundice and biliary obstruction. These include gall bladder carcinoma, cholangiocarcinoma and intra-hepatic biliary malignancies (cholangiocellular carcinoma) or carcinoma at the lower end of bile duct (peri-ampullary carcinoma). In the absence of treatment, most patients die of cholangitis, cachexia or hepatic failure within 3 to 6 months of diagnosis. Gall bladder Carcinoma Presence of gallstones has been proposed as a risk factor for cancers of the gall bladder and the extra-hepatic bile ducts. Other predisposing factors include anomalous junction of the pancreatic and biliary ductal systems, K-ras codon 12 mutation, blood groups A and AB, and Salmonella typhi carrier state. Gall bladder carcinoma usually presents at an advanced stage with abdominal pain and cholestatic jaundice. A hard gall bladder mass is often palpable along with hepatomegaly. Prognosis in such patients is poor. In some patients, the tumour is found incidentally after simple cholecystectomy, at gross or microscopic examination of the excised gall bladder. Conventional surgery is being gradually replaced by aggressive extensive surgical resection procedures, such as extended cholecystectomy which includes wedge resection of the hepatic gall bladder-bed and regional lymphadenectomy. In patients with unresectable tumours, palliation may be possible through endoscopic stent placement. Cholangiocarcinoma Hilar cholangiocarcinomas are characterised by a slow growth rate and a low propensity to metastasise. Papillary cholangio-

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carcinomas have the best survival rate but are infrequent. Preoperative diagnosis of cholangiocarcinoma may be established by a combination of brush cytology and forceps biopsy from the bile duct lesion.The established criteria for non-resectability of cholangiocarcinoma are: bilobar extensive intra-hepatic bile duct spread, involvement of the main portal vein, bilobar involvement of hepatic arterial or portal venous branches or both, and a combination of unilobar hepatic involvement with cholangiographic evidence of extensive contralateral ductal spread. In unresectable tumours, palliation may be possible by restoring bile flow, in order to relieve jaundice and prevent or treat complications like pruritus and sepsis. This is accomplished by endoscopic or percutaneous stenting across the obstructing lesion, or a surgical biliary enteric bypass. Combined external beam radiation and brachytherapy with intracavitary iridium seeds have been used. However, this combined therapy has not been shown to provide a definite survival advantage. Hence, the preferred mode of therapy, if feasible, is curative resection.

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Cancer of the Ampulla of Vater This tumour has a higher resectability rate and a better prognosis than other biliary cancers. This is mainly because these tumours present early with features of obstructive jaundice. USG shows a dilatation of the biliary system and/or the pancreatic duct. Diagnosis is established by an ampullary biopsy taken through a side viewing endoscope. In case the tumour is located submucosally, endoscopic USG guided fine needle aspiration may be helpful in getting the tumour tissue. The best treatment option for these patients is pancreato-duodenectomy (Whipple’s procedure). If the tumour is unresectable or pre-operative biliary drainage is needed, a biliary stent can be placed across the papilla endoscopically. RECOMMENDED READINGS 1.

Dowling RH. Pathogenesis of gallstones. Aliment Pharmacol Therap 2000; 14: 66-70.

2.

Wang D Q-H, Afdhal NH. Gallstone disease. In: Feldman M, Friedman LS, Brandt LJ, editors Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management, 9th edn; vol 1 New Delhi: ElsevierSaunders (2006) pp1089-120.

Section

15

Haematology Section Editor: Rajat Kumar 15.1 Haematopoiesis Shaji V. Ramachandran, Vikram Mathews 15.2 Anaemia—A Clinical Approach Renu Saxena, M. Mahapatra 15.3 Splenomegaly—A Clinical Approach Lalit Kumar, Anuj Kumar Bansal 15.4 Iron Deficiency Anaemia Subhash Varma 15.5 Megaloblastic Anaemia Tarun Kumar Dutta 15.6 Hereditary Haemolytic Anaemia M.B. Agarwal 15.7 Acquired Haemolytic Anaemia Farah F. Jijina 15.8 Aplastic Anaemia Dharma R. Choudhary, Tuphan Kanti Dolai 15.9 Acute Leukaemia S.H. Advani 15.10 Chronic Myeloid Leukaemia and Other Myeloproliferative Disorders Tapan Kumar Saikia 15.11 Myelodysplastic Syndromes Rajat Kumar, Seema Tyagi 15.12 Chronic Lymphocytic Leukaemia M. Mahapatra, Renu Saxena 15.13 Lymphoid Neoplasms Bharath Rangarajan, Purvish M. Parikh 15.14 Plasma Cell Dyscrasias Pankaj Manubhai Shah 15.15 Bleeding Disorders Kanjaksha Ghosh 15.16 Platelet Disorders S.K. Bichile 15.17 Disorders of Coagulation Jina Bhattacharyya 15.18 Hypercoagulable Disorders Mammen Chandy 15.19 Transfusion Medicine Neelam Marwaha 15.20 Haematopoietic Stem Cell Transplantation Velu Nair

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15.1 INTRODUCTION Healthy individuals require adequate production of blood cells on a daily basis to maintain normal function. This process needs to be tightly regulated and balanced to maintain homeostasis. Additionally, during this process, adequate haematopoietic stem cells (HSC) also have to be generated to maintain the pool of HSC. HSC and haematopoietic progenitor cells (HPC) are retained within the bone marrow by numerous ligands and cytokine gradients which are also important in regulation of differentiation and proliferation. The process of haematopoiesis is closely linked and regulated by the haematopoietic microenvironment in the bone marrow which includes mesenchymal derived stromal cells such as endothelial cells, fibroblasts, osteoblasts and adipocytes, cells of non-mesenchymal origin such as cells of the monocyte macrophage system and the extra-cellular matrix. Abnormalities at different stages in this process can result in various haematological disorders, such as aplastic anaemia, cytopaenias, leukaemia and myeloproliferative disorders. Haematopoiesis broadly consists of HSC proliferation and regulation, granulocytopoiesis, thrombopoiesis and erythropoiesis. Once HPC differentiate into mature blood elements, they leave the bone marrow by a still poorly understood mechanism. DEFINITION Haematopoiesis is a complex process by which HSC can both self replicate to maintain a pool of HSC and also differentiate into myeloid and lymphoid lineage committed HPC. These HPC can further terminally differentiate to produce all the cellular elements of the blood.

Haematopoiesis Shaji V Ramachandran, Vikram Mathews ONTOGENY OF HAEMATOPOIETIC TISSUES Currently, it is believed that haematopoiesis originates as early as the third week of conception, both from the aorto-gonadalmesonephros (AGM) region and from the extra-embryonic mesoderm in the yolk sac. Data from mice suggest that HSC arise in the AGM from a haemangioblast which can give rise to HSC and endothelial cells. In humans, HSC that arise from these regions colonise the foetal liver at 5 weeks of gestation and foetal liver haematopoiesis becomes active by 6 weeks and remains the dominant haematopoietic organ in foetal life. HSC seed the bone marrow by 8 weeks of gestation. In contrast to the foetal liver where haematopoiesis is predominantly erythroid, haematopoiesis occurring in the bone marrow is predominantly myeloid in foetal life. HSC also colonises the spleen by 12 weeks of gestation and the thymic rudiment by 8 weeks of gestation and these organs contribute to haematopoiesis in the foetal life (Figure 1). During foetal life and immediately after birth a large number of HSC and HPC are found in circulation. However, within 24 to 48 hours after birth circulating progenitors disappear from the circulation. In adults, haematopoiesis shifts almost entirely into the bone marrow. In utero and at birth, the entire bone marrow is involved in haematopoiesis while with increasing age haematopoiesis is limited to the flat bones such as the pelvic bones, skull and ribs, the proximal ends of long bones and the vertebrae. In post-natal life the bone marrow is normally the only site of haematopoiesis, however, at times of extreme need the liver, spleen and other reticulo-endothelial tissue can contribute to extra-medullary haematopoiesis.

Figure 1: Ontogeny of human haematopoiesis. HSC migrate and colonise different organs. After birth they are found mainly in the bone marrow. The HSC is believed to arise from the AGM and/or extra-embryonic yolk sac at different time periods in gestation, as illustrated above.

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AGM = Aorto-gonadal-mesonephros; HSC = Haematopoietic stem cell.

The factors that regulate HSC proliferation and differentiation including commitment remain poorly defined. There are two major theories of HSCs renewal versus differentiation and these are the Stochastic model and the haematopoietic inductive microenvironment. In the Stochastic model stem cell renewal versus differentiation is based on probability residing within the HSCs while in the inductive micro-environment theory it is linked to probability of the extrinsic environmental signals that it is exposed to. Figure 2 summarises the pathways of haematopoiesis starting from the HSC.

Haematopoietic Stem Cells Niche Stem cell niche is a specific site in adult tissues where stem cells reside and undergo self renewal and produce large numbers of progeny (differentiation). The concept of a HSC niche was first proposed by Schofield in 1978 to describe the physiologically limited micro-environment in which stem cells reside. Mesenchymal stromal cell derived osteoblasts are increasingly being found to play a very important role in the HSC niche formation (osteoblastic niche). These osteoblastic niches have been shown to provide the structural surface on which HSC reside and also provide important signals that regulate HSC proliferation and differentiation. Thus, osteoblast cells play an important role not only in skeletal development but also in haematopoiesis. Experimental animal models have demonstrated that conditional ablation of osteoblasts leads to depletion of HSC and increasing the number of osteoblasts by the administration of parathyroid hormone has been shown to enhance HSC self renewal and engraftment. The need for physical interaction in the HSC niche probably is important to regulate the number of HSC in the stem cell pool. This physical interaction could also be important in deciding on symmetrical (proliferation) versus asymmetrical (differentiation). As illustrated in Figure 3, a daughter cell that divides with the division plane perpendicular to the niche plane has the potential to have both daughter cells remain in contact with the niche cell and retain stem cell-ness, while a cell that has its

Haematopoiesis

HAEMATOPOIETIC STEM CELLS AND STEM CELL NICHES Haematopoietic Stem Cells HSC has been defined functionally by their ability to reconstitute both the lymphoid and myeloid haematopoiesis when transplanted into a recipient. Immunological characteristic of HSC has been the absence of lineage specific antigens (Lin–), in mice expression of specific antigens such as Sca1 and Thy1 and in humans expression of CD34 antigen. Another property that has been used to study stem cell populations is the ability of these cells to extrude a deoxyribonucleic acid (DNA) binding dye Hoechst 33342 which in turn is based on the property of these cells to often express drug efflux proteins. Based on this technique, a population of Lin– and CD34 negative cells have been identified which has the capability for long-term reconstitution following a transplant, suggesting that these cells are a subset of HSC, even though they are CD34 negative.

Figure 2: Model of the pathways of haematopoiesis (excluding erythropoiesis) and significant surface antigen expression at each stage. CFU-GEMM = Colony forming unit granulocyte/erythroid/macrophage/megakaryocyte; CFU-GM = Colony forming unit granulocyte/macrophage; CFU-M = Colony forming unit macrophage; CFU-G = Colony forming unit granulocyte; MPO = Myeloperoxidase; NK Cell = Natural killer cell; DC = Dendritic cell; LAP = Leucocyte alkaline phosphate.

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division plane parallel to the niche plane will give rise to a daughter cell that will not be in contact with the niche surface and has the potential to differentiate. The bone marrow microenvironment is very vascular with numerous sinusoidal vessels. It has been demonstrated that HSC even physiologically frequently leave the confines of the bone marrow and enter the systemic circulation (mobilisation) and also such mobilised HSC return to the bone marrow directed by various homing signals (homing). The regions adjacent to these sinusoidal vessels often house HSC and HPC and also function like a niche (vascular niche). The vascular niche may play an important role in mobilisation and in homing. It also appears to play a role in HSC proliferation and differentiation. Multiple signalling and adhesion molecules are involved in the stem cell maintenance. The main signalling pathway that is involved in this process includes stem cell factor (SCF), which is a cytokine that interacts with c-kit, a receptor that is present in the stem cells and progenitors. C-kit signalling is important for promotion of cell survival, proliferation, and migration. Flt3 signalling pathway is important differentiation of cell types. Thrombopoietin (TPO) and its receptor c-Mpl constitute a pathway that is important for the cell cycle regulation of haematopoietic stem cells. Interestingly, gain of function alleles of c-kit, Flt-3 and c-Mpl it were identified as participants in leukaemia or other cancers. For example, v-kit is a constitutively active kinase that was identified in a feline sarcoma virus. In addition, point mutations or amplifications that result in constitutively active signalling have been found in several types

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Figure 3: Haematopoietic stem cell (HSC) niches.

of solid tumours and in acute myeloid leukaemia (AML). For example, Flt-3 activating mutations are found in 30% of human AML cases, and v-Mpl is a constitutively active form of the TPO receptor that was identified in a mouse myeloproliferation inducing retrovirus. Tie-2 is another tyrosine kinase receptor, bound by angiopoietin, plays an important role in steady state haematopoiesis. Tie-2/Ang signalling has been proposed to be important for maintaining quiescence within the bone marrow niche, rather than promoting expansion and proliferation. Several pathways previously known to be essential for embryogenesis also play important roles during the maintenance of HSC. These include Wnt (wingless/Int-1), Hh (hedgehog) and phosphoinositide-3 kinase signalling pathways. The pattern and level of expression of these signalling and adhesive molecules in daughter cells probably plays a role in deciding the fate of the cell. ERYTHROPOIESIS The mature red cell is the final product in the long process of erythropoiesis that starts from a HSC that is committed to erythroid differentiation, this process is tightly regulated. Erythroid progenitors are sparse and difficult to isolate. The first recognisable class of progenitors is the burst forming unit – erythroid (BFU-E), named for their ability to generate multiclustered colonies of (erythroid bursts) haemoglobin containing cells. BFU-E represents the earliest progenitor cell committed exclusively to erythroid differentiation. This is a quiescent reserve of cells (only 10% to 20%) are in only cell cycle. However, once stimulated with the appropriate cytokines these

The earliest recognisable erythroid cell is the proerythroblast, it is 12 to 19 µm in diameter with a large oval nucleus which stains homogenously with indistinct nucleoli, and the cytoplasm is darkly basophilic. The basophilic normoblast follows with a diameter of 12 to 17 µm, nuclear chromatin shows coarse clumping which is often described as a cartwheel appearance, nucleoli are generally not seen.The polychromatic normoblast is about the same size as its precursor the basophilic normoblast but is distinguished by the less basophilic cytoplasm due to the increased accumulation of haemoglobin; the nucleus is also further condensed and is almost black on staining. The last nucleated erythroid precursor is the orthochromatic normoblast, this cell approaches the diameter of a reticulocyte (8 to 12 µm), the eosinophilic staining cytoplasm contains nearly the full amount of haemoglobin, the nucleus is fully condensed and pyknotic. Extrusion of the nucleus results in it becoming a reticulocyte. The reticulocyte is characterised by the presence of fine granular or reticular network of ribosomal ribonucleic acid (RNA) observed with supravital stains, such as brilliant cresyl violet or methylene blue.Reticulocytes are normally found in small numbers in the peripheral blood. Reticulocytes gradually lose their cytoplasmic RNA and mature into erythrocytes which are biconcave, relatively flat and non-nucleated disks of 7 to 8 µm in size.Normal erythrocytes survive for 100 to 120 days in the peripheral circulation. Regulation of Erythropoiesis The process of erythropoiesis is mainly regulated by erythropoietin (EPO) which is a cytokine produced in the kidney in the peri-tubular cells. Regulation of EPO mRNA and protein is primarily at the transcriptional level. In the setting of hypoxia, these cells are stimulated to secrete EPO by the hypoxiainducible transcription factor (HIF); this in turn acts on cells that have EPO receptors (BFU-E, CFU-E, etc.) and promotes their survival and proliferation and this activity is thought to be the primary regulatory mechanism for maintaining the homeostasis of red cell mass. A drop in red cell numbers causes tissue hypoxia, leading to increased EPO synthesis and the survival of more CFU-E that can rapidly mature into erythrocytes. Several other cytokines have been shown to synergise with EPO to enhance erythroid differentiation, including interleukin (IL) 6, IL3 and SCF. SCF receptor, c-kit is expressed by CFU-E and BFU-E. Lineage specific transcriptional factors are responsible for regulating the expression of erythroid genes in the course of erythroid differentiation.Two important transcription factors that are involved in the erythropoiesis are GATA-1 and EKLF (KLF1). GATA-1 forms complexes with multiple other proteins to upregulate the expression of erythroid specific genes. Disruption of GATA-1 gene leads to block of primitive erythropoiesis resulting

in embryonic lethality. FOG-1 (Friend of GATA) binds to GATA-1 and this association is required for many of the functions of GATA-1. The significance of this association is exemplified by the finding in individuals with severe congenital dyserythropoietic anaemia of GATA-1 mutations that disrupts its physical contact with FOG-1. GATA-1 also associates with CREB binding protein (CBP) which is a protein that acetylates histones suggesting that GATA-1 is involved in transcriptional activation of erythroid genes. Other proteins that are associated with GATA-1 are transcription factors stem cell leukaemia gene (SCL, TAL-1), LBD1 and LMO2. Distinct protein complexes of GATA-1 are required for activation of genes in primitive and definitive erythropoiesis.

Haematopoiesis

demonstrate significant proliferative capacity (≥30 to 40,000 colonies in vitro) in 2 to 4 weeks. A second more differentiated progenitor cell is the colony forming unit—erythroid (CFU-E). In contrast to BFU-E majority of these cells are in cycle, and hence, on exposure to appropriate cytokines rapidly proliferate, peaking within 7 days. It is important to understand that these cells are identified retrospectively and in vitro by their ability to form specific haemoglobin containing cell colonies in semisolid media (methylcellulose) with appropriate cytokines. It would not be possible with currently available techniques to identify these cells individually by their morphology and immunophenotype as being distinct from other progenitors with commitment to other lineages.

Several members of the Kruppel-like transcriptional factor (KLF) family are known to activate erythroid specific genes. KLF1 (EKLF) is expressed in both primitive and definitive erythropoiesis. This protein associates with SWI/SNF related chromatin remodelling complex suggesting that its activity in erythroid cells may in part be related to altering the configuration of chromatin. Activation of EKLF is regulated by GATA-1 illustrating the complex transcriptional regulatory mechanisms involved in both primitive and definitive erythropoiesis. KLF2 and KLF4 are required for the expression of genes in the embryonic stage. The continued identification of interacting transcription factors and their downstream targets will provide a better understanding of erythroid cell maturation and will facilitate the construction of increasingly complex models of the genetic regulatory networks that exist in erythroid cells. More recently micro-RNAs, small RNA molecules that target messenger RNAs in a sequence specific manner to modulate their stability or their ability to undergo translation, have been shown to play roles in erythropoiesis. Though several studies have been carried-out to unravel the molecules and mechanisms involved in erythropoiesis, it is not yet clear how the signalling pathways, micro-RNAs and transcription factors act together in regulating erythropoiesis. Haemoglobin synthesis Production of haemoglobin requires the co-ordinated production of haem and globin. Haem is the prosthetic group that mediates reversible binding of oxygen by haemoglobin. Globin is the protein that surrounds and protects the haem molecule. Haem synthesis Haem is synthesised in a complex series of steps involving enzymes in the mitochondria and in the cytosol of the cell. The first step in haem synthesis takes place in the mitochondria, with the condensation of succinyl CoA and glycine by 5aminolevulinic acid (ALA) synthase to form 5-ALA.This molecule is transported to the cytosol where a series of reactions produce a ring structure called coproporphyrinogen III. This molecule returns to the mitochondria where an additional reaction produces protoporphyrin IX.The enzyme ferrochelatase inserts iron into the ring structure of protoporphyrin IX to produce haem. Deranged production of haem results in a variety of anaemias (porphyrias). Iron deficiency, the world’s most common cause of anaemia, impairs haem synthesis thereby producing anaemia. A number of drugs and toxins directly inhibit haem production by interfering with enzymes involved in haem biosynthesis. Lead commonly produces substantial anaemia by inhibiting haem synthesis, particularly in children.

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Types of haemoglobin synthesis Haemoglobin molecules are tetrameric proteins with two distinct types of globin chains. In humans, there are 5 different types of haemoglobins which are produced at different stages of the development. The genes that produce different types of globin chains are present as clusters in chromosomes 11 and 16 with the genes present in the order in which they are expressed during development. In adults, haemoglobin (HbA) contains two α globin and two β globin chains (α2β2). The predominant haemoglobin produced at the embryonic stage is Hb Gower 1 and foetal stage is α2β2 (HbF; foetal haemoglobin). Table 1 summarises the haemoglobins seen in humans in different stages of development. Disorders that affect the synthesis rate of the globin chains cause thalassaemias which are the most common genetic diseases in humans. There are around 400 different reported mutations that can cause α and β thalassaemia. Other types of mutations in the globin genes that affect the structure of haemoglobins (not the quantity) are broadly classified as haemoglobinopathies which include sickle cell anaemia a common genetic disease in most populations. Table1: Normal Haemoglobin (Hb) seen at Different Stages of Development Embryonic Hb Gower 1 Gower 2 Portland

ξ2ε2 α2ε2 ξ2γ2

Foetal Hb HbF

α2γ2

Adult Hb HbA2 HbA

α2δ2 α2γ2

A better understanding of the mechanisms regulating the activation and silencing of the embryonic, foetal and adult globin genes has important clinical implications for the treatment and cure of patients with haemoglobinopathies, particularly sickle cell disease and the thalassaemia syndromes. GATA-1 and EKLF are two major transcription factors that have been found to be playing key functions in the activation of adult globin genes responsible for the transcriptional regulation of globin genes. Recent studies have identified a key regulator protein, BCL11A, which plays a role in stage specific expression of globin genes. This protein represses foetal globin gene expression in adults. Mutations in the BCL11A gene cause increased expression of foetal haemoglobin (HbF) in normal adults and in patients with thalassaemia and sickle cell disease. Such increases HbF in these conditions could ameliorate the phenotype of these diseases and hence manipulating this proteins levels in patients with sickle cell disease and homozygous β thalassaemia has the potential to be a therapeutic option for these diseases.

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GRANULOPOIESIS AND MONOCYTOPOIESIS Granulopoiesis The earliest identifiable cell of the myeloid lineage is the myeloblast. This cell is approximately 12 to 14 µm in diameter with a round or oval nucleus and basophilic cytoplasm. Nuclear chromatin is fine and 1 to 5 nucleoli are easily visible. The next cell in the differentiation process is the promyelocyte which is the largest cell in this differentiation series. Promyelocytes have variable nuclear morphology with less prominent nucleoli; the cytoplasm is deeply basophilic and contains variable number of peroxidase positive granules. Myelocytes are characterised by round to oval nucleoli with a characteristic nuclear

indentation and coarse chromatin structure. The cytoplasm is pale pink-brown and has numerous specific granules covering the nucleus and throughout the cytoplasm except at the nuclear indentation (centrosphere), which represents the Golgi apparatus. The myelocyte is also the first cell in differentiation in which specific granules appear and the last cell that is capable of cell division during myeloid differentiation. The metamyelocyte exhibits a characteristic bean shaped nucleus, the band form a band shaped or ‘S’ shaped nucleus without a definite nuclear constriction and the segmented neutrophil characterised by typical nuclear segmentation. The cytoplasm in all these cells is similar to that of a myelocyte except for the absence of a centrosphere. Maturation of eosinophils and basophils follows the same morphologic steps as that of a neutrophil until the appearance of specific granules. The eosinophil exhibits a bilobed nucleus, and the basophilic cytoplasm is filled with prominent orange-red granules. Basophils exhibit less segmentation of the nucleus and the cytoplasm is filled with deeply staining blue to purple metachromatic granules. The granules often obscure the nucleus and cytoplasm which stains pink to reddish pink. Monocytopoiesis The earliest cell of the monocyte/macrophage series is the monoblast which can be difficult to distinguish from a myeloblast. The cell is 12-18 µm in diameter, with a round or oval nucleus which is frequently convoluted. The chromatin is fine and the nucleoli are sometimes present. The cytoplasm is basophilic and devoid of granules. The promonocyte is a large cell with an indented nucleus, exhibiting fine chromatin and a single nucleolus. The cytoplasm stains light blue. The monocyte is the largest cell with a diameter of 13-20 µm, the nucleus is large, lobulated, or bean shaped, with coarse chromatin and lacks a nucleolus. The cytoplasm has a characteristic light blue appearance. Egress of monocytes from the blood into the tissues is associated with increased cell size and larger and more lightly staining nucleus. These cells, termed macrophages or histiocytes, are phagocytic and mobile. Lineage Commitment and Transcriptional Control of Granulopoiesis and Monocytopoiesis The mechanisms of lineage commitment remain poorly understood. In vitro studies of murine embryonic stem cells reveal a coordinated expression of growth factor receptor genes during cell maturation. Certain genes are expressed constitutively during development of these cells, such as the c-kit and the α sub-units of the growth factor receptor genes. Expression of the common β sub-unit of these growth factor receptor genes (IL-3, IL-5, GM-CSF, SCF) are induced early. In contrast c-fms, GCSFR and CD34 are induced later, at an intermediate stage of development, reflecting the initiation of myeloid commitment. At later stages, when a limited number of cytokine receptors are expressed or dominate in a progenitor cell, cytokines such as GM-CSF and G-CSF become important for neutrophil maturation, M-CSF and GM-CSF for macrophage development, IL-5 for eosinophil development and SCF, nerve growth factor and IL-3 for basophil and mast cell growth. The extent to which these growth factors and their receptor expression determine commitment remains unclear. Transcriptional factors such as PU-1 and EGR-1 play a role in macrophage development while genes such as fes and MZF-1 appear to be important in modulating granulocytic precursor proliferation.

Regulation of Thrombocytopoiesis Thrombopoietin (TPO) is a putative lineage specific regulator of platelet production. Data suggests the TPO production is regulated inversely by the platelet mass in the body. TPO is constitutively produced in the liver, kidney and probably the spleen and marrow as well. LYMPHOCYTES Lymphocytes and plasma cells are components of the immune system which also arise from HSC. Lymphocytes broadly include natural killer cells (NK cells), a component of the innate immune system, and T-cells and B-cells which are involved in adaptive immunity. Primary lymphoid organs where lymphopoiesis occurs include the bone marrow and thymus, while secondary lymphoid organs such as lymph nodes, spleen, mucosal and cutaneous associated are involved predominantly in immune sensitisation and selection. B-Cells B lymphocytes like all blood cells are the progeny of HSC. Once commitment to lymphoid development has occurred, a further bifurcation to T-cell and B-cell development occurs. The defining features of these commitment steps and their regulation remain poorly understood. Once committed to B-cell development there is less confusion as to precursor—progeny relationship and an orderly evolution from a precursor B-cell to a mature plasma cell occurs, antigen expression through these phases are unique and help identify the cells. This antigenic expression profile is summarised in Table 2. The end result of B-cell development is generation of plasma cells that are capable of secreting immunoglobulins. These immunoglobulins are composed of heavy and light chains; these chains undergo re-arrangement of their V, D and J loci on the gene giving rise to antigen binding specificity and an immunoglobulin repertoire. These immunoglobulins are expressed on the surface of the B-cell, if the newly produced B-cell does not encounter an antigen, it undergoes apoptosis

Table 2: Antigenic Expression During the Stages of Development of T-cells and B-cells B-cells Antigen Pro B-cell CD34 CD10 CD19 CD20 CD21 CD22 CD24 CD38 CD45 Cyt Ig SmIg

Pre B-cell

Immature B-cell

Mature B-cell

± + + – ± – – – + + –

– ± + + + ± ± – + + ±

– – + + + ± ± – + + +

+ – + – – – ± + ± – –

Haematopoiesis

THROMBOCYTOPOIESIS The morphologic features of platelet forming cells are distinctly different from erythroid or leucocyte cell lineages. Distinct differentiation and morphologic changes do not occur. These processes are instead replaced by a process of polyploidisation. In this process, successive nuclear divisions without concomitant nuclear divisions lead to megakaryocytes with 1-32 nucleoli. The first identifiable cell in this lineage is the megakaryoblast, a distinctly large cell with a high nuclear/ cytoplasmic ratio. The nuclear shape varies but frequently displays convolutions and deep furrows. The cytoplasm stains basophilic, does not contain granules and may exhibit fraying of the cytoplasmic membrane. Some megakaryoblasts may contain multiple nuclei. The pro-megakaryocyte exhibits a lobulated nuclear structure without nucleoli. The cytoplasm is basophilic, with azurophilic granules adjacent to the nucleus and formed platelets can be seen on the cytoplasmic surface. Mature megakaryocytes are the largest haematopoietic cell in the bone marrow. The nucleus is lobulated and exhibits coarse and clumped chromatin. Nuclear number varies from 4 to 8. Platelets can be seen in the periphery of the cytoplasm and are attached to the cell membrane. Platelets are believed to form by cytoplasmic budding from the megakaryocytes.

T-cells Antigen Prothymocyte CD1 CD2 CD3 CD4 CD5 CD6 CD7 CD8 CD38 TCR

– + – – – – + – + –

Early Late Thymocyte Thymocyte + + – + – – + + – –

– + + + + + + – – +

Mature T-cell

– + + (either CD4/CD8+) + + + + + (either CD4/CD8+) – +

while those that encounter an antigen recognised by the re-arranged immunoglobulin molecule undergo blast transformation and proliferate. T-Cells These cells again arise from HSCs. They are released and home to the thymus where they must receive signals provided by the thymic stromal cells (processed antigen) for them to survive and undergo maturation into mature T-cells.Within the thymus these T-cells up-regulate CD25 (IL-2 receptor) and are now called proT-cells. They then go through stages of early and late pre-T-cell development and eventually mature following commitment into either CD4 positive helper T-cells or CD8 positive cytotoxic T-cells. CONCLUSION Haematopoiesis is a complex process involving the HSCs, osteoblasts, and components of the bone marrow microenvironment, receptors and cytokines. While attempts are made to compartmentalise the process for the sake of understanding, this does not truly represent the physiological state and does gross injustice to the complexity involved. Many of the processes and regulatory elements are poorly understood or are still in the process of being described. Abnormalities that affect this process can lead to life-threatening complications such as aplastic anaemia or myeloproliferative disorders. Additionally, better understanding of the basic science of haematopoiesis has already translated into new therapeutic tools as evidenced by the numerous cytokines that are available in the market. RECOMMENDED READINGS 1.

Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol 2006; 7: 333-7.

2.

Hoffman R. Hematology: Basic Principles and Practice (3rd edition). Philadelphia: Churchill Livingstone; 2000.

3.

Taichman RS. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood 2005; 105: 2631-9.

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15.2 DEFINITION Anaemia is functionally defined as an insufficient red blood cells (RBC) mass to adequately deliver oxygen to peripheral tissues. It may be due to increased RBC clearance, decreased RBC production, or both and caused by intrinsic or extrinsic causes. According to WHO, haemoglobin (Hb) of less than 13.0 g/dL in adult male, less than 12.0 g/dL in adult non-pregnant female and less than 11.0 g/dL in pregnant female should be considered as evidence of anaemia. KINETIC CLASSIFICATION Although, there are many classification schemes for anaemia based on aetiology, red cell morphology, etc. kinetic classification of anaemia based on reticulocyte production index (RPI) is most relevant clinically. Anaemias can be categorised as either hypoproliferative or haemolytic (hyperproliferative) and thereafter investigated appropriately. Hypoproliferative anaemias are due to impaired RBC production and result from acquired nutritional deficiencies or systemic diseases. These are characterised by inadequate reticulocyte production (RPI 2.5) may be either congenital (membrane, enzyme or globin chain defects) or acquired (immune, microangiopathic, PNH, etc.) the former being more common in children and the latter in adults. In acute or chronic blood loss, increased RBC production occurs, provided that adequate nutrients are present. EPIDEMIOLOGY Nutritional deficiencies are the commonest cause of hypoproliferative anaemia in our country and affect both adults and children. Other common causes include the anaemia of acute or chronic inflammation and the anaemia of renal disease (due to low erythropoietin). Haematologic malignancies and solid tumours infiltrating the bone marrow (myelophthisis) are encountered mainly in adults. Haemoglobinopathies are more prevalent in certain geographical regions in our country like Hb-D in Punjab, Hb-E in Bihar, Bengal, Assam, North-Eastern states and Hb-S in Orissa and Maharashtra. Acquired and congenital RBC hypoplastic disorders are encountered more frequently in children. Here, we will restrict our discussion to approach of anaemia in adult patients.

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CLINICAL PRESENTATION Anaemia is not a disease, but it is a manifestation of an underlying pathology. It is never normal to be anaemic. The clinical presentations are related to anaemia itself or to the disorders causing anaemia.The signs and symptoms of anaemia will depend on how rapidly it appears, its severity, and the age of the patient. Patients with anaemia usually seek medical attention because of decreased work or exercise tolerance, shortness of breath, palpitation or fatiguability. When the

Anaemia—A Clinical Approach Renu Saxena, M Mahapatra haemoglobin falls below 7 g/dL, exercise capacity is markedly reduced. Older individuals with cardiovascular disease can develop angina and heart failure. Heart systolic murmurs are a common cardiac sign associated with anaemia and best heard in the pulmonary area. Pallor of skin and mucous membranes is a sign of anaemia. In the hands, the skin of the palms first becomes pale, but the creases may retain their usual pink colour until the haemoglobin concentration is less than 7 g/dL. Certain people routinely have pale-appearing skin without being anaemic. Patients with myxoedema may manifest pallor without anaemia. Skin and mucosal changes especially in nails and hairs are very common with anaemia. Thinning, loss of lustre and greying of hair may occur, the last especially with pernicious anaemia. The nails may lose their lustre, become brittle and break easily. This finding is commonly noticed in chronic iron deficiency anaemia. Headache, faintness, lack of mental concentration, tinnitus, and vertigo are common symptoms of severe anaemia. APPROACH TO EVALUATION OF ANAEMIA The correct diagnosis of anaemia requires a thorough history and physical examination along with complete blood cell count (CBC), reticulocyte count, and peripheral blood smear. History and Physical Examination A careful history and physical examination will provide clues to the potential cause as well as underlying systemic disorder (like renal failure, diabetes mellitus) or malignancy. Dietary history is very important, particularly in the young with food-fads and the elderly with anaemia. Pure vegetarian diet lacks B12 whereas insufficient green-leafy vegetables and overcooked food lacks folic acid. A detailed drug history is necessary to rule out drug induced bone marrow depression or autoimmune haemolytic anaemia. A past history of gastrectomy or ileal resection may point towards B12 deficiency anaemia. Menstrual and reproductive history is important to assess the iron status. Occupational history may be relevant in patients exposed to welding, paints and dyes resulting in exposure to lead or other potentially marrow toxic agents. A family history of anaemia, jaundice, gall stones or splenectomy may hint towards inherited haemolytic anaemia. Similarly, ethnicity of the patient helps in analysis of patients with suspected haemoglobinopathies. On examination, pallor may be accompanied by angular cheilitis (cracking at the edges of the lips) and koilonychia (spooning of the nails) in iron deficiency anaemia and hyperpigmentation of knuckles in megaloblastic anaemia. Presence of jaundice alongwith pallor would suggest the possibility of haemolytic anaemia. Splenomegaly in adults may indicate an acquired disorder, such as autoimmune haemolytic anaemia; infections like kala-azar; venous congestion; lymphoproliferative or myeloproliferative disorder. In young adults, it may be even due to a congenital haemolytic anaemia, such as thalassaemia intermedia, hereditary spherocytosis or even congenital

Reticulocyte Count The reticulocyte count provides important information about the kinetics of the red cell production in response to anaemia and helps in classification and directing the initial investigations of anaemia.Reticulocyte count can be done manually using supravital stains (like brilliant cresyl blue or new methylene blue) or more accurately by automated cell counters and flow cytometers using fluorescent dyes like thiazole orange that bind to the residual ribonucleic acid present in these newly released red cells. Automated reticulocyte counting also allows the evaluation of other parameters, such as reticulocyte haemoglobin content and the proportion of immature reticulocytes (immature reticulocyte fraction).The various parameters derived from reticulocyte count are given below. RPI cut-off of 2.5 is used to differentiate hypoproliferative and hyperproliferative anaemias (Table 1).

Red Cell Indices Automated cell counters provide detailed information regarding the size, shape, and haemoglobin content of RBCs. The two parameters most useful in classifying anaemia are the mean corpuscular volume (MCV) in femtolitres (fL) and the red blood cell (RBC) distribution width (RDW). RDW reflects the variation in RBC size and shape (anisopoikilocytosis). These parameters are useful because relatively reproducible changes in the MCV and RDW are associated with certain types of anaemia (Table 2). Particularly when combined with the reticulocyte count, the MCV and RDW can significantly narrow the differential diagnosis (Table 3). Table 2: Usefulness of the MCV and RDW in the Diagnosis of Anaemia Low MCV (< 80 fL) Normal RDW

Reticulocyte count = % reticulocytes in RBCs population Corrected reticulocyte count = % reticulocytes × (patient Hct/45) Reticulocyte production index = Corrected reticulocyte count × maturation time in peripheral blood in days* (Normal values of all of above 0.5-1.5%) Absolute reticulocyte count (ARC) = % reticulocytes × RBC count/L (Normal values for ARC are from 25000 to 75000/mL; values 100,000/mL is indicative of hemolysis or an appropriate erythropoietic response. ARC between 75,000 and 100,000/mL require interpretation in the context of other clinical data. Hct = Haematocrit; *Reticulocyte maturation time = 1 day for Hct 40%; 1.5 days for Hct 30-40%; 2.0 days for Hct 20-30%; 2.5 days for Hct 100 fL)

Anaemia of Acute blood loss chronic disease

Aplastic anaemia

α- or β-thalassaemia trait

Anaemia of chronic disease

Chronic liver disease

Haemoglobin E trait

Anaemia of renal disease

Chemotherapy/ antivirals/alcohol

Elevated Iron deficiency Early iron, folate, or Folate or vitamin RDW vitamin B12 deficiency B12 deficiency Sickle cell-βthalassaemia

Table 1: Kinetic Classification of Anaemia Hypoproliferative anaemias (RPI 1000 g) occurs in few conditions, e.g. myeloproliferative disorders (e.g. chronic myelogenous

Table 1: Causes of Splenomegaly According to Size of Spleen Massive

Moderate

Mild

Non-malignant Tropical splenomegaly Chronic malaria Kala-azar Polycythaemia vera Gaucher’s disease Thalassaemia major

Non-malignant Portal hypertension with congestive splenomegaly Chronic haemolytic anaemias Sarcoidosis Essential thrombocythaemia

Infections Bacterial Salmonella, tuberculosis, Sub-acute bacterial endocarditis

Malignant Chronic myeloid leukaemia Idiopathic myelofibrosis with myeloid metaplasia Hairy cell leukaemia Lymphomas

Malignant Lymphomas Chronic myeloid leukaemia Chronic lymphocytic leukaemia Acute leukaemias Amyloidosis

Fungal Parasite: Malaria, Leishmaniasis Megaloblastic anaemia SLE

Viral Infectious mononucleosis, viral hepatitis, CMV, AIDS

Note: All the diseases which cause moderate or massive splenomegaly may cause mild splenomegaly at an early stage of disease. CMV = Cytomegalovirus; AIDS = Acquired immunodeficiency syndrome; SLE = Systemic lupus erythematosus.

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CLINICAL PRESENTATION Mild splenomegaly may be asymptomatic. The most common symptoms produced by enlarged spleen are pain and a heavy sensation in the left upper quadrant; massive splenomegaly may cause early satiety. Occasionally, patient may present with severe pain in left hypochondrium or lower left chest due to rapid or acute enlargement of spleen resulting in stretching of the spleen with stretching of the capsule, infarction or inflammation of the capsule. Enlargement of spleen can be made on palpation

leukaemia, myelofibrosis, polycythemia vera), hairy cell leukaemia, lymphomas (splenic villous lymphoma), chronic lymphocytic leukaemia, Gaucher’s disease, autoimmune haemolytic anaemia and chronic malaria. Presence of pallor (anaemia) may indicate haemolysis, bone marrow infiltration and hypersplenism. Petechiae/purpura due to thrombocytopaenia is seen in conditions, e.g. bone marrow failure (e.g. leukaemia), autoimmune disorders and hypersplenism. Presence of fever or rigors is indicative of

LABORATORY ASSESSMENT Blood Counts Complete blood count with differential and peripheral blood smears is the most important test. Pancytopaenia may be present because of bone marrow infiltration. White blood cell (WBC) count may reveal atypical lymphocytes (e.g. due to viral infections), blasts (e.g. in leukaemia), neutropaenia, (e.g. due to viral infections), neutropaenia, or neutrophilia (e.g. due to infection or leukaemia). Haemoglobin concentrations, red blood cell smears and reticulocyte counts may demonstrate anaemia, abnormal erythrocyte morphology, reticulocytosis (e.g. due to haemolysis), or malarial parasites. The platelet count may be high in conditions like myeloproliferative disorders (e.g. cytomegalovirus, primary thrombocythemia, polycythemia vera), may be normal or low in congestive splenomegaly, acute leukaemia, Gaucher’s disease and immune thrombocytopaenia. Thrombocytopaenia may be present due to decreased production (e.g. due to bone marrow infiltration), increased

destruction (e.g. due to immunologic causes, drug reactions, or viral infections), or sequestration or hypersplenism. Bone Marrow Examination It is generally indicated for work-up whenever a malignant haematologic disease is suspected or disseminated infection like kala-azar or tubercular infection is suspected. Infection Work-up This should be done as clinically indicated. Smear or antigen test for malaria, kala-azar, cultures from blood, body fluids (for bacterial infection), viral studies (Hepatitis, human immunodeficiency virus) and antibody titers for toxoplasmosis may aid in the diagnosis of infection as cause of splenomegaly.

Splenomegaly—A Clinical Approach

infections such as malaria, infectious mononucleosis or bacterial endocarditis. Presence of icterus may suggest haemolytic anaemia or liver disease as possible cause of splenomegaly. Skin rash may occur in acute and chronic infective states, Systemic lupus erythematosus (SLE), infective endocarditis and rheumatoid arthritis. Cloudy cornea and cherry-red retinal spots in children may be suggestive of metabolic storage disorders, e.g. mucopolysaccharidoses. Presence of respiratory and cardiac symptoms may be secondary to congestive heart failure, severe anaemia or a new murmur may be clue to infective endocarditis as cause of mild splenomegaly. Presence of prominent veins over abdominal wall, ascites, enlarged or shrunken liver may be indicative of portal hypertension and liver pathology as possible cause of splenomegaly. History of joint pains (rheumatoid arthritis, SLE) or bone pains (e.g. leukaemia) may be an impor tant clue to diagnosis of splenomegaly. Splenomegaly may be seen in congenital haemolytic anaemias like beta-thalassaemia, hereditary spherocytosis and sickle cell anaemia in which family history may also be present. Non-cirrhotic portal fibrosis occurs in older children and young adults. Presence of generalised lymph node enlargement may suggest lymphohaemopoietic malignancies as a possible cause of splenomegaly. Primary tumours of spleen are rare except cysts; mostly metastasis from adjacent organs, such as stomach, pancreas and kidney can spread to spleen.

Evaluation for lymphohaematopoeitic disorders In myeloproliferative disorders, there may be mild anaemia with elevation WBC count (generally 10,000 to 20,000/mm3 in myelofibrosis and polycythaemia vera or more than 1,00,000/ mm3 in chronic myeloid leukaemia). On differential count myelocytes, metamyelocytes and basophils may be appreciated. Spleen may be enlarged in a number of lymphoproliferative disorders. Immunophenotyping from peripheral blood or bone marrow may be necessary for definite diagnosis. Liver disease evaluation Liver function tests may be abnormal. For portal hypertension, ultrasound and Doppler of portal venous system and endoscopy (if indicated to exclude oesophageal varices) may be considered. Evaluation for immunological disorders This may include erythrocyte sedimentation rate, C3, C4, antinuclear antibody, rheumatoid factor, urinalysis, blood urea nitrogen and serum creatinine. Evaluation for haemolytic disorders Reticulocyte count, blood smear, serum bilirubin, urinary urobilinogen, Coombs’ test, osmotic fragility, haemoglobin electrophoresis and other tests for haemolytic anaemia are performed, if indicated. RECOMMENDED READINGS 1.

Aster JC. Diseases of white blood cells, lymph nodes, spleen and thymus. In: Kumar V, Abbas AK, and Fausto N, editors. Robbins and Cotran: Pathologic Basis of Disease, 7th Ed. Philadelphia: Saunders; 2004: pp 702-5.

2.

Henry PH, Longo DL. Enlargement of lymph nodes and spleen. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL and Jameson JL, editors. Harrison’s Principles of Internal Medicine; 16th Ed, vol I. New York: McGraw Hill; 2005: pp 345-8.

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15.4 DEFINITION AND EPIDEMIOLOGY Though iron is the third most abundant element yet its deficiency is the commonest nutritional deficiency and a major health problem that is estimated to afflict over two billion people globally. More than half of patients with anaemia are assumed to have iron deficiency. Between 30% and 70% population in the developing world is iron deficient. The third national family health survey (NFHS-3) estimates suggest that 56% of women and 70% of children in India have anaemia. Over half of all cases of anaemia are secondary to iron deficiency. Iron deficiency passes through a latent phase to overt iron deficiency anaemia (IDA). IDA is associated with cognitive impairment, reduced work output and is an important contributor to increased maternal and perinatal mortality. IRON METABOLISM Body Iron Stores Average total human body iron is approximately 3 to 4 gm in men (50 mg/kg) and 2.3 gm (40 mg/kg) in women.Though iron is present in all cells and has several vital functions, nearly 70% of the body iron is present in haem compounds, especially haemoglobin and myoglobin; with small amounts being incorporated into enzymes that use iron in electron transfer (cytochromes, peroxidases, catalases and ribonucleotide reductase) and in enzymes containing iron-sulphur clusters (including cytochromes and aconitase). About 30% of iron, which is non-haem, is stored as ferritin or haemosiderin in the bone marrow, spleen and liver. Approximately 0.1% of body iron is in transit in the plasma, bound to the carrier protein, transferrin. The relative iron stores and their turnover are shown in Figure 1. Iron metabolism is discussed in details in chapter 5 of section 18. Iron Cycle and Iron Absorption Since most of the iron in body is recycled and normally the losses are minimal and limited to those through the epithelial

Figure 1: Iron stores and turnover.

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RBCs = Red blood cells; GIT = Gastrointestinal tract.

Iron Deficiency Anaemia Subhash Varma cells of skin, gut and genitourinary tract, the daily loss that needs dietary replenishment is approximately 1 mg in men and post-menopausal women and up to 2 mg in menstruating women. However, it can increase several fold in those with blood loss due to any cause. Since only 10% to 15% of ingested iron is absorbed, the dietary intake has to be higher. It is generally between 12 and 15 mg in normal diet. Iron absorption from the proximal small intestine is tightly regulated and increases in patients with iron deficiency. Several factors affect iron absorption (Table 1). Bioavailability of ingested iron in meat containing diets is approximately two to four times compared to a vegetarian diet. Phytates and phosphates present in some foods such as leafy vegetables and tannates in tea also reduce the bioavailability of iron in vegetarian food. Vitamin C enhances the iron absorption. Ingested iron could be in organic (haem) and inorganic form. Inorganic iron is generally in ferric form that needs to be reduced to ferrous form, a function that is accomplished by the gastric acid. Consequently, achlorhydria either due to disease or drugs like proton pump inhibitors reduces iron absorption. Table 1: Factors Affecting Iron Absorption Increased Absorption Dietary factors Increased haem-iron Animal protein Vitamin C

Decreased Absorption Vegetarian diet Achlorhydria Phytates Tannic acid (Tea) Alkali intake

Systemic factors Iron deficiency Iron overload Ineffective erythropoiesis Inflammatory disorders Thalassaemia, myelodysplasia Infection Increased erythropoiesis Haemorrhage (Haemolytic anaemia) Hypoxia

Iron is absorbed in the duodenum and upper jejunum involving different transport mechanisms for haem and non-haem iron. Understanding of molecular mechanisms involving mucosal uptake, transfer to lamina propria, iron transport, storage and release has improved tremendously in recent years. Several key players such as diavalent metal transporter 1 (DMT1), hephaestin, ferroportin and hepcidin act in synchrony to maintain iron homeostasis. Absorbed iron is transported after binding to transferrin to the proerythroblasts for haem synthesis and some is carried to hepatocytes and reticuloendothelial cells (RE cells) for storage. The iron released from the red cells is recycled through the transferrin as well as stored in RE cells. Ferritin is the principal storage protein and ferritin levels correlate with status of body iron store, however, it is an acute phase reactant and the levels can be high in inflammatory diseases even in absence of iron

AETIOPATHOGENESIS Iron deficiency results when demand outstrips supply and that may occur due to blood or haemoglobin loss, increased physiologic demands as in pregnancy, lactation and adolescence, decreased dietary intake or impaired absorption (Table 2). In a person with normal iron stores it passes through a pre-latent stage (iron store depletion) to latent stage (iron deficient erythropoiesis) and then to frank IDA (Table 3). With the progressive depletion of iron stores, serum iron levels fall and total iron binding capacity (TIBC) increases.When serum transferrin saturation falls to less than 16%, the supply of iron to marrow becomes sub-optimal. Initially free erythrocyte protoporphyrin levels increase and it finally results in decreased haemoglobin per cell and ultimately typical morphological changes of IDA appear. At times iron deficient erythropoiesis may result from impaired iron utilisation as in anaemia of chronic disease.Similar phenomenon occurs secondary to use of erythropoietin in chronic renal disease that is the result of impaired mobilisation of the large quantities needed for erythropoiesis. Table 2: Causes of Iron Deficiency Anaemia Increased Iron Requirements Blood loss, massive haemorrhage Gastrointestinal bleeding Haemorrhoids Duodenal or gastric ulcers or gastritis Nonsteroidal anti-inflammatory drugs, including aspirin Inflammatory bowel disease Diverticulosis Malignancy Arteriovenous malformation Varices Meckel’s diverticulum Milk-induced enteropathy (infants) Salicylate use Hookworm (Necator americanus and Ancylostoma duodenale) Schistosomiasis Trichuriasis Alveolar haemorrhage Haemoglobinuria Rapid growth in body size between 2 and 36 months of age Menstruation, pregnancy and lactation Inadequate Iron Supply Poor nutritional intake Malabsorption Gastric by-pass surgery for ulcers or obesity Achlorhydria from gastritis or drug therapy Severe malabsorption: coeliac disease Abnormal transferrin function Congenital atransferrinaemia Auto-antibodies to transferrin receptors Duodenal by-pass Drugs that increase gastric pH Tannins, phytates, bran Competing metals Regular Blood Donation Factitious Anaemia Genetic Iron Deficiency Anaemia Iron-resistant-iron deficiency anaemia Atransferrinaemia Acaeruloplasminaemia Mutations in genes encoding DMT1 and glutaredoxin-5

Table 3: Stages of Iron Deficiency Anaemia Pre-latent Reduction in iron stores without reduced serum iron levels Detected by a low serum ferritin measurement Hb (N), MCV (N), iron absorption (↑), transferrin saturation (N), serum ferritin (↓), marrow iron (↓) Latent Iron stores are exhausted but the blood Hb level remains normal Hb (N), MCV (N), TIBC (↑), serum ferritin (↓), transferrin saturation (↓), marrow iron (absent) Iron deficiency anaemia Blood Hb concentration falls below the lower limit of normal Hb (↓), MCV (↓), TIBC (↑), serum ferritin (↓), transferrin saturation (↓), marrow iron (absent)

Iron Deficiency Anaemia

deficiency. Excess iron is also stored as haemosiderin which is water insoluble protein iron complex.

Hb = Haemoglobin; N = Normal; MCV = Mean corpuscular volume; TIBC = Total iron binding capacity; ↓ = Decreased; ↑ = Increased.

CLINICAL FEATURES Patients with IDA could be incidentally diagnosed on laboratory investigations or may present with symptoms related to anaemia, the underlying cause or those peculiar to iron deficiency. Anaemia IDA can result in varying degree of anaemia that may be well tolerated in some persons. Severe IDA may be associated with fatigue, breathlessness, palpitations, dizziness, headache and irritability. Growth Iron deficiency impairs growth in infancy. In infants and preschool children, iron deficiency anaemia affects neurological development by decreasing learning ability and altering motor functions. Iron deficiency even without overt anaemia has been linked to delayed cognitive development in children and adolescents. Epithelial Tissue Changes Patients with long-standing iron deficiency may develop a constellation of symptoms and signs characterised by defective structure or function of epithelial tissue. Nails, tongue and mouth are especially affected. Fingernails may become brittle, fragile, or longitudinally ridged and ultimately develop koilonychia. Soreness of tongue, mild papillary atrophy, absence of filiform papillae and angular stomatitis are the most frequent epithelial changes. Some patients may complain of dysphagia secondary to post-cricoid oesophageal web or stricture with gradual onset of dysphagia to solids but not to liquids (PatersonKelly syndrome/Plummer-Vinson syndrome). Other Manifestations IDA has been associated with impaired immune function and resultant increase in infections. Pica or craving for unusual substances like ice, clay, starch or other unusual food is a well described feature that improves on treatment with iron. Iron deficiency has also been associated with decreased work performance and exercise tolerance. Restless leg syndrome, i.e. an urge to move the legs with or without paraesthesia that worsens at rest and improves transiently with activity, has been associated with iron deficiency, especially in the elderly. LABORATORY INVESTIGATIONS IDA is diagnosed by the presence of biochemical indicators of iron deficiency along with characteristic blood and bone

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marrow changes. Unfortunately, the classic combination of laboratory findings occurs consistently only when IDA is far advanced, when there are no complicating factors such as infection or malignant neoplasms and when there has been no previous therapy with transfusions or parenteral iron.Various tests and their limitations are listed in Table 4. Table 4: Utility and Limitations of Various Investigations in Iron Deficiency Test

Comments

Haemoglobin Transferrin saturation

Non-specific, not affected in early stages Low cost, widely available Marked diurnal variation in values, increased in ineffective erythropoiesis One of the last parameters to be affected, hence low specificity Needs specialised autoanalysers, affected late

MCV % hypochromic RBCs Reticulocyte Hb content RBCs zinc protoporphyrin

Serum ferritin

Bone marrow iron stain Soluble transferrin receptor

Early and sensitive sign False normal in thalassaemia and with increase in MCV Simple and precise for field surveys No additional information than % hypochromic RBCs Falsely high in lead toxicity, jaundice and haemodialysis patients Widely available, falsely high in inflammation, liver disease, alcoholism, malignancy, chronic infection and haemophagocytic syndrome Not done routinely due to expense, discomfort and technical difficulties like high inter-observer variability Also elevated in conditions of increased erythropoiesis, chronic haemolytic anaemias

MCV = Mean corpuscular volume; RBCs = Red blood cells.

Blood Parameters Erythrocytes IDA is characterised by a decrease in haemoglobin and red blood cell (RBC) counts along with decrease in the mean corpuscular volume (MCV) to less than 80 fL, mean corpuscular haemoglobin (MCH) to less than 28 pg/cell and mean corpuscular haemoglobin concentration (MCHC) to less than 30 g/dL. The content of reticulocyte haemoglobin (CHr) is an early, sensitive indicator of iron deficiency. CHr directly examines the haemoglobin endowment of the youngest circulating erythrocytes, allowing early detection of iron deficiency. Peripheral smear It shows characteristic findings in severe IDA. Anisocytosis is an important early sign in iron deficiency and when quantified has differential diagnostic value. An increased red cell distribution (RDW) on automated counter is indicative of anisocytosis. The red cells show microcytosis, hypochromia and poikilocytosis (Figure 2). Patients with parasitic diseases may show eosinophilia. Reactive thrombocytosis may be present in 50% to 70% cases, though some cases may have associated thrombocytopaenia. Biochemical Parameters

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Serum ferritin, serum iron and TIBC Low serum ferritin invariably signifies iron deficiency. It has high negative predictive value although it lacks sensitivity and a normal value does not reliably exclude iron deficiency. In uncomplicated IDA, the serum ferritin level is less than 12 μg/L.

Figure 2: Peripheral smear in iron deficiency anaemia.

However, higher serum levels are the rule in the presence of a complicating infectious or inflammatory disease. Serum iron concentration (normal 30 to 160 μg/dL) is reduced in iron deficiency, and the TIBC (normal 220 to 420 μg/dL) increased. TIBC may be reduced in patients who have hypoalbuminaemia, inflammation, or both. Transferrin saturation is always reduced to less than 16% in iron deficiency. Serum transferrin receptor (sTFR) fragments These are measured by immunologic methods, are substantially increased in iron-deficient patients. This is useful in distinguishing iron deficiency from the anaemia of chronic disease (ACD), particularly when analysed as the ratio of sTFR to the log of the ferritin value. When the ratio of sTFR to log ferritin is greater than 1.5, iron deficiency is usually present (with or without other processes); when it is less than 1.5, the patient most likely has impaired iron use due to ACD, without frank iron deficiency. Erythrocyte ferritin Erythrocyte ferritin concentration is increased in thalassaemias and sideroblastic anaemias and decreased in iron deficiency. Though opinions differ, it has been suggested that basic red cell ferritin is not influenced by inflammation, and therefore could detect iron deficiency more reliably. However, this test is still not widely available. Erythrocyte zinc protoporphyrin Free erythrocyte protoporphyrin (FEP), mainly zinc protoporphyrin, is increased in disorders of haem synthesis, including iron deficiency, lead poisoning and sideroblastic anaemia. FEP is useful in differentiating iron deficiency from thalassaemia in which its value remains normal.This test requires small blood samples, is quite sensitive in the diagnosis of IDA and practical for large-scale screening programmes designed to identify children with either iron deficiency or lead poisoning. In addition, FEP also has a retrospective application as it helps to diagnose iron deficiency anaemia for some time even after the commencement of therapy. Bone marrow Hypercellularity with erythroid hyperplasia and presence of micronormoblasts is variable depending on the severity of

DIFFERENTIAL DIAGNOSIS Differential diagnoses of IDA includes anaemia with microcytic hypochromic picture like thalassaemia minor and other haemoglobinopathies like Hb E disease, anaemia of chronic disorders and sideroblastic anaemia (Table 5). Table 6 summarises laboratory tests for differentiating IDA from other microcytic hypochromic anaemias. Table 5: Causes of Microcytic Hypochromic Anaemia Cause

Body Iron Stores

Iron deficiency anaemia Disordered globin synthesis Thalassaemia states Microcytic haemoglobinopathies Impaired iron utilisation Anaemia of chronic disease Infections Inflammation Disorders of haem synthesis Sideroblastic anaemias Hereditary Acquired

Decreased Increased

Increased

Increased

Blood Transfusion RBC transfusions are rarely indicated because in most instances anaemia responds well to supplementation and is well tolerated. However, elderly with cardiovascular disease and those with excessive loss may need RBC transfusion. Iron Replacement Both oral and parenteral forms of iron are available for therapeutic use. Most patients would benefit by oral iron which is cheap, inexpensive and easy to administer. Several salts of iron are currently marketed (Table 7). Ferrous sulphate is cheap, inexpensive and effective. Usual adult dose is 150-200 mg of elemental iron per day whereas children are given 3 mg/kg of elemental iron. The absorption is better when iron is taken on empty stomach. Iron absorption is inversely proportional to the level of haemoglobin. Haemoglobin in responsive patients would increase by 2 g/dL at 3 weeks. Most patients would report early subjective improvement and maximum reticulocyte response is noted between 5th to 8th day after the start of treatment. Haemoglobin would return to normal in approximately 2 months. However, the treatment should be continued for 4 to 6 months to replenish the iron stores. The maintenance dose is 60 mg of elemental iron per day.

Iron Deficiency Anaemia

anaemia. These morphologic changes are not sufficiently distinctive to be of diagnostic value. However, a decrease or absence of stainable iron in marrow macrophages is characteristic finding of iron deficiency in bone marrow aspirates. Anaemias other than IDA have normal or increased iron stores.

Some patients may not tolerate oral iron and develop epigastric discomfort, nausea, vomiting, diarrhoea or constipation. In such individuals the dose may be reduced or iron may be administered with meals. Since it would decrease the iron absorption, the treatment period is likely to be prolonged. Costlier formulations and enteric coated preparations that claim

Table 6: Laboratory Investigations for Iron Deficiency Anaemia Test MCV RDW Red cell morphology

Iron Deficiency

Decreased Increased Microcytic, hypochromic, pencil cells, anisocytosis Red cell count Decreased Serum iron Decreased Total iron binding capacity Increased Per cent saturation Decreased Ferritin Decreased Serum transferrin receptor Increased Free erythrocyte protoporphyrin Increased Haemoglobin pattern Normal on electrophoresis Marrow Iron Low or absent

Chronic Inflammation

Thalassaemia

Sideroblastic Anaemia

Normal or decreased Increased or normal Normocytic, normochromic or microcytic, hypochromic Decreased Decreased or normal Decreased Decreased to normal Increased or normal Normal Increased Normal

Markedly decreased Increased or normal Microcytic, hypochromic, basophilic stippling, target cells, polychromasia Normal Normal or increased Normal Normal or increased Normal Increased Normal Abnormal (Hb A 2 >3.5%)

Decreased Increased or normal Dimorphic

Normal or increased

Normal

Ring sideroblasts seen >15%

Normal Normal or increased Normal Normal or increased Normal Normal Increased Normal

MCV = Mean corpuscular volume; RDW = Red blood cell distribution width.

TREATMENT OF IRON DEFICIENCY Treatment of iron deficiency requires not only the correction of anaemia but also to replenish the depleted iron stores. Though iron deficiency is easily corrected by iron administration in most cases, a thorough search for finding and treating the underlying cause of deficiency is essential. Treating hookworm infection empirically is justified in Indian context. However, more sinister causes that result in occult blood loss must be considered and investigated especially in men and non-menstruating women.

Table 7: Oral Iron Salts Iron Preparation

Elemental Iron (%)

Ferrous sulphate

20

Exsiccated ferrous sulphate

30

Ferrous fumarate

33

Ferrous succinate

23

Ferrous gluconate

12

Ferrous carbonate

16

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less side effects are available but are generally not needed in practice. Parenteral Iron Therapy Parenteral iron therapy is indicated only in rare instances such as intolerance of oral iron therapy despite changes in dose and time of administration, malabsorption states, excessive continued losses, noncompliance, need for acute replacement as in pregnancy or in conjunction with erythropoietin in patients with renal failure and other causes of qualitative iron deficiency. Various preparations of iron that are available include low and high molecular weight iron dextran complexes, ferric gluconate, iron sucrose and iron sorbital complex (Table 8). New parenteral preparation, iron ferumoxytol and iron carboxymaltose have been reported to be safe. Parenteral iron can cause serious and life-threatening reactions such as hypotension, anaphylaxis or serum sickness like illness. Hence, these must always be administered under supervision. Parenteral iron other than iron sucrose can be administered to deliver the total dose that can be calculated as under: Total iron in mg = Weight in kg x 2.2 x 15 – patients haemoglobin in g/dL) + 1,000 for males/600 for females The total dose is diluted in 250 to 1,000 mL normal saline. 25 mg is given as test dose over 30 seconds and if no reaction is observed over 15 minutes then the remainder is given over 4 to 6 hours. The rate of rise of haemoglobin is similar to that with oral preparations. Table 8: Parenteral Iron Preparations Preparation

Comments

Iron dextran

50 mg/mL, intramuscular and intravenous use Test dose required Total dose infusion possible Potentially severe side-effects Iron sorbitol citrate Only intramuscular use, 50 to 100 mg/day Test dose required Iron sucrose 100 mg in 5 mL Only intravenous use. Maximum single dose 100 mg can be given as slow injection over 5 min or as infusion in 100 ml saline over 30 mins. Test dose not required, reactions very rare. Ferric gluconate 12.5 mg in 10 mL. Slow injection over 10 mins complex in sucrose or infusion in 100 mL saline over 1 hour (Sodium ferric Reactions very rare gluconate)

IRON REFRACTORY IRON DEFICIENCY Some patients continue to have iron deficiency despite supplementation (Figure 3). In some instances, it may be due to poor compliance, a wrong diagnosis or continuing losses that cannot be corrected. Iron malabsorption due to latent or overt celiac disease, autoimmune gastritis and Helicobacter pylori

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Figure 3: Iron refractory iron deficiency. GI = Gastrointestinal; DMT = Divalent metal transporter.

infections have been the commonest demonstrable cause of refractory IDA in adults. In addition inherited forms of IDA affecting iron uptake, transfer and release (due to increased hepcidin levels) have been described in children. A diligent search either for iron loss or iron malabsorption is often rewarding in refractory IDA. CONCLUSIONS Iron deficiency is the commonest nutritional deficiency and is responsible for more than 50% of anaemia worldwide. Iron deficiency results from an imbalance between the demand and supply of iron. It may occur secondary to decreased intake, increased requirements during pregnancy, lactation or growth spurt, inability to absorb iron from the gastrointestinal (GI) tract or increased losses from the gut, genitourinary tract or into other organs/tissues. Though easily treatable, a cause must be sought for in every case because it may be the harbinger of underlying sinister disorder, such as GI malignancy. Iron deficiency results initially in depletion of iron stores and progresses to the development of characteristic microcytic hypochromic anaemia. The diagnosis is established by biochemical parameters and it must be differentiated from other causes of hypochromic microcytic anaemia. Treatment is directed towards replacement of iron and treating the underlying cause. Oral ferrous sulphate is safe, cheap and effective in treating iron deficiency. In case of inadequate response besides looking at compliance, other reasons, such as continuing losses, co-morbidities, iron malabsorption and concomitant deficiencies should be sought. RECOMMENDED READINGS 1.

Andrews NC. Forging a field: The golden age of iron biology. Blood 2008; 112: 219-30.

2.

Gomber S, Bhawan, Madan N et al. Prevalence and aetiology of nutritional anaemis among school children of urban slums. Indian J Med Res 2003; 118: 167-71.

3.

Umbreit J. Iron deficiency: A concise review. Am J Hematol 2005; 78: 225-31.

15.5 INTRODUCTION A puzzling illness with idiopathic anaemia, debilitation, languor and finally, torpor and death was first described by Addison in 1849. In 1880, Ehrlich identified megaloblasts and proposed them as the precursors of the ‘giant blood corpuscles’. These events in course of time heralded the knowledge of disease known as megaloblastic anaemia. Castle described achylia gastrica and demonstrated that gastric juice contains an ‘intrinsic factor’ (IF) that combines with an ‘extrinsic factor’ in meat and allows it to be absorbed. Wills, who treated macrocytic anaemia with yeast, defined the need for folate, which was isolated and characterised in 1948. DEFINITION The megaloblastic anaemias are disorders caused by impaired deoxyribonucleic acid (DNA) synthesis due to deficiencies of vitamin B12 (cobalamin, i.e. Cbl) or folic acid (FA), which give rise to anaemia and macro-ovalocytic red cells (mean corpuscular volume [MCV] >100 fL) and bone marrow showing intense erythroid hyperplasia and megaloblastic changes. The megaloblast, the morphologic hallmark of the syndrome, is a product of impaired DNA formation due to deficiencies of vitamin B12 or FA.

Megaloblastic Anaemia Tarun Kumar Dutta PATHOGENESIS OF MEGALOBLASTIC ANAEMIA Megaloblastic anaemia results from abnormal maturation of haematopoietic cells due to impaired DNA synthesis. Cbl (vitamin B12) and FA are two essential vitamins for DNA biosynthesis. Deficiency of either vitamin results in what is called as nucleo-cytoplasmic asynchrony. All proliferating cells will exhibit megaloblastosis; hence changes are evident in the buccal mucosa, tongue, small intestine, cervix, vagina and uterus. In the haematopoietic system this asynchrony results in abnormal nuclear maturation with normal cytoplasmic maturation, apoptosis, ineffective erythropoiesis, intra-medullary haemolysis, pancytopaenia and typical morphological abnormalities in the blood and marrow cells. AETIOLOGY Aetiology of megaloblastic anaemia is multifactorial and may result from dietary deficiency, impaired absorption and transport or impaired utilisation of these vitamins in DNA synthesis (Table 1). The dietary patterns vary widely across India and studies need to be conducted region-wise to find out the variable aetiology of megaloblastic anaemia.

Table 1: Causes of Cobalamin and Folic Acid Deficiencies in India Common Causes of Cobalamin Deficiency in India Nutritional deficiency/inadequate intake (most important cause in India, including in strict vegans) Malabsorption Defective absorption of cobalamin from food Gastric achlorhydria Partial gastrectomy Drugs blocking gastric acid secretion Inadequate production of intrinsic factor (IF) Total gastrectomy Disorders of terminal ileum Tropical and coeliac sprue Intestinal resection Granulomatous diseases Competition for cobalamin Bacteria (Blind loop syndrome) Drugs Colchicine Neomycin Uncommon Causes of Cobalamin Deficiency in India Pernicious anaemia Congenital absence or functional abnormality of IF Crohn’s disease Selective cobalamin malabsorption: Imerslund-Grasbeck syndrome Fish tapeworm infestation (Diphyllobothrium latum) Transcobalamin II deficiency

Common Causes of Folic Acid Deficiency in India Nutritional deficiency Increased requirements Infancy and children Pregnancy Malignancy Chronic haemolytic anaemia Chronic exfoliative dermatitis Haemodialysis Malabsorption Tropical and non-tropical sprue Drugs: Phenytoin, barbiturates Impaired metabolism Inhibitors of dihydrofolate reductase Methotrexate, pyrimethamine Alcohol Uncommon Causes of Folic Acid Deficiency in India Rare enzyme defect – dihydrofolate reductase Drugs that impair DNA synthesis Purine antagonists: 6-mercaptopurine, azathioprine Pyrimidine antagonists: 5-fluorouracil, cytosine arabinoside Others: Hydroxyurea, procarbazine, zidovudine, acyclovir Metabolic disorder Lesch Nyhan syndrome, hereditary orotic aciduria Megaloblastic anaemia of unknown aetiology Refractory megaloblastic anaemia in myelodysplastic syndrome (MDS) 933

PREVALENCE AND CAUSATIVE FACTORS Very few studies have been conducted to study the prevalence of megaloblastic anaemia in the general population. Analysing the western literature, it is found that dietary and pregnancyrelated folate deficiencies are probably the most common causes of megaloblastic anaemias. The frequency of pernicious anaemia (PA) is 0.25-0.5 cases per 1,000 persons in their seventh decade of life. However, the frequency of PA is reported to be higher in Sweden, Denmark, and the United Kingdom (100-130 cases per 100,000 population). In a study conducted among North African population, 478 patients with megaloblastic anaemia were studied; 98% of patients had vitamin B12 deficiency. PA accounted for most of these cases, and median age at presentation was 45 years. In a study conducted in Hong Kong on 84 consecutive Chinese patients with megaloblastic anaemia (48 males and 36 females) median age at presentation was 67 years, and vitamin B12 deficiency was found in all cases and none had folate deficiency. Indian Scenario A study reported that 75% of a selected urban population from India, Pune (Maharashtra) had metabolic evidence (hyperhomocysteinaemia and methylmalonic acidaemia) of Cbl deficiency, which could only partly be explained by a vegetarian diet. Folate deficiency has traditionally been linked to poverty, which (by Indian standards) afflicts ∼33% of the population of India. In Delhi, a hospital-based study showed that 2.7% of all anaemia was megaloblastic anaemia.

requirement is 6-9 μg/day. Total body stores of Cbl are 2-5 mg, approximately one-half of which is in the liver. As a result, it takes years to develop vitamin B12 deficiency after absorption of dietary B12 ceases. Clinical Manifestations of Cobalamin Deficiency The classic picture of Cbl deficiency due to PA was that of a prematurely graying, mentally sluggish person with a shiny tongue (atrophic glossitis) and a shuffling broad gait. This classic picture of PA is now seen less frequently. It has been replaced by more subtle presentations. Because Cbl is required for all rapidly growing cells, including enteric mucosal cells and epithelial cells of the skin, patients with Cbl deficiency may complain of glossitis, vaginal atrophy, and malabsorption; they often have diffuse hyper-pigmentation particularly increased pigmentation over knuckles (Figures 1 and 2). The patient may have neuro-psychiatric problems consisting of paraesthesiae, numbness, weakness, impaired memory and personality changes. Examination reveals haematologic and neurologic abnormalities. When the anaemia is severe, there may also be thrombocytopaenia and neutropaenia (i.e. pancytopaenia). Thrombocytopaenia occasionally may be associated with frank mucosal bleeding.

In another study from Puducherry, megaloblastic anaemia was found in 38.4% out of 60 adult patients of macrocytic anaemia. There was a significant male preponderance in the study (65%), and majority were young. The megaloblastic anaemias observed were due to either vitamin B12 deficiency (78.3%) or combined vitamin B12 and folate deficiency (21.7%). None had lone folate deficiency. A significant proportion of nonvegetarians (73.9%) had megaloblastic anaemia. In a study at Delhi, megaloblastic anaemia was diagnosed in 175 patients with anaemia over a period of 6 months. Assays were done on 120 patients who could be followed-up and results showed Cbl deficiency in 78 patients (65%), combined Cbl and folate deficiency in 20 patients (12%) and pure folate deficiency in 8 patients (6%). The peak incidence of megaloblastic anaemia was in the age group of 10 to 30 years (48%), with female preponderance (71%).

Figure 1: Diffuse pigmentation of hand and knuckle hyper-pigmentation in megaloblastic anaemia.

More and more reports from India show vitamin B12 deficiency as a predominant cause for megaloblastic anaemia in contrast to folate deficiency, which was earlier believed to be a major cause. This may be attributed to the routine FA supplementation especially among women. Western data emphasises on PA as the major cause, but Indian data suggests nutritional deficiency of vitamin B12 and FA as major causes of megaloblastic anaemia. An attempt should always be made to find out the cause and treat accordingly.

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COBALAMIN DEFICIENCY Physiologic Considerations Animal products (meat and dairy products) provide the only dietary source of Cbl for humans. The minimum daily

Figure 2: Knuckle hyper-pigmentation in a 55-year-old woman with megaloblastic anaemia due to combined vitamin B12 and folic acid deficiency.

Other neurologic abnormalities that can be seen are axonal degeneration of peripheral nerves and central nervous system symptoms including memory loss, irritability and dementia. Patients may present with Lhermitte’s syndrome, a shock-like sensation that radiates to the feet during neck flexion. Of great clinical importance, not all patients with neurologic abnormalities secondary to Cbl deficiency are either anaemic or have macrocytic red cell indices. As an example, among 141 consecutive patients with neuro-psychiatric abnormalities due to Cbl deficiency, the haematocrit was normal in 34, the mean red cell volume was normal in 25 and both tests were normal in 19. FOLIC ACID DEFICIENCY Physiologic Considerations of Folic Acid Folate occurs in animal products and in leafy vegetables in the polyglutamate form. Normal daily requirements for unstressed individuals are about 200-400 μg/day; this increases to 500-800 μg/day in pregnancy and lactation. The most common cause of folate deficiency is nutritional due to poor diet and/or alcoholism. Although folate is plentiful in liver, greens and yeast, it is easily destroyed by heat during cooking. Body stores are small (5-10 mg) and individuals on a folate deficient diet can develop megaloblastosis within 4 to 5 months. Folate at physiologic levels enters cells by binding to a folate receptor. Once inside the cell, FA is polyglutamated, a form which is biologically active and cannot diffuse back into the plasma. Causes of Folate Deficiency Alcohol abuse produces a sharp fall in serum folate within 2 to 4 days by impairing its enterohepatic cycle and inhibiting its absorption. Thus, alcoholics on a low folate intake can develop megaloblastosis within 5 to 10 weeks. This period is shorter than the 4 to 5 months required in normals in part because alcoholics start with lower stores due to previous dietary habits. Other mechanisms of folate deficiency include increased requirements in pregnancy and in patients with haemolytic anaemias and exfoliative skin disease and drug-induced interference with folate metabolism. Pregnancy and lactation increase the need for FA and the daily requirement increases from 400 μg to 800 μg.

Several drugs interfere with FA metabolism. Trimethoprim is a weak inhibitor of dihydrofolate reductase and in high dose has been implicated in megaloblastic pancytopaenia. Methotrexate can also produce folate deficiency. Clinical Manifestations The haematologic manifestations of folate deficiency are similar to those of Cbl deficiency but neurologic abnormalities do not occur.

Megaloblastic Anaemia

Neurologic Abnormalities The neurologic problems, when present, consist of the classic picture of sub-acute combined degeneration of the dorsal (posterior) and lateral spinal columns. This lesion, specific for Cbl deficiency, is due to a defect in myelin formation of unknown mechanism. The neuropathy is symmetrical and affects the legs more than the arms. It begins with paraesthesiae and ataxia associated with loss of vibration and position sense, and can progress to severe weakness, spasticity, clonus, paraplegia and even faecal and urinary incontinence.

Another important difference is the time required for deficiency to develop.Because Cbl stores are so large in relation to daily intake, a year of inadequate intake of absorption is required before the onset of symptoms. On the other hand, symptoms of folate deficiency can occur within a few weeks after intake is diminished. Folate deficiency occurs in patient who abuse alcohol or other drugs and have a very poor dietary intake. Older and depressed patients who live alone and avoid cooking foods that contain folate may become deficient, as can patients with the malabsorption syndrome. Increased folate demands occur in patients with chronic severe haemolytic anaemia and pregnancy. Hyperhomocysteinaemia Both Cbl and FA are required for the metabolism of homocysteine to methionine. As a result, deficiencies in these vitamins can lead to elevations in plasma homocysteine levels, which is a risk factor for the development of atherosclerosis and venous thrombosis. DIAGNOSIS OF MEGALOBLASTIC ANAEMIA The evaluation of suspected Cbl or folate deficiency generally proceeds in two stages: Documenting the presence of the vitamin deficiency and then determining its cause (e.g. malabsorption, dietary lack or PA). The diagnosis of deficiency can most often be established by a combination of the following; red blood cell mean corpuscular volume (MCV), evaluation of the peripheral blood smear and bone marrow examination; measurement of the serum Cbl and the red blood cell (or serum) folate concentrations and evaluation of specific metabolites (e.g. methylmalonate and homocysteine). An elevation of the red blood cell MCV is one of the hallmarks of Cbl and folate deficiency. The degree of elevation of the MCV is often a clue as to whether a vitamin deficiency is present. The major haematologic finding is a macro-ovalocytic anaemia (Figure 3) (with elevated serum bilirubin and LDH levels that reflect the increased red cell breakdown due to ineffective erythropoiesis). The absolute reticulocyte count is normal or even distinctly low. The peripheral blood smear shows macroovalocytes, occasionally megaloblasts, and hyper-segmented neutrophils (greater than 5% of neutrophils) with 5 or more lobes or 1% with 6 or more lobes. Hypersegmentation is result of an alteration of late granulopoiesis. When the anaemia is severe, there may also be thrombocytopaenia and neutropaenia (i.e. pancytopaenia). Bone marrow aspiration and biopsy reveal a very hypercellular marrow with megaloblastic erythroid hyperplasia and giant metamyelocytes (Figure 4). 935

should be obtained as an initial screening test and that there is no basis for the routine testing of all samples for both serum folate and red cell folate. If the serum folate concentration is more than 4 ng/mL (9.1 nanomol/L), folate deficiency is effectively ruled out. If the Cbl and folate levels are equivocal, the next step should be evaluation of the metabolites methylmalonic acid (MMA) and total homocysteine. The measurement of the serum concentrations of the metabolities is helpful in clarifying the diagnosis in such a situation.

Figure 3: Peripheral smear showing macro-ovalocyte, hypersegmented neutrophil (arrow) and scanty platelets (Leishman’s stain × 1000).

Measurement of Methylmalonate and Homocysteine Serum concentrations of homocysteine and methylmalonic acid (MMA) are elevated in Cbl deficiency, due to a decreased rate of metabolism. In comparison, only homocysteine is elevated in folate deficiency, since folate does not participate in MMA metabolism. Hereditary homocysteinaemia can raise serum homocysteine levels. Serum and urinary levels of MMA are elevated in patients with methylmalonic aciduria and in patients with renal insufficiency or hypovolaemia. If a diagnosis of Cbl and/or folate deficiency has been established through the above testing, the next step is to determine the cause of the deficiency (e.g. PA, diet, malabsorption, drugs). The presence of anti-intrinsic factor antibodies and positive Schilling test are highly confirmatory for the diagnosis of PA. Vitamin B12 deficiency, PA, malabsorption, blind-loop syndromes and ileal disease can be reliably and quickly diagnosed using methods other than the Schilling test. Thus, Schilling test is not commonly employed these days. In the absence of facilities to estimate vitamin levels, a therapeutic algorithmic approach can be followed to find out cause of megaloblastic anaemia, whether due to vitamin B12 or FA deficiency (Figure 5). TREATMENT Treatment of Cobalamin Deficiency

Figure 4: Bone marrow aspirate showing a colony of megaloblastic erythropoiesis with sieve-like chromatin and a giant stab form (Leishman’s stain × 1000).

Cobalamin Levels In general, however, serum Cbl levels can be interpreted, as follows:  More than 300 pg/mL (normal result); Cbl deficiency is unlikely,  200 to 300 pg/mL (borderline result); Cbl deficiency possible,  Less than 200 pg/mL (low); consistent with Cbl deficiency (specificity of 95% to 100%).

936

Folate Levels The red cell folate concentration is theoretically a more reliable indicator of tissue folate adequacy, since it reflects a timeaveraged value of FA availability, and is therefore not subject to the short-term fluctuations noted above. As a result, it has been suggested that the less expensive serum folate concentration

PA is typically treated with parenteral (i.e. intramuscular) Cbl, in a dose of 1,000 μg (1 mg) every day for one week, followed by 1 mg every week for 4 weeks and then, if the underlying disorder persists, as in PA, 1 mg every month for the remaining life of the patient. Oral Formulations An alternative that appears to be as effective as parenteral therapy is based on the premise that there is presence of a second, lower efficiency transport system for Cbl that does not require IF or a functioning terminal ileum. Because of variability in absorption, lower doses are not completely effective in some patients with PA. The dose given in this situation (1-2 mg/day) is more than 200 times higher than the minimum daily requirement for normal subjects, and significantly higher than that available in most standard multivitamins and B12 supplements (100 μg/day). The effectiveness of this form of treatment should be monitored frequently with determinations of serum Cbl and methylmalonate concentrations. Laboratory Monitoring Laboratory studies should be monitored after Cbl therapy to document a haematologic and metabolic response: If the

Megaloblastic Anaemia Figure 5: Algorithmic approach to find cause of macrocytic anaemia/megaloblastic anaemia (in the absence of facility for vitamin B12 or folic acid estimation).

patient is anaemic, there will be a reticulocytosis in 3 to 4 days, peaking at days 6 to 7 days, followed by a rise in haemoglobin and a fall in MCV. The haemoglobin concentration begins to rise within 10 days and usually returns to normal within 8 weeks. A delayed response suggests the presence of an additional abnormality (e.g., iron deficiency, infection, hypothyroidism, malignancy). In patients with severe anaemia, serum iron levels fall within 24 hours and the serum LDH levels begin to fall within 2 days. Hyper-segmented neutrophils disappear at 10 to 14 days. Neurologic abnormalities, if present, improve more slowly over six months; the degree of improvement is inversely related to the extent and duration of disease. Treatment of Folate Deficiency Folate deficiency is treated with FA (1-5 mg/day) for 1 to 4 months, or until complete haematologic recovery occurs. A dose of 1 mg/day is usually sufficient, even if malabsorption is present. These doses are in excess of those recommended for disease prevention (e.g., recommended daily allowance

in normal adults, alcoholics, the elderly, prevention of neural tube defects). Folic acid can partially reverse some of the haematologic abnormalities of Cbl deficiency, but the neurologic manifestations will progress. Thus, it is important to rule out Cbl deficiency before treating a patient of megaloblastic anaemia with FA. If initiation of treatment is urgently required, blood samples should be obtained for the appropriate assays and the patient should be treated with both FA and vitamin B12 simultaneously until the results are known. RECOMMENDED READINGS 1.

Chudgar U. Megaloblastic anaemia. In: Shah SN, editor. API Textbook of Medicine; 8th Ed. Mumbai: The Association of Physicians of India; 2008: pp 798-802.

2.

Dutta TK, Panigrahi AK. Megaloblastic anaemia: prevalence and causative factors. In: Agarwal AK, editor. Medicine Update;2009: pp187-90.

3.

Unnikrishnan V, Dutta TK, Badhe BA, et al. Clinico-aetiologic profile of macrocytic anaemias with special reference to megaloblastic anaemia. J Hematolo Blood Trans 2008; 24:155-65.

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15.6 Once released from marrow, red cells circulate in blood for 120 days, after which they are removed by macrophages of reticuloendothelial system (RES) in the liver, spleen and marrow. Iron is recycled via transferrin to the marrow while the pigment protoporphyrin is broken down to bilirubin which is conjugated in liver and excreted into the gut where it is converted to stercobilinogen. Most of the stercobilinogen is excreted in faeces but some of it is partially reabsorbed and excreted in urine as urobilinogen and urobilin. A small fraction of protoporphyrin is converted to carbon monoxide and excreted via the lungs. Globin chains are broken into amino acids and are reutilised for general protein synthesis in the body. Normally, there is no intravascular haemolysis. Any haemoglobin released into the plasma binds to a protein called haptoglobin and this complex of haemoglobin and haptoglobin is removed from plasma by the RES. Haemolysis is characterised by premature removal of circulating red blood cells (RBCs) due to lysis within the circulatory system (intravascular haemolysis) or premature removal by the RES of the spleen, liver and bone marrow (extra-vascular haemolysis). Such accelerated RBC destruction is seen in various hereditary and acquired haemolytic disorders. Normal marrow has tremendous capacity to become hyperplasic and compensate for haemolysis, and hence, anaemia occurs only when this compensation is not adequate. The erythroid hyperplasia of marrow is reflected in blood as reticulocytosis unless there is ineffective erythropoiesis as in thalassaemia major. Shortened RBC survival can be demonstrated by chromium-labelled red cell survival studies. The site of destruction can also be determined by surface counting over liver and spleen.

Hereditary Haemolytic Anaemia MB Agarwal

Table 2: Aetiological Classification of Hereditary Haemolytic Anaemia Membrane defects Hereditary spherocytosis Hereditary elliptocytosis Hereditary stomatocytosis Hereditary acanthocytosis Enzyme defects (congenital non-spherocytic haemolytic anaemia) Deficiency of glucose-6-phosphatase dehydrogenase or other enzymes in the pentose phosphate pathway Deficiency of pyruvate kinase or other enzymes in the EmbdenMeyerhof pathway Associated with abnormalities of nucleotide metabolism Haemoglobin defects Thalassaemia syndrome β-thalassaemia major Hb-H disease Others Haemoglobinopathies Sickle cell anaemia Other abnormal haemoglobins (Hb-E, Hb-D, Hb-C, etc.) Unstable haemoglobin disease Others

Clinical Features Clinical findings in a case of hereditary haemolytic anaemia include pallor, icterus (Figure 1), splenomegaly, haemolytic facies, ankle ulcer, pigment gall-stones, growth retardation, pathological fractures and various crises, e.g. aplastic crises due to B19 parvovirus and megaloblastic crises due to folic acid (FA) deficiency.

HEREDITARY HAEMOLYTIC ANAEMIAS Haemolytic anaemias can be classified in various ways, e.g. inherited (hereditary) versus acquired, intra-corpuscular versus extra-corpuscular (Table 1) and acute versus chronic. Hereditary haemolytic anaemias are usually due to intra-corpuscular or intrinsic red cell defects. Table 2 gives a simplified aetiological classification of hereditary haemolytic anaemias. Table 1: Pathophysiologic Classification of Haemolytic Disorders

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Intrinsic (intra-corpuscular) defects: usually hereditary Red blood cell membrane defects Red blood cell enzyme defects Haemoglobinopathies Extrinsic (extra-corpuscular) defects: usually acquired Immune-mediated haemolysis Physical damage to red blood cells Toxins Thermal injury Mechanical disruption

Figure 1: Icterus in a case of haemolytic anaemia.

Laboratory Investigations Various laboratory investigations to be conducted for the diagnosis of hereditary haemolytic anaemias are presented in Tables 3, 4 and 5 which can be divided into four groups as given below.

Hereditary Haemolytic Anaemia

1. Those secondary to excessive red cell destruction, raised indirect serum bilirubin, increased urinary urobilinogen, decreased serum haptoglobin and haemopexin, increased serum lactic dehydrogenase, altered osmotic fragility, autohaemolysis and shortened red cell survival as shown by chromium labelled studies. 2. Features of increased red cell production which are reticulocytosis, macrocytosis, erythroid hyperplasia of the marrow and radiological changes in the bones (skull and tubular bones). 3. Changes in red cell morphology (Table 5). 4. Features of intra-vascular haemolysis are haemoglobinaemia (Figure 2), haemoglobinuria (Figure 3), haemosiderinuria and methaemalbunaemia. Table 3: Laboratory Evaluation of Red Blood Cells Production and Breakdown Bone marrow production ↑ Reticulocyte count, ↑ BM cellularity, 59Fe uptake Red blood cell destruction ↓ Hb/PCV, 51Cr RBC survival studies Red blood cell sequestration 51Cr RBC sequestration Red blood cell breakdown ↓ Haptoglobin, ↑ bilirubin, ↑ LDH, haemoglobinaemia, methemalbumin, ↑ BM iron Excretion Haemosiderinuria, haemoglobinuria BM = Bone marrow; Hb = Haemoglobin; PCV = Packed cell volume; RBC = Red blood cell; LDH = Lactate dehydrogenase.

Table 4: Urine and Serum Testing in Haemolysis Pigment

Normal Range Comments

Serum bilirubin

0.5 to 1.0 mg/dL 150 mg/dL,binds to haptoglobin or albumin Appears after haptoglobin saturation, haematuria and myoglobinuria must be excluded Qualitative determination by electrophoresis or serum spectrophotometric measurement

Haemolysis

Normal

Figure 2: Haemolysis showing pinkish vs normal plasma.

Table 5: Morphological Changes in RBCs in Hereditary Haemolytic Disorders Red Cell Abnormality

Major Diagnostic Possibilities

Permanently sickled cells Target cells* Spherocytes* Elliptocytes* Acanthocytes* Basophilic stippling*

Sickle cell disease Thalassaemia Hb-E, Hb-D, Hb-C disorders Hereditary spherocytosis Hereditary elliptocytosis Hereditary acanthocytosis, Spur-cell anaemia Pyrimidine 5’-nucleotidase deficiency, thalassaemia trait Hereditary non-spherocytic haemolytic anaemia, i.e. RBC enzymopathies (especially precipitated by drugs)

Bite cells/ Blister cells

* These can also occur in various acquired conclitions which are not listed here.

MEMBRANE DEFECTS Hereditary Spherocytosis Hereditary spherocytosis is the commonest hereditary haemolytic anaemias secondary to an erythrocyte membrane

Figure 3: Haemoglobinuria.

defect. It is due to defective structural protein (spectrin) of the red cell membrane. The greater the deficiency of spectrin, the more severe is haemolysis. There are different genetic lesions resulting in variable degree of haemolysis (Table 6). Hereditary spherocytosis is inherited as an autosomal dominant disorder but the phenotypic expression is variable. Very rarely, it is inherited as an autosomal recessive order. Loss of membrane is also responsible for the spherical shape of the red cells (Figure 4). As the spherical cells are unable to pass through the splenic micro-circulation, these die prematurely.

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Table 6: Heterogeneity of Hereditary Spherocytosis Protein Defect

Haemolysis

Inheritance Frequency Pattern (Autosomal)

Spectrin α-chain Spectrin β-chain Ankyrin defect Band 3 defect Protein 4.1 defect Protein 4.2 defect*

Severe Recessive Mild-to-moderate Dominant Mild-to-severe Dominant Mild-to-moderate Dominant Mild Dominant Moderate-to-severe Recessive

Rare Common (20 %) Common (60%) Common (20%) Common in N. Africa Common in Japan

* = No response to splenectomy.

spleen in the red cell destruction. The treatment is splenectomy which almost always normalises the haemoglobin, even though, microspherocytosis remains. As splenectomy in childhood increases the risk of life-threatening bacterial infections, it is avoided until the age of 5 years or more. Until then, FA should be given regularly. Pneumococcal vaccine is given prior to splenectomy and oral penicillin prophylaxis is given postsplenectomy to avoid sepsis due to encapsulated organisms. Mild cases do not need splenectomy unless gall-stones develop. Hereditary Elliptocytosis (Ovalocytosis) Hereditary elliptocytosis has clinical and laboratory features similar to that of hereditary spherocytosis except for the characteristic red cell morphology (Figure 6) and overall milder course. Majority of the patients can be left alone. Occasionally, splenectomy is required. Inheritance is autosomal dominant. Occasionally homozygous or doubly heterozygous cases of elliptocytosis may present with a more severe haemolytic anaemia called hereditary pyropoikilocytosis.

Figure 4: Hereditary spherocytosis.

Clinical Features Clinical features include moderate anaemia, variable degree of jaundice and splenomegaly. Pigment gall-stones are common and parvovirus B19 induced aplastic crises may cause sudden increase in severity of anaemia. Multiple members from different generations of a given family may be affected. Occasionally, severity of anaemia tends to be different in different members of a given family. Reticulocyte count varies from 10% to 20%. Blood film invariably shows microspherocytes (small dense cells shown in Figure 4). Red cell osmotic fragility is increased (Figure 5). In some patients, one may need 24-hour incubation at 37°C in order to demonstrate increased osmotic fragility. Auto-haemolysis is increased and is correctable by glucose. Coombs test is negative and radio-labelled chromium studies reveal severity of haemolysis and the dominant role of

Figure 6: Hereditary elliptocytosis.

Hereditary stomatocytosis (Figure 7) and hereditary acanthocytosis (Figure 8) are rare RBC membrane disorders.

Figure 7: Hereditary stomatocytosis.

Figure 5: RBC osmotic fragility (Normal, hereditary spherocytosis and mild hereditary spherocytosis).

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HS = Hereditary spherocytosis.

ENZYME DEFECTS G6PD Deficiency Glucose-6 phosphate dehydrogenase (G6PD) is an enzyme that functions to reduce nicotinamide adenine dinucleotide

Table 8: Clinical Features of G6PD Variants

Figure 8: Hereditary acanthocytosis.

phosphate (NADP + ) while oxidising glucose-6 phosphate. Various genetic variants of G6PD are known (Table 7). The commonest of these are Type A in Africans and B in the rest of the world. In all, over 400 variants of the enzyme have been characterised which show less or more activity than normal. It has been estimated that over 200 million people are deficient in G6PD enzyme. Usually, G6PD deficiency is an asymptomatic entity. The main clinical problems are shown in Table 8 and they are due to an acute haemolytic crises which occurs in response to an oxidant stress (drugs, infections or fava beans, Figure 9). Rarely, neonatal jaundice or even a congenital nonspherocytic haemolytic anaemia can occur. Table 7: Common G6PD Variants G6PD Variant

Haemolysis

Prevalence

G6PD A G6PD B G6PD AG6PD MED

No: Normal variant No: Normal variant Yes: Moderate Yes: Severe

Blacks All Blacks Whites

Figure 9: Fava beans.

The inheritance is sex-linked. Heterozygote female carriers have approximately half the normal red cell G6PD values and have an advantage of resistance to Falciparum malaria. Approximately 1% of Indian males are G6PD deficient. It is more common in Parsees (15%), Bhanushali (11%), Khatri (5%), Punjabi (3%), Kutchi (3%) and Muslims (2.5%). The worldwide distribution shows highest prevalence in the tropical zone chiefly West Africa, the Mediterranean, Middle East and SouthEast Asia. The deficiency is of variable degree. Most severely affected cases are seen in the Mediterranean countries and in

Clinical Features

G6PD A

G6PDMED

Drug-induced haemolysis Infection-induced haemolysis Favism Neonatal icterus Hereditary non-spherocytic haemolytic anaemia Degree of anaemia Chronic haemolysis

Common Common Non-seen Rare Not seen

Common Common Common Observed Rare

Moderate Not seen

Severe Rare

Hereditary Haemolytic Anaemia

orientals (Table 7). Rarely, severe cases also occur in Caucasians. The milder variants have mutations located at the amino-end of the gene, while the severe ones affect the carboxy-end.

Acute haemolytic episodes have sudden onset of severe pallor, icterus and red-coloured urine. Patient may develop renal failure as well as symptoms of hypoxia. Usually, the episodes are selflimiting as the younger red cells have nearly normal G6PD activity. However, in Mediterranean type, the haemolysis may not be selflimiting. It may not be possible to make a definite diagnosis during the acute haemolysis. However, between the crises, the enzyme deficiency can be detected by one of the various screening tests or by direct enzyme assay of red cells. During crisis, the blood film may show contracted and fragmented cells, bite cells and blister cells. Reticulocyte preparation may show Heinz bodies (oxidised denatured haemoglobin, Figure 10), particularly if spleen has been removed. The treatment includes stoppage of the offending drug (Table 9), blood transfusion, maintaining high urine output and if required, haemodialysis. If neonatal jaundice is severe, newborns may need phototherapy or even exchange transfusion. Table 9: Drugs or Chemicals that Cause Haemolysis in Patients with G6PD Deficiency Analgesics Acetanilide Antimalarials Primaquine Quinine Chloroquine Fluoroquinolone Norfloxacin Ciprofloxacin Sulphonamides Sulphacetamide Sulphamethoxazole Sulphanilamide Sulphapyridine Sulphasalazine

Sulphones Dapsone Thiazole sulphone Miscellaneous Acetylphenylhydrazine Chloramphenicol Doxorubicin Methylene blue Naldixic acid Napthalene (moth-balls) Niridazole Phenylhydrazine Toluidine blue Trinitrotoluena Vitamin K Vitamin C Nitrofurantoin

Other Red Cell Enzyme Deficiencies These are listed in Table 10. These will not be discussed further because of their rarity. HAEMOGLOBIN DISORDERS Thalassaemia Syndrome The thalassaemia syndrome consists of heterogenous group of inherited anaemias characterised by defective synthesis of one

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Figure 10: Heinz bodies in G6PD deficiency disorder.

Table 10: Hereditary Haemolytic Anaemias due to Rare Enzymopathies* Associated with pentose-phosphate pathway deficiencies Glutathione reductase γ-glutamyl cysteine synthetase Glutathione synthetase Associated with Embden-Meyerhof pathway deficiencies Pyruvate kinase Others Hexokinase Glucose phosphate isomerase Phosphofructokinase Triose phosphate isomerase Phosphoglycerate kinase aldolase Associated with abnormalities of nucleotide metabolism Adenylate kinase deficiency Pyrimidine 5’-nucleotidase deficiency Hyperactivity of adenosine deaminase * Commonest of these is G6PD deficiency which is not listed here.

or more of the globin-chain subunits of the Hb-tetramer. Taken as a group, the thalassaemia syndrome represents the most common gene disorder known to mankind. These are common in the tropical belt where Falciparum malaria has been endemic for Centuries (Figure 11). In some parts of the world, these constitute major public health problem.Thalassaemia is a Greek

942

Figure 11: Geographical distribution of thalassaemia and haemoglobinopathies (Pink).

word which means ‘the sea (water) in the blood’. Traditionally known as Cooley’s anaemia, this disorder was first described in a child of Italian origin by Thomas Cooley, a paediatrician from Philadelphia. It is extremely frequent in the Mediterranean region specially amongst Italians and Greeks. Individual subtypes are named according to the nature of globin chain deficiency. β thalassaemia suggests deficiency of β globin chain, α thalassaemia suggests deficiency of α globin chain and so on. β° thalassaemia suggests total absence of β globin chain products while β+ thalassaemia suggests partial reduction. The genes for globin synthesis are located on chromosomes 11 and 16. The abnormalities at chromosomal level range from total deletion, rearrangement to point mutation and over 100 subtypes of molecular defects are known. The thalassaemia belt extends along the shores of the Mediterranean sea and throughout the Arabian Peninsula, Turkey, Iran, India and SouthEast Asia (Figure 11). Gene frequency ranges from 1% to 15%. In India, thalassaemia is prevalent in North-West region, i.e. Punjab, Gujarat, Maharashtra and Karnataka. It is also seen in Bengal and Assam but relatively less common in the Southern states. On an average, 3% of Indians carry the β thalassaemia gene. The highest incidence is found in Lohanas and Sindhis who have migrated from Sindh in Pakistan to many parts of India at the time of partition. Clinically speaking, three common terms are used which connote the severity of disorder. These terms are thalassaemia major, intermedia and minor. Thalassaemia major is a severe disorder due to inheritance of two β thalassaemic genes (Figure 12). Child becomes anaemic within a few months of birth and the anaemia is so severe that regular transfusions are needed for survival. Thalassaemia minor, also known as thalassaemia trait or β thalassaemia heterozygous state is due to a single gene mutation together with a normal β globin gene on the other chromosome. It results in profound hypochromia and microcytosis despite minimal anaemia.

Figure 12: Inheritance of thalassaemia syndrome.

near normal survival. Life expectancy and quality of life in thalassaemia minor do not differ from normal individuals. Thalassaemia intermedia on the other hand, has variable severity.

Pathophysiologically, the relative excess of the unpaired α globin chains that accumulate produce damage to the membrane of red cells leading to haemolysis. In addition, short-life of RBC precursors in the marrow results in ineffective erythropoiesis.

Investigations Thalassaemia major leads to severe anaemia. Red cell morphology is strikingly abnormal with hypochromia, microcytosis, anisopoikilocytosis, tear drop cells and target cells. Nucleated red cells are abundant, however, reticulocyte count is low (2% to 8%). This is due to severe intra-medullary erythroid destruction. White blood cell count and platelet counts are normal unless hypersplenism develops. Marrow shows marked hypercellularity secondary to normoblastic hyperplasia. The osmotic fragility is significantly reduced, serum iron is increased and iron binding protein is fully saturated.

Clinical Features of Haemoglobin Disorders Thalassaemia minor is often an incidental diagnosis. It does not produce many symptoms or signs as anaemia is not very significant. There are no overt signs of haemolysis or marrow expansion. Patients with thalassaemia major develop profound anaemia within first few months of birth (anywhere from the age of 2 months to 2 years). This results in marked anorexia, failure to thrive, frequent infections and growth retardation. This also leads to production of high levels of erythropoietin which in turn causes extensive marrow expansion leading to characteristic chipmunk-facies due to frontal bossing and maxillary marrow hyperplasia. Enlarged spleen and liver lead to protuberant belly. Subsequently, patients develop massive splenomegaly, high output congestive cardiac failure, increased susceptibility to infection and even pathological fractures of long bones and vertebrae due to cortical invasion by erythroid element. Erythropoiesis may be so exuberant that masses of extra-medullary tissues may be formed in the paraspinal region, abdomen, pelvis and even in skull. Patients of thalassaemia intermedia survive long enough without medication and develop above mentioned features to the maximum extent. Unless transfused, these patients go on to develop hypersplenism, profound increase in the blood requirement, non-healing leg ulcers and gall-stones. Repeated transfusions in thalassaemia major and enhanced absorption of iron from the gut in thalassaemia intermedia, lead to iron overload with damage to heart, liver, pancreas and other endocrine organs including hypothalamus. Many patients die secondary to iron overload-related cardiomyopathy resulting in cardiac failure or arrhythmia. Absent or delayed puberty, retarded physical growth, diabetes mellitus, hypoparathyroidism and hypothyroidism are the other ironrelated problems. Blood transfusions also lead to transmission of viruses and hence chronic liver disease secondary to hepatitis-C or B. Transmission of human immunodeficiency virus (HIV) infection may lead to acquired immune deficiency syndrome (AIDS). Development of RBCs allo-antibodies can lead to difficulty in transfusions. With the development of modern hypertransfusion therapy and regular chelation, most of the clinical features mentioned above are largely preventable. Nonetheless, in India and many parts of the world, the clinical features mentioned above are common given the irregularity of blood transfusion and high cost of chelation therapy. An untreated child may succumb to anaemia itself during early childhood or even in infancy. Those who receive inadequate chelation, succumb between late second decade and early third decade of life. However, those receiving regular hypertransfusion and effective iron chelation can have

Hereditary Haemolytic Anaemia

The term thalassaemia intermedia applies to a clinical phenotype where although patient is significantly anaemic, regular periodic blood transfusions are not a must for survival.

Normal haemoglobins in healthy adults are shown in Table 11. The haemoglobin profile in β° thalassaemia major reveals predominantly Hb-F which is nearly 100%. It may vary from 10% to 90% in β+ thalassaemia. The red cell survival is diminished as seen with 55Cr tagged studies. RBCs half-life ranges from 6 to 20 days. Radiological changes include striking changes in the skull and facial bones resulting in hot-cross-bun configuration of the skull, widened diploic spaces and the classic hair-on-end appearance. Compression fractures of the vertebrae and marked osteoporosis are common. Table 11: Normal Haemoglobins in Adults Haemoglobin Type

Globin Chains

Percentage

Hb-A Hb-A2

α2β2 α2δ2

>95 255 µ/L)

>500 mL/24h >1000 mL/24h

Table 8: Clinical Grading of Acute Graft Versus Host Disease Grade Degree of Organ Involvement I II III IV

+ to ++ skin rash; no gut or liver involvement; no decrease in clinical performance + to +++ skin rash; + gut or liver involvement (or both); mild decrease in clinical performance ++ to +++ skin rash; ++ to +++ gut or liver involvement (or both); marked decrease in clinical performance Similar to grade III and profound decrease in clinical performance

HSCT PROGRAMME IN INDIA The institutes running HSCT programme in India are outlined in Table 9. Many more transplant centres are expected to open all over India as there is a lot of scope for this procedure considering the patient load of various haematological disorders. There is no functional donor registry in India, while this is wellestablished in Europe, North America and Japan.These registries improve the chances of finding a fully matched, unrelated, HLA donor to 60% to 80%, whereas, it is only 25% to 30%, when siblings form the donor pool. Table 9: Haematopoietic Stem Cell Transplantations (HSCTs) done in Various Centres Across India

>1500 mL/24h

Centres (period for which HSCT data is available)

No. HSCT

AlloHSCT

AutoHSCT

Severe abdominal pain with or without ileus

Christian Medical College, Vellore (1986-Dec 2009) AIIMS, New Delhi (1992-Dec 2009) Tata Memorial Centre, Mumbai (1983-Jun 2010) Sahyadri Speciality Hospital, Pune (1999-Mar 2010) Apollo Cancer Hospital, Chennai (1995-Dec 2009) Jaslok Hospital and Research Centre, Mumbai (2000-May 2010) Army Hospital, Delhi (1998-Jun 2010) Gujarat Cancer and Research Institute (1999-Jun 2010) Narayana Hrudayalaya, Bangalore (2004-Jun 2010) Rajiv Gandhi Cancer Centre, New Delhi (2001-Dec 2009) PGIMER, Chandigarh (2003-May 2010) SGPGIMS, Lucknow (1999-Dec 2009) Prince Aly Khan Hospital, Mumbai (2007-Jun 2010) Manipal, Bangalore (2004-Dec 2009)

1002

767

235

458 439

126 249

332 190

314

216

98

249

151

98

224

79

145

207 112

137 44

70 68

80

67

13

72

16

56

45 34 32

18 24 01

27 10 31

28

8

20

Figure 4: Scleroderma like skin chronic oral lesions due to chronic GvHD in a patient with allo-HSCT for CML.

Haematopoietic Stem Cell Transplantation

differentiation, elaborating IL-2 which stimulates mononuclear cells which in turn secretes IL-1, TNF-α and IFN-γ producing a cytokine storm. In addition the lymphocytes also have a cytolytic action.

FUTURE PROSPECTS IN HSCT HSCT has revolutionised the treatment of many, hitherto, incurable diseases. However, because of significant peri and posttransplant morbidity and mortality (5% to 30%) further research and trials are required to refine and optimise conditioning regimens and supportive care. Stem cell manipulation and T-cell depletion to improve transplant outcomes and minimise incidence of GvHD is another area of research. Gene therapy using 1009

haematopoietic stem cells is an exciting prospect. Adult stem cells and mesenchymal stem cells have been used in various trials for treatment of type 2 diabetes mellitus, neurodegenerative, heart and peripheral vascular diseases exploiting the potential of stem cell plasticity (or trans-differentiation). Other developing areas which would help improve transplant outcomes and minimise complications are given below:

6. Positive selection of CD34 cells and negative selection of allo-reactive T-cells responsible for GvHD RECOMMENDED READINGS 1.

2.

1. Non-myeloablative and cord blood transplantation 2. Matching for minor HLA antigens

3.

3. Ex vivo expansion of HSCs 4. New immunosuppressive agents and monoclonal antibodies to minimise GvHD risk 5. Improving GVL without worsening of GvHD

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4. 5.

EBMT-ESH Handbook on Haemopoietic Stem Cell Transplantation. Revised Edition 2008. Apperley J, Carreras E, Gluckman E, et al, editors. www.ebmt.org/EBMT_Handbook.html Kumar L, Ghosh J, Ganessan P, et al. High-dose chemotherapy with autologous stem cell transplantation for multiple myeloma: what predicts the outcome? Experience from a developing country. Bone Marrow Transplant 2009; 43: 481-9. Kumar R, Naithani R, Mishra P, et al. Allogeneic hematopoietic SCT performed in non-HEPA filter rooms: initial experience from a single center in India. Bone Marrow Transplant 2009; 43: 115-9. Nair V. Haematopoietic stem cell transplantation in autoimmune diseases. Indian J Rheumatol 2008; 3: 101-9. Nair V, Das S, Sharma A. Hematopoietic stem cell transplantation in children with genetic defects. Indian Pediatr 2009; 46: 241-3.

Section

16

HIV and AIDS Section Editors: Alaka Deshpande and B.B. Rewari 16.1 Epidemiology O.C. Abraham, Susanne A. Pulimood

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16.2 Virology, Immunology and Diagnosis V. Ravi, Anita Desai

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16.3 Pathophysiology and Clinical Features U.L. Wagholikar

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16.4 Antiretroviral Therapy B.B. Rewari, Sanjeev Sinha

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16.5 Drug Resistance Alaka Deshpande

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16.6 Non-Opportunistic Infections Anil Kumar Tripathi, Shailendra P. Verma

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16.7 Opportunistic Infections Natasha Edwin, Dilip Mathai

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16.8 Non-Pharmacologic Interventions and Prevention R. Sajithkumar

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16.1

Epidemiology OC Abraham, Susanne A Pulimood

INTRODUCTION The acquired immunodeficiency syndrome (AIDS) was first recognised among men who have sex with men (MSM) in the United States in 1981. The causative agent, human immunodeficiency virus (HIV) was discovered in 1983 by Luc Montagnier and Francoise Barre-Sinoussi at the Pasteur Institute, Paris, France and were awarded the 2008 Nobel Prize in Medicine for this discovery. Molecular studies have revealed that HIV originated from the cross-species transmission to man of the simian immunodeficiency virus (SIV), which naturally infects non-human primates in Africa and has very close genetic similarity to HIV. The HIV viruses are broadly classified into HIV 1 and HIV 2 and it is further subdivided into groups and subtypes (Table 1). Table 1: The Classification of HIV Type

Group

Subtype (clades)

Distribution

HIV 1

M (major)

A1, A2, A3, A4, B, C, D, F1, F2, G, H, J, and K

Global Subtype C prevalent in India most

HIV 2

O (outlier)

Limited to equatorial West Africa

N (non-major and non-outlier)

Limited to equatorial West Africa Limited to West Africa

The major routes for HIV transmission are: 1. Unprotected sexual intercourse with an HIV-infected partner. 2. Exposure to HIV-infected blood and blood products (e.g. blood transfusion, sharing of infected needles, needle-stick injuries, etc.). 3. Peri-partum (vertical) transmission from an HIV-infected mother to her child. GLOBAL AIDS SCENARIO HIV infection has evolved to become the greatest pandemic in human history. Since the beginning of the epidemic, almost 60 million people have been infected and 25 million people have died of HIV-related causes. Sub-Saharan Africa and Asia are the regions most affected by the HIV epidemic. India accounts for roughly half of Asia’s HIV prevalence. Table 2 shows the summary of United Nations AIDS global report for the year 2009. BURDEN OF HIV EPIDEMIC IN INDIA The first cases of HIV infection in India were documented in 1986 among female sex workers (FSWs) in Chennai, Tamil Nadu. Subsequently, cases of HIV infection have been reported from every state. The HIV epidemic in India has followed the ‘type 4 pattern’, where new infections occur first among the most vulnerable populations (such as FSW and injecting drug users 1012 [IDU]), then spread to ‘bridge’ populations (clients of sex workers

and sexual partners of drug users) and then finally enter the general population. Table 3 summarises the AIDS epidemic in India. Table 2: Global Summary of the AIDS Epidemic Number of people living with HIV in 2009 People newly infected with HIV in 2009 AIDS-related deaths in 2009

Total Adults Women Children under 15 years Total Adults Children under 15 years Total Adults Children under 15 years

33.3 million (31.4-35.3 million) 30.8 million (29.2-33.6 million) 15.9 million (14.8-17.2 million) 2.5 million (1.6-3.4 million) 2.6 million (2.3-2.8 million) 2.2 million (2.0-2.4 million) 370 000 (230 000-510 000) 1.8 million (1.6-2.1 million) 1.6 million (1.4-1.8 million) 260 000 (150 000 – 360 000)

Table 3: Summary of AIDS Epidemic in India Number of people Total living with HIV Males infection Females Children Prevalence among Overall adults Males Females

2.40 million (1.9-3.0 million) 61% 39% 3.5% 0.31% 0.44% 0.23%

These estimates are derived from sentinel surveillance (unlinked, anonymous HIV testing of consecutively collected samples from designated sites across the country for different target populations) conducted annually and is complemented by population-based surveys (e.g. National Family Health Survey). A critical review of the HIV epidemic in India reveals the following trends:  Young adults (15-49 years) account for 89% of the burden of HIV infection.  The male to female ratio is 3:2.  The states of Andhra Pradesh, Maharashtra, Karnataka, West Bengal, Tamil Nadu, Gujarat and Uttar Pradesh together account for 80% of the burden in India (Figure 1). The prevalence is 45%, especially >60% in males and >50% in females), raised serum ferritin, lowered serum soluble transferrin receptor levels and increased iron in liver and bone marrow (Perls’ Prussian blue staining) are found. Hepatic iron content of >40 µmol/g on dry weight indicates definite increase in liver iron; >71 µmol/ g dry weight is highly suggestive of HH. Hepatic iron index is

Table 6: Clinical Features of Iron Overload Heart Cardiomyopathy, dysrrhythmias, congestive heart failure Endocrine organs Growth and sexual developments are delayed in children Delayed puberty Diabetes mellitus Hypothyroidism and hypoparathyroidism Hypopituitarism Skin Excessive melanin skin pigmentation (bronze diabetes) Liver Haemosiderosis, cirrhosis, risk of hepatocellular carcinoma. Joints Arthropathy caused by pyrophosphate deposition Excessive infections Listeria, Yersinia enterocolitica, Vibrio vulnifcus, by ingesting uncooked seafood

the ratio of µmol iron/g dry weight divided by age in years. Ratio >2 generally separates patients with homozygous HH from heterozygotes or those with alcoholic liver disease. Increased urinary iron excretion in response to iron chelator therapy are abnormal, and liver function tests, endocrine abnormalities e.g. raised blood sugar, abnormal thyroid

Iron Metabolism and Iron Overload Syndrome Figure 10: Crypt programming Model of HFE-Related Hereditary Haemochromatosis. Cryptprogramming model, undifferentiated duodenal crypt cells, take up iron from the bloodstream by transferrin receptor 1 (TfR1), which is located on their basolateral membranes. Interaction of TfR1 with normal HFE senses the iron status. The cellular pool of iron will programme the mature absorptive enterocytes that will be derived from these cells by modulating the activity of specialised luminal iron transporters [e.g. divalent metal transporter 1, (DMT1)] and basolateral iron transporters (e.g. ferroportin). Due to presence of C282Y mutation, HFE is unable to interact with TfR1, leading to iron-deficient crypt cells, these cells are programmed to iron starvation, hence persistently absorbing iron from the intestinal lumen and transfer virtually all of it into the bloodstream, regardless of actual erythropoietic needs.

Figure 11: Hepcidin Model of HFE-Related Hereditary Hemochromatosis. Mutant HFE might alter signals or factors for appropriate synthesis or up-regulation of Hepcidin by hepatocytes, resulting in uncontrolled release of iron from macrophages and duodenal enterocytes. 1251

function tests are seen. ECG and echocardiogram are abnormal. Genetic testing for HFE gene mutation C282Y (incidence >80% in HH) can be done. Treatment Phlebotomy greatly reduces mortality from cardiac and hepatic failure. This should be at the rate of 350 mL of blood each week or more often if the haemoglobin concentration can be maintained greater than 12 g/dL. Treatment can be measured by monitoring serum ferritin and the phlebotomy may need to be continued for over 2 years. The aim is to maintain normal transferrin saturation and serum ferritin in the low normal range, ideal is to achieve a serum ferritin around 50 ug/dL as shown in Figure 12. Desferrioxamine as a continuous intravenous infusion may have a limited role to treat life-threatening cardiac failure. Treatment of endo-crinopathies and infections is required. Screening for hepato-cellular carcinoma should be done. All first-degree relatives over the age of 10 years should be tested for increase in transferrin saturation and ferritin and screened for HFE genotype. ATRANSFERRINAEMIA It is a rare autosomal recessive hereditary disorder. There is iron overload and hypochromic anaemia. There is reduced delivery of iron to bone marrow and reduced haemoglobin synthesis. Two mutations that have been identified are a deletion creating a frameshift resulting in a null transferrin allele and Ala 477Pro. ACAERULOPLASMINAEMIA It is an autosomal recessive disorder of iron overload. There is loss of function mutation in caeruloplasmin gene 3q23- q24. Caeruloplasmin has ferroxidative activity involved in the release

1252

Figure 12: Strategic algorithm for C282Y Homozygous patients with hemochromatosis and the desired serum ferritin values after phlebotomy. SF (serum ferritin), TS (transferrin saturation) and IO (iron overload).

of iron from cells. Patients have accumulation of iron in neural and glial cells of the brain, hepatocytes and pancreatic islet cells. Treatment Treatment consists of aggressive chelation with desferrioxamine and replacement of plasma or caeruloplasmin concentrate. Phlebotomy may exacerbate microcytic hypochromic anaemia and hence should be avoided.

18.6 INTRODUCTION Porphyrias are metabolic disorders resulting from the deficiency of a specific enzyme in the haem biosynthetic pathway. There are eight enzymatic steps in the conversion of glycine and succinyl-CoA to haem. The first and last three enzymes are located in the mitochondria whereas the other four are in the cytosol (Figure 1). Depending on the primary site of over production and accumulation of their respective porphyrin precursors or porphyrins, the porphyrias are classified as either hepatic or erythropoietic. Based on their clinical manifestations, porphyrias can be labelled as acute or cutaneous, but some of them have overlapping features. A definitive diagnosis requires demonstration of specific enzyme deficiency or gene defect. The important aspect including inheritance, enzyme deficiency, gene defect and excretion of precursors are shown in Table 1.

The Porphyrias Dhanpat Kumar Kochar, Abhishek Kochar higher than what has been described in many parts of the World. The disease has a female predilection (2:1). In their study, Wig and Malhotra have described a novel gene mutation in AIP in this region. HEPATIC PORPHYRIAS Acute Intermittent Porphyria This is an autosomal dominant inherited disease resulting from the half normal level of hydroxymethylbilane synthase (HMBS) activity. In the classic form of AIP, both the ‘non-erythroid’ housekeeping HMBS isoform and the ‘erythroid’ HMBS isoform are deficient. The disease manifestation occurs due to induction of this rate limiting hepatic enzyme in heterozygotes. It remains latent or asymptomatic in majority of heterozygous having HMBS mutations and almost always before puberty. The prepubertal latency of the disease signifies the role of steroid

Figure 1: Haem-biosynthesis pathway with enzymes (in boxes) of each step and its associated disease (in ovals).

PORPHYRIA IN INDIA The occurrence of acute intermittent porphyria (AIP) in India is mostly concentrated to Maheshwari and Kumhar communities of North West Rajasthan in and around Bikaner. In India, first case was reported by Wig and Malhotra in 1959. Estimated prevalence in India is 1 in 4.4 million but in Bikaner district it is around 1:12500 and around 1:400 to 1:600 in the specified communities, respectively. This prevalence is much

hormones in clinical expression of the disease and increased frequency in women suggest a role of oestrogens or progestins. Common precipitating factors are infection, porphyrinogenic drugs (Table 2), steroids, alcohol, low calorie diet and occasionally pregnancy, which is usually well tolerated. Clinical features AIP is characterised clinically by acute episodes of a variety of gastrointestinal and neurologic symptoms and between these 1253

episodes, the patient remains asymptomatic. Abdominal pain is constant, poorly localised and may be cramping in nature but sometimes it may be very severe and is associated with passage of red coloured (port wine) urine. Patient may have nausea, vomiting and severe constipation mimicking picture similar to intestinal obstruction. Fever, tenderness and leukocytosis are usually absent or mild because the symptoms are neurologic rather than inflammatory. Mental symptoms ranging from anxiety, insomnia,

depression to disorientation, hallucination and paranoia can occur in acute attacks. Patients may have severe disabling pain all over the body, especially in lower limbs. Peripheral neuropathy is due to axonal degeneration and is primarily motor neuropathy affecting the proximal muscles of upper and lower limbs. Deep tendon reflexes are decreased or absent as neuropathy advances, however, ankle reflex may remain intact up to late in the course of illness. Sometimes 7th, 10th and 11th cranial nerves may also

Table 1: Important Features of Different Porphyrias Disease Name

Deficient Enzyme (Activity % of Normal)

Gene Locus and Number of Mutations

Principal Symptoms (NV or P)

5 ALA dehydratase deficient porphyria (ADP)

ALA dehydratase (~ 5)

9q34 7 mutations

Neurovisceral

Acute intermittent porphyria (AIP)

HMB synthase (~ 50)

11q23.3 272 mutations

Neurovisceral

Porphyria cutanea tarda (PCT)

URO decarboxylase (~ 20)

1q34 60 mutations

Hereditary corpoporphyria (HCP) Variegate porphyria (VP)

Increased Porphyrin Precursors and/or Porphyrins Erythrocytes

Urine

Stool

Inheritance

Zn protoporphyrin

ALA Coproporphyrin III

—

AR

—

ALA, PBG Uroporphyrin

—

AD

Photosensitivity

—

Uroporphyrin 7-carboxylate porphyrin

Isocoproporphyrin

AD

Coproporphyrinogen 3q12 oxidase (~ 50) 36 mutations

Neurovisceral and Photosensitivity

—

ALA, PBG, Coproporphyrin III

Coproporphyrin III

AD

Protoporphyrinogen 1q22 oxidase (~ 50) 121 mutations

Neurovisceral and Photosensitivity

—

ALA, PBG, Coproporphyrin III

Coproporphyrin III Protoporphyrin

AD

Hepatic Porphyrias

Erythropoietic Porphyrias Congenital erythropoietic Uroporphyrinogen porphyria (CEP) synthase (~ 1-5)

10q25.2-6.3 35 mutations

Photosensitivity

Uroporphyrin I Uroporphyrin I Coproporphyrin I Coproporphyrin I

Coproporphyrin I AR

Erythropoietic proto porphyria (EPP)

18q21.3 74 mutations

Photosensitivity

Protoporphyrin

Protoporphyrin

Ferrochelatase (~ 20-30)

—

AD

AD = Autosomal dominant; ALA = 5' aminolevulinic acid; AR = Autosomal recessive; HMB = Hydroxymethylbilane; PBG = Porphobilinogen.

Table 2: List of Safe and Unsafe Drugs in Porphyria Safe Drugs ACE inhibitors Acetylsalicylic acid Adenosine Aminoglycosides Amphotericin B Anti-D immunoglobulin Cefotaxime Ceftriaxone Chlorpromazine Codeine Clonazepam Clozapine Dalteparin Desmopressin Dexamethasone Didanosine Estradiol patch or vaginal tablet Ethambutol Enoxaparin 1254

Furosemide Gabapentin Haloperidol Hydrocortisone Isoflurane Insulin Immunoglobulins Ibuprofen Ipratropium Lactulose Lamivudine Levothyroxin Lithium Loperamide Meropenem Metformin Morphine Multivitamin + iron Nitrates

Unsafe Drugs Naproxen Octreotide Olanzapine Ondansetron Orlistat Oxazepam Paracetamol Propranolol Propofol Propylthiouracil Quinolones Ranitidine Rosuvastatin Salbutamol Streptokinase Suxamethonium Vaccines Vigabatrin

Source : www.drugs.porphyria.com, www.porphyriaeurope.org, www.porphyriafoundation.com.

Antidepressants Artemether Amiodarone Azole antifungals Barbiturates Chloroquine CCB’s Chlorzoxazone Coxibs Carbamazepine (Cisapride) (Clopidogrel) Oestrogen Hydralazine Isoniazid IV lidocaine Ketamine Metronidazole Metoclopramide

Macrolides Methyldopa Nandrolone Phenytoin Progesterones Quinine (lesser than Chloroquine) Rabeprazole, Rifampicin Spironolactone Oral contraceptive pills Simvastatin (Sibutramine) Testosterones Thiopental Valproic acid (glimepride) (methylprednisolone) (lamotrigine)

A rare homozygous dominant form of AIP occurs when patients inherit HMBS mutations from each heterozygous parent leading to very low (40 23+ 25+ 27+ 32.5+ 37.5+ + + + + + With comorbidities

Basic Surgery

+

+

+

With comorbidities

+

*Can also be applied if waist circumference is 10 more than normal. Reproduced with permission from: J Assoc Physicians India. 2009 Feb; 57: 163-70

CONCLUSION Obesity is steeply increasing in India. Primary reasons are imbalanced foods and physical inactivity. Asian Indians have more body fat, more intra-abdominal and truncal subcutaneous fat and low muscle mass than white Caucasians; all conducive to the development of type 2 diabetes and cardiovascular disease. Morbidities occur at lower levels of BMI and WC in Asian Indians. Revised guidelines of BMI and WC mean that additional 15% additional population would be diagnosed as overweight/obese. More aggressive and early intervention according to revised guidelines will result in prevention of diabetes and reduction of epidemics of diabetes and CVD in Asian Indians. RECOMMENDED READINGS 1.

Dvorak RV, Sharma AM, Astrup A. Anti-obesity drugs: to be or not to be? Obes Rev 2010.

2.

Joshi SR (Editor). ICP API Technical Monoraph Obesity. Mumbai: ICP-API; 2009: 1-103.

3.

Misra A, Chowbey P, Makkar BM, et al. Concensus Group. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. J Assoc Physicians India 2009; 57: 163-70.

4.

Parikh RM, Joshi SR, Pandia K. Index of central obesity is better than waist circumference in defining metabolic syndrome. Metab Syndr Relat Disord 2009; 7: 525-7.

18.12 INTRODUCTION Type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) are important non-communicable diseases (NCDs) in developed, as well as developing countries. Asian Indians have an unusually high predisposition to develop both these NCDs. During the previous three decades, the prevalence of T2DM has doubled in India. Insulin resistance and clustering of other proatherogenic factors, which are frequently seen in Asian Indians, may be principal contributory factors for high prevalence of T2DM. DEMOGRAPHIC, NUTRITIONAL AND LIFESTYLE TRANSITION IN INDIA Important demographic and economic changes are occurring in South Asia. The life expectancy and the percentage of the elderly population have increased. Increasing migration from villages to cities, urbanisation and mechanisation have increased. All these factors have brought forth adverse lifestyle changes, such as nutritional imbalance, physical inactivity, stress, and increased consumption of alcohol and tobacco, leading to obesity, insulin resistance and metabolic syndrome. A complex array of factors leads to the metabolic syndrome in Asian Indians (Table 1). Insulin Resistance and the Metabolic Syndrome: Epidemiological Data Inordinate high prevalence of cardiovascular risk factors, their clustering, and high mortality due to CHD in South Asians was initially reported from UK in 1980s. Particularly abdominal obesity, hyperinsulinaemia and dyslipidaemia in South Asians were significantly more than British Caucasians. In particular, low HDL-C levels and hypertriglyceridaemia were prevalent in both genders and abdominal obesity was particularly prevalent in women. Overall, prevalence of the metabolic syndrome in migrant South Asians varies from 20% to 32% (Table 1). Table 1: Associations of Insulin Resistance and Other Cardiovascular Risk Factors in South Asians Factors With Evidence of Positive Association

Factors With Weak/No Evidence of Association

Excess body fat C-reactive protein Abdominal obesity Intramyocellular triglycerides High truncal subcutaneous fat Leptin Low birth weight High levels of procoagulant factors

Prevalence of the metabolic syndrome as defined by the National Cholesterol Education Programme, Adult Treatment Panel III (NCEP, ATP III) and other criteria indicates ranges from ~11% to ~41% in India. While these studies show high prevalence of the metabolic syndrome in Asian Indians living in India, truly representative data from all regions of India are not available. Definitions of the Metabolic Syndrome The NCEP, ATP III and International Diabetes Federation (IDF) definitions of the metabolic syndrome is based on simple

Metabolic Syndrome Anoop Misra clinical and biochemical parameters, which could be measured in any clinic or a simple laboratory. Other available definitions of the metabolic syndrome include measures which are expensive and difficult to analyse; fasting hyperinsulinaemia, microalbuminuria etc. The metabolic syndrome is mostly defined by modified criteria; central obesity (defined as waist circumference (WC) >90 cm for males and >80 cm for females, raised triglyceride (TG) levels: >150 mg/dL or on specific treatment for this lipid abnormality; reduced high density lipoprotein (HDL): less than 40 mg/dL in males and less than 50 mg/dL in females or on specific treatment for this lipid abnormality; raised blood pressure (BP): systolic BP >130 mm Hg or diastolic BP >85 mm Hg or on treatment of previously diagnosed hypertension; and raised fasting plasma glucose (FPG) >100 mg/dL or previously diagnosed diabetes. Three out of five criteria have to be present to define the metabolic syndrome. Body Fat Distribution of South Asians: Relationship with Insulin Resistance and Other Cardiovascular Risk Factors Excess body fat Several distinctive features of body composition of South Asians have been recorded. Most investigators agree that South Asians have high percentage of body fat. For example; despite lower average body mass index (BMI) value, the migrant Asian Indians have higher percentage of body fat as compared to white Caucasians and Blacks. Abdominal obesity High prevalence of abdominal obesity is particularly the characteristic of the South Asians and uniformly recorded by several investigators. Abdominal adiposity has also been reported in those with a BMI less than 25 kg/m2. Further, although the average WC in South Asians appears to be lower, abdominal adiposity is significantly more than the white Caucasians. Truncal subcutaneous fat A particularly distinctive body composition feature seen in South Asians is thick subcutaneous adipose tissue as highlighted by the investigators who used skinfold measurements in their investigations. Other Insulin Resistance-associated Factors in South Asians (Figure 1) High procoagulant tendency (high levels of plasminogen activator inhibitor-1, fibrinogen etc) has been demonstrated in South Asians with insulin resistance and other cardiovascular diseases. Low adiponectin levels have been reported in children, as well as in adults with insulin resistance and metabolic syndrome. Other associations include high levels of high-sensitivity C-reactive protein and pro-inflammatory cytokines (tumour necrosis factorα and interleukin-6), impaired flow-mediated, endotheliumdependent dilatation, polycystic ovarian syndrome, high levels of 1279 non-esterified fatty acids and high oxidative stress.

Figure 1: Complex interactions of genetic, perinatal, nutritional and other acquired factors in the development of insulin resistance, T2DM and CHD in Asian Indians. T2DM = Type 2 diabetes mellitus; CRP = C-reactive protein; CHD = Coronary heart disease.

Prevention and Control of the Metabolic Syndrome in Asian Indians 1. Intensive efforts should be made to make South Asians aware that they are at more risk for the development of T2DM and CHD. 2. The preventive measures should be particularly vigorous for those with the family history of T2DM or premature CHD. 3. The therapeutic lifestyle changes should be encouraged from the childhood. Regular physical activity should be advised and television and internet usage should be restricted. 4. Body weight and anthropometric indices should be maintained within normal limits. The physicians should be made aware that these provisional limits for defining normal BMI and WC might be revised in the future. (a) Based on the recent data, and provisional recommendations of World Health Organization, BMI should be maintained between 19 to 23 kg/m2. (b) The WC should be maintained below 90 cm for men and 80 cm for women. 5. Overweight individuals and those with abdominal obesity should be actively managed to lose weight by lifestyle measures. 6. Detection of one component of the metabolic syndrome should lead to search for the other components and its management. 7. Currently, no drug (e.g., metformin) is recommended for the management of insulin resistance and the metabolic syndrome. However, these guidelines may change in future, particularly for those who have prediabetes. 8. Adequate nutrition during the intrauterine period should be given to prevent early-life adverse events, which may 1280 promote insulin resistance in adulthood.

9. Research on insulin resistance and the metabolic syndrome in South Asians should be targeted on the following: (a) Prevalence of metabolic syndrome in various South Asian countries, (b) Aetiological factors of insulin resistance, particularly genetic studies, (c) Associations of specific macro- and micro-nutrients in South Asian diet with insulin resistance (e.g., omega-3 polyunsaturated fatty acids and dietary fibre), (d) Relationship with novel cardiovascular risk factors (e.g., C-reactive protein), (e) Intervention with insulin-sensitizers and other drugs, (f ) Prevalence of the metabolic syndrome and morbidity correlation in children, (g) Best methods of imparting lifestyle and diet-related health messages in children, and (h) Increasing awareness of ill effects of the metabolic syndrome in populations. 10. Finally, the National Control Programmes for diabetes and cardiovascular diseases should be adequately strengthened and modified in view of the recent knowledge and guidelines. RECOMMENDED READINGS 1.

2. 3.

4.

Misra A, Vikram NK. Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Nutrition 2003; 19: 457-66. Misra A, Vikram NK. Insulin resistance syndrome (metabolic syndrome) and Asian Indians. Curr Sci 2002; 83: 1483-96. Misra A, Vikram NK. Insulin resistance syndrome (metabolic syndrome) and obesity in Asian Indians: evidence and implications. Nutrition 2004; 20: 482-91. Vikram NK, Pandey RM, Misra A, et al. Non-obese (body mass index < 25 kg/m 2) Asian Indians with normal waist circumference have high cardiovascular risk. Nutrition 2003; 19: 503-9.

Section

19

Nephrology Section Editor: Vinay Sakhuja 19.1

Kidney—Structure and Functions Sanjay K. Agarwal 19.2 Kidney Disease—A Clinical Approach Vijay Kher 19.3 Acute Kidney Injury Alan F. Almeida, Jatin P. Kothari 19.4 Chronic Kidney Disease Ashok L. Kirpalani, Hardik Shah 19.5 Primary Glomerular Diseases Vinay Sakhuja, Sanjay D’ Cruz 19.6 Secondary Glomerular Diseases O.P. Kalra 19.7 Urinary Tract Infections R. Kasi Visweswaran, Praveen Namboothiri 19.8 Nephrolithiasis and Urinary Tract Obstruction P.D. Gulati 19.9 Vascular Injury to Kidney A.S. Narula, A.K. Hooda 19.10 Polycystic Kidney Disease and Inherited Tubular Disorders P.P. Varma, Ranjith Nair 19.11 Dialysis for Chronic Renal Failure N.K. Hase 19.12 Renal Transplantation George T. John

1282 1286 1291 1295 1302 1310 1316 1319 1323 1327 1333 1339

19.1

Kidney—Structure and Functions Sanjay K Agarwal

Kidneys are paired intra-abdominal organs lying opposite the upper lumbar vertebrae, and weigh 150 g each. Each kidney has an outer layer, the cortex, and an inner layer, the medulla. Both abut on to the renal pelvis; the cortex sends down columns of cortical tissue (columns of Bertin) separating the medullary pyramids (Figure 1). There are about 8 to18 medullary pyramids in each kidney.They terminate in the papillary tips, which project into the calyces. The hilum of the kidney takes the vasculature to and from the kidney along with its draining system, the pelvis and ureter. The vein is the most anterior and the ureter is most posterior of the three structures. The renal arteries are frequently multiple with up to 25% persons having more than one renal artery on each side.

Figure 2: Distribution of renal circulation.

each glomerulus, which rejoin to form the efferent arterioles. This then splits up again to form a second capillary network, which surrounds the tubules, both proximal and distal; this network itself empties into interlobar veins.

Figure 1: Cross section of kidney depicting major structures.

The renal arteries break up into arching branches known as arcuate arteries, which run at the cortico-medullary junction and are end-arteries, anastomosing solely through capillary channels. The interlobular arteries branch off the arcuate arteries and run at right angles towards the renal capsule, and branching again at right angles into afferent arterioles supplying the glomeruli; some branches go down into the medulla, first passing through the juxta-medullary glomeruli and then becoming large straight vascular channels known as ‘vasa recta’ which pass down into the depths of renal pyramids (Figure 2). Then they bend back up to reach the arcuate veins at the cortico-medullary junction. The tips of the papillae have a special arterial supply of their own from the ‘spiral arteries’, branches of the interlobular arteries in the pelvis of the kidney. 1282 The afferent arterioles break up into 20 to 40 capillary loops in

The anatomical and functional unit of the kidney is the nephron. This consists of a glomerulus with proximal convoluted tubules (PCT), loop of Henle (LOH), distal convoluted tubules (DCT) and collecting ducts (CDs) (Figure 3). There are approximately 1 million nephrons in each kidney. The majority of glomeruli are in the cortex. The PCT, DCT and blood vessels constitute the bulk of the non-glomerular cortical tissue. The medulla is composed of some LOH, vasa recta and a mass of CDs. This is an important structure responsible for the water conservation. Bowman’s capsule is a specialised invagination of the PCT and is lined by parietal epithelial cells (PEC) which are flatter and less noticeable than the larger, pale staining visceral epithelial cells (VEC) which line the outer side of the capillary tuft. Electron microscopy of the glomerulus reveals that the VEC do not lie in close opposition to the glomerular basement membrane (GBM); extension of the cytoplasm of the cells, called ‘foot process’, come into contact with the GBM at intervals leaving many areas of the GBM surface free of the epithelial cell contact. These areas have a mean width of 240 A° and are known as ‘slit pores’. The main filtration barrier is the GBM, consisting of a ramification of fibres with a mean diameter of lumen between the fibres of 52 A°.

At the point where the DCT are in contact with the afferent arteriole, the latter contains the juxta-glomerulus apparatus (JGA), a series of granular cells believed to be the source of the enzyme ‘renin’. The efferent arteriolar wall is composed of smooth muscle with an endothelial lining. The structure of peritubular capillaries is such as to promote ready exchange of materials between the tubular cells and capillaries. The PCT are confined to the cortex of the kidney; these connect the glomerulus proximally with the descending limb of LOH. LOH is shaped like a ‘U’ tube connecting PCT and DCT, dipping down a variable distance into the medulla.

Figure 3: Various parts of the nephron.

The GBM (Figure 4) runs through all the capillary walls, sandwiched between the foot processes of the VEC on the one side and the endothelial cells of vessels on the other side. It is continuous with the basement membrane of the tubules. Its thickness is 3000 A° in humans. Capillary walls are lined by endothelial cells, which lie on the basement membrane from the inner side. There are fenestrations in between the endothelial cells. They are closed by a diaphragm. The endothelial cells of the glomeruli are continuous with the endothelial lining of the afferent and efferent arterioles. Studies of hereditary proteinuric syndromes have highlighted the presence of various transmembrane proteins (nephrin, fatty acid transporter tumour suppressor homolog-1 (FAT1), and FAT2, podocin and CD2-associated protein (CD2AP) that participate in the formation of the slit diaphragm (SD), which is important in preventing protein leakage. Slit diaphragms are firmly attached to the actin cytoskeleton through linker proteins, including the catenins, zona occludens 1 (ZO-1), CD2AP, and Nck,

Kidney—Structure and Functions

which likely explains why genetic defects altering SD structure and function are usually associated with actin cytoskeleton reorganisation and foot process effacement.

There is no clear-cut place where thick ascending limb of LOH becomes DCT. The epithelium of DCT is columnar and the surface being covered with numerous microvilli. As the CDs are approached the cell height becomes smaller, giving way to the cuboidal cells of the CDs. At the site where DCT approaches the vascular pole of the glomerulus, the nuclei of the epithelial cells become crowded, come closer and appear darker staining than in other part of DCT. This hypernuclear area is known as ‘macula densa’. The cortical collecting ducts (CCDs) are a continuation of the DCT. These run into medullary collecting ducts. Medullary collecting duct cells have a cuboidal shape; have light cytoplasm and relatively few mitochondria.They in fact resemble ‘light cells’ of CCDs. The collecting ducts run into the ‘papillary ducts of Bellini’. In the papillary ducts, the cells are columnar in shape, have a basal nuclei and few mitochondria. The ducts of Bellini join the renal pelvis, which is covered with transitional epithelium. FUNCTIONS OF KIDNEY The kidneys maintain the internal environment within narrow limits in spite of great variation in intake and metabolic activity. The main functions of the kidney are regulation of body water, electrolytes, acid base balance, excretion of nitrogenous waste products, drugs and poisons, regulation of blood pressure, erythropoietin production and control of vitamin D metabolism. Glomerular Filtration The glomeruli filter about 180 litres of fluid each day although only approximately one and a half litres is passed as urine. Glomerular filtration rate (GFR) is defined as the amount of plasma being filtered by the glomeruli per minute. The normal GFR in Indians is approximately 75 to 79 mL/min/1.73m2. In women, the figure is slightly lower. GFR is determined by: (1) sum of hydrostatic and colloid osmotic forces across the glomerular capillary membrane which gives the net filtration pressure; and (2) glomerular capillary ultrafiltration coefficient Kf.

Figure 4: Glomerular basement membrane and its components.

Tubular Handling The permeability of solutes across the tubules is determined by their lipid solubility and membrane pores. Pores which handle the transfer of water are called aquaporins. There are many types of aquaporins though the two important types are, aquaporin-1 (AQP1), which is found in the PCT, descending limb of the LOH, and vasa recta and aquaporin-2 (AQP2), localised to the apical membrane of the CCT and connecting tubule. Not

1283

only does AQP2 provide the necessary pathway for water permeation that is regulated by ADH-dependent trafficking to the apical membrane, but it also has an immeasurably low permeability to urea and ions even as small as H3O+ or H+. Tubular Reabsorption and Secretion Reabsorption can be an active process, transport against the electrochemical gradient or a passive process with transport along the electrochemical gradient. Active transport energy is provided by the action of appropriate enzymes inside the tubular cells. Being an active process, there is a limit to the maximum amount transported, which is called tubular maximum (TM). Glucose is competitively reabsorbed in the proximal tubules along with xylose, fructose and galactose. Similar to glucose, amino acids are also absorbed in the proximal tubules. Glycine, arginine and lysine have TM but many others like histidine, methionine, tryptophan, leucine and phenylalanine have very efficient reabsorption mechanism without a measurable TM.There are enzymes involved in tubular secretion with a TM of some of the substances. In addition to para-aminohippuric acid, renal tubules secrete radio-contrast media, phenol red, penicillins, probenecid and many other drugs. Many of the substances being secreted from the tubules share common mechanisms and compete with each other. REGULATION OF BODY WATER Water filtered from the glomerulus is 180 litres per day of which about 99% is reabsorbed. Most of it is absorbed passively in proximal tubule with sodium (Figure 5). Tubular fluid remains isotonic in the PCT. What happens in LOH and beyond depends upon the presence and concentration of anti-diuretic hormone (ADH). If ADH is low/shut-off, water passes through the thin part of LOH but not through the thick part of LOH. The urine in DCT is hypotonic and in the absence of ADH, urine remains dilute as it passes down in the CD. The water channel responsible for the high water permeability of the luminal membrane in response

1284

Figure 5: Salt and water handling by the tubules.

to vasopressin in aquaporin-2(AQP2). The AQP3 and AQP4 are located on the basolateral membranes and are probably involved in water exit from the cell. During water deprivation, the solute content of medulla is much higher than that of the cortex. Solute content increases progressively as we approach the inner medulla. Osmolarity of tissue at inner medulla is same as that of urine passed while the osmolarity of cortex is same as that of plasma. Urine in CD is also hyperosmolar. The mechanism which accounts best for the phenomenon of urine concentration, is that of ‘countercurrent multiplier system’. The capillary loops of the medulla have comparatively low blood flow, and the exchange of gases and solutes occurs between the arterial and venous limbs working as a ‘counter-current exchanger’. Conserving a high content of solute and carbon dioxide (CO2) in the deeper zones of medulla. The LOH is the site of the counter-current multiplier system. Another important issue is the concept of ‘free-water’. Free water clearance (CH2O) is the volume of blood plasma that is cleared of solute-free water per unit time. Values less than zero imply that the kidney is conserving water resulting in the production of concentrated urine. Since urine flow is determined by the rate at which plasma is cleared of solutes and water (as discussed above), urine flow (V) is given as the sum of osmolar (Cosm) and free water clearance (CH2O) : V = Cosm + CH2O Since osmolar clearance is given as the product of urine flow rate and the ratio of urine to plasma osmolality, this is commonly represented as

Uosm CH2O = V – –– V Posm HANDLING OF SMALL IONS In the initial part of the proximal tubule, 60% of filtered sodium is actively reabsorbed. This is an isosmotic reabsorption. About 25% sodium reabsorption occurs in the thick ascending limb of LOH through the apically expressed sodium-potassium-chloride co-transporter (NKCC2), which uses the sodium gradient across the membrane to transport chloride and potassium into the cell. Sodium leaves the cell actively through the basolateral sodium– potassium ATPase (Na-K-ATPase). In contrast, chloride diffuses passively through two basolateral chloride channels, ClC-Ka and ClC-Kb. Distal tubular reabsorption of sodium occurs both in the DCT and in the CD. Sodium reabsorption is dependent on aldosterone, and corticosteroid, which cause an increase in sodium reabsorption and various natriuretic factors. The mechanism of absorption of sodium in the ascending LOH is by means of a sodium pump located in the tubular cells.The ‘sodium pump’ is thought to receive energy by the conversion of ATP to ADP. Na-K ATPase carries out this conversion. Potassium is reabsorbed and secreted by the renal tubule. More than half of filtered potassium is passively reabsorbed by the end of the PCT. Potassium is then added to tubular fluid in the descending limb of LOH. The major site of active potassium reabsorption is the thick ascending limb of the LOH, so that, by the end of the DCT, only 10% to 15% of filtered potassium remains in the tubule lumen. Potassium is secreted mainly by the principal cells of the CCD and outer MCD. Potassium reabsorption occurs via the intercalated cells of the MCD.

EXCRETION OF WASTE PRODUCTS Urea Handling The kidneys excrete urea entirely by means of glomerular filtration. Half the filtered urea is reabsorbed by the tubules. Urea contributes to the high medullary osmolality during the formation of concentrated urine. About 40% to 50% of the filtered urea diffuses out of the proximal tubule by a passive process. In the descending LOH, urea enters the tubular fluid from the medullary interstitium and CD, so that by the time the DCT is entered the tubular fluid once again contains an amount of urea equal to that present in the glomerular filtrate. As the tubular fluid passes down the CD, a large amount of urea is lost into the medullary interstitium. In the presence of vasopressin, the DCT and CD have an increased permeability to urea so that when concentrated urine is being formed an increased amount of urea diffuses into the medullary interstitium so increasing its osmolality, and thus extracts water from the LOH. Creatinine Handling Creatinine, a breakdown product of muscle metabolism is excreted primarily by glomerular filtration. It is related mainly to an individual’s muscle mass. As it is not significantly handled by tubules, creatinine is useful for making an estimation of GFR, though in many situations it is not critically reliable. However, it is definitely much better than urea. EXCRETION OF DRUGS AND POISONS The kidneys share with the liver the important job of disposing of drugs and poisons. Water-soluble drugs are primarily excreted in the urine. Kidneys are peculiarly vulnerable to toxic damage for two main reasons. First, they have a very rich blood supply in proportion to their weight, and secondly, excretion involves concentration of drugs in the renal tubules. This is why the renal tubules tend to take the brunt of the damage. In patients with kidney damage drugs excreted by the kidneys must be given with extreme caution because inadequate excretion can cause

toxic blood levels; and the high blood levels in turn may be toxic to the kidneys. REGULATION OF BLOOD PRESSURE Hypertension is more common in glomerular than in tubulointerstitial diseases. A well-known cause of renovascular hypertension is renal artery stenosis. A hormone called renin is manufactured in the kidneys by juxta-glomerular cells. Renin acts on angiotensinogen to ultimately produce angiotensin II, which has a vasoconstrictor effect on blood vessels. The kidneys of patients with essential hypertension excrete normal amounts of salt and water at higher-than-normal renal perfusion pressures.

Kidney—Structure and Functions

ACIDIFICATION OF URINE Acidification of the urine is closely related to bicarbonate reabsorption. Large amounts of hydrogen ion are being secreted into the proximal tubule. Secretion of hydrogen removes most bicarbonate from the proximal tubular fluid. The hydrogen ion coming from the tubular cells is exchanged for sodium ions. The source of the hydrogen ion is carbonic acid.The bicarbonate ions inside the cells, together with sodium ions, enter the interstitial fluid and then the peritubular capillaries. Carbonic anhydrase (CA) inside the cells causes a very rapid combination of water and CO2 to form carbonic acid. In the tubular lumen, CO2 produced by the action of hydrogen ion on bicarbonate can diffuse rapidly into the tubular cells. Hydrogen ion also combines with buffers, and with ammonia to form ammonium ion. A little hydrogen ion remains free in solution. The combination of hydrogen ion with buffer is measured as ‘titratable acidity.’ This is defined as the amount of alkali in mEq required to titrate the urine to a pH of 7.4. In the distal tubule, phosphate and creatinine are the two most important buffers. Ammonia, which is produced by mechanisms in the tubular cells, diffuses into the tubular urine where it reacts with free hydrogen ion to form ammonium ion (NH4+). This NH4+ cannot diffuse freely back through the tubular cell wall and so urinary ammonium ion is a measure of part of hydrogen ion secretion.

CONTROL OF ERYTHROPOIESIS The cells producing erythropoietin in the kidney are peritubular fibroblasts in the renal cortex. Erythropoietin concentrations are decreased or increased under a variety of conditions largely reflecting alterations of oxygen delivery to tissues. In addition to changes in oxygen delivery, some metabolic factors also influence erythropoietin production. In a somewhat simplified way, it is those conditions of reduced oxygen supply and increased oxygen demand that lead to increased circulating erythropoietin concentrations, whereas decreased concentrations are typical of conditions with increased oxygen supply or reduced oxygen demand. CONTROL OF VITAMIN D, CALCIUM AND PHOSPHATE METABOLISM Vitamin D is converted into its active 1,25 dihydroxyvitamin D in the proximal tubule by the enzyme-1α hydroxylase. Other than calcium, serum PO4 excretion stimulates the activity of this enzyme. In addition, kidneys also control calcium and PO4 excretion. After filtering at glomerulus, 60% to 70% of Ca is absorbed from PCT; 80% passive and 20% active. Ca is further reabsorbed in small amounts within the medullary segment of the TALOH. Active transcellular Ca transport can be stimulated by both parathyroid hormone (PTH) and active vitamin-D in the cTAL. In the early DCT, thiazide-activated Ca transport occurs. At DCT also Ca reabsorption is regulated by PTH and 1,25(OH)2D3. About 10% of the filtered Ca is reabsorbed in the DCT, with another 3% to 10% in the connecting tubule (CNT) by way of mechanisms similar to those in the DCT. Most of the inorganic PO4 is filtered at glomerulus and 80% to 90% is reabsorbed in the PCT by way of a sodium gradientdependent process (Na-Pi cotransport) and the rest is excreted in the urine. Most of the dietary, hormonal and metabolic factors that regulate renal tubular PO4 reabsorption modulate the PCT expression of the type II Na-Pi cotransport protein. Some amount of filtered PO4 is also reabsorbed in distal segments of the nephron. CONCLUSION Kidney is a complex, but vital human organ. The structural and functional unit of the kidney is the nephron. In addition to its excretory function, role of kidney in endocrine functions and in maintenance of blood pressure is equally important. RECOMMENDED READINGS 1.

Bichet DG, Fujiwara TM. Reabsorption of sodium chloride: lessons from the chloride channels. N Engl J Med 2004; 350: 1281-3.

2.

Schafer JA. Renal water reabsorption: a physiologic retrospective in a 1285 molecular era. Kid Int 2004; 66: S20-S27.

19.2

Kidney Disease—A Clinical Approach

INTRODUCTION Patients with kidney disease may have a variety of clinical presentations. Some have symptoms directly related to the kidney (gross haematuria, flank pain) while others may have extra-renal symptoms (oedema, hypertension, signs of uraemia). However, many patients are asymptomatic and are noted on routine examination to have an elevated plasma creatinine concentration or an abnormal urinalysis. Each of these groups requires a step-wise approach so as to arrive at a definitive diagnosis. Over the last few years, there have been certain changes in the terminology of kidney disease. Acute renal failure (ARF) is now termed as acute kidney injury (AKI) to reflect the entire spectrum of severity of ARF. Similarly chronic renal failure (CRF) is now termed as chronic kidney disease (CKD). The term renal has been replaced by kidney to make it more patient friendly. The term failure has been replaced by disease as failure seemed to connote a helplessness on part of the nephrologists in managing patients with kidney disease. The term end stage renal disease (ESRD) has also been changed to chronic kidney disease stage V [glomerular filtration rate (GFR) less than 15 mL/ min], as most of these patients can be given many years of good quality life with kidney transplantation or maintenance dialysis and cannot be considered as end stage. The diagnosis of kidney disease is based on the evaluation of signs, symptoms and a series of investigations. The diagnosis is complicated by the fact that most of the signs and symptoms are non-specific and also appear fairly late in the course of the disease. A simple approach to a patient with kidney disease is to match the patient’s clinical features into one of the following syndromes: 1. Asymptomatic urinary abnormality 2. Urinary tract infection (UTI) 3. Hypertension 4. Acute kidney injury 5. Rapidly progressive renal failure (RPRF) 6. Acute nephritic syndrome 7. Nephrotic syndrome (NS) 8. Chronic kidney disease 9. Urinary tract obstruction 10. Tubule function defects 11. Congenital/genetic syndromes SIGNS AND SYMPTOMS OF KIDNEY DISEASE The first step in evaluating a patient for kidney disease is to look for clinical features suggestive of kidney disease. These could be a change in urine output like polyuria or nocturia, which relates to loss of the concentrating ability of the kidney or 1286 oliguria (90

Diagnose and treat; treat coexisting conditions; slow progression; reduce risk of cardiovascular disease

Kidney damage with mildly decreased GFR

60 to 89

Estimate rate of progression

Moderately decreased GFR

30 to 59

Evaluate and treat complications

Severely decreased GFR

15 to 29

Prepare for dialysis and kidney transplantation

Kidney failure

400 mL/day), oliguric (50%, or oliguria of less than 0.5 mL/kg per hour for more than 6 hours. The diagnostic criteria are applied only after volume status has been optimised. The staging of AKI is shown in Table 1.

Myocardial, valvular, pericardial diseases, pulmonary hypertension, pulmonary embolism, mechanical ventilation, systemic vasodilatation, antihypertensive drugs

Renal vasoconstriction

Norepinephrine, liver disease, sepsis, hypercalcaemia

Impaired autoregulation

ACEi in renal artery stenosis NSAIDs inhibition of prostaglandin synthesis in states of renal hypoperfusion

Table 1: Staging of Acute Kidney Injury Stage S. Creatinine Criteria

Urine Output Criteria

1

Increased 1.5 to 2 fold*

2

Increased 2 to 3 fold*

12 hours

3

Increased >3 fold* or absolute value >4 mg/dL

3 months Anaemia

Absent

Present

Absent

Present

Usually absent at onset Absent (in early phase)

Present

Significant metabolic/immunologic disturbances, induction of a pro-inflammatory state exacerbated by malnutrition mandates provision of appropriate nutritional support in an attempt to improve outcomes. Nutritional recommendations should consider the cause of AKI and prefer the enteral route. A provision of a nutritional prescription of 25 to 35 kcal/kg/day and up to a maximum of 1.7 g amino acids/kg/day, especially in hypercatabolic patients is essential. Trace elements and water-soluble vitamins should be supplemented as required. Fluid and potassium intake need to be restricted in oliguric patients.

Elevated serum phosphorus, decreased serum calcium, elevated serum PTH Neuropathy Band keratopathy Renal bone disease Small kidneys on sonography

Present

Absent Absent Absent Absent

Present Present Present Present (in some kidney diseases normal/ large sizes) Tolerance to azotemia, acidosis Absent Present Stability of azotemia Absent (daily rise) Present Table 7: Differentiating Between Pre-renal and Intrinsic Acute Kidney Injury (AKI) Diagnostic Index

Pre-renal Intrinsic (AKI) (AKI)

Urinary Na+ concentration (mEq/L) Fractional excretion of Na+ (%) (UNa × PCr/PNa × UCr) × 100 Urinary urea nitrogen/Plasma Urea nitrogen ratio Urinary creatinine/ratio Urine osmolality (mOsm/kg H2O) Blood urea nitrogen/creatinine ratio Renal failure index (UNa/UCr/PCr) Urine sediment

1

>8

40 >500 >20 3 litres per day High citrate diet (citrus fruits), methionine rich foods (meat, poultry, dairy products) Low sodium (7.5 increases cystine solubility Potassium citrate (20 to 40 mEq) corrects hypocitraturia D-Penicillamine (250 to 1000 mg) binds cystine; has serious side effects; maintain urine cystine 130 mmHg) associated with hypertensive retinopathy with haemorrhages, soft exudates and often papilloedema. Besides the kidneys, there may be involvement of the central nervous system, cardiac failure, and microangiopathic haemolytic anaemia. Malignant hypertension is more common in third to fifth decades of life, males, smokers and in those with underlying hypertension of some duration. It may arise de novo in less than 1% cases. Renal involvement may manifest as urinary abnormalities like proteinuria which is occasionally in nephrotic range. About 20% patients have painless gross haematuria with micro-haematuria reported in about 50% patients. Patients with malignant hypertension may present with oliguric ARF or may have a progressive deterioration of kidney function with progression to ESRD. Autopsy studies show that the kidneys are characteristically normal in size but may be shrunken in those with pre-existing hypertension of long duration or underlying chronic kidney disease (CKD). Small pin point haemorrhages may be present on the surface of the kidney giving it a ‘flea bitten’ appearance. The hallmark of malignant nephrosclerosis is fibrinoid necrosis of the afferent arterioles. There is infiltration of the vessel wall with fibrin, and occasionally an inflammatory infiltrate giving the appearance of necrotising arteriolitis. The fibrinoid necrosis may extend into the glomeruli which may develop segmental necrosis, proliferative lesions and even crescents. The interlobular arterioles reveal proliferative endarteritis. Secondary to narrowing of the lumen there is ischaemic collapse of the glomerular tuft and necrosis of renal tubules. It has been proposed that activation of the renin angiotensin system and other neurohumoral factors leads to increased permeability of the vessel wall to plasma components like fibrin, which activates the clotting cascade leading to microangiopathic haemolytic anaemia and the vascular lesions. Alternatively, the vascular endothelium may be damaged secondary to the high pressure per se. All patients with malignant hypertension and renal damage should receive aggressive anti-hypertensive therapy to prevent further deterioration of renal function. In patients with impaired renal function [glomerular filtration rate (GFR) less than 20 mL/ minute] aggressive lowering of BP may precipitate oliguric ARF. This should not be considered as a contraindication to tight BP control as patients who have ESRD due to malignant nephrosclerosis are reported to have recovered renal function over a period of time despite being on dialysis. The mechanism 1324 of recovery of renal function after prolonged renal failure may

be related to partial reversal of the vascular lesions leading to reversal of ischaemic tubular necrosis or due to hyperfiltration by the remaining nephrons supplied by the patent interlobular arteries. BENIGN ARTERIOLAR NEPHROSCLEROSIS Benign arteriolar nephrosclerosis is a term used to describe histological changes in the kidneys secondary to chronic hypertension. The risk factors for Benign arteriolar nephrosclerosis include older age, black race and poorly controlled hypertension. The diagnosis is usually based on long standing hypertension being present with associated signs of other endorgan damage in the form of hypertensive retinopathy and left ventricular hypertrophy. The usual renal manifestations are proteinuria of less than 1 g per day with bland urinary sediment and mild to moderate elevation of serum creatinine. The progression of renal impairment , though slow, may lead to ESRD. The adjusted risk for ESRD is reported to increase with levels of BP. At histology, the arcuate and other larger arteries show fibrous intimal thickening, re-duplication of the internal elastic lamina and thickening of the media. The arterioles show hyaline arteriosclerosis with accumulation of hyaline in subendothelial areas which may extend into the media. This results in narrowing of the vascular lumen leading to ischaemic atrophy of the renal parenchyma. Early in the disease process, the glomeruli may be normal. With time there is complete glomerular obsolescence, tubular atrophy and interstitial fibrosis. Treatment is aimed at keeping the BP less than 130/80 mmHg. Most patients need a combination of drugs including a diuretic. Non-pharmacological measures like weight loss, exercise, and salt restriction should also be prescribed. The principles of management of CKD due to benign arteriolar nephrosclerosis remain the same as those for any other cause of CKD. SCLERODERMA RENAL DISEASE Kidney involvement in systemic sclerosis may present as slowly progressive CKD, or scleroderma renal crisis (SRC). An occasional patient may present with rapidly progressive glomerulonephritis. Factors predictive of SRC are diffuse skin involvement, rapidly progressive skin disease, new onset scleroderma (less than 4 years), anaemia, cardiac involvement, high-dose steroid use (>15 mg prednisolone per day), cyclosporine therapy, and presence of anti-RNA-polymerase antibody. Conversely, patients with anti-centromere antibody (ACA) are relatively protected. Occasionally, skin involvement may be minimal or even absent. In SRC, majority of patients present with accelerated/malignant hypertension, neuroretinopathy, headache, blurring of vision, encephalopathy, seizures, pulmonary oedema, microangiopathic haemolytic anaemia and thrombocytopaenia. Renal involvement manifests as oliguric ARF. Urinalysis shows non-nephrotic range proteinuria, haematuria and granular casts. The characteristic renal lesions occur in the arcuate arteries.There is proliferation of myointimal cells of the vessel wall with luminal narrowing which is indistinguishable from the changes of hyperplastic endarteritis seen in malignant/accelerated hypertension. Fibrinoid necrosis of the vessel wall and thrombosis are also common. Patients who have never had a renal crisis may

RENAL VEIN THROMBOSIS Renal vein thrombosis (RVT) may occur in a number of clinical conditions (Table 1). The most common cause is nephrotic syndrome associated with membranous nephropathy. RVT is known to aggravate proteinuria. In nephrotic syndrome, hypoalbuminaemia (serum albumin less than 2.5 g/dL) is an indicator of an underlying hypercoagulable state and increased risk of RVT. Table 1: Causes of Renal Vein Thrombosis Nephrotic syndrome: Increased plasma levels of factor V, VIII, XIII, fibrinogen, thrombocytosis, decreased plasma levels of factor XII, anti-thrombin III Neoplasms: Renal cell carcinoma, Wilm’s tumour Hypercoagulable states: Deficiency of protein C/protein S, oral contraceptives, cyclosporine Hypovolaemia Extrinsic compression: Lymph nodes, tumours, pregnancy Collagen vascular diseases: Systemic lupus erythematosus Renal transplant Blunt trauma Others: Acute pancreatitis, amyloidosis, tricuspid insufficiency, constrictive pericarditis

The clinical features of RVT depend on the rapidity of onset and whether RVT is unilateral,bilateral or in a solitary functioning kidney. Acute RVT presents with fever, loin pain, haematuria and renal enlargement. Deterioration of renal function has been described in bilateral RVT and in patients with a single kidney. Pain and swelling in the ipsilateral testicle may occur in males. The chronic form is usually clinically silent, but may present with increase in proteinuria and recurrent pulmonary thromboembolism. Imaging studies are required to establish the diagnosis of RVT. Conventional ultrasonography and renal Doppler studies have a low sensitivity and may show a swollen echogenic kidney with increased resistive indices. CT and magnetic resonance imaging (MRI) often provide a definitive diagnosis, thus avoiding the need for renal venography. Resolution of acute RVT has been demonstrated with thrombolysis, using either streptokinase or urokinase given systemically. Anticoagulants are recommended for prevention of pulmonary embolism. In nephrotic syndrome, they are continued until the serum albumin is more than 2.5 g/dL. If pulmonary embolism has occurred, initial anticoagulation with heparin for 5 to 7 days followed by oral drugs is recommended. Once oral anti-coagulant

therapy is established, the prothrombin time should be kept at about one and one-half to two times normal. Patients with RVT in pregnancy are best treated with heparin alone. If anti-coagulation is contraindicated and pulmonary embolism has occurred, inferior vena cava filters may be used. Thrombectomy in the treatment of RVT has no advantage over anti-coagulation and is indicated only in presence of renal cell carcinoma. RENAL ARTERY STENOSIS Renal artery stenosis (RAS) is narrowing of the lumen of the main renal artery or one of its branches leading to impaired blood flow to the kidneys. It may be unilateral or bilateral. The commonest cause in the elderly is atherosclerotic renal artery disease (bilateral in half the cases) while in young females the commonest cause is fibromuscular dysplasia. Non-specific aortoarteritis or Takayasu’s arteritis is a common cause of RAS below the age of 40 years in Afro-Asian countries and Japan.

Vascular Injury to Kidney

show on renal histology re-duplication of elastic fibres, sclerosed glomeruli, tubular atrophy and interstitial fibrosis reflecting the chronic changes of scleroderma. Aggressive management of hypertension with angiotensin converting enzyme (ACE) inhibitors has improved the cumulative 1 year survival from 15% to 76%. Angiotensin II receptor blockers, alpha-blockers and calcium antagonists are also helpful for refractory hypertension. Dialysis is required in approximately two-thirds of the patients. Approximately half of these patients will eventually recover sufficiently to discontinue dialysis. Delayed renal recovery may occur more than 24 months after the crisis and so decisions about renal transplantation should be postponed until that time. Recurrence of SRC is uncommon in transplant patients.

The reported incidence of RAS as cause of hypertension varies between 0.6% and 5% depending on the selection criteria and modalities of diagnosis used. The activation of renin angiotensin system and resultant hyper-reninaemia play a major role in initial phase of renovascular hypertension. Over time, salt and water retention following a sustained hyper-reninaemia state take over as the mechanism for hypertension at which stage renin levels may return to normal. Stenosis in the affected renal artery leads to reduction in post-stenotic pressure and renal perfusion. The kidney tries to restore the perfusion by autoregulation but if the stenosis persists, it leads to progressive loss of kidney function and the clinical entity is called ‘ischaemic nephropathy’. Clinical clues to the presence of RAS include, abrupt onset of hypertension before 30 or after 50 years of age, accelerated/ malignant hypertension, treatment-refractory hypertension, worsening of renal function after initiating ACE inhibitors, recurrent flash pulmonary oedema, unilateral small kidney and a biphasic renal bruit with systolic and diastolic components. A number of non-invasive modalities are used for the diagnosis of RAS with varying sensitivity and specificity (Table 2). Renal angiography, however, remains the gold standard as it provides direct visualisation of the affected renal artery and corrective angioplasty and stenting of the stenotic lesion can be performed in the same session. Colour Doppler ultrasonography is the best non-invasive screening test with a sensitivity of about 70%. The major limitation is that it is highly operator dependent and is technically difficult in obese patients. The sensitivity also decreases in the presence of multiple renal arteries, distal lesions, and total occlusion. In functionally significant renal artery stenosis, glomerular filtration rate Table 2: Investigations in Diagnosis of Renal Artery Stenosis Test

% Sensitivity % Specificity

Colour Doppler duplex sonography

Variable

Variable

Radio-isotope renography

65 to 75

65 to 85

Spiral computed tomography angiography

88 to 98

90 to 95

Magnetic resonance angiography

95 to 100

93 to 95

Conventional or digital subtraction angiography

100

100 1325

is maintained by stimulation of the renin-angiotensin-aldosterone axis. ACE-inhibitors cause reduction in renal blood flow and GFR and their use in association with 99mTc-labeled DTPA or 99mTc-labeled MAG3 scans are useful for the diagnosis. Management Treatment of renovascular hypertension should include ACE inhibitors/angiotensin receptor blockers (ARBs), and address all modifiable cardiovascular risk factors like hyperlipidaemia, obesity and smoking. ACE inhibitors may cause a rise in creatinine in patients with bilateral RAS and in RAS of a single functioning kidney. Revascularisation therapy with angioplasty with/without stent placement is indicated if adequate BP is not achieved despite optimal medical therapy or if the serum creatinine rises despite adequate BP control. A favourable response to intervention is seen in patients with rapid decline of renal function. Despite revascularisation, cure of hypertension is unusual, though seen more often in fibromuscular dysplasia than in atherosclerotic renal artery disease. Renal functional recovery or stabilisation of renal function is seen in approximately 70% of the patients. Surgical revascularisation is indicated in patients with total occlusion of the renal vessel in whom renal angioplasty/stenting is not

1326

possible. Nephrectomy has a role to play when a nonfunctioning kidney is implicated in the cause of RVH. Revascularisation therapy is best avoided if the resistivity index on Doppler sonography is more than 80%. The likely reason for the poor response is structural alterations in smaller arteries and arterioles distal to the RAS which manifests as increased vascular resistance. RECOMMENDED READINGS 1.

Badr KF, Brenner BM. Vascular injury to the kidney. Kasper DL, Fauci AS, Longo DL, et al, editors. Harrison’s Principles of Internal Medicine. 17th Ed. New York: McGraw Hill; 2008: pp 1707-10.

2.

Kanso AA, Abou Hassan NM, Badr KF. Micro and macrovascular diseases of the kidney. In: Brenner BM, Levine SA, editors. Brenner and Rectors. The Kidney; 8th Ed. Philadelphia: Saunders Elsevier; 2008: pp 1147-73.

3.

Lach FL, Yudd M. Renal artery thrombosis, thromboembolism, aneurysms, atheroemboli, and renal vein thrombosis. In: Schrier RW, editor. Diseases of The Kidney and Urinary Tract. 8th Ed. Philadelphia: Lippincott Willialms and Wilkins; 2007: pp 1787-800.

4.

Lewis J, Greco B. Atheromatous and thromboembolic renovascular disease. In: Feehally J, Floege J, Johnson RJ, editors. Comprehensive Clinical Nephrology; 3rd Ed. Philadelphia: Mosby Elseiver; 2007: pp 725-44.

5.

Nolan RC, Linas L. Malignant hipertensión and other hypertensive crises. In: Schrier RW, editors. Diseases of the Kidney and Urinary Tract. 8th Ed. Philadelphia: Lippincott Willialms and Wilkins; 2007: pp1370-1437.

19.10 DISORDERS OF CYSTIC NATURE AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE Definition Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder with autosomal dominant inheritance and is a result of mutation in PKD 1 or PKD 2 gene. The disease manifests with renal and extra-renal manifestations. Epidemiology The incidence varies from 1 in 400 to 1 in 1000 individuals and it occurs in all races and ethnicities. It accounts for 5% of all cases of end-stage renal disease (ESRD) across the world. Genetics ADPKD is caused by mutations in at least 2 different genes. Mutations in the PKD 1 gene which is present on the short arm of chromosome 16 (16p13), accounts for 85% of all cases, while the PKD 2 gene which is present on the long arm of chromosome 4 (4q21), accounts for the rest. Ninety per cent of all cases are inherited in an autosomal dominant fashion, while the rest are likely to be due to spontaneous mutations. Polycystin proteins are expressed in virtually all tissues. The PKD 1 gene codes for the protein Polycystin 1 while the PKD 2 gene codes for polycystin 2. Most mutations in either gene are single base changes, insertions or deletions of a small number of base pairs, resulting in truncated proteins and loss of function. These proteins are believed to function either independently or as a part of a complex, to regulate tubular epithelial cell gene transcription, differentiation, cell-to-cell interaction and apoptosis. Disruption of these proteins can lead to epithelial dedifferentiation, uncontrolled epithelial proliferation, apoptosis, altered polarity of tubular cells, with disorganisation of the extracellular matrix and excessive fluid secretion by the epithelial cells. They have also been localised to the primary cilia of the tubular epithelial cell which act as mechanosensors which transduce luminal signals into cellular responses that control cell proliferation, adhesion, differentiation and apoptosis. The penetration of these mutations is 100%. However, there is marked variability in the phenotypic expression of the disease within individuals of the same family. Less than 5% of nephrons become cystic. This variability in expression and focal nature of the renal disease with its extra-renal manifestations has been explained by the ‘two hit hypothesis’. This hypothesis implies that the presence of a germ line mutation is on its own not sufficient for cystogenesis, but a ‘second somatic mutation’ is essential to inactivate the other PKD allele. Mutations of the polycystin 2 gene usually result in a milder form of the disease, with an older age at diagnosis and later onset of hypertension and renal failure as compared to PKD 1 mutations.

Polycystic Kidney Disease and Inherited Tubular Disorders PP Varma, Ranjith Nair CYSTOGENESIS Renal cysts can arise from any segment of the nephron. About 10% of all cysts retain the morphologic characteristics of the segment they arise from. They initially arise as outpouchings from the tubules, which are initially filled with glomerular filtrate, however, they separate from the tubule as they increase in size, and thereafter grow in size due to exaggerated cell proliferation due to loss of cell-to-cell interaction, associated with increased secretion of fluid within the cyst lumen which is exclusively due to transepithelial secretion of water and solutes. Hence, cysts are not dead ends of tubules which store urine generated by proximal segments of the tubules, but they are complex structures that proliferate, synthesise proteins and secrete fluid and electrolytes and show apoptosis. The cysts are present throughout the renal parenchyma and are variable in size. They tend to compress and distort the normal renal parenchyma in between as they enlarge in size. Clinical Features There is marked variability in the course of the disease, starting from the age at detection to its course within members of the same family and between PKD 1 and PKD 2 gene mutation carriers. The mean age at presentation is 55 years in PKD 1 and 71 years in PKD 2 disease. However, marked phenotypic variability is the hallmark of ADPKD. One-third of adults are asymptomatic and their disease is detected during ultrasound of the abdomen conducted for an unrelated cause. With the increasing availability of sonology facilities, this proportion is likely to increase with time. The commonest presenting feature in symptomatic patients is flank or back pain, which can occur in 60% of adults.The pain is usually chronic dull aching in nature. This pain is more common in patients with large kidneys with high cyst burden. The pain could get acute in case of infection or haemorrhage into a cyst or due to renal colic due to a calculus or clot. Hypertension is detected in 80% of adults and in up to 30% of all children with ADPKD. It is usually due to increased activity of the renin-angiotensin system. Hypertension can precede renal dysfunction by decades in adults. Hypertension in ADPKD correlates with the renal volume. Gross haematuria can occur in 50% of adults. It is probably caused by cyst rupture into the pelvicalyceal system. More than half of all subjects with gross haematuria relate it to an inciting event such as infection or trauma. In case of associated colicky pain, infection, clot colic or renal calculus needs exclusion. There can be cyst haemorrhage within the kidney which does not communicate with the pelvicalyceal system (PCS) and could be clinically silent but for pain in the flank. Renal concentration defects can be demonstrated in potentially all adults with ADPKD, even in the presence of normal glomerular filtration rate (GFR). Nephrolithiasis occurs in 20% 1327

of patients. Urinary tract infections are a common occurrence in ADPKD patients. Urine cultures may be sterile in isolated cyst infections, while blood cultures would be positive in such cases. Cyst infections due to gram-negative organisms can be difficult to eradicate, requiring prolonged courses of parenteral antibiotics. Lipophilic antibiotics like fluoroquinolones, trimethoprim, clindamycin and macrolides accumulate well within the cyst, and can be used to eradicate cyst infection.

management of these patients is purely supportive. Control of hypertension is an important measure, with the target of 135/ 85 mmHg or less as per the JNC VII criteria. All classes of antihypertensives can be used, but for diuretics. No single class of anti-hypertensive has been shown to be superior to the other, though many authors prefer to use angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs).

Extra-renal manifestations are common. Hepatic cysts can occur in 60% to 75% cases. Most patients with hepatic cysts are asymptomatic with normal liver function tests, unless there is haemorrhage or infection in the cysts.Hepatic cysts occur with equal frequency in either gender but they tend to be larger in women. Cysts can also be demonstrated in the seminal vesicles (60%) and prostate (10%) besides pancreas (10%) and arachnoid cysts (5%). Cysts have also been described in the ovaries, testes and the spleen. Colonic diverticuli, abdominal wall and inguinal hernias occur more commonly in ADPKD patients than the general population.

Complications like urinary tract infection and cyst infection should be preferably treated with lipophilic antibiotics like fluoroquinolones, trimethoprim or macrolides. Pain relief due to cyst haemorrhage, clot colic or calculus may need opioids. Occasionally, surgical excision of haemorrhagic or infected cysts may become essential.

There is four-fold risk of intra-cerebral haemorrhage from an arterial aneurysm in ADPKD patients. Intracranial aneurysms can occur in up to 10% of these patients on routine magnetic resonance angiography (MRA) screening. However, most of these are small and usually do not enlarge or rupture with time. Aneurysmal haemorrhage occurs preferentially in young individuals ( wasting

Muscle tenderness

Absent

++

Nil

Fever, joint pain, rash Reflexes

–ve

++

Nil

Depressed

May be increased Depressed

Neck weakness

Rare (except myotonic dystrophy)

++

Rare

Swallowing defect

Rare

Common

Rare

RECOMMENDED READINGS 1.

Bickerstaff ER, Spillane JA. Neurologic Examination in Clinical Practice; 5th Ed. Oxford: Blackwell Scientific; 1989.

2.

Bradley WG, Daroff R B, Fenichel G M, Jankovic J. Diagnosis of Neurologic disease in Neurology in Clinical Practice. Principles of Diagnosis and Management, Vol. 1. Elsevier; 2004: pp 3-9.

20.2

Neurological Disorders—A Clinical Approach

A thorough neurological evaluation is of paramount importance and is integral for correct diagnosis virtually in every clinical encounter. Relevant history and focused clinical examination are the keys to achieve the correct diagnosis. The standard practice is to record the patient’s chief complaints, and take a history of the development of the symptoms, followed by the history of illnesses and surgeries, the family history, the personal and social history, and a review of any symptoms involving the main systems. A thorough neurological examination then follows and a differential diagnosis is constructed. What is unique to neurological examination is the extreme attention to ‘localisation’. In general, the history provides the best clues for aetiology and the examination for localisation. HISTORY The chief complaint (or the several main complaints) is the usual starting point of the diagnostic process. An example might be, a patient presenting with the triad of complaints of headache, clumsiness and double vision. The complaints serve to focus attention on the questions to be addressed while taking the history and provide the first clue to the anatomy and aetiology of the disease underlying the complaints. In this case, it may suggest the presence of posterior fossa tumour affecting the cerebellum and the brainstem. The mode of onset is critically important in determining the aetiology. For example, a sudden onset usually indicates a vascular aetiology such as stroke. A course characterised by exacerbations and remissions may suggest multiple sclerosis, whereas a slowly progressive course may indicate a neoplasm or degenerative disorder. Paroxysmal episodes may suggest the possibility of seizures, migraines, periodic paralyses, etc. Patient may provide a clear history or at times (especially in the elderly) may give tangential information not really required. Direct questioning is often required to keep the patient or health provider focused and also to clarify the symptoms. However, it is important not to lead the patient. Patients sometimes agree with everything that the physician may suggest even if it is incorrect. Reliability of patient’s history is of paramount importance. Reliability depends on the patient’s intelligence, memory, language function, educational and social status. Getting information from an observer other than the patient is important for diagnosing and characterising common neurological conditions such as epilepsy or dementia. In children, the history is always the composite perceptions of the child and the parent. Patients and physicians may use the same word to mean very different things. The word ‘chakkar’ may not really mean ‘vertigo’ but may mean, seizure, syncope, dizziness, fatigue, etc. Patients may describe a limb being ‘numb’ when what they actually mean ‘paralysis’. ‘Blurred’ vision may mean decreased in vision or ‘diplopia’ which many a time is not ‘complained’ as double vision.The neurologist must understand the nature, onset, duration, and progression of each symptom

MV Padma Srivastava and the temporal relationship of one symptom to another. One must ascertain if the symptoms are getting better, are constant or getting worse? What are the aggravating and relieving factors, if any. In infant and young children, the timing of developmental milestones will be of great relevance in many neurological illnesses. In summary, the history of the presenting illness or chief complaint should include the following information: 1. Symptom onset ( acute, subacute, chronic, or relapsing). 2. Duration. 3. Course of the condition (static, progressive, relapsing and remitting). 4. Associated symptoms such as pain, headache, vomiting, weakness and seizures). Both the absence of expected features and the presence of unexpected features may assist in the diagnosis. A patient with numbness of the feet might have a peripheral neuropathy, but the presence of the backache and loss of sphincter control suggests that a spinal cord or cauda equina lesion is more likely. The review of history should include the elements of nervous system function that did not surface in taking the primary complaints. The history should cover following fields of cognition, personality and mood change; hallucinations; seizures and other impairments of consciousness; orthostatic faintness; headaches, special senses, speech and language function, swallowing, limb movements, strength and sensation, pain, gait and balance and sphincter, bowel and sexual functions. A positive response may help clarify a diagnosis. For example, if a patient complaining of ataxia and hemiparesis admits to unilateral deafness, this may suggest a acoustic neuroma. Headaches in a patient with paraparesis suggest a parasagittal meningioma rather than a spinal cord lesion. Personal History The personal history in terms of occupation, marital status, and alcohol, tobacco and illicit drug use and the medical history of the parents, siblings and children looking for evidence of familial disease is essential. Many neurological disorders are hereditary. Hence a history of similar diseases in the family members or of consanguinity may be of diagnostic importance. However, an expression of a gene mutation may be quite different from one family member to another with respect not only to the severity of the neurological dysfunction but also to the organ systems involved. For instance, the mutations of the gene for MachadoJoseph disease (SCA-3) can cause several phenotypes. A patient with Charcot-Marie-Tooth disease (hereditary motor-sensory neuropathy) may have a severe peripheral neuropathy, whereas relatives may have only pes cavus. Reported diagnoses may be inaccurate. Some clinical situations such as epilepsy and other neurological conditions presumed 1351

to have a social ‘stigma’ may be kept secretive and patients may show great reluctance to divulge the correct information. The history of ‘seizures’ in the family members will invariably be ‘negative’ unless relentlessly and laboriously pursued. If there is a possibility that the disease is inherited, it is helpful to obtain information from parents and grandparents and to examine the relatives at risk. Minimum data for all first and second-degree relatives should include, age, cause of death and any significant neurological or systemic diseases.

        

History of Previous Illnesses

Tools required will include an ophthalmoscope, a reflex hammer, and a tuning fork as minimum essentials for performing the examination.

The record of history should include dates and details of all surgical procedures, significant injuries including head trauma and fractures, hospitalisations, and conditions requiring medical consultation and medications. For paediatric patients, information on the pregnancy and state of infant at birth should be recorded. Seizure and worsening headaches in a patient who previously had surgery for lung cancer suggests a brain metastasis. Chronic low-back pain in a patient complaining of numbness and weakness in the legs on walking half a mile suggests neurogenic claudication from lumbar canal stenosis. Review of Symptoms in Non-Neurological Systems Neurological function is adversely affected by dysfunction of many systemic disorders including that of the liver, kidney, gastrointestinal tract, and blood vessels. Several neurological diseases are characterised by multi-organ involvement such as vasculitis, sarcoidosis, mitochondrial disorders and storage diseases. History of gastric surgery may lead to vitamin B12 deficiency. Sarcoidosis may cause recurrent Bell’s palsy, diabetes insipidus, ophthalmoplegia and peripheral neuropathy. Disorders of the liver, kidney and small bowel can be associated with a wide variety of neurological disorders. Systemic malignancy can cause direct and indirect (paraneoplastic) neurological problems. Medications are also often the cause of neurological disturbances, particularly, antiepileptic agents, chemotherapeutic agents, etc. Isoniazid may cause a peripheral neuropathy. Lithium carbonate may produce tremor and ataxia. Neuroleptic agents can produce a parkinsonian syndrome or dyskinesias. Special emphasis needs to be given to intake of ayurvedic medications especially those that contain heavy metals and other over the counter drugs. NEUROLOGIC EXAMINATION The neurological examination is one of the most unique in all of clinical medicine. Unlike many other fields of medicine in which diseases are visible, or palpable, neurology is characterised by conditions that may be detected only be applying specific examination techniques and logical deduction, except when certain cutaneous markers or other stigmata suggest the diagnosis. Steps in the Neurologic Examination For the purpose of simplicity, the neurological examination is divided into several steps. When mastered these steps become second nature to the examiner. These steps include the following:  Higher mental functions 1352  Speech and Language

Cranial Nerves Motor System Sensory System Reflexes Cerebellum Meninges Spine Gait Systemic examination

Examination of the Higher Mental Functions This includes testing of memory, orientation and intelligence besides other aspects of patients’ psychic state. Any suspicion of disorder in higher mental functions will require a very detailed assessment including detailed lobe function tests which will be out of purview of this chapter. Memory It is the ability to register and recall prior sensory input. Recent and remote memory functions are differently affected depending on the disease process. Past memory is relatively preserved in chronic dementing processes, with major disturbances in the attention span and recent memory. On the contrary, all aspects of memory are impaired in acute encephalopathies. Orientation It is an individual’s cognitive sense of his status in time, place and person. These functions are affected in the same order as they are in organic disease. In other words, the sense of time is first to be impaired in organic dysfunction and the sense of person is the last to be lost. However, the order may be disturbed in psychological dysfunction. Intelligence It is the ability to quickly and successfully apply previous knowledge to a new situation and to use reason in solving problems. Vocabulary, fund of knowledge, calculations, abstraction and judgment are good indicators of intelligence. Due regard and allowance is given to literacy state of the individual. A mini-mental state examination is given in annexure/echapter as examination of neurological disorder. Mini-mental state examination (MMSE) See previous chapter on Basic Considerations in Neurology Speech and Language Abnormalities include aphasia, or acquired language dysfunction; dysarthria or acquired dysfunction in articulation and dysphonia or acquired dysfunction in phonation. Dysphasia or aphasia In dysphasia the ability to process language is impaired, resulting in an inability to understand (i.e. receptive or sensory or Wernicke’s aphasia), transfer signals from the Wernicke’s are to the Broca’s area (i.e. conduction aphasia), or properly execute speech (i.e. expressive, motor or Broca’s aphasia). The combination of Broca’s aphasia and Wernicke’s aphasias is referred to as mixed aphasia.

Type of Fluency aphasia Broca’s Non-fluent Wernicke’s Fluent

Compreh- Naming ension Intact Impaired Impaired Impaired

Conduction Fluent

Intact

Impaired

Global

Impaired

Impaired

Non-fluent

Localisation Broca’s area Wernicke’s area Fasciculus arcuate Non localising

Transcortical aphasia These are caused due to the involvement of the association cortices sparing the primary language areas. They are distinguished from primary aphasia by the preservation of repetition. Dysarthria It is the inability to articulate spoken words. The quality of the oration in impaired but the content remains intact (e.g. slurred speech). The patient’s ability to understand and synthesise speech remains intact. It results from paralysis of pharyngeal, palatal, lingual or facial musculature. It is also observed with cerebellar lesions (staccato/scanning/explosive speech) or extrapyramidal disorders (monotonous and hypo-phonic as in Parkinson’s disease) etc. Dysphonia Dysphonia is the impairment or inability to phonate. Neurologic causes include unilateral recurrent laryngeal nerve paralysis and lesions of the vagus nerve. Examination of the Cranial Nerves There are 12 cranial nerves; their anatomy and examination are given in chapter 7 section 20. Examination of the Motor System Trophic state Assess the size, shape and symmetry of a muscle. Atrophy, hypertrophy or abnormal bulge or depression will be important diagnostic findings. Hypertrophy with weakness is seen commonly with Duchenne muscular dystrophy.

0 1 2 3 4 5

– – – – – –

Muscle strength The MRC grading of muscle power is the standard method of testing for muscle power. Score 0 1 2 3 4 5

An increase in tone is noted when there is an increase in the resistance to passive movements of the limbs. The movements are either flexing or extending the limbs, rotating the limbs or shaking the hands at the level of wrists. The increase in tone is classified as follows (Ashworth Scale):

Description Absent voluntary contraction Feeble contractions that are unable to move a joint Movement with gravity eliminated Movement against gravity Movement against partial resistance Movement against full resistance or normal power

A central lesion usually produces greater weakness in the extensors than in the flexors of the upper extremities and the reverse in the lower extremities. Upper motor lesions are associated with weakness, spasticity (increased tone), hyperreflexia, primitive reflexes, and the Babinski sign. Primitive reflexes include the grasp, suck and snout reflexes. Lower motor neuron lesions are characterised by weakness, hypotonia (flaccidity), hyporeflexia, atrophy and fasciculations. Fasciculations are involuntary movements which occur as fine rippling movements under the skin, at random intervals and distribution.They are indicative of a lower motor neuron disease. They are due to denervation of whole motor units. Atrophy of the muscle groups are usually associated with fasciculations as typically seen in motor neuron disease (MND). Fibrillations are spontaneous contractions of the individual muscle fibres and are therefore not visible to the naked eye. Examination of individual muscled groups  The deltoid muscle is innervated by the C5 nerve root via the axillary nerve. 

Ask the patient to abduct both the arms or each arm separately to 90° and raise them above against resistance. Compare the strength of each arm. Alternately, ask the patient to raise both their arms in front of them simultaneously as strongly as they can.

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Ask the patient to extend and raise both arms in front of them. Ask the patient to keep their arms in place while they close their eyes. If there is an upper motor weakness, there will be a positive pronator drift, in which the affected arm will pronate and fall. In upper motor neuron weakness, supination is weaker than pronation in the upper extremity, leading to a pronation of the affected arm.

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The biceps muscle is innervated by the C5 and C6 nerve roots via the musculocutaneous nerve.



Test the strength of lower arm flexion by holding the patient’s wrist from above and instructing them to ‘flex their hand up to their shoulder’. Provide resistance at the wrist. Repeat and compare to the opposite arm.

Tone Muscle tone is the permanent state of partial contraction of a muscle and is assessed by passive movement. The muscle may be hypertonic and hypotonic. Hypotonia is defined as decreased tone and may be seen in lower motor neuron lesions, spinal shock and some cerebellar lesions. Hypertonia may manifest as spasticity or rigidity. Pyramidal lesions result in spasticity that may manifest as a clasp-knife phenomenon. Rigidity refers to increased tone associated with extrapyramidal lesions; it may result in a cogwheel (stepwise) or lead-pipe (uniform) resistance to passive movement.

Normal to decrease (flaccidity) Normal Mild increase Moderate increase Severe increase Associated with spasms

Neurological Disorders—A Clinical Approach

Essential Elements of Common Aphasia

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

The triceps muscle is innervated by the C6 and C7 nerve roots via the radial nerve.



Have the patient extend their forearm against the examiner’s resistance. Make certain that the patient begins their extension form a fully flexed position because this part of the movement is most sensitive to a loss in strength. Note any asymmetry in the other arm.

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The wrist extensors are innervated by C6 and C7 nerve roots via the radial nerve. The radial nerve is responsible for all the extensor muscles in the upper and lower arm.



Test the strength of wrist extension by asking the patient to extend their wrist while the examiner resists the movement. This tests the forearm extensors. Repeat with the other arm.

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Finger flexion is innervated by the C8 nerve root via the median nerve. Observe for intrinsic hand, thenar and hypothenar muscle wasting. Test the patient’s grip by having the patient hold the examiner’s fingers tightly and instructing them not to let go while the examiner attempts to remove them. Normally, the examiner cannot remove their fingers. Note for any asymmetry in both the hands.

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Finger abduction is innervated by the T1 nerve root via the ulnar nerve.

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Test the intrinsic hand muscles by having the patient abduct and ‘fan out’ all of their fingers. Instruct the patient to not to allow the examiner to compress them back in. Normally, one can resist the examiner from replacing the fingers.

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Thumb opposition in innervated by the C8 and T1 nerve roots via the median nerve.

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Test the strength of the thumb opposition by asking the patient to touch the tip of their thumb with their little finger. Apply resistance to the thumb with the examiner’s index finger. Repeat with the other thumb and compare.

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The hamstrings are innervated by the L5 and S1 nerve roots via the sciatic nerve.



Test the flexion of the hip by asking the patient to lie down and raise each leg separately while the examiner resists. Repeat and compare the test flexion at the knee by holding the knee from the side and applying resistance under the ankle and instructing the patient to pull the lower leg towards their buttock as hard as possible. Repeat with the other leg.

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

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Ankle dorsiflexion is innervated by the L4 and L5 nerve roots via the peroneal nerve. Test dorsiflexion of the ankle by holding the top of the ankle and have the patient pull their foot towards the body as strongly as possible. Repeat with the other foot. This tests the muscles in the anterior compartment of the lower leg. Ankle plantar flexion is innervated by the S1 and S2 nerve roots via the tibial nerve. Ask the patient to ‘press down’ as hard as possible. Repeat with the other foot and compare. This tests the gastrocnemius and soleus muscles in the posterior compartment of the lower leg.

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The extensor hallucis longus muscle is almost completely innervated by the L5 nerve root. Ask the patient to move the large toe against the examiner’s resistance towards the body. This test the extensor hallucis longus.

Involuntary movements Involuntary movements include fibrillations, fasciculations, asterixis, tics, myoclonus, chorea, dystonia, athetosis, hemiballismus, seizures, etc. and will be described in detail in respective chapters. Sensory System Non-cortical sensory system Light touch, pain, heat, cold and vibration sensations can be included in this group. Light touch is tested by touching the skin with a wisp of cotton or tissue. Pain is tested by using a sharp object such as an open safety pin. Temperature can be tested by touching the patient’s skin with two test tubes, one with warm water and the other with cold water. Vibration is tested with a 128 Hz or 256 Hz tuning fork. Compare findings on the two sides, and also with corresponding areas on the examiner. Pain and light touch sensation The corresponding nerve root for each area tested is indicated in parenthesis: 1. Posterior aspect of the shoulders (C4) 2. Lateral aspect of the upper arms (C5) 3. Medial aspect of the lower arms (T1) 4. Tip of the thumb (C6) 5. Tip of the middle finger (C7) 6. Tip of the little finger (C8) 7. Thorax, nipple level (T5) 8. Thorax, umbilical level (T10) 9. Upper part of the upper leg (L2) 10. Lower-part of the upper leg (L3) 11. Medial lower leg (L4) 12. Lateral lower leg (L5) 13. Sole of foot (S1) 14. Peri-anal area (saddle area) (S2, S3, S4) Alternating between pinprick and light touch, touch the patient in the above 14 areas. Touch one body part followed by the corresponding body part on the other side with the same instrument. This allows the patient to compare the sensations and note asymmetry. Position sense is tested by asking the patient with eyes closed to report if his/her large tow is ‘up’ or ‘down’ when the examiner manually moves the patient’s toe in the respective direction. Repeat on the opposite foot and compare. Fine touch, position sense (proprioception) and vibration sense are conducted together in the dorsal column system. Rough touch, temperature and pain sensation are conducted via the spinothalamic tract. Cortical sensory system The cortical sensory system includes the somatosensory cortex and its central connections. This system enables the detection of the position and movement of the extremities in space (kinaesthetic sensation), size and shape of objects

Stereognosia Test stereognosis by asking the patient to close his/her eyes and identify the object that is placed in their hand. Place a key, or pen or coin in the hand. Repeat this test with the other hand using a different object. Astereognosis refers to the inability to recognise objects placed in the hand with eyes closed. Without a corresponding dorsal column system lesion, these abnormalities suggest a lesion in the sensory cortex of the parietal lobe. Graphaesthesia Ask the patient to close his/her eyes and identify the number or letter that the examiner writes with the finger or back of the pen on his/her palm. Repeat on the other hand and compare. Apraxias are problems with executing movements despite intact strength, coordination, position sense and comprehension. This finding is associated with cortical damage. Extinction or simultagnosia Patient must sit with eyes closed. Touch the patient on the trunk or legs in one place and then tell the patient to open their eyes and point to the location where they noted the sensation. Repeat the manoeuvre a second time, touching the patient in two places on opposite sides of their body simultaneously. Then ask the patient to point to where they felt sensation. Normally they should point to both areas. If not, sensory extinction is present. Examination of Reflexes The different reflex responses may be divided into three categories on the basis of their clinical significance. Primitive reflexes These include the glabellar tap, rooting, sucking, and palmomental reflexes. As a rule, these signs are generally absent in adults. When present, these signs signify diffuse cerebral damage, particularly the fontal lobes. Superficial reflexes These are segmental reflex responses that indicate the integrity of cutaneous innervation and the corresponding motor outflow. These include the corneal, conjunctival, abdominal, cremasteric, anal wink and the plantar (Babinski) reflexes. The corneal and conjunctival reflexes may be elicited by gently touching the appropriate structure with a sterile wisp of cotton. The normal response is bilateral winking. The abdominal reflex can be elicited by drawing a line away from the umbilicus along the diagnals of the four abdominal quadrants. A normal reflex draws the umbilicus toward the direction of the line that is drawn. The best known amongst these group of reflexes is the plantar reflex. The most commonly performed manoeuvre is stroking the lateral aspect of the sole with sharp object (but not noxious). The normal response is plantar flexion of the great toe. Dorsiflexion of great tow with and without fanning of toes describes the Babinski’s response.

Deep tendon reflexes These are mono-synaptic spinal segmental reflexes. When they are intact, integrity of the following is confirmed: cutaneous innervation, motor supply and cortical input to the corresponding spinal segment. These reflexes include the biceps, brachioradialis, triceps, patellar or knee and ankle jerks. The spinal roots that subserve these reflexes are: Muscle

Spinal Roots

Biceps Brachioradialis Triceps Knee Ankle

C5, C6 C6 C7 L2 to L4 S1

Grading of Reflexes

Neurological Disorders—A Clinical Approach

(stereognosis), tactile sensations of written patterns on the skin (graphaesthesia) and tactile localisation and tactile discrimination on the same side or both sides of the body.

Score Reflexes 0 1 2 3 4 5

Absent Hypoactive or present only with re-enforcement Readily elicited with a normal response Brisk with or without evidence of spread to neighbouring roots Associated with a few beats of unsustained clonus Sustained clonus

Individual reflexes The biceps and brachioradialis reflexes are mediated by the C5 and C6 nerve roots. The biceps reflex is elicited by placing the examiner’s thumb on the biceps tendon and striking the thumb with reflex hammer and observing the arm movement. Repeat and compare with the other arm. The brachioradialis reflex is observed by striking the brachioradialis tendon directly with the hammer when the patient’s arm is resting. Note the reflex supination. Repeat and compare with the other arm. The triceps reflex is mediated by the C6 and C7 nerve roots, predominantly by C7. The triceps reflex is measured by striking the triceps tendon directly with the hammer while holding the patient’s arm with the other hand. Repeat and compare with the other arm. The knee jerk is mediated by the L3 and L4 nerve roots, mainly by L4. With the patient supine, lift the knee and stroke the quadriceps tendon directly with the reflex hammer. Or, with the lower leg hanging freely off the edge of the examination table, stroke the tendon. Repeat and compare to the other leg. The ankle jerk is mediated by the S1 root. The ankle reflex is elicited by holding the relaxed foot with one hand and striking the Achilles tendon wit the hammer and noting plantar flexion. Compare with the other foot. There are certain reflexes which are elicited when there is a suspicion of pyramidal involvement indicating heightened reflexes. These include: Jaw jerk: Elicited by asking the patient to partially open his mouth, placing the thumb over the patient’s chin and striking the thumb with the hammer. Closing movement of the jaw indicates lesion above the midbrain. 1355

Finger flexion: Elicited by tapping the balls of the fingers with hammer. Hoffman’s response: This is elicited by holding the patient’s middle finger between the examiner’s thumb and index finger and using the thumb nail, press down on the patient’s finger nail. A positive Hoffman’s response is when the other fingers flex transiently after the click. Wartenburg: Pull the flexed fingers of the patient outward with the examiner’s hand. The thumb should extend outward. The above three reflexes indicate upper motor neuron lesion affecting the upper extremity. Cerebellar Signs The cerebellum provides an important feedback loop for coordination of muscle activity by integrating the functions of the cortex, basal ganglia, vestibular apparatus and spinal cord. Midline cerebellar dysfunction results in ataxia of gait, difficulty in maintenance of upright posture and truncal ataxia. Acute neocerebellar hemispheric lesions result in additional signs. The following are the various cerebellar signs: 1. Ataxia, atonia 2. Intention tremor 3. Dyssynergia 4. Dysmetria 5. Dysrhythmia 6. Dysdiadochokinesia 7. Dysarthria 8. Nystagmus and various other eye signs 9. Pendular knee jerks 10. Rebound phenomenon Meningeal Signs Signs of meningeal irritation indicate inflammation of the dura, these signs are described below: 1. Nuchal rigidity or neck stiffness is tested by placing the examiner’s hand under the patient’s head and gently trying to flex the neck. Undue resistance implies diffuse irritation of the cervical nerve roots from meningeal inflammation. 2. Brudzinski’s sign is flexion of both knees during the manoeuvre to test nuchal rigidity. This indicates diffuse meningeal irritation in the spinal nerve roots. 3. Kernig’s sign is elicited by flexing the hip and knee on one side while the patient is supine, then extending the knee with the hip still flexed. Hamstring spasm results in the posterior thigh muscle and difficulty with knee extension. With severe meningeal inflammation, the opposite knee may flex during the test. Gait and Spine Neurological examination will be incomplete without watching the patient stand and walk. In certain situations, abnormality of gait will be the only sign. Different gait disorders can be the hemiparetic gait, the ataxic gait, the shuffling gait, the steppage gait, the spastic or scissor gait and antalgic gait. Spine must be checked for any abnormalities such as scoliosis, gibbus and also finally look for neurocutaneous markers 1356 including pes cavus.

Gait is evaluated by having the patient walk across the room under observation. Gross gait abnormalities should be noted. Ask the patient to walk heel to toe across the room, then on their toes only, and finally on their heels only. Normally, these manoeuvres are possible without too much difficulty. Also note the arm swing while walking. Any slowing or decrease in arm swing would indicate a subtle extrapyramidal involvement or mild weakness of upper motor neuron type. Walking on heels is the most sensitive way to test for foot dorsiflexion weakness and walking on toes is the best way to test early foot plantar flexion weakness. Abnormalities in heel to toe walking (tandem gait) may be due to weakness, incoordination, vertigo, sensory ataxia (poor position sense), and leg tremors. Rhomberg’s test Perform the Romberg’s test by having the patient stand still with their heels together. Ask the patient to remain still and close their eyes. If the patient loses their balance, the test is positive. To achieve balance, a person requires the following inputs to the cortex. 1. Visual confirmation of position 2. Non-visual confirmation of position (including proprioceptive and vestibular input) 3. A normally functioning cerebellum. If the patient loses their balance after standing still with eyes closed, and is able to maintain balance with their eyes open, then there is likely to be lesion in the cerebellum. The full neurological examination is too lengthy to perform in practice. Instead, the experienced neurologist uses the focused neurological examination to examine in detail the neurological functions that are relevant to the history, and performs a screening neurological examination to check the remaining parts of the nervous system. This approach should confirm, refute or modify the initial hypotheses of disease location and causation derived from the history. The standard neurological examination is less effective when used to monitor the course of a disease or its temporal response to treatment. Special quantitative functional tests and rating scales are needed to measure change in neurological function over time. General physical examination The nervous system is damaged in numerous medical disease and a general examination is an integral part of the examination of patients with neurological disorders. For instance, atrial fibrillation, valvular heart disease, or an atrial septal defect may cause embolic strokes. Hypertension increases the risk of all types of stroke. Signs of malignancy raise the possibility of metastatic lesions of the nervous system or paraneoplastic syndromes. Some diseases, such as vasculitis and sarcoidosis, affect both the brain and other organs. The skills of a neurologist are learned. Seeing many cases of disease teaches the neurologist which symptoms and signs should be present, and just as important, which should not be present. However, there is no substitute for experience and pattern recognition. The diagnosis of a neurological disease is a combination of science and experience and the management of neurological disease is an art.

20.3 Neurophysiological techniques help in understanding the functional aspect of central and peripheral nervous system. It involves the recording, display, measurement and interpretation of action potentials arising from the central nervous system (CNS) [electroencephalography (EEG) and evoked potentials], peripheral nerves (nerve conduction studies), neuromuscular junction (repetitive nerve stimulation) and muscles (electromyography). Knowledge about the generation of waveforms or potentials is essential for proper conduct and interpretation of the electrodiagnostic test. ELECTROENCEPHALOGRAPHY The EEG rhythms depend on the spontaneous intrinsic activity, which is modulated by the afferent inputs from thalamus and brainstem. The EEG abnormality, therefore, may occur either due to disruption of cortical network or sub-cortical inputs to cortical neurons. On scalp recorded EEG, the voltage of EEG signals are attenuated due to impedance of CSF, meninges, skull and scalp. The amplitude of the cortical EEG ranges between 500 to 1,500 μV whereas in the scalp it is 10 to 100 μV. EEG Recording and Reporting For routine EEG, electrodes are placed using ’10-20’ system of electrode placement (Figure 1). The recording electrodes interconnect into chains and the potential difference between pairs of electrodes is recorded. Electrode pairs are interconnected in different arrangements to comprehensively evaluate the whole brain activity which are known as montages. Routine EEG is recorded for 30 to 45 minutes including two activation procedures; hyperventilation and intermittent photic

Figure 1: Schematic diagram shows ‘10-20’ system of electrode placement for electroencephalography recording.

Clinical Neurophysiology J Kalita, UK Misra stimulation. Sometimes, EEG during sleep or in sleep deprived state is useful. The EEG reporting needs knowledge of age, artifacts, sleep transient, normal variants and epileptiform and nonepileptiform abnormal discharges. The EEG report should include description of waveforms, interhemispheric coherence, reactivity and abnormal discharges (Table 1). Table 1: Important Points in Electroencephalography Reporting Waveforms: frequency, voltage, morphology, spatial distribution, modulation of frequency and voltage Interhemispheric coherence Symmetry: voltage and frequency Synchrony: voltage and frequency Reactivity: eye opening, pain, touch, sound, mental activity Abnormal discharge: epileptiform, non-epileptiform and others

Basic EEG Rhythm The basic EEG rhythms are named on the basis of their frequency into alpha, beta, theta and delta (Table 2). In normal adults, the awake pattern of EEG rhythm is of alpha range which is dominant in the occipital area. Alpha waves are sinusoidal waveform whose amplitude is reduced on eye opening (Figure 2; Table 3). Beta activity (10 to 20 μV) is normally present in the frontocentral area and is more marked in tense individual and those on barbiturate or diazepam. Table 2: Electroencephalography Rhythms Alpha: 8 Hz to 13 Hz Beta: 14 Hz to 40 Hz Theta: 4 Hz to 7.5 Hz Delta: 0.1 Hz to 3.5 Hz

Figure 2: Electroencephalography of a normal adult individual shows posterior alpha activities. The amplitude of alpha activities is augmented when the eyes are closed.

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Table 3: Characteristics of Alpha Rhythm

Table 4: Clinical and Electroencephalography Correlates of Sleep

8 Hz to 13 Hz, 50 μV in amplitude Maximum in posterior head region Increased voltage in occipital, wax and wanes, varies at different time in the same individuals Best seen in closed eyes and mentally relaxed state Blocked by open eyes and mental effort

Stages of Sleep

Clinical

Non-rapid eye movement sleep Stage I

Drowsiness

In normal adults, temporal theta activity may be seen. Delta activity is absent in normal adults during awake state but seen during sleep. Slow activities (delta and theta) are predominant waveforms in newborn but these are replaced by alpha and beta with the maturation of EEG; 8 Hz posterior rhythm develops by 3 years, 10 Hz by 10 years and alpha remains same till the age of 90 years. Sleep EEG During non-rapid eye movement (NREM) sleep, EEG tends to synchronise and during rapid eye movement (REM) sleep, it is desynchronised. The sleep spindles are 12 Hz to 14 Hz activity, which wax and wane in amplitude and are prominent in frontocentral region. It appears by 2 months of age. Vertex sharp waves are positive followed by large negative deflection of 70 ms to 200 ms duration, maximum in vertex and appear by 5 months of age. K-complexes are characterised by initial biphasic (100 ms) followed by fast activities (Figure 3). It appears by the age of 5 months and is prominent in frontocentral area.The EEG and clinical correlates of different stages of sleep are presented in Table 4.

EEG

Alpha drop out, POSTS, vertex sharp waves (VS) Stage II Light sleep 4 Hz, with fast waves, VS, sleep spindle, K-complex Stage III Deep sleep Slowing, K-complex, some spindle and VS Stage IV Very deep sleep Fast activity Rapid eye movement Desynchronisation of EEG sleep activity EEG = Electroencephalography; POSTS = Posterior occipital sharp transient of sleep.

Table 5: Limitations of Electroencephalography Surface EEG does not unambiguously determine the synaptic events contributing to EEG waveforms EEG changes are rarely disease specific Many focal brain dysfunctions may not be recorded by EEG, especially if deep seated or in the sulci

Abnormal EEG The abnormal EEG may be categorised broadly into three types: (i) epileptiform discharges; (ii) periodic or quasi-periodic discharges; and (iii) non-epileptiform paroxysmal EEG abnormalities. Epileptiform discharges The inter-ictal epileptiform discharges are spike, sharp waves, poly or multiple spikes, runs of rapid spikes, small sharp spike and spike and slow wave complex. Ictal EEG discharges include 3 Hz spike and slow waves (absence/generalised epilepsy; Figure 4), generalised theta/delta (tonic seizure), periodic generalised theta or delta (myoclonic seizures), generalised electrodecremental (infantile spasm), focal periodic or dysrhythmic slow waves (epilepsia partialis continua), temporal, fronto-temporal or temporal low voltage wave (complex partial seizure) and localised beta (neonatal seizure). Spike and sharp wave Spikes are mono-, bi- or tri-phasic waveform of 20 ms to 70 ms duration whereas the duration of sharp waves is 70 ms to 200 ms.

Figure 3: Electroencephalography recording during sleep shows K-complexes and sleep spindles.

Utility of EEG EEG is crucial for the diagnosis and classification of epilepsy. Certain patterns of EEG are disease specific such as Creutzfeldt Jakob disease and subacute sclerosing panencephalitis. EEG also helps in prognostication of the patients. However, EEG is not a screening test and is not a replacement for proper history and clinical examination. While ordering EEG requisition, a precise clinical description is helpful in interpretation of the EEG. Limitation of EEG EEG although helps to understand the underlying brain function, but its limitations should also be appreciated which 1358 are summarised in Table 5.

Figure 4: Electroencephalography record of a 6-year-old boy with absence seizure shows generalised 3 Hz spike and slow wave discharges during hyperventilation.

complexes in Lennox-Gastaut syndrome (Figure 6) and subacute sclerosing panencephalitis (Figure 7).

Periodic or quasiperiodic discharges Periodic discharges are sharp or long duration (up to 150 ms), high amplitude (100 μV to 300 μV) waveforms occurring at periodic interval. These may be focal, widely scattered or generalised. Various patterns of periodic/quasiperiodic discharges are described which include: (1) burst suppression in hypoxic encephalopathy, barbiturate, nitrous oxide and cyclopropane poisoning; (2) generalised repetitive sharp transient in Creutzfeldt Jakob disease and anoxic encephalopathy; (3) periodic lateralised epileptiform discharges in herpes simplex encephalitis (Figure 5), temporal lobe abscess and syphilis; (4) generalised tri-phasic waves in metabolic encephalopathy; and (5) generalised periodic slow wave

Non-epileptiform paroxysmal EEG abnormalities Non-epileptiform paroxysmal EEG abnormalities are as follows: 1. Widespread intermittent slow activity associated with active or diffuse brain dysfunction. 2. Bilateral persistent EEG slowing associated with impaired consciousness (Figures 8A and B). 3. Focal persistent EEG slowing associated with focal cerebral dysfunction.

Clinical Neurophysiology

Spike and sharp waves both stand out of background.The location of spike or sharp waves suggests the possible seizure focus.

EVOKED POTENTIALS Evoked potentials (EPs) are electrical signals generated in the nervous system in response to sensory stimuli except motor evoked potential which is recorded from the target muscle by

Figures 5A and B: (A) EEG record shows periodic lateralised epileptiform discharges (frontal predominance) with background delta slowing in a patient with febrile encephalopathy with seizure; (B) Cranial MRI of the same patient shows bilateral temporal T2 hyperintensity suggestive of herpes simplex encephalitis.

Figure 6: EEG record of a 4-year-old boy with Lennox-Gastaut syndrome shows generalised slow spike and slow wave discharges with some periodicity during sleep.

Figure 7: EEG record of an 8-year-old boy with subacute sclerosing panencephalitis shows pseudoperiodic discharges on EEG. The R complexes are coming at a rate of 2.5 to 3 interval.

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Figures 8A and B: (A) EEG record of a 23-years-old lady with viral encephalitis shows delta slowing; (B) MRI of the same patient shows bilateral thalamic T2 hyperintensity with a hypointense rim suggestive of Japanese encephalitis.

applying magnetic or electrical stimuli over the motor cortex. Commonly used evoked potentials are visual evoked potential, brainstem auditory evoked potential, somatosensory evoked potential and motor evoked potentials. Cognitive and other event related potentials are yet to establish its role in the clinical practice. Visual Evoked Potential (VEP) VEP is obtained by averaging the responses from occipital scalp electrode in response to more than 100 sequential visual stimuli. Pattern reversal stimuli are more sensitive than flash (stroboscope) as the flash evoked VEP has great variability, insensitive to clinical lesions and provide limited information about the visual pathway. The interpretation of VEP is based on P100 latency which is an electropositive wave appearing at about 100 ms in the normal individual (Figure 9). Uniocular prolongation of P100 latency after full field mono-ocular stimulation suggests an abnormality anterior to the optic chiasma on that side. Bilateral P100 latency prolongation may be due to involvement of both the optic nerves, chiasma or posterior to the chiasmal lesion. Unilateral visual cortical lesion does not alter the P100 latency. VEP is abnormal in 70% to 80%

patients with definite multiple sclerosis without visual symptoms (Figures 10A and B). VEP is abnormal in leucodystrophy, subacute combined degeneration, optic nerve tumour or tumour compressing the optic nerves and Leber’s hereditary optic atrophy. VEP is normal in psychogenic blindness. Brainstem Auditory Evoked Potentials (BAEPs) BAEPs refer to the series of signals generated in the auditory nerve and brainstem in response to auditory stimuli. BAEPs are recorded from the ipsilateral and contralateral mastoids or ear referred to vertex (Cz).There are 5 major waveforms (wave I, II, III, IV and V) and their absolute peak latency, peak to trough amplitudes and interpeak latencies (IPL) of I-III, I-V and III-V are measured (Figure 11). BAEPs are resistant to various metabolic encephalopathies and deep anaesthesia. The generators of various waveforms of BAEPs are summarised in Table 6. BAEPs are abnormal in acoustic neuroma, cerebellopontine angle tumours, pontine lesion, multiple sclerosis and other demyelinating diseases. Table 6: Generators of Brainstem Evoked Potential Waveforms

Generators

I II III IV V

VIII nerve Cochlear nucleus Superior olivary nucleus Lateral lemniscus Inferior colliculi

Somatosensory Evoked Potential (SSEP) SSEP evaluates the integrity of sensory pathway from peripheral nerves to the cortex. Usually median, posterior tibial and or peroneal SSEPs are carried out (Figures 12 and 13). Figure 9: Pattern shift visual evoked potential in a normal individual, Sweep 1360 speed 50 ms/div, sensitivity 2μV/div.

Central sensory conduction time is prolonged or unrecordable in various conditions affecting the sensory pathway in the spinal cord (posterior column) and brainstem (lemniscus), thalamus

Clinical Neurophysiology Figures 10A and B: (A) Pattern shift visual evoked potential in a 32-year-old lady with multiple sclerosis shows prolongation of P100 latency (122 ms). Sweep speed 50 ms/div, sensitivity 2μV/div; (B) Cranial MRI reveals multiple periventricular hyperintense lesions on FLAIR sequence suggestive of multiple sclerosis.

Figure 11: Normal brain auditory evoked potential.

Figure 13: Normal tibial somatosensory evoked potential.

and thalamocortical pathway. 90% patients with multiple sclerosis have SSEP abnormalities. The other conditions such as hereditary ataxia, subacute combined degeneration, vitamin E deficiency, leucodystrophies, spinal sand brainstem tumours, stroke and cervical spondylosis may also result in SSEP abnormality.

Figure 12: Normal median somatosensory evoked potential.

Motor Evoked Potential (MEP) MEP assesses the fast conducting motor pathways and is performed by stimulating the motor cortex using a magnetic or electrical stimulator and recorded from the target muscles (abductor digiti minimi in the upper limb and tibialis anterior 1361 in the lower limbs).

Central motor conduction time is abnormal in patients having involvement of motor pathway due to stroke, trauma, tumour, demyelinating and dysmyelinating conditions. Repetitive transcranial magnetic stimulation has also been used for therapeutic purposes such as movement disorder and depression. Evoked potentials are also used for intra-operative monitoring and EEG for carotid endarterectomy. NERVE CONDUCTION AND ELECTROMYOGRAPHY Nerve conduction studies (NCS), electromyography and repetitive nerve stimulation (RNS) evaluate the functional integrity of peripheral nerves, muscles and neuromuscular junction, respectively. Nerve Conduction Studies Electrical stimulation of the nerve fibres results in impulses that travel along the motor, sensory or mixed nerves and produce a compound action potential. Most of the peripheral nerves can be evaluated which are accessible for stimulation. Motor NCS The motor NCS is done by supramaximal stimulation of the motor/mixed nerve at two points and recording from the target muscle (Figure 14).

Figure 15: Schematic diagram shows method of orthodromic sensory nerve conduction. The sensory nerve conduction velocity is ‘b/a’ m/sec; where ‘b’ is the distance between the stimulating and recording electrodes in mm and ‘a’ is the onset latency of sensory potential.

stimulations may be applied along the nerve at a distance of 1 cm and the CMAP or SNAP is recorded (inching technique). NCS may be affected by age, height, anomalous innervation, temperature, stimulus artefacts, electrode noise, submaximal stimulation, co-stimulation of adjacent nerves, misplacement of recording or reference electrode and error in the measurement of nerve length. In full term neonate, the NCV is half the adult value and one-third in premature baby due to incomplete myelination. NCV reaches adult value by 3 years to 5 years. Mean NCV declines by 10% by 60 years of age. Late responses (F wave, H reflex and axon reflex) Late responses are the potentials appearing after the motor response (M wave) following mixed nerve stimulation. There are three important late responses—H reflex, F wave and axon reflex; of these F wave is clinically more useful.

Figure 14: Schematic diagram shows method of motor nerve conduction study. The nerve conduction velocity is ‘c/(b–a)’ m/sec, where ‘c’ is the distance between proximal and distal stimulation in mm,‘a’ is the distal latency in ms and ‘b’ is the proximal latency in ms. R = Recording electrode; S = Stimulating electrode; G = Ground electrode.

Sensory NCS Sensory NCS is either recorded orthodromically or antidromically. The antidromic sensory NCS is done by stimulating the sensory nerve 20% to 30% above the sensory threshold and recording from the sensory receptors, i.e. sensory innervated areas by the nerves. The reverse is done in orthodromic recording.The latency (onset/peak), amplitude (base to peak or peak to peak) and NCV are measured (Figure 15). Distance between stimulating and recording electrode in mm Sensory NCV =

m/s Latency in ms

The parameters of NCS should by compared with the normal laboratory values. For localising focal nerve lesion such as the 1362 carpal tunnel syndrome or other entrapment neuropathies,

F wave: F wave is a late response resulting from the antidromic stimulation of motor neuron involving conduction to and from the spinal cord. It is elicited by supramaximal stimulation of peripheral mixed or motor nerves and recorded from the distal muscles. For clinical practice 10 to 20 F waves are adequate.The F wave parameters used in clinical practice are minimal F latency, chronodispersion, persistence, amplitude and repeated waves. Markedly prolonged F wave latency is highly suggestive of demyelinating neuropathy (Figure 16). It may also be prolonged in radiculopathy. Electromyography Electromyography (EMG) is the study of the electrical activity of resting muscle and muscle in action.Teflon coated concentric and monopolar needles are equally satisfactory. The needle is inserted slightly away from the neuromuscular junction to avoid endplate noise as well as pain. Electromyographer should know the anatomical landmark and the method of activation and relaxation of the sampled muscle. The principles used during EMG are: (a) during insertion or movement of the needle, insertional activity is produced due to injury of muscle fibres which is short lasting; (b) moving the needle for a short distance and pausing for a few seconds helps in the evaluation of spontaneous activity with the single cutaneous insertion. Relocating the needle in four quadrants of the muscle

Repetitive Nerve Stimulation RNS helps to evaluate the diseases of neuromuscular junction (NMJ), such as myasthenia gravis, Lambert-Eaton myasthenic syndrome, botulism and congenital myasthenia. RNS is done by applying supramaximal stimulation of motor or mixed nerve and recording from the muscle supplied by that nerve. The rate of stimulation depends on the type of NMJ disorder. Low rate stimulation (2 to 3 Hz, 3 to 5 impulses) is used to evaluate the post-synaptic defect (myasthenia gravis) and high rate stimulation (20 to 50 Hz) for 2 to 10 seconds to evaluate the pre-synaptic defect (Lambert-Eaton myasthenic syndrome).

Clinical Neurophysiology

and (b) ‘myopathic—short duration, low amplitude, polyphasic with early recruitment’.

In low rate RNS, decrement is calculated by the baseline CMAP amplitude to that of lowest CMAP, i.e. 3rd on 4th CMAP; using the following equation: Baseline CMAP amplitude – lowest CMAP amplitude Decrement (%) = Figure 16: Median F wave study in a patient with acute inflammatory demyelinating neuropathy showing prolonged minimal latency (43.8 ms) and increased chronodispersion (8 ms).

completes the evaluation; (c) motor unit potential (MUP) is evaluated when the muscle is minimally contracted. The needle should be pushed deep or pulled out to get a sharp MUP; and (d) increasing intensity of contraction of sampled muscle shows the recruitment pattern and at the maximal contraction, interference pattern is seen. The characteristic of insertional, various spontaneous activities and MUPs are shown in Table 7. The normal MUPs are usually bior tri-phasic and vary from 0.3 mV to 5 mV in amplitude and 3 to 13 ms in duration. The number of phases equals the number of negative and positive peaks extending to and from the baseline or the number of baseline crossings plus one. Normal MUPs have 4 or less phases and approximately 5% to 15% of MUP may have >5 phases which may increase to 25% in the proximal muscles. Two patterns of abnormal MUPs are found: (a)‘neurogenic—long duration, high amplitude, polyphasic with poor recruitment’; Table 7: Characteristics of Spontaneous Activities on Electromyography Potential

Morphology

End plate spike Biphasic, initial negative Fibrillations Bi/triphasic, initial positive Positive sharp Biphasic, initial positive waves and slow negative wave Myotonia Brief spike, positive

Complex Brief spike, positive repetitive discharges Fasciculations Like MUP Neuromyotonia Like MUP MUP = Motor unit potential.

Firing Rate

Firing Pattern

5 Hz to 50 Hz

Irregular

0.5 Hz to 10 Hz

Regular

0.5 Hz to 10 Hz

Regular

20 Hz to 150 Hz

Wax and waning amplitude Stable

5 Hz to 100 Hz

× 100 Baseline CMAP amplitude

More than 10% decrement in any muscle is suggestive of postsynaptic NMJ disorder. In high rate RNS, incremental response is measured as follows: Amplitude of highest response (last) – amplitude of 1st response Increment (%) = × 100 Amplitude of 1st response High rate RNS is painful and usually carried out in distal muscles such as abductor digiti minimi or tibialis anterior by stimulating ulnar nerve at wrist and peroneal nerve at fibular head, respectively. More than 50% incremental response in any muscle is suggestive of Lambert-Eaton myasthenic syndrome. Incremental response suggests pre-synaptic NMJ disorder. The classical findings on RNS in pre-synaptic and post-synaptic disorders are summarised in Table 8. Table 8: Classical Repetitive Nerve Stimulation (RNS) Findings in Pre-synaptic and Post-synaptic Disorders Pre-synaptic

Post-synaptic

CMAP amplitude

Normal

Low

Low rate RNS

Decrement

Decrement

High rate RNS

Normal/decrement

Increment

CMAP = Compound muscle action potential.

Single fibre EMG may be done in patients with myasthenia gravis whose RNS test is negative. Electrodiagnostic tests are important tools in the evaluation of neurological disorders. It is important to decide the appropriate test for appropriate clinical setting to get its highest yield. RECOMMENDED READINGS

0.1 Hz to 10 Hz Irregular 150 Hz to 250 Hz Waning

1.

Misra UK, Kalita J. Clinical Electroencephalography; New Delhi: Elsevier India; 2005.

2.

Misra UK, Kalita J. Clinical Neurophysiology; 2nd Ed. New Delhi: Elsevier India; 2006. 1363

20.4 Neuroimaging has evolved into a super-speciality of Radiology and has found a place as a separate subject leading to degree. It is essential for the budding physicians to have at least basic knowledge of this subject. We are introducing the subject with a view to give a bird’s eye view of Neuroimaging. PLAIN RADIOGRAPHY This is often the first imaging modality to be used for skull and spine. However, skull radiography has lost most of the indications as the changes are seen late and are indirect in nature. Computed tomography (CT ) has overtaken skull radiograms in trauma, due to its superior contrast and spatial resolution. In addition, the underlying brain can also be assessed on CT. In spine, lateral and frontal radiographs of cervical, dorsal or lumbar spine are still in clinical use as it provides gross information about presence of degenerative changes, assessment of bone density and allows dynamic radiography to evaluate atlantoaxial dislocation, and spondylolisthesis. In trauma, the radiography has been superceded by CT. MYELOGRAPHY/CT MYELOGRAPHY Myelography, once a useful technique to evaluate intraspinal pathology, is now seldom performed, as the spinal imaging has been taken over by MRI. Myelography, if at all performed, is combined with CT to evaluate the desired region. It is helpful in patients in whom MRI is contraindicated and in some cases to demonstrate the site of a cerebrospinal fluid (CSF) leak or for diagnostic evaluation of spinal or skull base where there is poor correlation of physical findings with MRI studies. The procedure for myelography/CT myelography consists of performing a lumbar puncture and injecting water soluble, non ionic iodinated contrast medium in the strength of 180 mg I/mL for lumbar region and higher concentration up to 300 mg I/mL for cervical region if myelography is performed first. There is a waiting period of about 20 minutes to 30 minutes when a higher concentration is used.

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DIAGNOSTIC ANGIOGRAPHY Invasive diagnostic angiography has been mostly replaced by CT angiography and MR angiography for the evaluation of the blood vessels in the brain and neck. The basic reason is that it is invasive and thus associated with a small but definite incidence of complications. Special equipment, digital subtraction angiography system, is needed for these studies, which allows online visualisation of injected blood vessels. Presently, it is most often used for interventional procedures. Diagnostic angiography is reserved for cases where these studies are equivocal or where intra-cranial cross circulation is to be studied pre-operatively. It is also performed for post-operative evaluation of aneurysms, and arteriovenous malformations. In spine, it still finds a primary role in the proper evaluation of vascular malformations.The procedure is performed via transfemoral route under local anaesthesia and

Neuroimaging Rakesh K Gupta, Sunil Kumar selective cannulation of the desired artery is done under fluoroscopic guidance. This is followed by injection of iodinated contrast medium and fast acquisition as the contrast flows through the vessel. COMPUTED TOMOGRAPHY The hardware of CT consists of a gantry that houses the X-ray tube and a detector assembly which typically contains 4, 16, or more rows of detectors along with a patient table which synchronises with the gantry for its movement. For usual brain studies the patient lies supine on the table that moves during scanning either incrementally or continuously while the X-rays are being emitted. The scan time is usually in seconds. The slice thickness varies from sub millimetre to 5 mm depending upon the clinical indication.The X-rays pass through the patient’s head or spine and the exiting X-ray photons are detected by the detector assembly. The signals produced are processed and finally cross sectional images are reconstructed which can be viewed on a monitor. In the volume CT scanners, the data sets can be used to create three-dimensional (3D) images those can be viewed from any angle. This is very useful in analysing vascular structures such as arterial or venous systems, known as CT angiography. Different tissues in the body absorb different amount of X-rays and thus these can be differentiated, e.g. bone, brain parenchyma, CSF or water, fat and air. These have fairly constant attenuation values, called as Hounsfield units. Tissues with high Hounsfield units, such as bone, calcification, acute blood in parenchyma (haematoma), appear bright at the windows and level customised for brain parenchyma to appear greyish. At this window and level settings, fluids such as CSF, fat, and air appear dark. Hounsfield unit of water is zero. If in doubt, Hounsfield units can be quantified for tissue characterisation. Iodinated contrast media can be administered to enhance abnormal tissue with abnormal blood brain barrier. Thus a comparison with non enhanced images can help in delineating intra-cranial space occupying lesions such as tumours, granulomas, abscesses, or abnormal meninges. Indications Due to its high speed of scanning, wide gantry, no restrictions for the anaesthesia equipment and the monitoring systems, and its ability to show acute blood unequivocally, CT brain is most useful in patients with suspected intra-cranial bleed, and cases of trauma where a quick scan is enough to evaluate the bones, parenchyma and epidural space. Very fast contrast enhanced studies with 3D reconstruction are useful for analysing arteries or veins of the brain at a high spatial and contrast resolution obviating the need for a conventional or digital subtraction intra-cranial angiogram. This fast imaging has also been utilised to study first passage of contrast medium through the brain, i.e. perfusion imaging and analysed for parameters such as volume, regional cerebral blood flow, mean transit time and

Contraindications Patient population at risk such as pregnant women, small children, should be examined with caution. Iodinated contrast medium should also be injected with caution as it may cause renal dysfunction. Hence, it is contraindicated in patients with deranged renal function, diabetes, multiple myeloma, thyroid toxicity, dehydration, etc.

Certain congenital lesions have fatty elements which are detected easily on non-contrast study like lipomas. However, complete evaluation of a space occupying lesion is usually done with both non-enhanced and enhanced studies.

Neuroimaging

permeability. These parameters have been found to be useful in grading of brain tumours and stroke management.

Brain Normal appearance Normal brain can be easily distinguished into parenchyma, ventricular system containing the CSF, other CSF spaces such as cisterns and sulci, bony calvarium, and normally aerated paranasal sinuses. At times, certain areas of brain show physiological calcification such as pineal gland, globus pallidi, falx, etc. Grey and white matter may be distinguished on proper window settings. Abnormal appearance Non-enhanced CT is extremely useful in the evaluation of brain trauma, where it can show the bone injury, extradural/subdural haematoma, parenchymal haematoma (Figures 1A and B), and brain contusion. It can also suggest brain swelling in the form of effacement of sulci. Herniation of brain secondary to mass effect can also be detected. CT is also useful in detecting acute blood, hence it is often the first imaging modality where haematoma is to be excluded, for example, in a hypertensive patient with sudden alteration in sensorium, to confirm or exclude subarachnoid haemorrhage in a patient with sudden and severe headache, in the post-operative period after brain surgery, and similar clinical situations. CT angiography has replaced diagnostic angiography in the workup of patients with subarachnoid haemorrhage. The vascular abnormalities such as aneurysms (Figures 2A and B), arteriovenous malformations etc are well-delineated on CTA. Brain tumours can also be detected on CT but with inferior resolution compared to MRI especially in the posterior fossa. Presence of a mass can be inferred on a non enhanced CT by the mass effect caused by it which displaces the normal brain structures and the brain symmetry is lost. In severe cases, there is herniation of vital parts of brain through the spaces bound by rigid dural structures, which may cause irreparable damage. Non contrast studies also detect the presence of calcium in the lesion which may help in tissue characterisation. In addition, erosion or thickening of adjacent bones is also a useful indicator of the aetiology. After contrast administration, most of the tumours enhance thereby making its detection evident. The degree of enhancement may depend upon the histological grade of the tumour or its composition. The enhancement occurs due to a disruption of the blood brain barrier which allows leakage of contrast in the interstitium. Similarly, CT can detect all the non-neoplastic lesions that disrupt the blood brain barrier and enhance, thereby confirming the location and number of the lesions. Anatomical localisation is helpful as certain lesions tend to manifest in certain sites. The pattern of enhancement also helps in improved tissue characterisation as some lesions enhance homogenously, e.g. meningiomas, primary lymphomas, etc. CT is also useful in post shunt evaluation in cases of hydrocephalus.

Figures 1A and B: Axial non-enhanced CT scan (A) showing a hyperdense area in left basal ganglia, suggestive of intraparenchymal haemorrhage with mass effect compressing the left lateral ventricle. Haemorrhage into subarachnoid spaces is also noted posteriorly. Axial CT scan (B) of another patient showing cresentic hyperdensity along the right fronto-parietal convexity suggesting subdural haematoma.

Figures 2A and B: Axial CT angiographic volume rendered (A) and maximum intensity projection (B) images demonstrated an anterior communicating artery aneurysm.

Spine CT is the imaging modality of choice in spinal trauma where bony evaluation is needed for management planning. Imaging is performed in axial plane with the patient supine. As the images can be post processed for 3D models, evaluation becomes easier. Similarly CT is advocated in bony craniovertebral anomalies, in some cases of disc herniation, and in the assessment of ossified or calcified lesions. For evaluation of intradural conditions, CT myelography is performed. CT is also indicated for imageguided biopsies of the bony lesions. MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) is an imaging technique based on the interaction of radiofrequency induced proton shifts in a strong magnetic environment. Signal intensity is directly proportional to the field strength of the magnet used. However, in view of human safety and problems in maintaining a high degree of field homogeneity, clinical scanners currently do not exceed 3 T. Magnetic resonance (MR) scanner designed for optimal clinical study consists of a superconducting magnet of 1.5 T or 3 T (1 Tesla=10,000 Gauss) along with a moving table on which patient lies supine (although smaller strengths of 0.2 T to 0.4 T systems of permanent magnet are commercially 1365

available, these have certain limitations). This is housed in a specially shielded room. Other cabinets and operator’s console are placed separately. For imaging, radiofrequency waves are introduced after the patient lies within a coil which is matched to the region of interest to be imaged. These waves are switched on and off and the resulting signals are processed in the presence of locally varying fields which are known as gradients to form images that can be acquired in any desired plane. During the off phase, the excited protons relax and this is measured either as T2 (spin-spin or horizontal relaxation) and T1 (spinlattice or longitudinal relaxation) relaxation. These are used to create T2 and T1 weighted images. In the normal brain, cortex, white matter, CSF, fat, air have all different appearances on T2 and T1 images. The radiofrequency waves and gradients can be combined in different ways that are known as sequences. Most commonly the sequences are used to form anatomical images but the signals can also be acquired and processed to obtain metabolite (MR spectroscopy), functional MRI (fMRI), water diffusion (diffusion weighted imaging and diffusion tensor imaging) and tissue perfusion information. Sequences can also be designed to detect the blood flow and present the information as angiograms (MR angiography). MR angiography can also be obtained after injection of a MR detectable contrast agent combined with fast imaging. These contrast agents are usually based on gadolinium compounds which shorten T1 relaxivity (enhancing lesions appear brighter). Lately, iron oxide particles based contrast agents have been introduced that work on reducing T2 relaxivity and have found uses in liver, etc. Study times typically for a MR examination vary between 15 minutes and 45 minutes depending upon the clinical protocol. Indications T2 and its derivatives such as fluid attenuated inversion recovery (FLAIR) are the mainstay of any imaging protocol as these bring out most of the abnormalities separately from normal brain. Usually the accompanying oedema appears bright and lesion itself may vary from hyperintense, isointense to hypointense. This is supported by a T1 weighted image which gives excellent anatomical details. Further depending upon the clinical indication protocols may consist of diffusion weighted sequences that highlight acute stroke due to restriction of water movement, MR angiography to study blood vessels in the neck or brain, contrast enhanced studies for further characterisation of the lesion, and advanced studies such as perfusion or functional imaging. Currently, MR is the investigation of choice for the evaluation all neurological disorders. Contraindications and Safety Issues There are three main reasons to be cautious before subjecting a patient with an implanted device for MR study. The object may move if iron is present.This may cause injury which can be quite severe depending upon its proximity to vital organs. Second problem is of heating of the device by the deposition of radiofrequency waves and cause thermal injury to surrounding areas. Lastly, the devices may be affected by the presence of varying electromagnetic fields and may stop functioning or may malfunction. Patients with implanted pacemakers, or electromagnetically activated devices such as cochlear implants etc. cannot undergo MR examination as it causes device malfunction due to the presence of a strong magnetic field and 1366 varying gradients. Similarly, objects such as bullets, pellets or

other iron foreign bodies may move in the presence of a strong magnetic field. Some of devices may move just after their implantation in the patient’s body and need 6 weeks to 8 weeks for local stability due to fibrosis before they are safe for MR imaging. Most of the other devices are considered safe. They may, however, produce artefacts if the scanning is done in their location. Devices made of titanium produce less obscuring of the area compared to stainless steel or other metals. Children and disoriented adults require some form of sedation to make them lie quietly without moving for the duration of the study. This needs constant monitoring and oxygenation for which specially designed MR compatible anaesthesia trolleys, laryngoscope and monitoring devices are a must. About 0.5% to 2% of patients may be claustrophobic and may not be able to undergo MRI. Brain Normal appearance Normal grey matter appears slightly brighter on T2 compared to white matter and darker than white matter on T1 images. Fat appears brightest and CSF appears darkest on T1. Fat shows intermediate to bright intensity and CSF also appears brightest on T2 images. Air and bony cortex remains dark on both T1 and T2 sequences. Blood vessels with fast flow show ‘flow void’ or appear dark on both the T1 and T2 images whereas slow flow such as seen in some veins appears brighter. MR shows exquisite anatomical details that far surpass those seen on CT. Metallic devices have susceptibility effect and appear dark on both T1 and T2 images accompanied by a bright area. Imaging can be done in any plane without changing patient’s position. In addition 3D imaging can be performed that allows thin slices and reformatting. MR spectroscopy of normal brain demonstrates three main peaks those of N-acetyl aspartate (NAA), creatine (Cr) and choline (cho). Normal brain does not show lactate or lipid peaks. These peaks are displayed on a scale based on chemical shifts and are constant in position along x-axis irrespective of the strength of the magnet. The higher field systems have better spectral demonstration due to improvement in resolution. Abnormal appearance The abnormalities are detected on MR directly accompanied by their mass effect or oedema, if any. Neoplasm Most of the tumours appear hyperintense on T2 and FLAIR and iso to hypointense on T1 images (Figures 3A to F and 4A to C). Accompanying oedema and necrosis within the tumour appears brighter on T2 (but less bright than CSF) and darker on T1 images (less dark than CSF). Cystic changes parallel CSF intensities on T1 and T2 images. MR can directly show the mass effect and herniation, if present. In neoplastic lesions, the contrast studies are a part of the imaging protocol which assesses the enhancement of the lesions. Contrast studies also delineate the tumour in its entire extent, and also show dural invasion, if present, as thick focal dural enhancement. The multiplicity such as those of metastases is also better evaluated on contrast studies as small cortical lesions without significant oedema may be isointense and thus not apparent on noncontrast studies. Neoplasms, especially high grade, are associated with more necrotic areas and significant mass effect whereas low grade gliomas are homogenous and usually

Figures 3A to F: (A) Axial T2, (B) FLAIR, (C) Post-contrast, (D) H-MR Spectroscopy, (E) Diffusion tractography and (F) Perfusion weighted scans in a patient with a large left temporal lobe Glioblastoma Multiforme. T2, FLAIR and post-contrast scans show a mixed signal, heterogeneously enhancing mass in the left temporal region. MR spectroscopy shows increased choline and lipid peaks, DTI shows entrapment of normal white matter fibres by the tumour and perfusion weighted image, and reveals increased relative cerebral blood volume in the periphery of the lesion.

occluded intra-cranial blood vessels in the affected territory in case of a large vessel disease. In cases of embolic stroke MR angiogram of brain and neck can demonstrate the culprit plaque in the origin of internal carotid artery in the neck. Combined with perfusion imaging, diffusion imaging can show the penumbra or the region at risk if ischaemia continues. Treatment options can be chosen and initiated early based on MR imaging to maximise the recovery of the patient. Haematomas secondary to hypertension can also be documented and can be reasonably differentiated from other pathological bleeds on the basis of its appearance. Bleeds can also be categorised into acute, subacute and chronic stages based on imaging findings (Figures 6A and B). Other vascular conditions such as arteriovenous malformations, and aneurysms larger than 3 to 4 mm can be easily diagnosed on MRI. MR venography (MRV) can also be performed which depicts only the larger veins and venous sinuses with consistency. Diagnosis of cerebral venous sinus thrombosis can be confirmed or excluded based on MRV appearances.

Neuroimaging

exhibit minimal mass effect. Further characterisation can be done by MR spectroscopy which shows elevated peak of choline and reduced peak of NAA. Lipid peak may be present in glioblastomas. High grade neoplasms also have high rCBV in comparison with low grade gliomas. fMRI may be required by the neurosurgeons to identify known functional areas in the vicinity of the lesion, as due to mass effect, these areas may be shifted. Identification of calcification is difficult on routine MR imaging sequences, however, newer sequences are being developed that can overcome this disadvantage.

Figures 5A to C: Axial T2, T1 and Diffusion weighted MR sequences show an area of (A) T2 hyperintensity, (B) hypointense on T1 weighted image and (C) with restricted diffusion in the left MCA territory suggesting acute nonhaemorrhagic infarct.

Figures 4A to C: (A) Axial T2, (B) T1 and (C) post-contrast T1-weighted MR images show ‘ice cream cone’ appearance of schwannoma that consists of a large mixed signal, heterogeneously enhancing left CP angle mass and a smaller intracanalicular component. The ipsilateral CP angle cistern is enlarged.

Because of its multiplanar capability, the lesions in the base of skull region including sella can be aptly demonstrated. Trauma In trauma, even as CT is the primary investigation of choice, MR does have the capability to show bleed in different stages, whereas CT demonstrates it only in the acute stage. MR can additionally show small contusions or shear injury to deeper structures with clarity. Vascular MR is the earliest to confirm the presence of acute stroke within 2 hours on diffusion weighted images where the affected site becomes bright (Figures 5A to C). Other MR sequences may a take a day or more to show similar changes, though oedema or mass effect may manifest earlier. MR angiogram may show

Figures 6A and B: Axial MR images show an area of hyperintensity on both (A) T1 and (B) T2 weighted sequences in the right temporal lobe suggesting subacute intraparenchymal haemorrhage.

Infections Central nervous system Infections are common in our part of the world. If recognised, most of them are fully treatable after initiation of correct therapy, else complications ensue which can be lifethreatening. In acute viral encephalitis, characteristic bilateral asymmetric signal intensity changes in inferior frontal or in temporal lobe suggest herpes encephalitis. Other viral encephalitis can have non-specific imaging features, but changes are usually bilateral and may be multifocal. In other infections, MRI can document the presence and location of the lesions which usually display ring enhancement. MR can characterise brain abscesses 1367

by demonstrating high signal intensity on diffusion-weighted imaging (DWI) (Figures 7A to E). MR spectroscopy shows peaks of amino acids in addition to acetate and succinate. Common causes of seizures in this part of the world include granulomas secondary to neurocysticercosis (NCC) and tuberculomas. Both may exhibit similar MR imaging pattern, though presence of a scolex is diagnostic of neurocysticercosis. At times T2 and T1 images show a scolex; more frequently thin slice imaging is needed for its demonstration. Further characterisation may be done on MR spectroscopy where NCC shows peaks of succinate and acetate without amino acids. Tuberculosis occupies a special place in developing nations. Its common CNS manifestations include tubercular meningitis and tubercular granulomas also known as tuberculomas.Tuberculomas share the imaging features with other granulomas. However, these may be differentiated on a special imaging sequence, magnetisation transfer, on which the wall of the tuberculomas appear bright and on quantification, shows a lower magnetisation transfer ratio compared to lesions with similar MR appearance (Figures 8A to E). On MR spectroscopy, tuberculomas display prominent lipid peak amidst absence of normal brain peaks. Meningitis of any aetiology will show diffuse linear meningeal enhancement and may show evidence of its complications such as hydrocephalus and infarcts.

Figures 8A to E: (A) Axial T2, (B) T1. (C) MT-T1, (D) post-contrast and (E) MR spectroscopy scans in a patient with right parietal tuberculoma. The lesion appears hypointense on T2, hypo to isointense on T1 with a peripheral bright rim on MT-T1 sequence which enhances on post-contrast image. MR spectroscopy shows prominent lipid peak.

syndrome, abnormalities of delayed myelination or abnormal myelination, herniation of brain through bone defects— cephaloceles, changes secondary to perinatal insults, and many other conditions. Usually non-enhanced MR imaging in axial and sagittal plane will delineate all these disorders in their entirety. Degenerative neurodegenerative diseases can also be studied by MRI and show a variety of changes. These include changes in signal intensities, or changes in volume as in dementias.

Figures 7A to E: Pyogenic abscess in the right temporal lobe of a 32-year-old man. (A) Axial T2 WI image shows a large well-defined T2 hyperintense lesion with thin hypointense rim, perifocal oedema and mass effect. (B) T1 weighted image shows isointense rim of the lesion. (C) Diffusion restriction noted on diffusion weighted image. (D) Post-contrast T1 weighted image shows rim enhancement of the lesion. (E) In vivo proton MR spectroscopy from the cystic cavity shows presence of cytosolic amino acids (Cy), lactate (L), acetate (Ac) and succinate (Suc) characteristic of an abscess.

MR is also helpful in the recognition of osmotic demyelination secondary to rapid correction of hyponatraemia which causes central pontine T2 hyperintensity. Similarly certain other encephalopathies such as hypertensive encephalopthy, ADEM may be suggested on the basis of imaging findings in the presence of appropriate clinical scenario. Congenital Developmental brain lesions can be in the form of structural 1368 anomalies such as holoprosencephaly, heterotopia, Dandy Walker

Spine MR has revolutionised the imaging of spine and its constituents. It offers assessment of the spinal cord, intradural CSF space and epidural tissues directly in any desired plane. Usually sagittal and axial planes form the mainstay of spinal imaging. Spinal cord and nerve roots appear grey on both T2 and T1 images, and the CSF bright on T2 and dark on T1 images. The vertebrae appear relatively brighter compared to adjacent muscles on both T1 and T2 imaging. The vertebral bodies have a thin hypointensity of cortex all round. The normal dura mater may be directly seen especially in the presence of intra-canalicular fat. MR also demonstrates the normal and abnormal intervertebral discs. Abnormal appearance Neoplasm: MR can show marrow changes much before any bony destruction takes place. Most abnormalities of the vertebral bodies appear hyperintense on T2 and hypointense on T1 and enhance on contrast-enhanced T1 studies. These changes may occur in a single vertebra or multiple vertebrae which may be contiguous or far apart. Neoplastic conditions such as metastases and multiple myeloma may also have associated pre or paravertebral soft tissue but this is not large, usually does not exceed 8 mm in thickness, and enhances homogenously, unlike peripheral enhancement in abscess formation. Other bony tumours are less frequent in spine and usually involve posterior elements. MR can identify the tumour and define its

MR can also demonstrate the nerve roots along their course within the CSF space as well as through the neural canal. Root changes in arachnoiditis such as thickening, clumping, and abnormal enhancement are all documented well on MRI. In addition, CSF loculation and abnormal meningeal enhancement can also be seen in arachnoiditis.

Neuroimaging

extent. Lesions extending to epidural space can also be easily delineated. Similarly intradural extramedullary lesions like meningiomas, neurofibromas, etc. and intramedullary tumours such as astrocytomas, ependymomas, etc. can be delineated in their entirety for the surgical excision (Figures 9A to C). Drop metastases from intra-cranial tumours such as medulloblastomas, glioblastomas, etc. are seen as small nodular enhancing areas within the CSF space.

Vascular In spinal AVMs, MR shows serpiginous, long channels of flow void within the CSF space posterior or occasionally anterior to the cord. Trauma In trauma, MR is useful in the assessment of the spinal cord and informs about its integrity and presence of haematoma. Degenerative

Figures 9A to C: (A) Sagittal T2, (B) T1 and (C) post-contrast T1 weighted MR images in a patient with cervical cord astrocytoma show diffusely expanded cervical spinal cord which is hyperintense on T2 and hypointense on T1 weighted sequences with patchy enhancement following contrast administration.

Normal disc can be identified by its typical appearance of hyperintensity with a thin central hypointensity on T2 images. Disc desiccation causes the entire disc to become hypointense. Disc bulges, and herniations can be differentiated on MR. MR can also show far lateral disc herniations directly that cause root compression as these exit the canal. Similarly, abnormalities of alignment are clearly shown. Congenital

Infection In infections, solitary or more frequently two or more contiguous vertebrae are involved with hyperintensity on T2 and hypointensity changes on T1 images. Intervening disc is often involved, but this involvement may be late in tuberculosis. Infective conditions frequently cause abscess formation in the adjacent soft tissues which can be easily appreciated on T2 (these show almost fluid intensity) and postcontrast T1 imaging (abnormal soft tissue shows peripheral enhancement) (Figures 10A to C). On DWI, these show low AIDS-dementia complex values.

Figures 10A to C: (A) T2 weighted sagittal image shows hyperintense destructive process involving the D12-L1 and L3-L4 vertebrae and the intervening disc. There is evidence of a hyperintense pre-vertebral collection and intra-canalicular collection causing extradural compression. (B) The vertebrae and collection appear hypointense on T1 weighted image. (C) Post-contrast T1 weighted sagittal images show enhancement of the abnormal tissue along with rim enhancement of the pre-vertebral collection.

MR is especially useful in the evaluation of congenital malformations. Meningocoeles can be fully evaluated for their contents, presence of neural placode (Figures 11A and B) and associated Chairi II malformation or syringomyelia can be established along with intra-cranial ventricular assessment. MR is especially useful in skin covered malformations and in cases with suspected tethering where it can show low lying cord, or thick filum terminale. Any associated intradural tumours such as dermoid, epidermoids can also be seen. Diastematomyelia can be diagnosed on delineation of two cords within the same dural sheath or in different sheaths. Bone spur, if present, is easily seen.

Figures 11A and B: (A) Sagittal T2 and (B) T1 weighted MR scan in an infant with meningomyelocele. The spinal cord is tethered into a CSF filled dural sac that protrudes dorsally through a dysraphic lumbosacral spine. A small lipoma is also noted within the sac.

1369

INTERVENTIONAL PROCEDURES Interventional procedures have become accepted in clinical management in certain diseases as they offer much less invasion compared to operative procedures, thereby reducing complications. These procedures are frequently performed under local anaesthesia and via a percutaneous route. The most common interventional procedures are embolisation of intracranial and spinal arteriovenous malformations including fistulas, coiling of intra-cranial aneurysms, stenting of internal carotid plaques in the neck, and recanalisation in some cases of acute intra-cranial thrombosis. Pre-operative embolisation is also performed to reduce vascularity in some tumours such as meningiomas, glomus tumours. In the spine, vertebroplasty

1370

is performed in cases of painful benign collapse of vertebrae. This consists of injecting bone cement through percutaneous route into the affected vertebral body which seals the microfractures responsible for pain in these cases. RECOMMENDED READINGS 1. 2.

Atlas SW, editor. Magnetic Resonance Imaging of the Brain and Spine; 3rd Ed. Philadelphia: Lippincott Williams & Wilkins; 2002. Gillard J, Waldman A, Barker P, editors. Clinical MR Neuroimaging; 1st Ed. Cambridge: Cambridge University Press; 2005.

3.

Gupta RK, Lufkin RB, editors. MR Imaging and Spectroscopy of Central Nervous System Infection; 1st Ed. New York: Kluwer Academic/Plenum Publishers; 2001.

4.

Osborn AG, editors. Diagnostic Neuroradiology; St Louis: Mosby; 1994 (Indian reprint 2008).

20.5 INTRODUCTION Epilepsy is one of the oldest diseases known to mankind.The word seizure is derived from the sixth century Latin word ‘seiz’ that means to ‘take possession of’. The word epilepsy is derived, from the Greek word ‘Epilepsia’ which means to ‘seiz’. EPIDEMIOLOGY Worldwide, there are about 50 million people with epilepsy and 90% of them live in developing countries. The prevalence of epilepsy ranges from 5 to 10 per 1000 in most countries, but it is likely to be higher in developing countries than in developed countries.The incidence of epilepsy in developed countries ranges from 24 to 53 per 100,000 population. The age specific incidence is highest at extremes of age. In developed countries it had probably reduced in young people and had increased in those aged more than 60 years.The natural history of untreated epilepsy is not readily available. It is possible that about 20% to 30% of patients are likely to have spontaneous remission while about 35% of patients may continue to get seizures in spite of treatment with two or more anti-epileptic drugs (AED). Persons with epilepsy carry 2 to 3 times increased risk (standardised mortality ratio) of death when compared to others. Sudden unexplained deaths in epilepsy (SUDEP) account for 2% to 18% of all deaths while status epilepticus accounts for 12.5% deaths. Treatment Gap The proportion of persons that fail to receive treatment, expressed as a percentage of those who require treatment, is termed as treatment gap. Treatment gap for epilepsy varies widely between countries and within countries. The treatment gap is highest in low income countries such as India (75%) moderate in medium income countries (~50%) and least in high income countries (40 kg/m2. Over weight or obesity is common in patients with OSAS. Low BMI in COPD indicates the presence of ‘pulmonary cachexia’ or ‘pulmonary sarcopaenia’, a systemic manifestation of COPD. Pulse, respiratory rate, temperature, and blood pressure have been traditionally considered as the vital signs. Pulse oximetry is now viewed as ‘the fifth vital sign’. It is useful to record the baseline saturation of a patient as it may warn the clinician of significant desaturation during an acute illness later. Baseline or exercise desaturation can also aid in diagnosis and oxygen therapy in chronic respiratory disease, like ILD and COPD. Exercise test for this purpose is per formed under super vision while the patients are encouraged to walk at their own pace on a flat surface for 6 minutes, alternatively till the target heart rate (200-age) is reached or until limited by shortness of breath or fatigue. Clinically significant desaturation is considered to be any saturation decrease of 4% or more or to a nadir of 88%.

Pulmonary Disorders—A Clinical Approach

Table 1: Dyspnoea Severity Modified Medical Research Council MMRC Scale

General examination findings, like clubbing and pallor, point towards chronic inflammatory diseases and malignancies. Elevated jugular venous pressure (JVP) and pedal oedema in chronic pulmonary cases help to diagnose cor pulmonale with right heart failure. Clubbing is an important clinical finding in a pulmonary case (Figure 1). Clubbing is described in 4 grades (Table 2). The common causes for finger clubbing are shown in Table 3. Presence of enlarged cervical lymph nodes is an important finding, particularly in cases of lung cancer and mediastinal masses. These provide accessible site for fine needle aspiration cytology or biopsy (FNAC/B). Cervical and axillary lymph nodes must be meticulously examined before embarking on expensive and invasive procedures, like computed tomography (CT ) and bronchoscopy. The finding of crepitus in the neck is a pointer to the presence of pneumo-mediastinum, engorged neck veins to superior vena cava (SVC) obstruction, and an enlarged thyroid gland explain symptoms of upper airway obstruction. Associated hypothyroidism may explain OSAS and hyperthyroidism may be responsible for worsening asthma control. Table 2: Grades of Clubbing Grade

Description

Grade 1

Nail may seem to be loose within the soft tissue (increased bogginess) when palpating the fingernail

Grade 2

Nail extends from the bed (the profile angle) at 180 degrees or greater (normal 160 degrees) demonstrated by ‘window sign’ or Schamroth sign

Grade 3

Increased curvature of nails with grade 1 or 2 changes, appear like ‘parrot beak’ or ‘drum stick’

Grade 4

Osteoarthropathy (pain and swelling of ankle/wrist joints, elbow/knee joints and hip/shoulder joints with finger clubbing). Osteoarthropathy may be confirmed by showing periosteal new bone formation of long bones. 1691

Table 3: Causes of Finger Clubbing Respiratory Chronic suppurative pulmonary disease—bronchiectasis, lung abscess, empyema Malignant lung cancer, malignant mesothelioma Idiopathic interstitial pneumonia (IIP) (especially, idiopathic pulmonary fibrosis) Pleural fibroma Cardiac Cyanotic heart disease Subacute infective endocarditis Atrial myxoma Gastrointestinal Inflammatory bowel disease Hepatic cirrhosis Neurological Hemiplegic stroke Metabolic Disease Thyroid acropachy

Figure 1: Shamvoth schematic diagram showing a normal finger showing a ‘diamond-shaped window’ when the dorsal surfaces of the terminal phalanges on opposing fingers are placed together, while the clubbed finger will show no space visible between the opposing nails.

Other Familial Idiopathic

RESPIRATORY SYSTEM EXAMINATION Respiratory system examination includes: (a) respiration rate, rhythm and accessory muscles use; (b) upper respiratory tract-nasal discharge, sinus tenderness and examination of the oral cavity; and (c) examination of the chest. Suitable chest examination requires the patient’s chest,neck and abdomen to be appropriately exposed. Chest examination is best performed in the sitting or standing position. In patients who have difficulty in sitting, support can be given by someone standing in front and holding his/her hands. In those who are too sick to stand or sit, rolling on one side and then the other for examination of the back helps. Chest examination is performed under the headings of inspection, palpation, percussion, and auscultation (IPPA). The clinical findings are described in terms of areas over the chest (anteriorly—supraclavicular, clavicular, mammary and inframammary, axilla-axillary and infra-axillary, and posteriorly—suprascapular, interscapular, scapular and infrascapular). The corresponding areas of various lung lobes are shown in surface marking in Figures 2A and B and help in localising the diseased lobe. Inspection and Palpation Inspection and palpation of the chest are performed to assess where disease is bilateral—indicated by equal chest movements (asthma, COPD, ILD) or unilateral—indicated by reduced chest movements and if unilateral; whether associated with increase in hemithoracic volume (bulging of the chest, elevated shoulder, increased spino-scapular distance and shift of the trachea and cardiac impulse/apex beat to opposite side) found in pleural effusion, pneumothorax, hydropneumothorax; reduction in hemithoracic volume (flattening of the chest, depressed shoulder, reduced spino-scapular distance and shift of trachea and cardiac impulse/apex beat to same side) found in collapse, cavity, pleural thickening and no change in volume (no bulging or flattening, both shoulders at same level, equal spino-scapular distance, central trachea, and cardiac impulse/ apex beat in the 5th intercostal space in the mid clavicular line) 1692 noted in consolidation.

Figures 2A and B: Surface marking of lung lobes over the anterior and posterior chest. RUL = Right upper lobe; LUL = Left upper lobe; RML = Right middle lobe; RLL = Right lower lobe; LLL = Left lower lobe.

irregular walled cavity or high pitched with metallic intonation (amphoric) heard over smooth walled cavity or broncho pleural fistula.The same mechanism that produces bronchial-breathing allows spoken sounds to be transmitted well as increased vocal resonance (VR)/bronchophony (loud and clear)/aegophony (with a nasal twang) and also whispered sounds ‘positive whispering pectoriloquy (WP)’. The breath sounds (and spoken sounds-VR) are reduced or absent when the lung and chest wall is separated by fluid or air, as in pleural effusion or pneumothorax and due to inability of breath sounds to reach the lungs in collapse with obstructed bronchus. Figure 3 briefly depicts the flow chart of respiratory examination. MAKING A CLINICAL DIAGNOSIS The findings of history and clinical examination are analysed to make a clinical diagnosis (Figure 3). A summary of findings in various pulmonary disorders is shown in Table 4.

Pulmonary Disorders—A Clinical Approach

Percussion and Auscultation Percussion adds to the findings of inspection and palpation. The technique of digital percussion was described by Barth and Roger (1865). The percussion notes vary from tympanic (over the stomach gas bubble—‘Traube’s space’) to dull (over the heart and liver). In pathological cases, hyper-resonant notes are heard in cases of pneumothorax and emphysema, whereas dull notes are produced over consolidation, collapse or pleural effusion. Auscultation via a stethoscope is an integral part of chest examination. Auscultation terms simplified by Forgacs (1978) are established by the International Lung Sounds Association (ILSA). The sounds heard at auscultation are breath sounds (normal or bronchial) and voice sounds (increase vocal resonance/bronchophony or aegophony) and adventitious sounds; continuous sounds (wheezing and rhonchi) and intermittent sounds (coarse and fine crackles). Other adventitious sounds are those that originate in the upper airways (stridor) or in the pleura (friction rub) and interstitium (squawk—inspiratory squeaking sound). The normal breath sounds are the result of turbulent airflow through the larger airways. At the chest wall, the higher frequencies are attenuated by the lung parenchyma resulting in vesicular breath sounds. In the presence of consolidation or collapse with a patent bronchus, these higher frequencies are transmitted, leading to ‘bronchial breathing’. Bronchial breathing is usually high pitched (tubular) and heard over consolidation; collapse with a patent bronchus and just above the level of pleural effusion due to collapse (relaxation or passive collapse) of lung. Bronchial breathing may be low pitched (cavernous), heard over an

A clinical diagnosis must consist of: 1. Pathological diagnosis (What is the lesion?) 2. Anatomical diagnosis (Where is the lesion?) 3. Guess to aetiology (What is the likely cause?) 4. Additional diagnosis (e.g. cor pulmonale, anaemia, jaundice, goitre, etc.) For example Left lower lobe collapse due to lung cancer with anaemia, where: Pathological diagnosis (What is the lesion?): collapse Anatomical diagnosis (Where is the lesion?): left lower lobe

Figure 3: Flow chart of respiratory examination. COPD = Chronic obstructive pulmonary disease; TB = Tuberculosis; PE = Pulmonary embolism; BS = Breath sounds; VR = Vocal resonance; WP = Whispering pectoriloquy. 1693

Table 4: Clinical Findings in Various Pulmonary Disorders Disorders

Symptoms

General Examination

Respiratory Examination

Diffuse lung disorders Asthma

Dyspnoea, cough, wheeze

Rhonchi

COPD

Cough, mucoid sputum, dyspnoea, wheeze

Emphysematous chest, rhonchi, crackles

Bronchiectasis

Cough, copious mucopurulent sputum, dyspnoea, haemoptysis

Clubbing

Coarse crackles, rhonchi

ILD

Dry cough, dyspnoea, no wheeze

Clubbing

Fine end inspiratory crackles, squawks

Localised lung disorders Consolidation

NCV, dull note, bronchial BS, ↑ VR, WP+, coarse crackles

High fever, cough, purulent sputum, chest pain

Collapse (patent bronchus) Cough, sputum, haemoptysis, dyspnoea (also fibrotic/cicatricial collapse)

↓ Volume, dull note, BS bronchial, ↑ VR, WP+, coarse crackles

Collapse (obstructed bronchus)

Cough, sputum, haemoptysis, dyspnoea

↓ Volume, dull note, BS absent, ↓ VR

Fibrosis

Dry cough

↓ Volume, impaired note ↓ BS, crackles

Pleural effusion

Dry cough, pleuritic chest pain

Dull note, ↓ BS, ↓ VR, shifting dullness +, (initially NCV, subsequently ↑ volume)

Pneumothorax

Dyspnoea, dry cough, pleuritic chest pain

↑ Volume, hyper-resonant note, absent BS, ↓ VR

Hydropneumothorax

Cough (dry or with sputum), dyspnoea, pleuritic chest pain

Hyper-resonant note followed by dull note, shifting dullness, ↓ BS, ↓ VR, succussion splash

Hydropneumothorax with bronchopleural fistula

Cough with copious purulent sputum, posture dependent, dyspnoea, chest pain

Pleural thickening (fibrothorax)

Dry cough, dyspnoea

Clubbing

Hyper-resonant/dull note shifting dullness, BS-amphoric, ↓ VR, WP+, succussion splash ↓ Volume, dull note, ↓ BS, ↓ VR

COPD = Chronic obstructive pulmonary disease; ILD = Interstitial lung disease; NCV = No change in volume; BS = Breath sounds; VR = Vocal resonance; WP = Whispering pectoriloquy.

Guess to aetiology (What is the likely cause?): lung cancer Additional diagnosis: anaemia Based on the clinical diagnosis, further imaging and laboratory tests are performed to make a final diagnosis.

2.

Maitre B, Similowski T, Derenne JP. Physical examination of the adult patient with respiratory diseases: inspection and palpation. Eur Respir J 1995; 8: 1584-93.

3.

Mikami R, Murao M, Cugell DW, et al. International symposium on lung sounds. Synopsis of the proceedings. Chest 1987; 92:342-5.

RECOMMENDED READINGS

5.

Tierney LM, Whooley MA, Saint S. Oxygen saturation: a fifth vital sign? West J Med 1997; 166:285-6.

4.

Yernault JC, Bohadana AB. Chest percussion. Eur Respir J 1995; 8:1756-60.

1.

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American Thoracic Society (ATS) Statement. Guidelines for the six-minute walk test. Am J of Respir and Crit Care Med 2002; 166:111-7.

23.3 INTRODUCTION In patients with pulmonary disorders, investigations play a very important role in narrowing down the diagnostic possibilities. Broadly, the procedures can be divided into invasive and noninvasive methods (Table 1).Though there may be an overlapping between non-invasive and invasive procedures, this classification, to a large extent, helps in improving the understanding about various diagnostic procedures used in pulmonary disorders. In fact, the gold standard for any diagnosis is histopathology, cytology or microbiologic confirmation of the disease. In the last two decades, the use of various diagnostic modalities for obtaining tissue specimens for confirmation of diagnosis in various respiratory disorders has been a very major development in pulmonary medicine. Table 1: Diagnostic Procedures in Pulmonary Disorders Non-invasive Imaging studies like chest radiograph, ultrasonography (USG) and computed tomography (CT) to assess the anatomy Pulmonary function tests to assess physiology and gas exchange Microbiological isolation Serum markers Arterial blood gas (ABG) analysis Overnight polysomnography Invasive Fibreoptic bronchoscopy, endobronchial USG Thoracoscopy, video-assisted thoracoscopy (VATS) Mediastinoscopy Definitive tests to confirm the diagnosis by obtaining tissue during bronchoscopy/thoracoscopy/USG and CT-guided procedures

The following sections represent an overview of the various investigative procedures in pulmonary disorders. NON-INVASIVE DIAGNOSTIC PROCEDURES Chest Radiography Chest radiography is the sheet anchor for diagnosis in pulmonary disorders as it is easily available as well as economical. In fact, some clinicians may like to call it an extension of the stethoscope. However, it is important to appreciate that a good clinical examination cannot have any replacement and radiology is complementary and not a substitute for clinical examination. In the last few years, digital radiography has revolutionised the quality of radiography as compared to the conventional filmbased radiography. Normally, a chest radiograph with a posteroanterior (PA) projection is the standard protocol, where the film cassette is placed against the anterior chest wall. However, the patient should be able to sit or stand for the PA view. In critically ill patients or those who are not able to sit up, an antero-

Pulmonary Disorders— Diagnostic Procedures Gautam Ahluwalia, Surendra K Sharma posterior (AP) view is performed where the film cassette is placed behind the back. While interpreting the AP view, there is a word of caution; the heart size may be falsely enlarged as the distance between the heart and the cassette increases. Therefore, cardiomegaly on an AP view need not be ‘true’ cardiomegaly. The clinicians should analyse the chest radiograph in a systematic order to avoid missing an abnormality and gain maximum information from a standard PA radiograph. One should start with the quality of chest radiograph and positioning of patient, then comment on soft tissues, bony cage, followed by tracheobronchial tree, hilum, mediastinum, lung parenchyma, and costophrenic angles. This should be followed by a comment on cardiac size. The quality of the radiograph is very important. A technically sound radiograph should demonstrate the entire dorsal spine with mid point of right diaphragm at the level of the anterior end of the 6th rib, implying that it is a deep inspiration film, which is very important. A correct positioning of the patient is indicated when medial end of both clavicles is equidistant from the vertebral spinous processes. It is essential to appreciate that history of the patient, for which the chest radiograph has been performed, is very important. One should always ask for an old chest radiograph for comparison. This also results in avoiding many expensive investigations for a ‘lesion’ which has been present for many years like the presence of fibrotic strands in the apex in a patient with previous history of tuberculosis (TB). A few of the common abnormalities on the chest radiograph are pulmonary nodules/masses, cavitary lesions, pneumonia/ consolidation, and pleural effusion. Pulmonary nodules/masses These could be solitary or multiple. In a solitary lesion, the doubling time is very important. Most malignant lesions have a doubling time between 4 weeks and 24 weeks. In other words, a lesion which has doubled in less than 2 weeks or after 24 weeks is unlikely to be of malignant aetiology. The increase in diameter of more than 25% on the chest radiograph signifies a pathological doubling of the lesion. The other soft pointers toward a benign solitary nodule are significant calcification and smooth margins. However, it is important to note that these soft markers can be deceptive. A nodule in a patient with history of smoking should always necessitate further evaluation. A comparison with old radiographs (if available) is very helpful. Multiple pulmonary nodules are mainly due to malignant deposits of varied aetiology. Another important term is miliary mottling. These are small nodules of less than 5 mm in diameter. The commonest cause in India is miliary TB. However, the differential diagnosis of miliary mottling includes metastasis, 1695 fungal infections, pneumoconiosis, and sarcoidosis.

Cavitary lesions The two important differential diagnosis are bronchial carcinoma and lung abscess.The common aetiologies of infections in a lung abscess are Mycobacterium tuberculosis, Klebsiella, Staphylococcus, and anaerobes. The presence of air-fluid level suggests the diagnosis of a cavitary lesion (Figure 1).

mention. In a resource-limited setting like India, chest radiograph is an economical modality to evaluate patients in the ICU. In fact, chest radiograph has become an important diagnostic armamentarium in the ICU setting. It is used to evaluate the position of the monitoring and support equipment like central venous catheter, endotracheal tube, tracheostomy tube, chest tube, pulmonary artery catheter, enteric tube, and intra-aortic balloon pump. The chest radiograph is also an important tool to diagnose pneumothorax, pneumonia, pulmonary oedema, atelectasis, and pleural effusion, which are frequently encountered complications in the management of patients on ventilators and other life-saving devices. Ultrasonography and Computed Tomography These techniques have improved the diagnostic armamentarium in respiratory diseases tremendously.

Figure 1: Chest radiograph (PA view) showing a cavitary lesion with an air-fluid level in the right lung.

Pneumonia/consolidation The important radiological sign of a pulmonary consolidation is air bronchogram, which is a radiolucent bronchi (black) in the background of an opaque lung (white). The other important sign is the opacification of the lung with undulating margins obscuring the underlying blood vessels. A lobar consolidation follows the contours of the lobe and has a sharp margin in the corresponding fissure. Infections are the commonest cause of consolidation. However, the unusual differential diagnosis including fluid overload, bronchioloalveolar carcinoma, collagen vascular diseases, and pulmonary haemorrhage should also be considered in the appropriate clinical setting. Pleural effusion The earliest sign of pleural effusion on the chest radiograph (PA view) is blunting of the lateral costophrenic angle. A minimal amount of fluid (approximately 200 mL) is required to produce appreciable blunting. A large free pleural effusion appears as a dependent opacity with lateral upward sloping of a meniscusshaped contour. A massive pleural effusion appears as an opaque hemithorax with mediastinal shift to the opposite side. The lateral decubitus view was very important in diagnosing minimal pleural effusion (less than 100 mL), which is not picked up on a routine PA view. With technologies like ultrasonography (USG) and computed tomography (CT) becoming more freely available, this view is used infrequently. However, it is very important to know the importance of this projection, especially in resource-limited setting areas like India where the newer technology is still lacking in the underdeveloped regions of our country. Intensive care unit (ICU) imaging With the evolution of advanced critical care in our country, the 1696 role of the chest radiograph in this setting needs special

Ultrasonography is a good investigative modality for the peripherally placed lesions in the lung. USG guided procedures help to secure biopsy specimens for tissue diagnosis. The major indication of USG is to detect minimal pleural effusion which is not picked up on PA view and to differentiate between pleural thickening vis-à-vis an effusion. The presence of septation in the fluid is a pointer that the effusion is exudative, though final confirmation is obtained on examination of the fluid. A large collection of fluid or pus in the pleural cavity can be drained with USG guidance. Similarly, USG is most useful to drain multiple localised collections of fluid in the pleural cavity. Computed tomography is another very important investigation which is far superior to the conventional chest radiograph, though the basic principles of physics are the same as in chest radiography. One needs to have a clear understanding of the various terminologies used like spiral CT, high resolution CT (HRCT), lung window, and mediastinal window. The mediastinal window helps in assessing the lesions in the major tracheobronchial tree and in the mediastinum like lymph nodes and great vessels. The mediastinal window also helps in commenting on density difference like calcification as well as caseation in intrathoracic lymph nodes (Figure 2). The lung window helps in assessing the parenchymal abnormalities in the lung (Figure 3). The problem with the conventional CT is that the patient needs to hold his breath for a clear image on the CT, otherwise there

Figure 2: Mediastinal window showing intrathoracic lymph nodes with necrosis.

Figure 3: Lung window showing bilateral ground glass opacification.

is blurring of image due to respiratory movement. Moreover, due to respiratory movement, small lesions may be missed. This problem has now been overcome by spiral CT. Spiral CT is a technological evolution where the entire thorax is imaged by holding the breath once only for a few seconds. In fact, even in a dyspnoeic patient, fairly clear images can be obtained, which is not possible on conventional CT machines. As the image acquisition is faster, the amount of contrast required is also less. A technical advancement over single slice spiral CT is multidetector row CT (MDCT) or earlier known as multi-slice spiral CT. In MDCT, multiple slices are acquired at the same time. Consequently, the speed of scanning as well as resolution is enhanced significantly. In fact, MDCT allows coronal, sagittal, and oblique imaging at higher spatial resolution as compared to conventional CT. Dynamic MDCT with intravenous contrast or CT pulmonary angiography (CTPA) is becoming the investigation of choice for pulmonary emboli phasing out ventilation-perfusion (V/Q) radionuclide scans. Moreover, threedimensional anatomy of the tracheobronchial tree can also be constructed using MDCT unlike conventional CT. In fact, the tracheobronchial tree is visualised as clearly as bronchoscopy. This is called virtual bronchoscopy. Research tools are also being developed to employ xenon gas to enhance regional ventilation of lungs using MDCT (Xenon enhanced MDCT or XE-MDCT). The modality of HRCT (thin transverse slice of 1 to 2 mm vis-àvis the normal slice thickness of 10 mm) is extremely helpful in diagnosis of diffuse lung parenchymal disease. These scans can be performed on both conventional and MDCT. Therefore, it is important to appreciate that HRCT and MDCT are not synonymous. To summarise, the broad diagnostic indications for CT include further evaluation of lung, mediastinal, and hilar abnormalities in the presence of non-diagnostic radiographs. It is also important in evaluation of mediastinal lymphadenopathy, diffuse lung disease, lung tumours, haemoptysis with nonlocalising chest radiograph, and pulmonary embolism. The only limitation is its cost in a resource-limited setting like India. The hazards of radiation exposure to the patient should also be kept in mind, especially in a pregnant woman.

Pulmonary Function Tests Pulmonary function tests are important to assess the physiological function of the lungs. These include tests of respiratory mechanics and pulmonary gas exchange. The standard protocol involves a computerised spirometer and additional facilities for measuring carbon monoxide (CO) diffusion as a measure of diffusion capacity reflecting gas exchange. Of course, the acid-base disorders also reflect on the physiological function of the lungs, but they are outside the purview of this chapter. Ideally, PFT values have to be compared with the predicted values in a population which need to be epidemiologically established in every country. In India, most centres with PFT machines have to depend on the western data for normal values, which may not be representative of our country due to different body habitus.

Pulmonary Disorders—Diagnostic Procedures

Magnetic Resonance Imaging The primary advantage of MRI over CT is the lack of ionising radiation. It is also important to realise that as far as respiratory imaging is concerned, MRI offers no diagnostic advantage over CT. In fact, MRI is an inferior modality to assess lung parenchyma as compared to CT. However, the evolution of newer MRI scanners with dynamic gadolinium-enhanced imaging and ultrafast proton will result in increased utility of MRI in evaluation of lung diseases, especially in perfusion abnormalities like pulmonary embolism in pregnant females. The use of hyperpolarised gas imaging with helium and xenon are also being evaluated in malignant lung pathology. The assessment of diaphragm abnormalities, chest wall motion assessment, and breathing mechanics is potentially feasible for clinical usage in future with the advent of advanced ultrafast proton imaging MRI scanners.

Basically, respiratory mechanics involve compliance of lung and chest wall on one hand and airway resistance on the other. The direct measurements of lung compliance and airway resistance involve estimation of oesophageal pressure, pleural pressure and trans-diaphragmatic pressure, which is not feasible for day-to-day clinical practice. The practical measure of lung compliance in PFT is measurement of lung volumes, whereas the practical corollary for airway resistance is based on forced expiration manoeuvres by patients. In restrictive lung diseases, PFT demonstrates decreased vital capacity (assumed to be same as forced vital capacity (FVC) for practical purposes), whereas obstructive disease is reflected by decreased forced expiratory volume in one second (FEV1). For interpretation, we look at the ratio of FEV1/FVC to differentiate between restrictive and obstructive lung disease rather than FEV1 alone. The reason is simple. In a patient of restrictive lung disease as FVC is reduced, consequently FEV1is also reduced as the lungs have ‘less air to be expelled’. Therefore, if one looks at FEV1 only, PFT of a patient with restrictive airway disease may give a false impression of obstructive airway disease due to reduced FEV1. However, when we look at the ratio of FEV1/FVC; as both values are reduced, the FEV1/FVC ratio is normal.On the other hand, in obstructive airway disease, there is air trapping and FVC is increased whereas due to obstruction in the airways, FEV1 is decreased; hence FEV1/FVC ratio is reduced. Another important difference to understand is between peak expiratory flow rate (PEFR) and FEV1. PEFR can be easily

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measured at home and is a very important objective parameter for asthma patients to know whether the disease is under control or is worsening so that they can report to the hospital at the right time. However, PEFR is always effort dependent, and hence, the patient should do it 2 to 3 times and note the best value. However, FEV1 done as part of PFT is relatively effort independent and gives a better reflection of the airway obstruction. The assessment of respiratory muscle function is important to diagnose neuromuscular disorders affecting the respiratory system and occasionally in restrictive lung disease patients when restriction is extraparenchymal in the chest wall. Briefly, the respiratory muscle function is measured as PEmax (indicating maximum expiratory muscle pressure) and PImax (indicating maximum inspiratory muscle pressure). Though expiration is a passive process, abdominal muscles play an important role. On the other hand, inspiration is an active process and the diaphragm is an important inspiratory muscle. Logically, expiratory muscles are most active at end-inspiration (PEmax) when the lung volume is maximum; whereas inspiratory muscle act at lower lung volumes, i.e. end-expiration (PImax). The pulmonary gas exchange parameter practically used in dayto-day clinical practice is carbon monoxide diffusing capacity (DLCO). It is a sensitive test to assess the integrity of the alveolocapillary membrane. It is classically reduced in interstitial lung disease. However, it is also dependent on the surface area of the alveolo-capillary membrane. In other words, if patient has significant reduced surface area as in emphysema or pneumonectomy, DLCO would be reduced. Therefore, to remove this confounding factor, transfer coefficient (KCO) is a more reliable parameter which represents the uptake of CO per litre of effective alveolar volume. A more detailed assessment of the physiology of compliance of respiratory apparatus as well as the exact level of airway obstruction (from larynx to terminal airways) can be performed by studying the flow-volume curves or loops and measurements of static and dynamic compliance and airway resistance (R aw) which is readily determined by body plethysmography and specific conductance (SGaw) which is inverse of R aw divided by lung volume at which the measurement was made. Another modality of assessment of respiratory function is the exercise test, which helps to quantify the exercise performance and objective assessment of disability due to disease, where clinically a patient may have recovered. For example, in miliary TB even after complete clinical and radiological recovery, a proportion of patients, despite successful treatment, develop exercise limitation that is detected on exercise test. These tests need a detailed understanding of the respiratory physiology and mechanics for a correct interpretation and their day-to-day use is quite limited. Nevertheless, they are very important for operational research to understand the basic pathophysiology of various respiratory disorders.

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Microbiological Techniques These techniques have a very important role in the diagnosis of infections of the respiratory system. However, it is very important to understand that in our country all microbiology laboratories may not be equipped with facilities for some of

the advanced microbiological investigations; therefore the treatment of a critically ill patient should not wait for the outcome of these investigations. The clinicians should empirically cover for the prevalent organisms. On the other hand, if the clinical setting does not support the results of a microbiological investigation, we need to re-check for any contamination of the sample. Sputum is the most commonly accessible material for a microbiological investigation. The collection of the sputum is very important, otherwise the report may be non-contributory and only add to the cost of care to the patient. It is very important to differentiate sputum from saliva. Grossly, a good sputum sample is thick (semi-solid), which is coughed out deeply from the lungs and is at least 2 mL. Microscopically, a good sputum sample should have less than 10 squamous epithelial cells and more than 25 neutrophils per low power field. If the patient is unable to produce adequate sputum, then it should be ‘induced’ with hypertonic saline given through a nebuliser mask. The transportation of the sample to the laboratory is equally important and should be done as early as possible. The role of blood culture is also very important, but again the collection of blood for culture is more vital. All clinicians should be conversant with the correct technique of collecting a blood sample; otherwise the results can be misleading in the management of patients. There are newer antigen markers in sera/sputum for atypical pneumonia organism like Mycoplasma, Legionella which can rapidly diagnose these infections. The role of Ziehl-Neelsen (carbol-fuchsin) staining in the sputum smear for diagnosis of M. tuberculosis has been well established over the years. However, newer staining techniques like fluorochrome (auramine-rhodamine) staining are more sensitive as well as time conserving for identifying the mycobacteria. The culture of mycobacteria on Lowenstein-Jensen medium is a time consuming process and is not of much value as far as immediate patient management is concerned. It takes 6 to 8 weeks for the culture to be reported. Newer culture methods like BACTEC radiometric system yield relatively earlier results. Polymerase chain reaction M. tuberculosis ribosomal RNA in respiratory tract specimens can now be identified within 24 hours. In fact, the rapid tests do not replace acid-fast staining, which provides an index of contagiousness, or mycobacterial cultures, permit drug susceptibility testing. Tuberculin skin test Tuberculin skin test (TST) (Mantoux test) is another investigation which is frequently done to diagnose latent TB infection (LTBI). However, its diagnostic reliability is always in relation to the clinical context and a positive TST (more than 10 mm induration) in the absence of clinical symptoms should not be considered diagnostic of active TB in our country because of false positivity due to Bacillus Calmette-Guérin (BCG) immunisation. A lower threshold of 5 mm is used to diagnose LTBI in human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS).

Nuclear Medicine Imaging The role of positron emission tomography (PET) and PET-CT using radiopharmaceutical fluoro-2-deoxy-D-glucose (FDGPET) in the evaluation of focal lung lesions, especially solitary pulmonary nodule is emerging. The low false-negative rate of FDG-PET helps in excluding malignancy and allows follow-up of benign lesions as compared to CT. Serum Markers There are some serum markers which are helpful in the diagnosis of pulmonary disorders. Increased angiotensinconverting enzyme (ACE) levels in blood are most frequently used in the evaluation of sarcoidosis. However, increased ACE levels are not specific for sarcoidosis. Some of the other pulmonary conditions with increased ACE levels include emphysema, occupational lung diseases, and lung cancer. Other serum markers useful in the diagnosis of pulmonary disorders include anti-neutrophil cytoplasmic antibody (ANCA) levels in blood for the diagnosis of Wegener’s granulomatosis (WG). Proteinase 3 ANCA (PR3 ANCA) is more specific for WG. Alpha 1-antitrypsin deficiency resulting in early-onset panacinar emphysema is diagnosed by estimating serum levels of alpha1-antitrypsin. The presence of high levels of immunoreactive trypsinogen (IRT), a pancreatic protein is being used as a screening modality in infants with cystic fibrosis (CF). The mutation observed in CF patients result from deletion of three base pairs in CF transmembrane conductance regulator nucleotide sequence.This deletion causes loss of the amino acid phenylalanine located at position 508 in the protein. This mutation is referred to as ÄF508, which signifies severe clinical manifestations in patients of CF. The role of tumour markers is also evolving in patients with lung cancer. Tissue polypeptide specific antigen ( TPS) and cytokeratins CYFRA 21-1 are useful serum markers for the diagnosis of non-small cell lung cancer. Neuron specific enolase (NSE) is a useful tumour marker for monitoring course of patients with small cell lung cancer. Arterial Blood Gas Analysis The measurement of arterial blood gas analysis (ABG) is an extremely important tool to assess the pH, oxygen, carbon dioxide, and bicarbonate levels in blood.These parameters reflect the exact gas exchange occurring in lungs and integrity of the ventilatory control mechanism. Arterial blood gas analyses also reflects the various pulmonary-renal interactions occurring to maintain the normal acid-base physiology in the body. Polysomnography This is an overnight test performed in the sleep laboratory to diagnose apnoea. Cardio-respiratory, thoraco-abdominal, and

electroencephalography parameters and oxygen saturation are recorded. Apnoea-hypopnoea index (AHI) > 5 events per hour are used to diagnose obstructive sleep apnoea. INVASIVE DIAGNOSTIC PROCEDURES Pleural Fluid Analysis Diagnostic thoracocentesis and analysis of the pleural fluid is an essential procedure in the evaluation of a patient with pleural effusion. The evaluation includes biochemical, microbiological, and cytopathological analysis. Enzymes and Cytokines In recent years, adenosine deaminase (ADA) and interferongamma (IFN-γ) have emerged as important diagnostic tools in the diagnosis of tuberculous pleuritis. In a patient with pleural effusion, an elevated level of ADA (> 36 IU/L) in the pleural fluid is suggestive of TB. In fact, there are two isoenzymes of ADA: ADA1 and ADA2. The pleural fluid in tuberculous pleurisy primarily contains ADA2. However, for all practical purposes, the total level of ADA is measured in the fluid. Among the cytokines, studies have suggested that elevated pleural fluid IFN-γ can be used as a marker for the diagnosis of TB. In fact, it is now well documented that significantly higher IFN-γ: interleukin lukin-4 ratio in the pleural fluid compared to peripheral blood in patients with pleural tuberculosis.

Pulmonary Disorders—Diagnostic Procedures

Interferon gamma release assays Interferon gamma release assays are used to diagnose LTBI. Their diagnostic utility in active TB has not been established. These tests include quantiferon-TB Gold (QFT-G), quantiferonTB Gold in- tube test (QFT-GIT) and T-spot TB test. Early secreted antigen target-6 kDa protein (ESAT-6), culture filtrate protein10 (CFP-10) and TB7.7 are three antigens used in these tests. The patient makes one visit to the health care facility and results are available in 24 hours.

Though elevated levels of IFN-γ in the pleural fluid are more sensitive for TB, ADA estimation is a cost effective investigation in the resource-limited setting of our country where the prevalence of TB is high. Bronchoscopy Fibre-optic bronchoscopy (FOB) is an outpatient procedure and is used to visualise the tracheobronchial tree. The role of FOB has also been established in diffuse lung disease. Fibre-optic bronchoscopy is also useful in obtaining histopathological, microbiological (Gram’s stain, acid-fast bacilli stain, fungal stain, cultures), and cytological samples for the confirmation of diagnosis. The various techniques used with FOB are endobronchial brushings, washings, and biopsy. This technique is important in a proximal lesion of the tracheobronchial treelike bronchogenic carcinoma. On the other hand, bronchoalveolar lavage (BAL) provides samples from the peripheral airways and alveoli. In patients with miliary TB, it has been shown that significantly higher levels of IL-4 are present in the peripheral blood as compared to BAL. In patients with diffuse lung disease, BAL is an important tool in association with transbronchial lung biopsy. A newer technique is transbronchial needle aspiration to sample the subcarinal mediastinal lymph nodes. Endoscopic bronchial ultrasonography (EBUS) is also becoming a very useful adjunct to evaluate mucosal and sub-mucosal lesions in the tracheobronchial tree. Endoscopic bronchial ultrasonography also increases the diagnostic sensitivity in obtaining fine needle aspiration cytology (FNAC) or biopsy of suspicious lesions. The use of rigid bronchoscopy had become restricted to the management of exsanguinating haemoptysis or in small children. However, with the advent of tracheobronchial stents, the use of rigid bronchoscopy is again gaining ground.The other 1699

newer therapeutic uses of bronchoscopy include cryotherapy and laser therapy for bronchogenic carcinoma. Another important therapeutic procedure is removal of aspirated foreign body from the tracheobronchial airways. Radiologically Guided Procedures The role of USG/CT-guided FNAC and biopsy of various pulmonary abnormalities is a relatively less invasive modality to establish the diagnosis in these disorders. These procedures are quite safe and can be performed on an outpatient basis by experienced radiologists. Thoracoscopy and Mediastinoscopy Just as bronchoscopy is used for the tracheobronchial tree, thoracoscopy is used to visualise the pleura, and mediastinoscopy is used to visualise the structures of the mediastinum. The main advantage is obviously a direct visualisation of the suspicious tissue which can be biopsied for further analysis. However, these are invasive surgical procedures performed under general anaesthesia with consequent morbidity and mortality. These procedures are generally performed when one has exhausted relatively less invasive means of establishing a diagnosis. In recent years, video-assisted thoracoscopic (VATS) procedures have further improved this technique. The main diagnostic indication of thoracoscopy and VATS are pleural biopsy for undiagnosed pleural effusions

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and wedge lung biopsy for diffuse lung disease. At the same time, therapeutic procedures in the form of pleurodesis for intractable pleural effusion, bullectomy for large bullae and lung volume reduction surgery for chronic obstructive pulmonary disease can also be performed. Mediastinoscopy is very useful to appropriately stage the lung cancers preoperatively as the hilum is best visualised by this procedure. RECOMMENDED READINGS 1.

Ahluwalia G, Sharma SK, Dattagupta S, et al. The role of transbronchial lung biopsy in diffuse pulmonary disease – a review of 25 cases. Indian J Chest Dis Allied Sci 1999; 41:213-7.

2.

American Thoracic Society Workshop. Rapid diagnostic tests for tuberculosis: what is the appropriate use? Am J Respir Crit Care Med 1997; 155:1804-14. Lynch DA. Clinics in Chest Medicine. Contemporary Chest Imaging, Vol. 29. Philadelphia: Saunders; 2008.

3. 4.

McAdams HP, Samei E, Dobbins J, et al. Recent advances in chest radiography. Radiology 2006; 241:663-83.

5.

Sharma SK, Ahluwalia G. Effect of antituberculosis treatment on cardiopulmonary responses to exercise in miliary tuberculosis. Indian J Med Res 2006;124:411-8.

6.

Sharma SK, Mitra DK, Balamurugan A, et al. Cytokine polarization in miliary and pleural tuberculosis. J Clin Immunol 2002; 22: 345-52. Tak S, Ahluwalia G, Sharma SK, et al. Haemoptysis in patients with a normal chest radiograph: Bronchoscopy-CT correlation. Australasian Radiology 1999; 43:451-5.

7.

8.

Tsai TH, Yang PC. Ultrasound in the diagnosis and management of pleural disease. Curr Opin Pulm Med 2003; 9:282-90.

23.4

Upper Respiratory Tract Infections

INTRODUCTION Upper respiratory tract infections (URTIs), amongst the most common acute conditions presenting in the outpatient setting, is an important cause of morbidity and economic loss globally. Disease transmission occurs via the inhalation route and direct contact. Viruses are the most frequently implicated aetiological causes but URTIs due to primary bacterial infection or superinfection are also frequently encountered. Viral infections need to be distinguished from bacterial URTIs, as targeted treatment is available for bacterial infections. COMMON COLD AND INFLUENZA ‘Common cold’ is an upper respiratory tract infection (URTI) caused by viruses (Table 1).The term ‘influenza’ refers to a severe form of the common cold caused by the influenza virus. A new subtype of swine-origin influenza A (H1N1) virus, which has now taken the form of a pandemic, has segments from four influenza viruses, i.e. North American swine, North American avian, Human influenza, and Eurasian swine. Its incubation period is 1 to 7 days. Table 1: Five Groups of Viruses Causing Common Cold and Influenza Influenza viruses Picornaviruses (Coxsackie, Reo, Echo, and rhinovirus) Respiratory syncytial virus Parainfluenza virus Adenovirus

Clinical Features Sneezing, rhinorrhoea, nasal congestion, sore throat, nonproductive cough, pain in the eyes, and headache are the usual symptoms. Sometimes, constitutional symptoms such as malaise and myalgias may be prominent (influenza or parainfluenza virus). Fever is uncommon in adults. Occasionally, conjunctivitis (adenovirus), laryngitis (parainfluenza virus), and skin rash (enteroviruses) may also be present. Physical examination reveals post-nasal discharge, erythema around the nose, and glossy nasal mucous membranes. The pharynx may appear congested and exudates could be present on the tonsils. Jugulodigastric lymph nodes may be enlarged and tender. In influenza, extremes of age and pre-existing medical conditions attract a higher risk of complications like sinusitis, otitis media, croup, bronchiolitis, status asthmaticus, pneumonia, myositis, myocarditis, pericarditis, rhabdomyolysis, seizures, encephalitis, toxic shock syndrome, secondary bacterial pneumonia with or without sepsis. Diagnosis Real-time polymerase chain reaction (RT-PCR), or isolation of the virus in culture, or a four-fold rise in virus specific neutralising

DG Jain antibodies are used for confirmation of the diagnosis (before administration of antiviral drugs) from clinical specimens, i.e. nasopharyngeal swab, throat swab, nasal swab, wash or aspirate or tracheal aspirate in case of intubated patients. Management Common cold is usually treated empirically due to the nonavailability and cost involved in laboratory testing. The mainstay of management is symptomatic and supportive treatment directed at alleviating the symptoms of common cold rather than addressing the aetiological causes. Bed rest, adequate fluid intake, anticholinergic nasal sprays (e.g. ipratropium nasal spray) for rhinorrhoea, saline nasal drops, nasal decongestants (e.g. xylometazoline nasal spray) for nasal obstruction are used for symptomatic relief. In case of influenza, nosocomial and household spread of disease can be minimised by early institution of infection control measures and isolation of the patient in a well-ventilated isolation room/ward with beds kept at least one metre apart. Prompt treatment should be instituted with a generally welltolerated antiviral drug (e.g. oseltamivir) to prevent severe illness and death. Antiviral prophylaxis should be provided to health care personnel managing the patient. Supportive therapy includes intravenous fluids, parenteral nutrition, oxygen therapy, ventilatory support, antibiotics for secondary infection, vasopressors for shock, paracetamol or ibuprofen for fever, headache, myalgia. Aspirin/salicylate medication is contraindicated in influenza as it may cause Reye’s syndrome. Patients should be monitored for lower respiratory tract infection and for hypoxia. Close contacts of suspected, probable, and confirmed cases should be advised voluntary home quarantine for at least 7 days after the last contact with the infected person. RHINITIS It is defined as inflammation of the membranes lining the nose. Rhinitis is characterised by nasal congestion, rhinorrhoea, sneezing, itching, and/or postnasal discharge. It is classified as allergic and non-allergic (Table 2). Allergic Rhinitis The inflammation in the nose is immunoglobulin E (IgE)mediated in allergic rhinitis and is due to acute exposure to the inciting allergens which induce the early symptoms such as sneezing, itching, and clear rhinorrhoea within minutes of exposure. Late phase symptoms (nasal congestion and obstruction) appear 4 to 6 hours after exposure. The nasal mucous membrane appears boggy and pale. Acute infectious rhinitis is usually viral in origin. Secondary bacterial infection involving the sinuses is a common complication in which patients have mucopurulent or purulent nasal discharge, facial pain and pressure, and fever may be present.

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Non-Allergic Rhinitis Patients with non-allergic, non-infectious rhinitis without eosinophilia, and some with vasomotor rhinitis, present with nasal obstruction, rhinorrhoea, and congestion that may be precipitated or exacerbated by certain odours, alcohol, spicy foods, emotions, and environmental factors such as temperature, barometric pressure changes, and bright lights. Chronic nasal obstruction is frequently associated with sleepdisordered breathing. Table 2: Aetiological Causes of Rhinitis Allergic rhinitis Seasonal (e.g. pollens) Perennial (e.g. house dust mite) Occupational (e.g. animal antigens) Non-allergic rhinitis Infectious rhinitis Acute (viral, bacterial) Chronic Specific: bacterial, fungal Non-specific: immune deficiency Atrophic rhinitis (Klebsiella ozaenae) Non-allergic, non-infectious rhinitis without eosinophilia Non-allergic rhinitis with eosinophilia syndrome Vasomotor rhinitis Runners (rhinorrhoea predominates) Dry patients (nasal obstruction and airflow resistance predominate) Hormonal Menstruation Pregnancy Hypothyroidism Occupational (e.g. wood dust) Food-induced and gustatory rhinitis Drug-induced rhinitis Antihypertensives ACE-Inhibitors Reserpine Phentolamine Alpha-methyldopa Beta-blockers Chlorpromazine Aspirin and other NSAIDs Oral contraceptives Rhinitis medicamentosa Alpha-adrenergic vasodilators Oxymetazoline Phenylephrine ACE = Angiotensin converting enzyme; NSAIDs = Non steroidal antiinflammatory drugs.

Diagnosis Identification of the aetiological causes is based on the pattern, chronicity, and seasonal variation of symptoms (or the lack of these), history of medication, presence of co-existing conditions, occupational exposure, environmental history and identification of the precipitating factors. Physical examination 1702 should also focus on identifying surgically correctable

conditions such as deviation of the nasal septum (DNS), polyps, or enlarged turbinates. Allergen skin or in vitro testing is useful in detecting allergic rhinitis. Management Management of rhinitis includes antihistamines, topical corticosteroids, and avoidance of inciting factors. Second generation, non-sedating oral antihistaminics (e.g. loratadine, cetirizine, fexofenadine) are effective in reducing symptoms of itching, sneezing, and rhinorrhoea. The World Health Organization (WHO) recommends using a combination of a non-sedating anti-histamine with anti-leukotriene for treating allergic rhinitis. Intranasal anti-histaminics (e.g. azelastine), while useful in relieving rhinorrhoea, have a bitter taste and may cause sedation due to systemic absorption. Topical corticosteroids (e.g. budesonide, mometasone furoate, beclomethasone) provide ample relief in patients with allergic rhinitis. Other useful drugs for rhinorrhoea include anti-cholinergic agents (e.g. ipratropium bromide), nasal decongestants (e.g. oxymetazoline). Oral corticosteroids and allergen immunotherapy may be helpful in some patients. PHARYNGITIS Pharyngitis is defined as the inflammation of the pharynx, hypopharynx, uvula and tonsils. It is usually infectious in aetiology and majority of the cases are of viral origin. Other causes of pharyngitis include allergy, trauma, toxins and neoplasia. Pharyngitis caused by group A β-haemolytic Streptococci is more common in children aged 4 to 7 years. In persons with orogenital contact, gonococcal pharyngitis can occur. Oral thrush caused by Candida may develop in immunosuppressed persons. Clinical Features Pharyngitis may present with throat discomfort, odynophagia, cough, and constitutional symptoms such as fever, headache, malaise and myalgias. Clinical examination reveals tonsillopharyngeal erythema, exudates and rarely foul smelling grey-white pharyngeal membrane (diphtheria). Swollen tender cervical lymphadenopathy, conjunctivitis (adenovirus), maculopapular rash (infectious mononucleosis) may also be present. Cough, rhinorrhoea, and conjunctivitis are frequently associated in viral pharyngitis. Differential diagnosis includes more dangerous conditions, such as epiglottitis, laryngitis, laryngotracheitis, and peritonsillar abscess. Diagnosis Diagnosis is established by throat swab culture and serological testing. Prompt recognition and treatment of group A βhaemolytic streptococcal pharyngitis is of paramount importance as this is associated with the development of rheumatic heart disease. Management Treatment of pharyngitis is mainly symptomatic and supportive. Some patients may require antibiotic treatment. Empiric antimicrobial therapy should cover all likely pathogens in the given setting and should be tailored as per the culture and sensitivity report. Anti-fungal and anti-viral agents may be required in certain cases. Viral pharyngitis is mostly a selflimiting disease which resolves spontaneously. However, the clinician should be aware of the potential complications of pharyngitis (Table 3).

Suppurative Sinusitis Otitis media Epiglottitis Mastoiditis Peritonsillar abscess Retropharyngeal abscess Suppurative cervical lymphadenitis Pneumonia Non-suppurative Airway obstruction Acute inflammatory demyelinating polyneuropathy Thrombocytopaenia Myocarditis, pericarditis Encephalitis, meningitis Streptococcal toxic shock syndrome Acute rheumatic fever

study. Radiographs of the paranasal sinuses [occipitomental (Water’s) view and submentovertical view] and computed tomography are useful to demonstrate sinusitis radiographically. Magnetic resonance imaging is a superior modality for evaluating neoplasms, orbital and intracranial complications, and fungal sinusitis. Management Sinusitis is treated by controlling the predisposing factors (Table 4), analgesics for fever and pain relief and appropriate antibiotics.Nasal saline spray, topically administered decongestants (xylometazoline), steroids (fluticasone, beclomethasone), and cromolyn sodium, may be used for symptom relief. Surgery is indicated in patients with chronic sinusitis refractory to medical treatment, recurrent sinusitis, large obstructing polyps (Figure 1), suspicion of tumour, sinus mucocele,pyocele,intracranial extension, cavernous sinus thrombosis, and fungal sinusitis. Surgical options include functional endoscopic sinus surgery, and Caldwell-Luc operation.

Upper Respiratory Tract Infections

Table 3: Complications and Sequelae of Pharyngitis

SINUSITIS Inflammation of the paranasal sinuses results in sinusitis. Numerous factors predispose to the development of sinusitis (Table 4). Table 4: Conditions Predisposing to the Development of Sinusitis Anatomic abnormalities of the osteomeatal complex (e.g. deviated nasal septum, concha bullosa, bone spurs) Allergic rhinitis Vasomotor rhinitis, rhinitis medicamentosa, cocaine abuse Nasal polyps Nasotracheal, nasogastric intubation Tumours causing obstruction Dental disease/surgery Recurrent upper respiratory infections Immune deficiency (e.g. common variable immunodeficiency) Cystic fibrosis Kartagener’s syndrome and other immotile cilia syndromes Tobacco smoking Environmental pollution

Clinical Features Patients with acute sinusitis present frequently with persistence of symptoms even after the common cold has subsided, with nasal congestion, mucopurulent or purulent nasal discharge, headache, facial pain or heaviness, and fever. Pain increases in bending forwards. Localised tenderness indicates involvement of a group of sinuses. Maxillary sinuses are more commonly affected. The nasal mucosa appears oedematous with copious secretions. In chronic sinusitis, pain and fever are seldom present and the predominant symptoms are nasal obstruction, purulent nasal discharge, postnasal drip, chronic cough, hyposmia and halitosis. Clinical examination reveals an inflamed, thickened mucosa with polypoidal changes. Diagnosis Nasal endoscopy is useful for direct visualisation and for obtaining samples for microbiological and histopathological

Figure 1: Radiograph of paranasal sinuses showing maxillary sinusitis on the right and a polyp on the left. Courtesy: Dr. S.N. Gosavi.

RECOMMENDED READINGS 1.

Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. American Academy of Allergy, Asthma, and Immunology. Ann Allergy Asthma Immunol 1998; 81: 478-518.

2.

Murray JAM, Maran AGD. Section 1 – The Nose; Section 2 – The Head and Neck. In: Maran AGD, editors. Logan Turner’s Diseases of the Nose, Throat and Ear; 10th Ed. London: Hodder Arnold; New Delhi: Jaypee; 2006: pp 1-103.

3.

Sharma SK, Mohan A. Viral upper respiratory tract infections. In: Rakel RE, Bope ET, editors. Conn’s Current Therapy 2007. Philadelphia: Saunders; 2007: pp303-6.

4.

Staevsks MT, Baraniuk JN. Differential diagnosis of persistent nonallergic rhinitis and rhinosinusitis syndromes. Clin Allergy Immunol 2007; 19: 35-53.

5.

Wong DM, Blumberg DA, Lowe LG. Guidelines for the use of antibiotics in acute upper respiratory tract infections. Am Fam Physician 2006; 74: 956-66.

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23.5

Bronchial Asthma Virendra Singh, Ajeet Singh

DEFINITION Bronchial asthma is a chronic airway disorder which can affect people of all age groups. According to the global initiative for asthma (GINA), asthma is defined as a chronic inflammatory disorder of airways which is associated with airway hyper-responsiveness. It leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or early morning. These episodes are usually associated with widespread but variable airflow obstruction within the lungs that is often reversible either spontaneously or with treatment. In asthmatic patients, airway inflammation usually persists even during asymptomatic periods. Though symptoms and bronchospasm are intermittent, airway inflammation is persistent. Based on the concept of persistent airway inflammation, two important principles have emerged. First, the disease is chronic, often life-long; second, its severity fluctuates and sometimes there may be prolonged remissions.

Trigger Factors Wide range of factors can trigger symptoms in a patient with asthma, important among these are as follows:

EPIDEMIOLOGY Prevalence of asthma varies considerably within countries and between countries. It is more prevalent in developed countries than developing ones, more in children (15%) than adults (10% to 12%), more in urban than rural areas, reasons of which are not fully understood. Nearly 8% to 10% of the total population suffers from it. In India, the prevalence of asthma has been found to be around 7% in the majority of surveys done. However, it has been reported to vary from 2% to 17% in different study populations, the disease can start at any age, but in a majority it starts before 10 years of age. It is twice as common among boys than girls, whereas in adults the male to female ratio is usually equal.

Infections Patients often give history of an upper respiratory tract infection before an attack of asthma. These symptoms are usually due to rhinovirus infection. Viral infections are the major triggering factors for asthma exacerbations, but it is uncertain that they play an important role in aetiology of bronchial asthma. Recently, atypical micro-organisms like Mycoplasma and Chlamydia have also been identified in the mechanism of severe asthma.

AETIOPATHOGENESIS Aetiologic factors of asthma are divided into two groups: inducing factors and trigger factors. Inducing factors induce asthma in susceptible persons and these include genetic factors, obesity, viral infections in early life and exposure to tobacco smoke. Trigger factors such as allergens, vigorous exercise, viral infections, etc. can provoke symptoms in subjects already having asthma. Some factors such as viral infection and occupational sensitisers act as both inducer and trigger factors. Inducing Factors Asthma occurs more commonly in relatives of atopic individuals, and therefore, atopy has been recognised as an important risk factor for developing asthma. A distinct gene for atopy on chromosome 11q has been identified. Similarly, a gene at chromosome 5q has been linked to the synthesis of immunoglobulin (Ig)E. Tobacco smoke, maternal smoking during pregnancy or infancy, rhino-syncytial virus infections and exposure to high concentration of allergens during infancy 1704 can also induce bronchial asthma.

Allergens Inhaled allergens are the common triggering factors responsible for provoking symptoms of asthma. House dust mite is the commonest allergen. Pollen, mold, animal dander and cockroaches are other common allergens provoking asthma. Environment Asthma is usually worse on a cold and dry day, especially when there is a strong wind. Traffic pollution can aggravate symptoms in asthmatic patients. Air pollutants such as sulphur dioxide, ozone, diesel particles can also precipitate asthmatic symptoms. Indoor air pollution is also an important trigger factor. Cooking gas fumes and even passive cigarette smoking can trigger symptoms in asthmatic subjects. Paints, sprays and fumes can also precipitate severe symptoms in patients with asthma.

Drugs Beta-blockers and cholinergic drugs used for Myasthenia gravis and prostaglandins-2 (PGF-2) used for inducing abortion are known to cause bronchoconstriction in patients with bronchial asthma. Aspirin and nonsteroidal anti-inflammatory drugs are known to trigger asthma in almost 5% of the patients. Aspirinsensitive asthma is more common in intrinsic variety of asthma, especially those having nasal polyps. Majority of aspirinsensitive patients tolerate paracetamol quite well. Food Food allergens are not so common triggers of asthma. Egg, milk, and wheat are implicated in causing asthma in a few cases. The yellow colouring agents of food such as tartrazine and food preserving agents such as sulphites can also aggravate asthma in some patients, often those who are sensitive to aspirin. Physical characteristics of food such as cold edibles are usually not implicated in aggravation of asthma. However, Indians are reported to be more sensitive and they exhibit bronchoconstriction to edibles such as ice. Diet rich in anti-oxidants such as vitamin C and vitamin A, selenium, magnesium and omega-3 polyunsaturated fats or high in sodium and omega-6 polyunsaturated fats are associated with increased risk of bronchial asthma. Some asthmatics may show aggravation of symptoms to sea food items.

Psychological factors Stress can influence asthma in some patients. However, it is rarely a major contributor to the severity of asthma. Occupation Occupational asthma is caused by a specific agent present at the work place. Occupational asthma affects almost 10% of the young adults. More than 200 agents have been linked with triggering of asthma at work places. Chemicals such as isocyanates, platinum, chrome, nickel, reactive dyes of diazonium salt, pharmaceutical agents, wood dust and cotton dust are among the common causes of occupational asthma. Gastro-oesophageal reflux Gastro-oesophageal reflux has been associated with triggering of asthma. Microaspirate of gastric contents and nervous reflex causing bronchoconstriction are common mechanisms proposed to explain GER-induced asthma. PATHOLOGY Gross Appearance Patients dying from acute episodes of asthma have bulky and over distended lungs which fail to deflate when the chest is opened. The airways are thickened and plugged with sticky secretions.

Microscopic Appearance The main features of asthmatic airways include marked thickening of basement membrane, bronchial smooth muscle hypertrophy and damaged epithelium, much of which is shaded. The bronchial wall contains inflammatory cells and the most important cell is eosinophil. Other cells include neutrophils, lymphocytes and plasma cells. The mucous or bronchial secretions of an asthmatic patient contain eosinophils, eosinophil cationic protein, desquamated airway epithelial cells termed as creola bodies, Charcot-Leyden crystals, and thick thread-like sputum called Curschmann’s spirals. The mucus is often impacted in the small airways in severe asthma.

Bronchial Asthma

Exercise Vigorous exercise, particularly on a cold and dry day, will cause symptoms in 80% of the patients with asthma. Exercise related exacerbation is also termed as exercise-induced asthma.

PATHOGENESIS OF ASTHMA Initial Sensitisation It is now clear that T-lymphocytes play a key role in asthmatic airway inflammation and sensitisation. There are two types of T-lymphocyte helper (Th) cells.Th1 controls synthesis of Igs such as IgA and IgM whereas Th 2 controls IgE production. Usually, there is a balance between Th1/Th 2 switch. Exposure to an inducing factor sensitises T cells of a person with genetic susceptibility with bronchial asthma, and it shifts the Th1/Th 2 switch in favour of Th 2 dominance. Once sensitised, these Th 2 cells get into airway mucosa and governs IgEmediated responses of allergic reaction (Figure 1). In a normal individual, when a noxious allergic substance enters the airway, IgA is released. However, in a sensitised person IgE is released. Once sensitised, the dose of the noxious agent that provokes asthma on subsequent exposure is much less.

Figure 1: Pathogenesis of asthma. Ig = Immunoglobulin.

1705

Provocation of Asthma When an allergen is inhaled by an asthmatic patient, airway obstruction starts within minutes and the peak effect is observed within 20 to 30 minutes. This is an early phase reaction or early response and is due to the direct action of mast cell derived mediators on the smooth muscles of the airways. When inhaled allergens come in contact with mast cells located in airway mucosa, then histamine and arachidonic acid derivatives such as leukotrienes and PGF are released. In some cases, the reaction soon terminates and resolution starts with the decrease in short-lived mediator concentration. Whereas in many cases, a second phase of airway obstruction occurs 6 to 10 hours later. This is called late phase reaction or late response and it is inflammatory in nature (Figure 1). CLINICAL FEATURES Symptoms Episodic breathlessness, wheezing, cough and chest tightness are important symptoms of bronchial asthma. These symptoms show a characteristic pattern of diurnal variability of worsening during night and early morning. It may lead to disrupted sleep due to cough and wheeze. There is an increased mucous production, which is thick, mucoid and difficult to expectorate. History of recurrent episodes of asthma caused by one or more trigger factors is important for the diagnosis of bronchial asthma. However, between episodes, patients usually remain symptom-free. Asthmatics are frequently associated with other atopic conditions, such as eczema, urticaria, allergic rhinitis, and hay-fever. Physical Examination Rhonchi are heard as the most prominent sign of asthma, especially during expiration. At the time of asthma exacerbation signs such as increased respiratory rate, flaring of alae nasi, use of accessory muscles of respiration, and pulsus paradoxus may be detected. In view of the diurnal variation of airflow obstruction, asthmatic symptoms and signs vary with worsening during night and improvement during day. Therefore, physical examination during day may be normal, and hence, the absence of signs does not exclude the diagnosis of bronchial asthma. DIFFERENTIAL DIAGNOSIS Wheezing and dyspnoea are prominent symptoms of asthma, and conditions presenting with these symptoms may pose diagnostic problem. The differentiation of chronic obstructive pulmonary disease (COPD) from asthma can pose clinical difficulty. History of smoking, exertional dyspnoea, and lack of symptoms-free periods favour a diagnosis of COPD, whereas nocturnal worsening, chest tightness, episodic pattern and good response to bronchodilators and steroids favour diagnosis of asthma. Bronchodilator reversibility shown in spirometry is diagnostic of bronchial asthma.

1706

Acute left ventricular failure may cause wheezing and dyspnoea especially during nights. Dyspnoea starting 1 to 2 hours after sleep, history of heart disease, inspiratory crepitations and gallop rhythm supports the diagnosis of left ventricular failure, whereas early morning dyspnoea and response to bronchodilators are characteristic of asthma.

Upper airway obstruction with a tumour or lymphadenopathy is occasionally mistaken for asthma. It usually presents with rapidly progressive airway obstruction and inspiratory stridor. Spirometry shows reduced inspiratory flow and tracings of flowvolume curve becomes flat instead of being curved normally. Hyperventilation syndrome, foreign body aspiration, bronchiectasis pulmonary tuberculosis and acute pulmonary thromboembolism are also sometimes confused with asthma. Careful history and documentation of variable and reversible airway obstruction can differentiate asthma from these conditions. DIAGNOSIS Blood Examination Usually, patients have an eosinophil count in the range of 5% to 15%, or the absolute eosinophil count is more than 400. Total serum IgE and specific IgE are elevated in bronchial asthma. Sputum Induction Sputum examination can provide a useful clue about the severity of airway inflammation. Sputum is induced after administration of hypertonic saline with a nebuliser. In patients with asthma, the number of eosinophils are increased in the induced sputum. Estimation of eosinophilic cationic protein in sputum or urine is also found to be a useful test for assessment of the severity of airway inflammation. Airway Hyperresponsiveness Increased airway hyperresponsiveness (AHR) is a characteristic of bronchial asthma. It can be measured by methacholine or histamine challenge test. This test is useful in the diagnosis of asthma when the patient is in remission with normal lung functions. Chest Radiograph Radiograph of the chest may show hyperinflation in a patient with asthma. It may also reveal complications of severe asthma such as rib fracture, pneumothorax, and pneumomediastinum. High Resolution Computerised Tomography of Chest Routinely, this investigation is not required in patients with bronchial asthma unless some associated lung disease is suspected. High resolution computerised tomography shows areas of thickening of the bronchial wall in patient with severe asthma. Identification of Trigger Factors A good history is important in identification of trigger factors. Particular care should be taken in evaluation of environmental factors and occupation of the patient. Household work, especially in the kitchen, is an important provoking factor in many housewives whereas agricultural work such as grain storage, cutting of crops, pesticide spray and exposure to cold during irrigation may be important in rural asthmatics. It is also important to ask about both nocturnal and exercise-induced symptoms. Skin Prick Test Sensitivity to a particular antigen can be identified by injecting a small amount of allergens into the skin. Wheal and flare appear at the site of injection of a sensitised allergen. Skin prick test to common inhalant allergens is usually positive in allergic asthma. Allergens can also be identified by estimation of specific IgE in

Measurement of Lung Functions Various types of lung function tests are available, but measurements of peak expiratory flow rate (PEFR) by a peak flow meter and forced expiratory volume in one second (FEV1) by a spirometer are most useful in a making diagnosis and assessing the severity of asthma. Peak expiratory flow rate Peak expiratory flow rate represents maximal expiratory effort performed after full inhalation. Peak expiratory flow rate is reduced with increasing severity of airway obstruction. It can be measured with a handy tool called peak flow meter. This equipment is very useful in monitoring the severity of asthma and designing a treatment plan on an individual basis. Usually, PEFR values of a patient is compared with the predicted normal values. However, there is a large variation in normal predicted values, and therefore personal best PEFR value is taken as normal reference value. Personal best value is the highest recorded PEFR value of a person taken over a few days during asymptomatic period. Normally, there is variation in PEFR values taken at different times of the day. The magnitude of variation between morning and evening PEFR values is called PEFR variability and it is proportional to the severity of asthma. Another useful index is PEFR reversibility. After baseline PEFR, beta-2 agonist drugs such as salbutamol or terbutaline are administered through an inhaler or nebuliser. The PEFR noted 15 minutes after the bronchodilator administration, shows the magnitude of reversibility. More than 20% reversibility or variability is diagnostic of bronchial asthma.

ASSESSMENT OF SEVERITY Severity of asthma is highly variable. Assessing the severity of asthma on the basis of one parameter does not represent a true picture. Therefore, GINA guidelines suggest a method of assessing asthma severity on the basis of parameters such as symptoms, activity limitation, lung function tests, inhaler use, and frequency of exacerbations. On the basis of these parameters, asthma is categorised into controlled, partly controlled and uncontrolled as described below. Indices Determining Control of Asthma 

Day-time symptoms less than twice per week



Short-acting beta agonist (SABA) inhaler use less than twice per week



Without any night-time symptoms



Without limitation of activity



Normal PEFR and FEV1 values

Controlled Asthma is said to be controlled if all indices are fulfilled and patient did not have an exacerbation in the last one year. Partly controlled Asthma is said to be partly controlled, if any of the indices is more severe than described above or the patient had an exacerbation during the last one year. Poorly controlled Asthma is said to be poorly controlled, when more than 3 indices are more severe than described above, or the patient had an exacerbation during the last week.

Lung Volumes and Diffusing Capacity Lung volumes, such as residual volume and total lung capacity, are increased in a patient with asthma. Carbon monoxide diffusing capacity (DLCO) is either normal or increased in the asthma patients. Diffusing capacity of the lung for carbon monoxide is reduced in patients with COPD, therefore, it is useful in differentiating COPD from asthma.

MANAGEMENT OF ASTHMA Patient Education It is aimed to enable asthmatic patient to treat himself under guidance of his doctor. It is achieved by proper education of the patient. Patient education is as important as drug treatment. Every patient with asthma should learn to take medicines regularly, correctly and understand the difference between relieving and preventive medicines. Identification and avoidance of risk factors and triggers involved in asthma are also important components of patient education. Monitoring the severity of the disease by symptom score or peak-flow meter, action plans for a situation like exercise-induced and acute attack, and misconception about the disease should also be addressed.

Oximetry In assessing severity of acute severe asthma, pulse oximetry is a useful tool. It detects hypoxaemia in severe asthma. Normally, oxygen saturation should be more than 90%. Pulse oximetry is also helpful in monitoring oxygen therapy.

Identify and reduce exposure to risk factors Asthma exacerbation can be caused by a variety of trigger factors. Early identification of a trigger factor and preventing its exposure improves asthma control and reduces requirement of medicines.

Arterial Blood Gas Analysis Periodic measurement of arterial blood gases proves useful in monitoring of patients with acute asthma. Arterial blood gas analysis give basic information about pH, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2) and bicarbonate (HCO3). In severe asthma, PaO2 decreases but PaCO2 remains normal. When PaCO2 starts rising, it is an indication of requirement for assisted ventilation.

Assess, monitor and treat asthma Asthma control is assessed and then patient is treated to achieve the control. Once adequate control is achieved, the patient is monitored regularly to maintain the control.

Spirometry Asthma is diagnosed by demonstration of reversible airway obstruction in spirometry. A ratio of FEV1 and forced vital capacity (FVC) less than 0.7 is diagnostic of airway obstruction. After bronchodilator administration, FEV1 increases by more than 12% and 200 mL in asthmatic patients. It is called reversibility of airway obstruction which is characteristic of asthma.

Bronchial Asthma

the blood through radioallergosorbent test (RAST). However, SPT is cheaper and more sensitive than RAST.

Manage exacerbation The aim of treatment during management of an exacerbation is to relieve bronchospasm and hypoxia as quickly as possible. 1707

A future plan is made to prevent recurrence of episodes of exacerbation. Special Situation At times, asthma management requires attention to special situations such as allergic rhinitis, pregnancy, aspirin sensitivity, occupational compulsions, and gastro-oesophageal reflux. DRUG THERAPY Mode of Administration Asthma drugs are administered as injection, tablet, syrup, or in aerosol form. Aerosol administration through inhaler devices is the preferred mode of administration. With aerosols, the dose and the side effects of the drug are much less and the therapeutic effect is better. Drugs such as theophyllines and anti-leukotrienes are not available in aerosol form. In order to get optimal therapeutic effect, the technique of aerosol use should be correct. Devices used for delivering inhaled medications include metered dose inhaler (MDIs), dry powder inhaler (DPIs) and nebulisers (jet nebulisers and ultrasonic nebulisers).With steroid MDIs and DPIs, hoarseness of voice and oral candidiasis are common in some patients. Rinsing the mouth after the use of inhaler, use of a spacer device with MDI and the use of MDIs and DPIs before food are some of the measures to prevent local adverse effects of inhaled corticosteroids. When used with spacer, delivery of MDI drug into airways also improves. Commonly Used Drugs Drugs for asthma are divided into two categories: bronchodilators or relievers, and controllers or preventers (Table 1). The bronchodilators work quickly and relieve the symptoms and acute attack of asthma rapidly. Beta-2-agonists, anticholinergics, and theophyllines are included in this category. The controller medicines prevent the onset of symptoms by controlling inflammation. Inhaled corticosteroids (ICS), systemic corticosteroids, anti-leukotrienes, and cromones are included in this category. The broad guidelines of asthma management are given in Figure 2. Bronchodilators Drugs Bronchodilators are the drugs which primarily act on smooth muscles of airways and cause rapid relief of symptoms. There are 3 classes of bronchodilator medicines—β-2 agonists, anticholinergics, and theophyllines. Beta-2-agonists The most commonly used bronchodilators are beta-2-agonists. Inhaled preparations are better because even in a small dose they cause equal or better bronchodilatation and the action is much quicker. Salbutamol and terbutaline are short-acting β-2 agonist (SABA) having a duration of action of 3 to 6 hours. Salmeterol and formoterol are long acting β-2 agonists (LABA) having a duration of action over 12 hours. Short-acting β-2 agonists are very good for the treatment of an attack of asthma and for pre-treating the symptoms associated with exercise. Since long-term regular use of SABA is associated with poor control of asthma, therefore, SABA should not be used on a regular basis. Long acting β-2 agonists are also not used regularly as monotherapy. Since LABA does not control airway inflammation, therefore, it should be used in combination with ICS. However, recently use of LABA in 1708 combination with ICS has also been restricted. It has been

Figure 2: Steps of asthma management based on GINA guidelines. Goal of therapy is to achieve asthma control. SABA is used at all steps. SABA = Short-acting β-2 agonist; ICS = Inhaled corticosteroids; LABA = Long-acting β-2 agonist; IgE = Immunoglobulin E; p.r.n.= as and when required.

advised that combination of LABA and ICS should be used only in those patients whose asthma fails to be controlled with controllers such as ICS alone. Anticholinergics Interestingly, Datura plant was used as the first inhaled medicine and the hookah, the local filtered tobacco inhaler, as the first inhaler device.These two were both discovered and invented in India.With the introduction of more selective anti-muscarinic drugs, interest in these drugs was renewed. Ipratropium bromide is a short-acting muscarinic antagonist of this class. It can be used as reliever therapy in patients who do not respond to beta-2-agonists. Theophyllines Two types of formulations of theophylline are available: shortacting and sustained-release. Short-acting theophylline has erratic absorption and therefore, can lead to rise in serum concentration to toxic levels unpredictably. Sustained-release theophylline has more uniform absorption and a longer half-life. It inhibits both early and late asthma reactions after an allergen exposure. It also has some anti-inflammatory properties. Controller Drugs Inhaled corticosteroids Corticosteroids are the most effective controller and antiinflammatory medicines reducing the number of inflammatory cells and their activation in the airways. It improves lung functions, decreases airway hyper-responsiveness, reduces and prevents symptoms. Inhaled corticosteroids are preferred over tablets or syrup for long-term therapy. Inhaled corticosteroids are safe and effective for long-term treatment of asthma. Beclomethasone, budesonide, fluticasone and ciclesonide are commonly used inhaled steroid preparations. Systemic glucocorticosteroids Systemic glucocorticosteroids are important in the treatment of exacerbation of asthma because they prevent its progression.

Drug Category and Name

Mode of Administration

Dose

Indication

Side Effects

Oral, inhalation Oral, inhalation

2 to 4 mg, 100 to 200 mcg 5 mg, 250 to 500 mcg

Reliever Reliever

Tremors, tachycardia

Inhalation Inhalation

4.5 to 9.0 mcg/q 12 hourly 50 to 100 mcg/q 12 hourly

Controller Controller

Mouth-throat irritation Hypokalaemia

Methylxanthines Theophylline Aminophylline Doxophylline

Oral Oral and slow IV Oral

100 to 300 mg/q 8 hourly 250 to 500 mg 400 mg/od

Reliever

Cardiac arrhythmias Tachycardia Mouth-throat irritation Hypokalaemia, hypotension Tremors, death

Anticholinergics Ipratropium bromide

Inhalation

40 mcg/qid

Reliever

Dry mouth, blurred vision, Glaucoma, urinary retention

20 to 40mg 0.5 to 5 mg/qd 4 to 20 mg/qd 100 mg bolus–100 mg/q 8 hourly 200 to 2,000 mcg 200 to 1,600 mcg 100 to 1,000 mcg 80 to 1,280 mcg

Controller Controller Reliever Reliever Controller Controller Controller Controller

Osteoporosis, diabetes Arterial hypertension

Hydrocortisone Beclomethasone Budesonide Fluticasone Ciclesonide

Oral Oral IV IV Inhalation Inhalation Inhalation Inhalation

Mast cell stabilisers Sodium cromoglycate Ketotifen

Inhalation Oral

1 mg/dose(2 puffs/q 8 hourly) 1 to 2 mg/q 12 hourly

Controller Controller

Cough, throat irritation Sedation, dry mouth

Anti-IgE-antibody Omalizumab

Subcutaneous

150 to 375mg, 2 to 4/week

Severe allergic asthma uncontrolled with inhaled steroids

Headache, anaphylaxis sinusitis

Leukotriene modifiers Montelukast Zafirlukast Zileuton

Oral Oral Oral

5 to 10 mg/day at bed-time

Controller

Well-tolerated

Beta-2-agonist Short-acting β agonists (SABA) Salbutamol Terbutaline Long-acting β agonists (LABA) Formoterol Salmeterol

Corticosteroids Prednisolone Dexamethasone

Bronchial Asthma

Table 1: Drugs Used in Management of Asthma

Cataract, glaucoma Adrenal suppression Obesity, muscle weakness

IV = Intravenous; d = Day; od = Once a day.

During exacerbation, a short course of oral corticosteroid (40 to 60 mg prednisolone) is given daily for 5 to 10 days. When the patient symptomatically improves, the oral corticosteroid can be stopped or tapered off but ICS must be continued. Leukotriene modifiers The inflammatory cells like mast cells and eosinophils in asthmatic patients produce cysteinyl leukotrienes which are potent bronchoconstrictors. Cysteinyl leukotriene (CysLT1) receptor antagonist drugs like montelukast, pranlukast, zafirlukast and 5-lipoxygenase inhibitor zileuton can prevent such bronchoconstriction, improve symptoms and reduce airway inflammation. These medicines are used as add-on therapy. Leukotriene inhibitors are especially useful in patients with aspirin-induced asthma. Cromones Sodium cromoglycate and nedocromil sodium can cause inhibition of mast cell and sensory nerve activation, and therefore, are effective in trigger-induced asthma such as exercise-induced

asthma, allergen and sulphur dioxide- induced asthma.These are very safe but have a short duration of action. Anti-IgE-antibody IgE mediates important allergen-induced reaction in asthmatic airways. Omalizumab is an antibody which neutralises circulating IgE and inhibits IgE-mediated reactions. This is used only in patients with severe allergic asthma having elevated levels of IgE and who remain uncontrolled with a maximal dose of ICS. Antigen-specific immunotherapy The role of antigen-specific immunotherapy in patients with asthma is limited. Proper immunotherapy requires identification of single clinically relevant allergen. Objective evidence suggests that immunotherapy with highly purified allergens is useful in dust mite, pollen and animal dander allergies. Some authorities believe that immunotherapy is more effective in patients having 1709 dominant nasal symptoms.

ALTERNATIVE THERAPIES Majority of alternative or complementary therapies are not useful in asthma. Yoga, hypnosis, and acupuncture have shown small beneficial effects in some studies; however, well-planned randomised controlled trials are lacking. DIFFICULT ASTHMA Five per cent of asthmatic patients are difficult to control with the available conventional therapy for asthma. The most common reason for uncontrolled asthma is non-compliance of medication. There are several factors which make asthma more difficult to control, e.g. exposure to high concentration of allergens or exposure to unidentified occupational agents. Viral, bacterial, and mycoplasma infections can sometimes lead to refractory bronchospasm. Uncontrolled gastro-oesophageal reflux and simultaneous use of drugs such as beta-blockers, aspirin, and cyclo-oxygenase inhibitors are also important risk factors of difficult asthma. Refractory asthma is difficult to treat unless primary factors are adequately controlled. Compliance, proper use of inhalers, identification, and elimination of underlying triggering factors are important steps in the management of difficult asthma. ACUTE SEVERE ASTHMA This is an extreme stage of severity of asthma formerly termed as status asthmaticus. Clinical features of acute severe asthma include coughing, wheezing, shortness of breath, and chest wall recession (indrawing in the flesh between the ribs and sternum), inability to complete a sentence in one breath, use of accessory muscles, respiratory rate >25 per minute, pulse >110 per minute and presence of pulsus paradoxus. Pulsus Paradoxus In normal individuals the systolic blood pressure falls by 2 to 4 mm Hg with normal inspiration and 10 mm Hg with deep inspiration. When systolic pressure falls more than 10 mm Hg during inspiration, the pulse is called as pulsus paradoxus. Presence of pulsus paradoxus indicates presence of severe asthma and in such patients PEFR is usually less than 60% of the predicted or best. Pulsus paradoxus may also be present in other conditions such as cardiac tamponade, constrictive pericarditis, and superior vena cava obstruction. If the condition worsens, airways become further narrowed and the movement of air decreases. In such situations, sometimes wheezing ceases. It indicates that the airways are extremely narrowed and very little air is moving in and out. This is also called silent chest type asthma. Features of life-threatening asthma include silent chest, cyanosis, or feeble respiratory effort, bradycardia, hypotension and PEFR 5% patients with longstanding sarcoidosis. As fibrosis sets in, pleural adhesions to the diaphragm, bullae, cysts and honeycombing are observed in the end-fibrotic stage of the disease. Involvement of larynx, trachea and bronchi can lead to stridor, airway obstruction and bronchiectasis. Pleural effusion, pneumothorax and pleural thickening are uncommon findings. Nasal stuffiness and palatal obstruction or disfigurement from lupus pernio has been described. Contrast-enhanced computed tomography (CECT ) demonstrates the lymphangitic distribution. The characteristic CECT findings are ground-glass attenuation (Figure 3), central bronchovascular thickening and nodularity (Figure 4), thickening of inter-lobular septae, miliary nodules, conglomerate masses, consolidation and architectural distortion, parenchymal and pleural nodules. Contrast-enhanced computed tomography also demonstrates paratracheal, hilar and mediastinal lymphadenopathy. Table 2: Chest Radiographic Stages in Sarcoidosis Stage

Finding

Frequency

0 I II III IV

Normal chest radiograph Bilateral hilar lymphadenopathy (BHL) BHL and pulmonary infiltrations Pulmonary infiltrations without BHL Pulmonary fibrosis

5% to 10% 50% 25% 15% 5% to 10% 1759

Figure 4: CECT chest showing nodular sarcoidosis.

Figure 2: Chest radiograph (postero-anterior view) showing bilateral hilar lymphadenopathy and pulmonary infiltrates (stage II sarcoidosis).

aspiration, and bronchoalveolar lavage (BAL) are all useful to obtain tissue sample for the diagnosis of sarcoidosis. The bronchoscopic appearances of sarcoidosis are plaques, nodules, and erythema and cobblestone appearance. Bronchoalveolar lavage reveals lymphocytic alveolitis with an elevated CD4+/CD8+ ratio. Cardiac Sarcoidosis In clinical series, cardiac dysfunction is uncommon (5% to 10%) compared with autopsy studies where a higher prevalence of cardiac sarcoidosis (76%) has been described. Granulomas and scars are commonly found in the left ventricular free wall and the interventricular septum with involvement of the conducting system. Cardinal cardiac manifestations include arrhythmias of all types, conduction abnormalities, congestive heart failure, and sudden death. Other cardiac manifestations include papillary muscle dysfunction, infiltrative cardiomyopathy and pericarditis. Doppler echocardiography may show cardiac dysfunction, especially diastolic dysfunction.Thallium-201 (201Tl) scintigraphy shows segmental areas of decreased thallium uptake and this corresponds to granulomata or fibrosis. The perfusion defects in sarcoidosis decrease in size during exercise and this is in contrast to the findings in cardiac ischaemia (‘reversed distribution’). Endomyocardial biopsy may be useful to demonstrate noncaseating granulomas in cardiac sarcoidosis.

Figure 3: CECT chest showing ground-glass attenuation.

Pulmonary functions and gas exchange Pulmonary function test results are often normal in early stages. The main pulmonary function abnormalities in advanced disease are restrictive ventilatory defect and reduced diffusion capacity for carbon monoxide (DLCO). Airway obstruction is also observed when the bronchial mucosa is involved. Pulse oximetry is often normal when measured at rest but may show desaturation after exertion in patients with extensive lung involvement. Arterial blood gas analysis at rest and during exercise is more sensitive than pulse oximetry. Reversible airway obstruction mimicking bronchial asthma and airway hyperreactivity have also been reported in Indian patients. Bronchoscopy Flexible fibre-optic bronchoscopy (FOB), transbronchial lung 1760 biopsy (TBLB), endobronchial biopsy, transbronchial needle

Skin Involvement Skin involvement is common (25%) and the cutaneous manifestations range from small purplish macules, papules to plaques, and subcutaneous nodules. Alopaecia and hypo- and hyper-pigmented areas are also noticed. Sometimes, sarcoidosis can occur in scars and tattoos. Erythema nodosum is a manifestation of acute sarcoidosis and usually lasts for about 3 weeks. Lupus pernio is an indurated, lumpy, violaceous lesion on the nose, cheeks, lips or ears and can be extremely disfiguring and may erode into underlying cartilage and bone. Neurosarcoidosis Neurological manifestations are rare (30 ), as per the American Academy of Sleep Medicine. After a diagnosis of sleep apnoea is established, a continuous positive airway presure (CPAP) titration is done and the ‘split-sleep ‘ study does away with the conventional two-night sleep study. Infant and pediatric sleep studies are possible with the help of specialised personnel using paediatric specific equipment. TREATMENT Treatment options for OSA are outlined in Table 2. Table 2: Treatment Options for Obstructive Sleep Apnoea Syndrome General measures Change of position during sleep Avoidance of alcohol and sedatives Oxygen therapy Sleep hygiene Specific measures Oral appliances Continuous positive airway pressure Bi-level positive airway pressure Auto-adjusting positive airway pressure Surgical treatment Nasal Reconstruction Uvulectomy Pillar procedure Tonsillectomy and/or adenoidectomy Uvulopalatopharyngoplasty Laser-assisted pharyngoplasty Linguloplasty Genioglossus advancement Thyrohyoid suspension Maxillomandibular advancement Tongue base surgery Radiofrequency ablation Tracheotomy

A repeated PSG with the oral appliances in place is essential, in order to make appropriate adjustments. Continuous Positive Airway Pressure Treatment Positive airway pressure (PAP) devices act like a pneumatic pump supplying positive pressure to the upper airways, thereby preventing collapse and occlusion during sleep. CPAP has been demonstrated to reduce the AHI and improve subjective and objective sleepiness. Despite its demonstrated efficacy, the adherence to therapy is suboptimal. An estimated 15% to 30% of the patients do not accept CPAP treatment and upto 25% of the patients discontinue the treatment within the first year. Average adherence to PAP has been estimated at 65%. Other PAP delivery modes which may provide greater comfort and better adherence are the auto-adjusting PAP (APAP), Bi-level PAP (BiPAP) and flexible PAP (C-Flex). The APAP devices have the ability to simultaneously detect and prevent upper airway obstruction using the lowest possible pressure during sleep. Bi-PAP devices deliver two independently adjusted levels of pressure: high pressure during inhalation and a low pressure during exhalation. C-Flex devices lower the pressure level at the beginning of exhalation, returning to set pressure before exhalation ends. It is thought that the flexible amount of pressure relief causes an increase in comfort to the patient, thereby resulting in better therapeutic adherence. There are ongoing studies on the use of cognitive behavioural therapy and theory based music intervention as means of improving adherence to CPAP therapy. Surgical Treatment Once surgical treatment is indicated,conservative procedures must be tried first and only after that, comes the aggressive procedures and second-line treatments. Since the introduction of uvulopalatopharyngoplasty (UPPP) in 1981, it is the most common procedure for treating OSA. CLINICAL OUTCOMES AND MORTALITY IN OSA The various clinical outcomes in patients with OSA are listed in Table 3.The risk of death among patients with untreated severe OSA is about three times that of the general population or of those patients with mild OSA. The increased risk of mortality was seen in younger patients, prompting the suggestion that diagnosis and treatment be done early. Table 3: Clinical Outcomes in Obstructive Sleep Apnoea Death Cardiovascular Non-fatal myocardial infarction Non-fatal stroke Heart failure Arrhythmias Pulmonary hypertension Systemic hypertension Traffic accidents Daytime sleepiness

Oral Appliances Oral appliances are now being considered as first-line treatment for patients with mild to moderate OSA, though previous literature was contrary to this. Oral appliances have been found to be as useful as CPAP in improving subjective sleepiness. A retrospective study done in patients with severe OSA, reporting 1766 to a single dental sleep clinic, showed reduction of AHI by 50%.

RECOMMENDED READINGS 1.

Kumar VM. Sleep and sleep disorders. Indian J Chest Dis Allied Sci 2008; 50: 129-35.

2.

Punjabi NM.The epidemiology of adult obstructive sleep apnoea. Proc Am Thorac Soc 2008; 15;5: 136-43.

3.

Vijayan VK, Patial K. Prevalence of obstructive sleep apnoea syndrome (OSAS) in Delhi, India. Chest 2006; 130: 92s.

23.16 DEEP VENOUS THROMBOSIS Deep venous thrombosis is commoner than generally perceived; one of four patients admitted for a general medical condition to a hospital develops deep venous thrombosis. Incidence in Indian population varies between 8% and 28% in hospitalised patients; 50% and 60% in patients undergoing hip/knee surgeries. Deep venous thrombosis (DVT) is most common in the lower limbs, particularly in the venous sinuses of the soleus muscle in the calf and in the femoral and iliac veins. It is much less frequent in the upper limbs, but the axillary vein may be involved as a complication of trauma, long venous-infusion catheters, neoplasm or radiotherapy. Virchow’s triad attributes venous thrombosis to three factors: relative venous stasis, endothelial injury and increased coagulability (Table 1). Table 1: Predisposing Factors for Deep Vein Thrombosis Venous stasis Immobility (bed rest, surgery, limb paralysis), low cardiac output Varicose veins Venous injury Trauma, intravenous cannulation Increased coagulability Malignant disease, drugs (e.g. oestrogens, oral contraceptives), dehydration, polycythaemia, nephrotic syndrome, ulcerative colitis, lupus anticoagulant Inherited coagulation defects Antithrombin-III, protein C, protein S deficiency, factor V Leiden mutation, anticardiolipin antibodies Increasing age

Pathology Normal endothelium is non-thrombogenic. However, change or injury to the endothelium can trigger the activation of platelets finally leading to adhesion and aggregation of platelets. Endothelium can also be activated to release activators of certain coagulation factors (factor X) due to injury or as result of hypoxia following stagnation of blood due to venous stasis. Activated clotting factors lead to fibrin formation. Initially, the thrombus consists mainly of dense layers of platelets and fibrin. Later, the jelly-like mass of fibrin and red cells may become detached to form an embolus. After a few days, inflammatory changes occur in the wall of the vein, the thrombus may undergo lysis and organisation. Diagnosis Most patients have no physical signs. DVT and pulmonary thromboembolism (PTE) may occur in healthy people with no predisposing cause. In a patient suspected to have DVT, a detailed history is elicited and careful inspection of the extremity is performed. One would look for redness, warmth, tenderness on calf compression (Moses’ sign), measure the leg circumference and try to elicit Homan’s sign (calf pain on

Pulmonary Embolism and Deep Vein Thrombosis Jamshed D Sunavala, Shruti M Tandan dorsiflexion of foot with the knee bent). However, very often the patient is completely asymptomatic. Recent evidence suggests that 1% of all asymptomatic calf DVT patients that go home will die of PTE. A high level of suspicion is, thus, necessary to detect patients with increased risk of DVT as shown in Well’s DVT scoring system (Table 2). Table 2: Well’s DVT Scoring System: Score 3—High Risk History Paralysis, paresis or plaster immobilsation of the legs Major surgery in past 4 weeks, or being bedridden for 3 or more days, or travel lasting longer than 4 hours in the previous 6 weeks Cancer treatment in previous 6 weeks, or on palliative treatment Clinical findings Entire leg swollen Calf swollen; in the symptomatic leg, the circumference is 3 cm more than the other leg, measured 10 cm below the tibial tuberosity Tenderness along deep veins Pitting oedema (worse in the symptomatic leg) Collateral superficial veins (non-varicose) Other alternate diagnosis For example: musculoskeletal injuries, haematoma, chronic oedema, superficial phlebitis in varicose veins of the leg, cellulitis of the leg, arthritis of the leg, Baker’s cyst

Score +1 +1

+1

+1 +1

+1 +1 +1 –2

Investigations Duplex ultrasound The technique called duplex ultrasound, which includes venous compression ultrasound (CUS) and the Doppler ultrasound, has a high sensitivity (90% to 100%) and specificity (80% to 100%) for diagnosis of DVT in the thigh. It is less sensitive (75%) for detection of DVT in the calf veins. In CUS, a vein with an indwelling thrombus is not obliterated by external compression; thus, failure to obliterate the femoral vein by external compression is an indirect evidence of femoral vein thrombosis. This method uses a two-dimensional B-mode ultrasound. Doppler ultrasound, on the other hand, uses the Doppler shift method to detect the velocity of flow in an underlying vessel. This combined duplex approach is more accurate than either method alone. Impedance plethysmography Impedance plethysmography (IPG) is a reliable method for detecting thrombi in the deep veins of the thigh (sensitivity and specificity ~ 90%). However, IPG can miss thrombi in the calf veins where its sensitivity is less than 70%, as calf thrombi 1767 produce relatively little venous obstruction.

Contrast venography Though it remains the ‘gold standard’ for confirmation of DVT, contrast venography is an invasive test and involves administration of contrast medium. It is contraindicated in patients with renal insufficiency and is not accurate in patients with recurrent DVT because of the difficulty in visualising an intraluminal defect in veins that have been thrombosed previously. It is seldom used presently. Treatment Therapeutic anticoagulation is the mainstay of management of DVT (Table 3), which also includes treatment with analgesics for local pain, elastic bandaging and elevation of the leg, prevention of further clotting, and prophylaxis against recurrent pulmonary emboli. The purpose of the bandage is to compress superficial veins and so promote increased blood flow through the deep veins. Table 3: Therapeutic Anticoagulation in VTE Initiation Admit for close observation. Check baseline coagulation profile Initiate intravenous UFH 80 μ/kg as bolus followed by 18 μ/kg/hr Monitor ACT/aPTT 6 hourly, titrate infusion to maintain 1.5 to 2 times normal value Initiate VKA on day 1 of therapy Check INR on day 3 Heparin (UFH/LMWH) may be stopped after a minimum of 5 days and once INR >2 for >24 hours LMWH in a dose of 1 mL/kg SC q12h may be an alternative, but UFH is preferred in renal failure Maintenance Therapeutic anticoagulation is mandatory for 3 to 6 months in all patients with first episode of VTE with a reversible risk factor (e.g. pregnancy/trauma) Prolonged, i.e. lifelong anticoagulation is required in patients with recurrent (>1) episode, unprovoked first episode (no identifiable risk factor, low risk of bleeding), patients with malignancy VTE = Venous thromboembolism; UFH = Unfractionated heparin; LMWH = Low molecular weight heparin; VKA = Vitamin K antagonist.

Consequences of DVT may vary from complete resolution of the clot to death due to pulmonary embolism. Morbidity associated with DVT includes post-thrombotic syndrome that includes chronic venous hypertension causing limb pain, ulcers, hyperpigmentation, swelling, dermatitis, venous gangrene, and lipodermatosclerosis. Elastic compression stockings protect against post-thrombotic syndrome by decreasing the incidence to half. VTE is being recognised as a relapsing disorder in a number of patients, particularly those with thrombophilia, malignancy and in patients with more than one episode of DVT. These patients require long-term anticoagulation. Persistently elevated Ddimer levels (after stopping anticoagulation) or persistent residual venous thrombosis on Doppler help to identify this subset of patients following the first episode of DVT. Prophylaxis Almost all critically ill patients and some post-operative patients have significant risk factors for venous thromboembolism. A reasonable strategy is to extend anticoagulation prophylaxis 1768 to all immobilised critically ill patients and also to moderately

high-risk general surgical patients, unless there are contraindications to such therapy. Prophylaxis for DVT includes pharmacological and/or mechanical prophylaxis (Table 4). Certain high risk groups (poly trauma/bariatric surgery) require a combination of both methods. Table 4: Deep Venousthrombosis Prophylaxis Methods of prophylaxis Mechanical

Graded compression stockings Sequential compression device Venous foot pump

Pharmacological

Low-dose UFH LMWH fixed-dose irrespective of body weight (e.g. Enoxaparin 40 mg SC q24h) Fondaparinux 2.5 mL SC q24h VKA

Patient groups

Recommendation

Low risk: 50% in PV bed

>50% ↓ in PV bed

95%) but poor specificity for identifying patients with PTE. This is because D-dimer may be elevated in a number of other conditions that are often commonly associated with VTE, e.g. pregnancy, sepsis,

Ventilation-perfusion scan In lung perfusion scan, a suspension of particles of macroaggregated human albumin labelled with technetium99m is injected intravenously. The area of the lung which is underperfused shows up a ‘cold spot’ or ‘avascular’ area in the scan. A normal perfusion scan virtually excludes the diagnosis of PTE. In a ventilation scan, radioactive xenon-133 is inhaled and exhaled by the patient, while the gamma camera records its distribution throughout the alveolar gas exchange units. The test is based on the assumption that ventilation is preserved in areas of reduced perfusion due to pulmonary embolism and is abnormal when perfusion defects are due to pulmonary lung disease. V/Q scanning is useful in patients with moderate-tohigh clinical suspicion where contrast dye is to be avoided. (Figure 3 for algorithm for diagnostic strategy). CT pulmonary angiography CT pulmonary angiography (CTPA) is a minimally invasive investigation, widely available in most major hospitals, and offers the advantage of direct visualisation of pulmonary emboli within the pulmonary arteries. It also provides information about parenchymal abnormalities that may help in establishing an alternative diagnosis. CTPA is more accurate in detecting central or lobar PTE and less sensitive in detecting subsegmental PTE. Hence, CTPA cannot rule out the possibility of subsegmental PTE and this is the main disadvantage from conventional pulmonary angiography. However, isolated subsegmental PTE is uncommon and in presence of a negative CTPA one can safely withhold anticoagulation and on the other hand, a CTPA showing a PTE (Figure 1) may be treated without further tests. Conventional pulmonary angiography Formerly the ‘gold standard’ for diagnosis of PTE, the use of pulmonary angiography has declined with the advent of modern CTPA. It is more often used as an imaging modality as a part of local thrombectomy. Cardiac markers Cardiac troponins often elevated in massive PTE are indicative of significant right ventricular dysfunction, thus, helpful in prognostication rather than diagnosis. BNP elevation may indicate RV strain and stretching of RV muscle, which may suggest a serious prognosis. However, it may be elevated in other coexisting conditions like CHF and hence is of little value. Treatment of Massive PTE Massive PTE is a life-threatening medical emergency which is often undiscovered until autopsy. Diagnosis heavily relies on clinical suspicion together with CTPA or V/Q scanning. Unfortunately, most patients with massive PTE are clinically unstable and this may delay proper diagnostic evaluation and specific therapeutic intervention. However, the central aim initially is to counter the respiratory and haemodynamic consequences of the embolus till such time as reasonable diagnostic evaluation is possible (Figure 3). Echocardiography

is an excellent bedside technique, which helps in recognising RV failure and haemodynamic instability, so that proper therapy is instituted in this selected group of patients. After initial supportive measures, most patients may be reasonably stable to be transported to CTPA for further evaluation. Initial management in the presence of hypotension would include volume resuscitation. However, fluids should be administered cautiously particularly in the presence of marked increase in pulmonary vascular resistance and RV failure, where volume resuscitation may further compromise RV function resulting in more drastic reduction in the cardiac output. Among the vasoactive agents, norepinephrine and dobutamine have been reported to show haemodynamic improvement most consistently. If the patient remains haemodynamically stable, with or without supportive treatment, prompt anticoagulation with heparin should be started (Table 3). However, if in spite of initial resuscitation and all supportive measures, the cardiac output is not adequately restored and the patient remains haemo-dynamically unstable, one must consider therapeutic options aimed directly at reducing the embolic burden like intravenous or catheter-directed thrombolytic therapy (can be administered within 14 days of diagnosis of PTE) or surgical embolectomy. Further, thrombolytic therapy may be considered in some cases of PTE with RV dysfunction or elevated cardiac troponin levels. When there are contraindications to its use (Table 6) or if the hypotension is refractory despite thrombolytic therapy, embolectomy should be considered. Certain other scenarios such as trapped embolus within the right atrium or right ventricle may necessitate surgery. Approved dosage regimes for thrombolytic therapy in acute PTE are shown in Table 7.

Pulmonary Embolism and Deep Vein Thrombosis

trauma, recent surgery. Albeit the test has a high negative predictive value, i.e. a normal value can virtually exclude the possibility of venous thromboembolism especially in patients with low clinical suspicion.

Table 6: Contraindications to Thrombolytic Therapy Absolute Active internal bleeding Bleeding diathesis Recent GI bleeding/proven peptic ulcer (in last 3 months) Previous haemorrhagic stroke/CVA in last 6 months/intracranial tumour Recent (110 mm Hg) Allergy to earlier treatment with streptokinase (use alternate agent) Relative Pregnancy, post-partum state Chronic liver disease Cardiopulmonary resuscitation Haemorrhagic retinopathy Table 7: Thrombolytic Treatment of Pulmonary Thromboembolism Streptokinase 250,000 U IV (as loading dose) over 30 minutes followed by 100,000 U/hour for 24 hours Urokinase 4,400 U/kg body weight IV (as loading dose over 10 minutes) followed by 4400 U/kg/hour for 24 hours Tissue plasminogen activator 100 mg IV over 2 hours

Placement of inferior vena caval (IVC) filters may prevent additional, potentially fatal emboli in a selected group of patients with massive emboli. The main indications for using 1771

IVC filters are recurrent PTE despite anticoagulation, patients who develop bleeding on anticoagulation, large free-floating thrombus in the ileofemoral veins, immediately following surgical catheter embolectomy and in high-risk patients where anticoagulation and thrombolytic therapy is contraindicated. More recently, temporary (retrievable) filters have been placed in patients with short-term risk of bleeding. Interestingly, IVC filters are a potential nidus for thrombus formation and often mandate a low level of anticoagulation. Chronic thromboembolic pulmonary hypertension (CTPH) represents partly a failure of initial treatment of PTE and develops in less than 4% of patients following the first episode, and the incidence increases following recurrent VTE. In patients with recurring episodes of PTE and no known predisposing factors or in patients with a strong family history of PTE, it is mandatory to do an assay of protein C, protein S, homocysteine and AT-III and look for factor V Leiden mutations. In cases of AT-III deficiency or homozygous factor V Leiden, longterm or even lifelong anticoagulation is recommended. However, all patients should receive heparin prophylaxis during surgery or trauma. Pregnancy Physiological changes in pregnancy and post-partum period may predispose to development of DVT in the legs and pelvic veins. VTE was previously observed to be more common in the post-partum period possibly related to earlier practices of prolonged bed rest after delivery or use of oestrogen to suppress lactation. Now, it is equally common to document DVT in all trimesters of pregnancy. Important risk factors include increased parity, obesity, prolonged immobility, operative or difficult instrumental delivery and previous history of VTE. Multiple risk factors are often present during pregnancy. Interestingly, there is a striking propensity for left leg involvement (nearly 80%) when DVT occurs in pregnancy probably due to the tortuous course of left leg venous drainage through the pelvis. Mortality has been reported at 15% in undiagnosed patients and in Western countries, PTE is an important cause of maternal mortality. Clinical diagnosis of VTE is notoriously unreliable because the physiological changes in pregnancy can complicate the interpretation of the usual signs and symptoms of VTE; elevated D-dimer levels are common in uncomplicated pregnancy. Ultrasound and Doppler studies of the leg veins are the investigations of choice. Diagnostic work-up for thrombophilia is not indicated in all cases of DVT in pregnancy except in selected cases with strong clinical suspicion of hypercoagulable state. Main aims of management include restoration of venous patency to prevent post-phlebitic syndrome in the future and prevent PTE. Bed rest and elevation of the affected leg promotes venous return and decreases oedema. However, as soon as symptoms permit, the patient should be ambulated as there is no evidence to show that prolonged bed rest prevents detachment of the embolus. Coumarin is not used in pregnant patients as it produces haemorrhagic complications in the foetus and carries the risk of warfarin embryopathy (manifests as skeletal or CNS defects), hence intravenous and 1772 subcutaneous heparin or LMWH is the treatment of choice.

Management of Bleeding Caused by Anticoagulant Treatment In an emergency for rapid reversal of anticoagulation following warfarin treatment, both vitamin K (10 mg IV slowly) and fresh frozen plasma (FFP) must be given to correct the international normalised ratio (INR). Recombinant factor VIIa (rVIIa) can also be used in an emergency as it is effective for a prompt and complete reversal. Protamine is used for immediate reversal of standard heparin (1 mg of protamine for every 100 units of standard heparin if the last dose of heparin was given within 30 minutes and 0.5 to 0.75 mg/100 units of heparin if it was 30 to 60 minutes since the last dose) and LMWH (1 mg of protamine for every 1 mg of LMWH). Protamine does not fully reverse LMWH but can neutralise the antithrombotic effect. Because of the longer half-life of LMWH, a second dose of protamine may be required. NON-THROMBOTIC PULMONARY EMBOLISM Amniotic Fluid Embolism Amniotic fluid embolism is a rare complication of pregnancy wherein amniotic fluid and foetal cells enter the maternal pulmonary circulation and trigger an anaphylactic reaction or complement activation or both. This leads to pulmonary vasospasm and pulmonary hypertension causing hypoxia which damages myocardial and pulmonary capillaries, resulting in LVF and ARDS. This manifests as an acute catastrophe during labour and less commonly following an abortion or amnioinfusion. The patient may develop shock, respiratory distress, seizures, neurological manifestations and even cardiac arrest. Patients who survive this phase may progress to develop uterine atony and disseminated intravascular coagulation (DIC) leading to massive post-partum haemorrhage. Therapy is usually supportive. Steroids may have a role as anaphylaxis is postulated. Air Embolism Air embolism is often an iatrogenic complication that occurs frequently during neurosurgical procedures in the sitting position, less commonly during central line insertions, thoracocentesis, haemodialysis, radiographic procedures, penetrating chest injuries, etc. Air may enter the pulmonary circulation causing right ventricular outflow obstruction or alternately enter the cerebral circulation. Typically about 5 mL/kg of air is fatal but in the cerebral circulation, 2 to 3 mL and in the coronary circulation, 0.5 mL may be dangerous. Patients often present with a sudden cardiovascular collapse, dyspnoea or arrythmias. Movement of air through a patent foramen ovale may result in an arterial air embolism that may manifest as a myocardial infarction or stroke. Transoesophageal echocardiography/precordial duplex ultrasound or cranial Doppler are useful diagnostic modalities. Placing the patient in the left lateral Trendelenberg’s position may preclude the air from moving into the right ventricle. High flow oxygen, attempts at air aspiration from an indwelling CVC, hyperbaric oxygen in the case of Caisson’s disease are some of the suggested therapeutic modalities. Fat Embolism Fat embolism may occur due to the mechanical dislodgement of fat globules into veins which subsequently move into

>38.5°C, retinal changes of fat globules, elevated ESR, drop in haemoglobin or platelets, jaundice, renal dysfunction) plus fat microglobulinaemia. Treatment involves management of the orthopaedic condition, DVT prophylaxis, supportive care and steroids. RECOMMENDED READINGS 1. 2. 3.

Antithrombotic and Thrombolytic Therapy; 8th Ed. ACCP Guidelines. Chest 2008; 133:381S-545S. Clive Tovey, Suzanne Wyatt. Diagnosis, investigation, and management of deep vein thrombosis. BMJ 2003; 326:1180-4. Tapson VF. Acute pulmonary embolism. N Engl J Med 2008; 358:1037-52.

Pulmonary Embolism and Deep Vein Thrombosis

cerebral circulation by arteriovenous shunts. These emboli cause microcirculatory defects, platelet aggregation and vasoactive amine release. An alternate theory is that trauma/ sepsis causes the systemic release of free fatty acids or chylomicrons which coalesce and cause the above effects. Hence, fat embolism is common following trauma, orthopaedic procedures, parenteral lipid administration and in patients with multiple medical problems. Diagnosis of fat embolism may be defined based on presence of one major (respiratory distress, radiological signs, cerebral signs devoid of other aetiologies and petechial rash) and four minor criteria (pulse >110/m, fever

1773

23.17 DISEASES OF THE PLEURA The visceral pleura that lines the lungs, folds back itself at the hilum to form the parietal pleura which lines the inner thoracic wall, the mediastinum and the diaphragm. The cavity between the visceral and parietal pleura is termed the pleural space and it normally contains a very thin layer of fluid (0.13 mL/kg) which acts as a lubricant. Only the parietal pleura is pain sensitive as it contains sensory nerve fibres, supplied by the intercostal and phrenic nerves. Pleurisy Inflammation of the pleura results in pleurisy (or pleuritis). Pleurisy may start as dry pleurisy (Table 1), but may later on resolve or develop into wet pleurisy (pleural effusion). Patients with pleurisy present with a localised, sharp, stabbing pain on the affected side that worsens on inspiration, coughing, and sneezing (pleuritic pain). Physical examination may reveal reduced movements on the affected side. A pleural rub may be heard on auscultation. Table 1: Common Causes of Dry Pleurisy Epidemic myalgia (pleurodynia, Bornholm disease) Extension of infection from the underlying lung (e.g. pneumonia) Tuberculous pleurisy Chest trauma Serositis due to connective tissue diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus) Pulmonary infarction Pleural malignancy (metastatic, primary) Radiation injury Uraemia

Pleurodynia (also called epidemic myalgia, Bornholm disease), caused by Coxsackie B virus infection, is a form of dry pleurisy which may occasionally be complicated with pleural effusion. It occurs in epidemics and commonly affects children and young adults. Patients present with fever, severe incapacitating pleuritic chest pain. On the affected side, movements of the thorax are reduced, the chest wall muscles are tender and a pleural friction rub may be heard. This condition should be differentiated from chest pain due to other causes such as, herpes zoster, intercostal myalgia, costochondritis, and rib trauma. Treatment is symptomatic and supportive and includes relief of pain by administration of analgesics. Pleural Effusion and Empyema Abnormal, excess accumulation of fluid in the pleural space is termed as pleural effusion. Presence of pus in the pleural space is termed empyema. Various causes of pleural effusion are listed 1774 in Table 2A.

Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall Alladi Mohan

Table 2A: Causes of Pleural Effusion Transudate* Congestive heart failure† Constrictive pericarditis† Restrictive cardiomyopathy† Cirrhosis of liver (hepatic hydrothorax)† Nephrotic syndrome† Acute glomerulonephritis† Severe hypoproteinaemia† Myxoedema† Meigs’ syndrome (ovarian tumour and usually right-sided pleural effusion) Peritoneal dialysis† Superior vena cava obstruction† Exudate* Inflammatory diseases of pleura Tuberculosis† Bacterial pneumonia Viral infections Fungal infections Parasitic infections Pulmonary embolism† Collagen vascular disease e.g. Rheumatoid arthritis†, systemic lupus erythematosus† Disorders of adjacent structures Oesophageal rupture Diaphragmatic hernia Liver abscess Subphrenic abscess Pancreatitis† Neoplastic diseases Mesothelioma Metastatic† Mediastinitis Chest wall injury Haemothorax Chylothorax Uncommon causes Sarcoidosis† Yellow nail syndrome† Drugs† Nitrofurantoin, dantrolene, methysergide, metoprolol, amiodarone, procainamide, bromocriptine, procarbazine Occupational asbestos exposure† Uraemia† Urinothorax Post-radiation therapy *Described in Table 2B; †May present with bilateral pleural effusion.

Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall

Clinical Features Patients with pleural effusion manifest symptoms due to inflammation of pleura, compromise of pulmonary mechanics or interference with gas exchange. Most present with pleuritic chest pain that corresponds to the affected area. Sometimes, pleuritic pain may be referred to the abdomen. Pleuritic pain in the lower chest with ipsilateral shoulder pain indicates diaphragmatic involvement. A dull aching pain may be evident in patients with malignant pleural effusion. Dry cough with minimal scanty sputum and dyspnoea are usually present. History of expectorating copious purulent sputum may suggest an empyema rupturing into a bronchus (bronchopleural fistula). Fever is a prominent symptom in empyema where it may be high grade, remittent and associated with chills and rigors, and in pleural effusions of infective or inflammatory aetiology. Physical examination reveals: reduced movements; impaired tactile and vocal fremitus; a stony-dull note on percussion. In pleural effusion, the highest point of the stony-dull note is evident in the axilla (Ellis ‘S’ shaped curve phenomenon). Breath sounds may be diminished or absent on the affected side. Aegophony may be heard at the upper level of the pleural effusion. Mediastinal shift to the opposite side may be evident in a large pleural effusion. Classical pleural friction rub, which is coarse, creaky and leathery in character, audible during the latter part of inspiration and the early part of expiration (to-and-fro pattern) may be present in the early stages of the disease; it may disappear when the pleural surfaces separate as a result of collection of excessive fluid, but may reappear in the stage of resolution. In empyema, intercostal fullness, bulging, redness and tenderness may be evident. With large pleural effusions, haemodynamic disturbances may be evident. Diagnostic Evaluation Chest radiograph The chest radiograph findings of a pleural effusion range from blunting of costophrenic angle (small effusion) (Figures 1A and B) to dense opacification of the entire hemithorax with mediastinal shift to the opposite side (large effusion) (Figures 2A to E). Elevation of hemidiaphragm is seen in sub-pulmonic effusion. Encysted or interlobar effusions are better appreciated in the lateral view. Lateral decubitus chest radiograph obtained with the patient lying on the affected side can help in identifying small effusions. Pleural plaques (asbestosis) and pleural calcification (Figure 3) may also be present. Ultrasonography Ultrasonography of the chest is useful for detecting small pleural effusions (Figure 1), identifying multiloculated effusions and in localising the site for a diagnostic thoracocentesis. Computed tomography Computed tomography (CT) of the chest is useful for delineating loculated pleural effusion or empyema (Figures 4A and B), detecting mediastinal or hilar lymphadenopathy or lung lesions, such as tumours. Thoracoscopy Video-assisted thoracoscopic surgery ( VATS) is a helpful procedure for obtaining tissue and fluid for ascertaining the aetiological diagnosis.

Figures 1A and B: (A) Postero-anterior view of chest radiograph (arrow), and (B) Ultrasonography of chest showing a small right-sided pleural effusion (asterisk). Ultrasonography helps in identifying small pleural effusions, facilitates quantification of the pleural fluid volume and also helps in the detection of loculation and septation.

Diagnostic thoracocentesis Diagnostic thoracocentesis helps in categorising the pleural fluid as transudate or an exudate (Table 2B). A transudative pleural effusion occurs due to systemic factors, whereas an exudative pleural effusion occurs due to alteration in the local factors which influence the formation and absorption of pleural fluid. In acute infections, predominance of polymorphs may be present; in chronic infections, like tuberculosis (TB), lymphocytes predominate. In some cases, eosinophils predominate. Transudative pleural effusions are usually clear, have low specific gravity, protein levels, lactate dehydrogenase (LDH) levels and very few cells. In transudative pleural effusion, pleural fluid glucose levels run parallel with blood glucose levels; pleural fluid glucose levels are reduced in exudative 1775

Figures 2A to E: (A) Contrast-enhanced CT chest topogram(arrow) showing a moderate right-sided pleural effusion, (B) In the transverse CT (mediastinal window) image of the same patient, pleural effusion (asterisk) and the collapsed lung border (arrows) are also evident, (C) Chest radiograph (postero-anterior view) showing a massive left-sided pleural effusion and complete opacification of the left hemithorax with mediastinal shift to the right side, (D) Contrast-enhanced CT chest topogram of another patient showing a massive right-sided pleural effusion, (E) In the transverse CT (mediastinal window) image of the same patient, massive right-sided pleural effusion (asterisk) and mediastinal shift to the left side (arrow) can be seen.

pleural effusion. In rheumatoid pleural effusion, glucose levels may be very low (36 IU/L), interferon-gamma (>112 pg/ mL) levels are elevated in TB pleural effusion. Table 2B: Criteria Used for Categorising a Pleural Effusion as an Exudate Light’s criteria Pleural fluid protein: serum protein ratio >0.5 Pleural fluid LDH: serum LDH ratio >0.6 Pleural fluid LDH >two-third of the upper limit of normal serum LDH Others Pleural fluid protein >3 g/dL Pleural fluid LDH >200 IU/L Pleural fluid cholesterol >45 mg/dL Pleural fluid-to-serum cholesterol ratio >0.3 Serum albumin-pleural fluid albumin gradient 0.6

1776

Figure 3: Chest radiograph (postero-anterior view) showing right-sided pleural calcification (arrow) that developed as a sequelae of a tuberculous pleural effusion.

Aspiration of frank pus suggests empyema. A milky-white fluid suggests chylothorax or a chyliform (pseudochylous) effusion (Table 3). Haemorrhagic pleural effusions may suggest pleural malignancy. Pleural fluid seldom reveals acid-fast bacilli

Pleural biopsy Needle biopsy of the pleura using Abram’s punch biopsy needle or Cope’s needle, radiologically-guided Tru-cut needle biopsy can help in confirming histopathological diagnosis. Sometimes, VATS or open pleural biopsy may be required to confirm the diagnosis. Management In pleural effusion due to systemic causes like congestive heart failure, pulmonary embolism, treatment of the underlying cause facilitates the resolution of the effusion. In patients with synpneumonic effusion who continue to run fever, diagnostic thoracocentesis is indicated to rule out empyema. In India, TB is the most common cause of pleurisy with effusion in young adults. Among middle-aged and elderly subjects who are smokers, malignant pleural effusion should be considered. Under the Revised National Tuberculosis Control Programme (RNTCP), patients with large or massive TB pleural effusion receive directly observed treatment, short course (DOTS), category I treatment and those with small to moderate TB pleural effusions, defined as pleural fluid volume less than 1,500 mL on ultrasonography of the chest, receive DOTS, category III treatment. A short course of prednisolone (0.5 mg/kg daily for 4 weeks) may be helpful in some cases to provide relief from toxaemic symptoms and to facilitate rapid absorption of fluid.

Figures 4A and B: (A) Postero-anterior view of chest radiograph (arrow) showing a right-sided loculated pleural effusion, (B) Contrast-enhanced transverse CT (mediastinal window) image shows loculated pleural effusion on the right side (arrows).

Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall

on smear examination. Culture of pleural fluid for bacteria, mycobacteria or fungi can help in ascertaining the aetiological diagnosis. Cytopathological examination of pleural fluid confirms the presence of malignant pleural effusions. Molecular diagnostic methods such as polymerase chain reaction can be helpful in confirming the diagnosis in certain situations.

In malignant pleural effusion, treatment is aimed at the underlying malignancy. Rapidly reaccumulating pleural effusion requiring frequent thoracocentesis may require pleurodesis by injecting a sclerosant, such as, sterile talc or tetracycline. Intrapleural streptokinase administration may help if bacterial empyema is loculated; tube thoracostomy is often required in

Table 3: Differentiation of Chylothorax from Pseudochylothorax Variable

Chylothorax

Pseudochylothorax*

Prevalence Aetiology

Uncommon Usually caused by thoracic duct transection (trauma, surgery); or obstruction (e.g. non-Hodgkin’s lymphoma). Other causes: filariasis, lymphangioleiomyomatosis, congenital absence of thoracic duct, yellow nail syndrome Acute to subacute Milky; sometimes serous or haemorrhagic

Rare Often post-inflammatory; can be a feature of long-standing pleural effusions (e.g. tuberculosis, rheumatoid arthritis, empyema) Insidious Milky; satin-like sheen may be present

Usually not present Lymphocyte rich Exudative Cholesterol 60 to 200 mg/dL;Triglycerides >110 mg/dL; Cholesterol/triglyceride ratio 250 mg/dL;Triglyceride levels usually normal; may be elevated sometimes. Cholesterol/triglyceride ratio >1 Absent Present Present (rhomboid shaped) No change No detection of dye/radioactivity

Onset Appearance Pleural fluid analysis Evidence of thickened/calcified pleura Cell count Total proteins Lipid profile Others Chylomicrons Lipid-laden macrophages Cholesterol crystals Addition of ethyl ether to milky fluid Testing after consumption of butter containing radioiodine-labelled triglycerides; or containing lipidophilic dye (e.g. Sudan III) * Also called cholesterol effusion, chyliform effusion

Present Absent Absent Clears it by dissolving triglycerides Detection of dye/radioactivity

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such cases. In chronic empyema, Elossier flap procedure, decortication may be required. Pneumothorax Definition Presence of air in the pleural space results in pneumothorax. It may occur spontaneously or as a consequence of iatrogenic injury or trauma to the chest. Spontaneous pneumothorax may develop in otherwise healthy individuals (primary) or it can occur as a complication of underlying lung disease (secondary), e.g. due to the rupture of a subpleural emphysematous bulla, pleural bleb or as a complication of barotrauma due to mechanical ventilation. Primary spontaneous pneumothorax Various types of spontaneous pneumothorax are shown in Table 4. Clinical Features Primary spontaneous pneumothorax is commonly encountered in males, aged 15 to 30 years; tobacco smoking, tall stature and the presence of apical subpleural blebs are risk factors. Secondary pneumothorax, more common in older individuals affects patients with pre-existing lung diseases. Common presenting symptoms include sudden-onset chest pain on the affected side

and breathlessness. In the closed type, breathlessness is mild. In the open type, breathlessness may be more severe and secondary infection of pleura is common.Tension pneumothorax is an acute medical emergency, the patient is severely dyspnoeic; cyanosis, marked tachycardia, profuse sweating may be present. Physical signs vary according to the type and size of the pneumothorax. Mediastinum is shifted to the opposite side. On the affected side, intercostal fullness, diminished movements, hyper-resonant percussion note, reduced or absent breath sounds may be evident. In hydropneumothorax or pyopneumothorax, a horizontal ‘fluid level’ marks the interface between the liquid and the air. Other important physical signs include amphoric breath sounds (in bronchopleural fistula, tension pneumothorax) succussion splash (hydropneumothorax). Recurrent spontaneous pneumothorax can occur in patients with emphysematous bullae or lymphangioleiomyomatosis. Investigations Chest radiograph findings include mediastinal shift to the opposite side, presence of air in the pleural cavity as a translucent shadow along with the sharply defined edge of the collapsed lung (Figures 5A and B). Hydropneumothorax and underlying pulmonary disease may also be seen (Figure 5B).

Table 4: Types of Spontaneous Pneumothorax

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Type

Pathophysiology

Salient Features

Closed

The communication between the lung and pleural space seals off as the lung deflates and does not reopen

Open

The communication between the lung and pleural space fails to seal. Air continues to transfer freely between the lung and pleural space. Usually develops following rupture of a tuberculosis cavity, an emphysematous bulla or lung abscess into the pleural space

The mean pleural pressure remains negative. Air in the pleural space gets reabsorbed spontaneously, the underlying lung re-expands over a few days or weeks. Infection is rare The mean pleural pressure remains equal to atmospheric pressure; lung cannot expand. Bronchopleural fistula, spread of infection from the airways into the pleural space resulting in empyema are common

Valvular (tension)

The communication between the airway and the pleura acts as a one-way valve allowing air to enter the pleural space during inspiration but not to escape on expiration. This results in large amounts of air being trapped in the pleural space

The intrapleural pressure may become more than the atmospheric pressure. This may cause mediastinal shift towards the opposite side, compression of the opposite normal lung, impairment of systemic venous return and may result in cardiovascular compromise Rarely, in patients with splinting of the mediastinum due to scarring (e.g. sequelae of tuberculosis) or malignancy, a ‘tension’ pneumothorax may occur without mediastinal shift

Figures 5A and B: (A) Chest radiograph (postero-anterior view) showing a left-sided pneumothorax (white asterisk), collapsed lung border (arrow) in a patient being treated for pulmonary tuberculosis. Parenchymal infiltrates in the right upper zone (black asterisk) are also evident, (B) Chest radiograph (postero-anterior view) showing a right-sided hydropneumothorax (asterisk); collapsed lung border (thin arrows) and a horizontal fluid level (thick arrow) are also seen.

Treatment The therapeutic approach to the management of a patient with pneumothorax is shown in Figure 6. Tension pneumothorax is a medical emergency and requires immediate release of tension in the pleural space using a wide-bore plastic cannula connected to a water-seal drainage system.Tube thoracostomy, appropriate antibiotic therapy and/or anti-tuberculosis treatment may be necessary.

and the tumour is incidentally diagnosed on chest radiograph taken for some other reason. Some patients may present with cough, breathlessness, chest pain and constitutional symptoms, such as fever and arthralgias. Digital clubbing and pulmonary osteoarthropathy are prominent features in some patients. Treatment is by surgical resection. Malignant Mesothelioma Aetiology Asbestos exposure is strongly associated with the development of malignant mesothelioma. It occurs in the fourth or fifth decade of life; males are more frequently affected. Clinical features Salient clinical manifestations include chest pain, cough, fever, weight loss, anorexia and pleural effusion. Rarely, hoarseness of voice and dysphagia occur. Diagnosis The chest radiograph shows moderate to large unilateral pleural effusion or nodular or smooth unilateral pleural thickening. The CT of the chest may show a ring-like extension of tumour on the pleural surface. Diagnostic thoracocentesis, pleural fluid cytology, closed needle biopsy of the pleura, radiologically guided pleural biopsy may help in confirming the diagnosis. However, open biopsy at thoracoscopy or thoracotomy, electron microscopy and immunohistochemical staining may be required to distinguish malignant mesothelioma from metastatic adenocarcinoma.

Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall

Chest radiograph helps identifying underlying pulmonary parenchymal lesions and in differentiating pneumothorax from large emphysematous bullae and cysts of the lung.

Course and prognosis The median survival time ranges between 4 months and 12 months from the time of diagnosis. Regardless of therapy, the prognosis is best for epithelial cell type. The sarcomatous cell type carries a poor prognosis; in the mixed or biphasic types, prognosis falls in between the two other types. Treatment Treatment includes surgical debulking (pleurectomy with decortication or extrapleural pneumonectomy) followed by chemotherapy and high-dose radiation therapy to destroy residual tumour cells.

Figure 6: Algorithm for the management of a patient with pneumothorax.

Recurrent pneumothorax Recurrent pneumothorax in individuals with a low respiratory reserve in whom further recurrence may be hazardous and in those indulging in activities such as flying or diving should be treated by surgical pleurodesis by pleural abrasion or parietal pleurectomy at thoracoscopy or thoracotomy. TUMOURS OF THE PLEURA Benign and malignant tumours of the pleura have been described. Metastatic tumours arising from primary tumours of the lung or breast are more common than primary pleural tumours. Pleural Fibroma Pleural fibroma is a benign tumour, most commonly encountered in middle-aged persons. The patients are usually asymptomatic

DISEASES OF THE MEDIASTINUM The mediastinum comprises the area between the two pleural sacs and is arbitrarily divided into anterosuperior, middle and posterior compartments (Table 5). Acute Mediastinitis Various causes of acute mediastinitis are listed in Table 6. Acute mediastinitis is usually secondary to spontaneous or iatrogenic perforation of a thoracic viscous (e.g. oesophagus); or after median sternotomy for cardiac surgery. Rarely, inhalational anthrax can cause primary acute mediastinitis. Patients with oesophageal rupture present with severe chest pain, breathlessness, and look acutely ill.Treatment includes parenteral antibiotic therapy, surgical exploration of the mediastinum and primary repair of the oesophageal tear, drainage of the pleural space and the mediastinum. Patients with mediastinitis following median sternotomy commonly present with wound drainage, sepsis or a widened mediastinum. Mediastinal needle aspiration confirms the diagnosis.Treatment includes parenteral antibiotics, 1779 immediate drainage, and debridement.

Table 5: Distribution of Lesions in Various Mediastinal Compartments Mediastinal Compartment Antero-superior mediastinum The antero-superior mediastinum extends from the manubrium sterni and the first ribs to the diaphragm. Its posterior border is defined by the anterior aspect of the pericardium inferiorly and curves posteriorly to include the arch of the aorta and great vessels. This compartment encloses the ascending aorta, superior vena cava, azygous vein, thymus gland, lymph nodes, fat, connective tissue, transverse aorta and great vessels Middle mediastinum The middle mediastinum (visceral compartment) is bounded above by the superior pericardial reflection and below by the diaphragm. The posterior border extends to the spine. This compartment encloses the heart and pericardium, trachea and major bronchi, pulmonary vessels, lymph nodes, fat and connective tissue Posterior mediastinum The posterior mediastinum (paravertebral compartment) extends from the superior aspect of the first thoracic vertebral body to the diaphragm anteriorly and then posteriorly to the posteriormost curvature of the ribs. It encloses the sympathetic chain, vagus nerves, oesophagus, thoracic duct, various lymph nodes and the descending aorta Table 6: Causes of Acute Mediastinitis Oesophageal perforation Instrumental (e.g. oesophagoscopy, sclerotherapy) Forceful vomiting (Boerhaave’s syndrome) Trauma Foreign body Operative injury Caustic ingestion Cancer Tracheobronchial perforation Direct extension of infection from retropharyngeal space; odontogenic infection (descending necrotising mediastinitis), pancreatitis, lung, pleura, pericardium, lymph node, paraspinal abscess Post-sternotomy mediastinitis Anthrax mediastinitis

Granulomaotus Mediastinitis and Mediastinal Fibrosis Diseases such as TB, sarcoidosis, silicosis, histoplasmosis, and several other fungal diseases can cause granulomatous mediastinitis. Several conditions, such as drugs (e.g. methysergide), silicosis, multisystem fibrosing disorder, radiation, among others can cause fibrosing mediastinitis. These patients present with signs of compression of some of the mediastinal structures, like superior vena cava syndrome, tracheobronchial obstruction, compression of pulmonary vessels, or nerves. Pneumomediastinum Presence of air in the interstices of the mediastinum is termed pneumomediastinum or mediastinal emphysema. Pneumomediastinum commonly results from microscopic alveolar rupture but can also be caused by air escaping from the upper respiratory tract, intrathoracic airways or gastrointestinal tract. Gas producing bacterial infection of the visceral space, outside air reaching the mediastinum following trauma or surgery are other mechanisms. Patients present with sudden severe pain in the substernal region and breathlessness. Subcutaneous 1780 emphysema in the suprasternal notch and a crunching or

Common Lesions

Rare Lesions

Thymomas Lymphomas Germ cell tumours Lymph node TB

Vascular lesions Mesenchymal tumours Endocrine tumours

Lymph node TB Foregut cysts Lymphomas

Pleural cysts Pericardial cysts Neuroenteric cysts Gastroenteric cysts Hydatid disease

Neurogenic tumours

Vascular lesions Mesenchymal lesions Lymphatic lesions

clicking noise synchronous with the heartbeat and best heard in the left lateral decubitus position (Hamman’s sign) can be heard. The chest radiograph shows air in the mediastinum parallel to the heart and aorta. Treatment of the underlying disorder may provide relief from symptoms. Rarely, needle aspiration or surgical incision may be required to relieve mediastinal compression. Mediastinal Cysts and Tumours Mediastinal tumours (Table 5), (Figures 7A to D), when small, are asymptomatic and may be detected as an incidental finding on the chest radiograph. Patients may present with manifestations due to compression of various mediastinal structures by the mass. These include dyspnoea, cough, stridor, wheezing, haemoptysis, obstructive pneumonia and the middle lobe syndrome (compression of the trachea and the major bronchi); distended, non-pulsatile neck veins, oedema and cyanosis of face, neck and arms (superior vena cava syndrome); hoarseness of voice, bovine cough (left recurrent laryngeal nerve); diaphragm paralysis (phrenic nerve); dysphagia (oesophagus) and Horner’s syndrome (sympathetic trunk). Patients of intrathoracic lymph node TB or lymphoma may present with systemic manifestations such as fever, weight loss and toxaemia. Chest CT is helpful in localising these lesions.Transthoracic needle biopsy,VATS or media-stinoscopy and biopsy help in confirming the diagnosis. Thymic tumours Thymoma is a common anterior mediastinal tumour and is frequently associated with Myasthenia gravis and pure red cell aplasia. Surgical resection is indicated as malignant thymomas are difficult to diagnose clinically. Thyroid lesions Mediastinal thyroid lesions include a cervical goitre, extending retrosternally into the anterior mediastinum and rarely, primary intrathoracic goitre. The lesion can be recognised by radioactive iodine scanning. Treatment is by resection. Germ cell tumours Germ cell tumours include teratoma and teratocarcinoma, seminoma, embryonal cell carcinoma and choriocarcinoma.

Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall Figures 7A to D: (A) Contrast-enhanced CT chest (arrows) showing anterior mediastinal mass, (B) (asterisk) aortic aneurysm mimicking a middle mediastinal mass, (C) (asterisk) middle mediastinal lymph node mass, and (D) (arrow) a posterior mediastinal mass.

Teratomas, the most common germ cell tumours, are common in the anterior mediastinum. In teratomas, structures originating from all three germ cell layers may be found; ectodermal derivatives predominate. When only the epidermis and its derivatives are present, the lesion is termed dermoid cyst. Usually, they do not produce symptoms. Patients become symptomatic when infection sets in or malignant transformation occurs. Calcification is common and teeth may be identified. Chest CT is useful in delineating these lesions. Rarely, mediastinal seminoma and teratoma may be metastatic. Neurogenic tumours Neurogenic tumours are located mainly in posterior mediastinum. These tumours appear as dense, round or oval, radioopaque densities occupying the paravertebral gutter on the chest radiograph. Many neurogenic tumours may be hormonally active. Others Rarely developmental cysts, such as, bronchogenic, pericardial or enteric cysts, hydatid cysts, primary carcinoma of the mediastinum, extra-medullary haematopoiesis in patients with chronic haemolytic anaemia can present as mediastinal tumours.

DISORDERS OF THE DIAPHRAGM The diaphragm is the major muscle of respiration which separates the thoracic and abdominal cavities. Anatomical and neurological disorders affecting it render the diaphragm ineffective in providing adequate intrathoracic pressure resulting in a decrease in the amount of oxygen provided to the alveoli. Anatomical Disorders These can be congenital or acquired and result in diaphragmatic hernia. Bochdalek hernia results from herniation through a defect in the posterolaterally located Bochdalek foramen. Herniation thorough the foramen of Morgagni in the anterior midline through the sternocostal hiatus of the diaphragm is less common. Neonates with these conditions present with respiratory distress and need urgent surgical repair. In hiatus hernia, the abdominal contents herniate through the oesophageal hiatus. In sliding hiatus hernia, the gastro-oesophageal junction moves above the diaphragm together with part of the stomach. In rolling or para-oesophageal hiatus hernia, a part of the stomach herniates through the oesophageal hiatus and lies beside the oesophagus, without displacement of the gastro-oesophageal junction. 1781

Eventration of diaphragm (Figures 8A to C) develops as a result of congenital or acquired decrease in muscle mass and increase in fibrous tissue and results in elevation of one hemidiaphragm (Table 7). Usually, most patients are asymptomatic and no treatment is required for this condition.Traumatic diaphragmatic rupture can occur due to both penetrating and blunt trauma and requires surgical intervention.

Table 7: Causes that Result in Elevation of the Diaphragm Causes of elevation of one hemidiaphragm Thoracic causes Phrenic nerve palsy Splinting of diaphragm (e.g. fractured rib, pneumonia, pleurisy) Sub-pulmonic effusion Post-operative (lobectomy, pneumonectomy) Abdominal causes Tumours, cysts and other causes of hepatomegaly Amoebic liver abscess Subphrenic abscess Distended stomach Interposition of colon between liver and right hemidiaphragm (Chilaiditi syndrome) Elevation of both domes of diaphragm Increased intra-abdominal pressure (e.g. obesity, ascites, pregnancy, abdominal tumours) Spinal cord injury Neuromuscular disorders

Disorders of Innervation The transmission of respiratory stimulus from the brain to the diaphragm via the phrenic nerve can be interrupted by traumatic injury or disease processes, e.g. malignancy, spinal cord disorders, syringomyelia, poliomyelitis and motor neuron disease. Most patients with unilateral diaphragmatic paralysis remain asymptomatic. Bilateral diaphragmatic paralysis can present with severe exertional dyspnoea and marked orthopnea. Evidence of paradoxical movement on performing the sniff test and observing the diaphragmatic movement on fluoroscopy or ultrasonography is a helpful manouevre in evaluating diaphragmatic paralysis and differentiating it from eventration of diaphragm. DISORDERS OF THE CHEST WALL The chest wall is a critical component of the respiratory pump and comprises of the bony structures (ribs, spine), respiratory muscles and nerves connecting the central nervous system with the respiratory muscles. Several congenital abnormalities, such as pectus excavatum (funnel chest), pectus carinatum (pigeon chest) and Poland’s syndrome (aplasia or hypoplasia of the sternocostal portion of the pectoralis major muscle, syndactyly), Jeune’s syndrome (asphyxiating thoracic dystrophy) can impair chest wall function. In rickets, widening of the costochondral junctions (rachitic or rickety rosary), horizontal depression along the lower anterior chest (Harrison sulcus) due to pulling of the softened ribs by the diaphragm during inspiration may be seen. In scurvy, the sternum is depressed and scorbutic rosary can be seen. While rickety rosary is knobby and nodular, scorbutic rosary is more angular and has a step-off at the costochondral junction.

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Figures 8A to C: (A) Contrast-enhanced CT chest topogram (arrow) and (B) transverse CT showing eventration of diaphragm (arrows), (C) Contrast-enhanced CT chest of another patient showing diaphragmatic hernia on the left side and the migration of stomach (arrow) and spleen (asterisk) into the left side of the thorax.

Chest wall cold abscess and sinuses can occur due to TB, thoracic actinomycosis. When an empyema goes undetected over a long period of time, it erodes through the chest wall, forms a subcutaneous abscess and spontaneously drains

Conditions causing kyphosis (spinal deformity with anteroposterior angulation) and scoliosis (lateral displacement or curvature of the spine) can result in severe rib distortion affecting the respiratory function. Fibrothorax as a result of underlying pleural or pulmonary disease also presents with the physiologic manifestations similar to those seen in chest wall disorders. Chest trauma can result in flail chest, usually due to sequential double rib fractures in more than one site or fracture of ribs and the sternum. Because of the rib fractures, there is uncoupling of a part of the chest wall from the rib cage resulting in paradoxical motion. In ankylosing spondylitis, the anterior chest wall can be affected by enthesitis (inflammation of the muscular or tendinous attachments to bone) of the manubriosternal symphysis and sternoclavicular joints. Fixation of the chest wall through fusion of the costovertebral joints can also develop. Chest wall tumours can present as a palpable mass with or without pain and systemic symptoms. Large tumours of the chest wall (Figure 9) can result in pulmonary restriction. Surgical excision is usually required.

Figure 9: Contrast enhanced CT chest of a patient showing a chest wall tumour (arrows) on the right side.

of primary mediastinal malignancies: a report of 91 cases from a single institute. Ann Thorac Med 2009; 4: 140-2. 3.

Gopi A, Madhavan SM, Sharma SK, et al. Diagnosis and treatment of tuberculous pleural effusion in 2006. Chest 2007; 131: 880-9.

4.

Heffner JE. Discriminating between transudates and exudates. Clin Chest Med 2006; 27: 241-52.

5.

Kumar A, Mohan A, Sharma SK, et al. Video-assisted thoracoscopic surgery (VATS) in the diagnosis of intrathoracic pathology: initial experience. Indian J Chest Dis Allied Sci 1999; 41: 5-13.

6.

Mohan A, Ibrarullah M, Sonawane R, et al. Achalasia cardia: uncommon presentation. Indian J Chest Dis Allied Sci 2001; 43: 103-5.

7.

Sharma SK, Suresh V, Mohan A, et al. A prospective study of sensitivity and specificity of adenosine deaminase estimation in the diagnosis of tuberculosis pleural effusion. Indian J Chest Dis Allied Sci 2001; 43: 149-55.

8.

Shrivastava CP, Devgarha S, Ahlawat V. Mediastinal tumours: a clinicopathological analysis. Asian Cardiovasc Thorac Ann 2006; 14: 102-4.

ACKNOWLEDGEMENT The author wishes to thank the Department of Radiodiagnosis, Sri Venkateswara Institute of Medical Sciences, Tirupati, for providing the radiological images.

RECOMMENDED READINGS 1.

Agrawal V, Sahn SA. Lipid pleural effusions. Am J Med Sci 2008; 335: 16-20.

2.

Dubashi B, Cyriac S, Tenali SG. Clinicopathological analysis and outcome

Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall

on to the surface of the body and may present as a chest wall swelling with an expansile cough impulse (empyema necessitans).

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23.18

Atelectasis and Pulmonary Fibrosis

ATELECTASIS The term atelectasis is derived from the Greek words ateles and ektasis, which mean incomplete expansion. Atelectasis is defined as diminished volume affecting all or part of a lung. Several types of atelectasis exist; each has a characteristic radiographic pattern and aetiology. Classification and Pathophysiology Atelectasis is divided physiologically into (a) obstructive and (b) non-obstructive. Obstructive Atelectasis Obstructive atelectasis, also known as resorptive atelectasis, is the most common type. It results from reabsorption of gas from the alveoli when communication between the alveoli and the airway is obstructed.The obstruction can occur at the bronchial or bronchiolar level.The most important condition producing intrinsic bronchial obstruction is bronchogenic carcinoma (Table 1). Other causes of bronchial obstruction include other primary lung and metastatic neoplasms, inflammatory aetiologies (especially tuberculous or fungal infection), aspirated foreign bodies, mucous plugging, a malpositioned endotracheal tube and extrinsic compression of an airway by neoplasm, lymphadenopathy, aortic aneurysm or cardiac enlargement. Some conditions may decrease deep breathing or suppresses a person’s ability to cough, such as large doses of opioids or sedatives, general anesthesia, chest or abdominal surgery, certain neurologic conditions, chest deformities, abdominal swelling, immobility of the body and some tight bandages. Such conditions can cause or contribute to atelectasis because of pooling of secretions, mucous or blood in bronchi. People who smoke or who have lung disorders (e.g. chronic obstructive pulmonary disease, cystic fibrosis) have a greater risk of developing atelectasis. Following obstruction of a bronchus, the circulating blood absorbs the gas in the peripheral alveoli, leading to retraction of the lung and an airless state within a few hours. In the early stages, blood perfuses the airless lung; this results in ventilationperfusion mismatch and arterial hypoxaemia. Filling of the alveolar spaces with secretions and cells may occur, thereby preventing complete collapse of the atelectatic lung. With passage of time, the uninvolved surrounding lung tissue distends, displacing the surrounding structures. The heart and mediastinum shift toward the atelectatic area, the diaphragm is elevated and the chest wall flattens. The rate at which atelectasis develops and the extent of atelectasis depend on several factors. These include the extent of collateral ventilation that is present and the composition of inspired gas. The collateral ventilation is provided by the pores of Kohn and the canals of Lambert. The obstruction may lead 1784 to superadded infection in the atelectatic lung. If the obstruction is removed, any complicating post-obstructive infection

Rupak Singla

Table 1: Causes of Atelectasis Causes of obstructive atelectasis Causes within bronchial lumen Neoplasm Benign (adenoma) Malignant (carcinoma bronchus, lymphoma, metastatic breast, thyroid, melanoma, sarcoma, seminoma, renal cell carcinoma, osteosarcoma, chondrosarcoma) Alveolar cell carcinoma Inflammatory aetiology (e.g. tuberculosis, fungal infection) Aspirated foreign body Mucous plug Malpositioned endotracheal tube Causes in the bronchial wall Stricture or Stenosis Causes outside the brochus Neoplasm Lymphadenopathy (hilar/mediastinal) Aortic aneurysm or Cardiac enlargement Causes of non-obstructive atelectasis Relaxation atelectasis Pleural effusion Pneumothorax Large emphysematous bullae Compression atelectasis Chest wall, pleural, or intraparenchymal masses Loculated collections of pleural fluid Adhesive atelectasis Hyaline membrane disease Acute respiratory distress syndrome Smoke inhalation Cardiac bypass surgery Uraemia Prolonged shallow breathing Cicatrisation atelectasis Idiopathic pulmonary fibrosis Sarcoidosis Pneumoconiosis Collagen vascular diseases Chronic tuberculous and fungal infections Radiation fibrosis Replacement atelectasis Bronchoalveolar cell carcinoma

subsides and the lung returns to its normal state. If the obstruction is persistent and infection continues to be present, fibrosis develops and the lung may become bronchiectatic. Non-Obstructive Atelectasis Non-obstructive atelectasis can be caused by loss of contact between the parietal and visceral pleurae, compression, loss of surfactant and replacement of parenchymal tissue by scarring or infiltrative disease (Table 1). Subtypes of non-obstructive atelectasis are described below:

Platelet atelectasis This also called discoid or subsegmental atelectasis, this type is seen most commonly on chest radiographs. It probably occurs

because of obstruction of a small bronchus and is observed in states of hypoventilation, pulmonary embolism or lower respiratory tract infection. Small areas of atelectasis occur because of inadequate regional ventilation and abnormalities in surfactant formation from hypoxia, ischaemia, hyperoxia and exposure to various toxins. A mild-to-severe gas exchange abnormality may occur because of ventilation-perfusion mismatch and intra-pulmonary shunt. Post-operative atelectasis This is a common pulmonary complication in patients following thoracic and upper abdominal procedures. General anaesthesia and surgical manipulation lead to atelectasis by causing diaphragmatic dysfunction and diminished surfactant activity. The atelectasis is typically basilar and segmental in distribution.

Atelectasis and Pulmonary Fibrosis

Relaxation or passive atelectasis This results when a pleural effusion or a pneumothorax eliminates contact between the parietal and visceral pleurae. Generally, the uniform elasticity of a normal lung leads to preservation of shape even when volume is decreased. The different lobes also function differently, e.g. the middle and lower lobes collapse more than the upper lobe in the presence of pleural effusion, while the upper lobe may be affected more by pneumothorax. Compression atelectasis This occurs from any space-occupying lesion of the thorax compressing the lung and forcing air out of the alveoli. Such space-occupying lesions include pleural tumours, large pulmonary parenchymal masses, large emphysematous bullae and lobar emphysema. The mechanism is similar to relaxation atelectasis. Adhesive atelectasis This results from surfactant deficiency. The surfactant has phospholipid dipalmitoyl phosphatidyl-choline, which prevents lung collapse by reducing the surface tension of the alveoli. Lack of production or inactivation of surfactant, which may occur in adult respiratory distress syndrome (ARDS), radiation pneumonitis, or blunt trauma to the lung, causes alveolar instability and collapse leading to adhesive atelectasis. Cicatrisation atelectasis This results from diminution of volume as sequelae of severe parenchymal scarring. A number of conditions can result in pulmonary fibrosis and cicatrisation atelectasis, such as idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis, collagen vascular diseases, chronic tuberculous and fungal infections, and radiation fibrosis. Replacement atelectasis This occurs when the alveoli of an entire lobe are filled by tumour (e.g. bronchioalveolar cell carcinoma) resulting in loss of volume. Other Types of Atelectasis Several other types of atelectasis observed in clinical practice are described below: Right middle lobe syndrome This is a disorder of recurrent or fixed atelectasis involving the right middle lobe and/or lingula. The right middle lobe, due to its anatomical separation from the upper and lower lobes and poor collateral channels of ventilation, collapses more frequently and rarely re-expands (Brock’s syndrome). It can result from either extraluminal (bronchial compression by surrounding lymph nodes) or by intraluminal bronchial obstruction. It may develop in the presence of a patent lobar bronchus without identifiable obstruction. Inflammatory processes and defects in the bronchial anatomy and collateral ventilation have been designated as the non-obstructive causes of middle lobe syndrome. Rounded atelectasis This represents folded atelectatic lung tissue with fibrous bands and adhesions to the visceral pleura. Incidence is high in asbestos workers (65% to 70% of cases), most likely due to a high degree of pleural disease. The mean age at presentation is 60 years and the affected patients are typically asymptomatic.

EPIDEMIOLOGY OF ATELECTASIS The incidence and prevalence of atelectasis are not well documented. However, in India, cicatrisation atelectasis following tuberculosis (TB) is extremely common. Age The age at presentation depends upon the underlying cause. The mean age at presentation for rounded atelectasis is 60 years. Sex Atelectasis has no sex predilection. Race Atelectasis has no racial predilection. Mortality/morbidity Patient mortality depends on the underlying cause of atelectasis. In post-operative atelectasis, the condition generally improves. The prognosis of lobar atelectasis secondary to endobronchial obstruction depends on the treatment of the underlying malignancy. CLINICAL PRESENTATION OF ATELECTASIS Most symptoms and signs of atelectasis are determined by the rapidity with which the bronchial occlusion occurs, the size of the lung area affected, and the presence or absence of complicating infection. Rapid bronchial occlusion with large area of lung collapse causes pain on the affected side, sudden onset of dyspnoea, and cyanosis. Hypotension, tachycardia, fever and shock may also occur. Slowly developing atelectasis may be asymptomatic or may cause only minor symptoms. Middle lobe syndrome often is asymptomatic, although irritation in the right middle and right lower lobe bronchi may cause a severe, hacking, non-productive cough. PHYSICAL EXAMINATION OF ATELECTASIS The physical examination findings show dullness to percussion over the involved area and diminished or absent breath sounds. Chest excursion in the area is reduced or absent. The trachea and the heart are deviated toward the affected side. A monophonic or fixed rhonchus may also be heard over obstructed atelectasis. In upper lobe collapse, these signs may be absent. In cases of post-obstructive pneumonitis, clinical findings of signs of volume loss with a dull note on percussion, tubular bronchial breath sounds, bronchophony, with coarse 1785 crepitations may be observed.

INVESTIGATIONS OF ATELECTASIS Imaging Studies Chest radiograph Radiography is the initial investigation for suspected lung atelectasis. Chest radiographs show direct and indirect signs of lobar collapse. These have been described in Table 2. Table 2: Radiographic Signs of Atelectasis

Middle lobe collapse obscures the right heart border (positive Silhouette sign) on a postero-anterior (PA) film (Figure 2). On lordotic view, a triangular opacity may be observed (Figure 3). The lateral view shows a triangular opacity overlying the heart because the major fissure shifts upward and the minor fissure shifts downward (Figure 4). On computed tomography, the atelectatic right middle lobe appears as a triangular opacity against the right heart border with the apex pointing laterally and is termed the ‘tilted ice cream cone sign’.

Direct Signs Displacement of septa/fissure Loss of aeration leading to radio-opacity Crowding of bronchial and vascular markings Indirect Signs Elevation of hemidiaphragm Shift of trachea or mediastinum Narrowing of rib cage Over inflation of remaining lung Shift of hilum

Atelectasis of each segment or lobe of the lung results in a particular pattern of blurring of the normal boundaries (Silhouette sign) of mediastinal structures. Upper lobe atelectasis may obliterate the superior mediastinal border. The collapsed right upper lobe shifts medially and superiorly, resulting in elevation of the right hilum and the minor fissure (Figure 1). Rarely, the right upper lobe may collapse laterally, producing a mass like opacity that may look like a loculated pleural effusion. The minor fissure in right upper lobe collapse is usually convex superiorly but may appear concave because of an underlying mass lesion. This is called the sign of ‘Golden S’.

Figure 2: Chest radiograph (PA view) showing right middle lobe collapse obscuring the right heart border (positive Silhouette sign).

Figure 3: Chest radiograph (lordotic view) showing the right paracardiac triangular shadow suggestive of the right middle lobe atelectasis.

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Figure 1: Chest radiograph (PA view) showing collapsed right upper lobe shifting medially and superiorly, resulting in elevation of the right hilum.

Lower lobe atelectasis does not obliterate the cardiac borders, and causes a retro-cardiac triangular opacity (Figure 5). On frontal views, the hilum shifts downward, and the rotation of the heart produces flattening of the cardiac waist, which is known as the

Atelectasis and Pulmonary Fibrosis

cut-off of air in the bronchus called ‘bronchial cut-off sign’ (Figure 7). The mediastinal shift separates atelectasis from massive pleural effusion.

Figure 4: Chest radiograph (lateral view) showing a triangular opacity of right middle lobe atelectasis overlying the heart because the major fissure shifting upward and the minor fissure shifting downward.

Figure 6: Chest radiograph (PA view) showing complete atelectasis of the left lung leading to opacification of the entire hemithorax and an ipsilateral shift of the mediastinum.

Figure 5: Chest radiograph (PA view) showing the left lower lobe atelectasis seen as retro-cardiac triangular opacity.

Figure 7: Chest radiograph (PA view) showing sudden cut-off of air in the right main bronchus called ‘bronchial cut-off sign’.

flat-waist sign. On lateral radiographs, opacity makes the posterior third of the left diaphragm indistinct. A CT shows the atelectatic lower lobe in the inferior posterior location. Complete atelectasis of a lung leads to opacification of the entire hemithorax and an ipsilateral shift of the mediastinum (Figure 6). In case of intraluminal growth, there may be sudden

Computed tomography (CT) CT is useful in evaluating the mediastinum, chest wall, hilum, pleura and adjacent lung. CT is also very sensitive for detecting the site of obstruction and whether a neoplasm is responsible for the same. In compressive atelectasis, air-bronchogram is present but not in obstructive atelectasis. CT may also be useful to 1787

demonstrate associated bronchiectasis in chronic atelectasis.With the advent of spiral CT and three-dimensional reconstructions, virtual, three-dimensional images can be obtained and virtual bronchoscopy has become possible. Magnetic resonance imaging (MRI): In some patients, MRI can provide comparable and/or complementary information. Other imaging tests: In recent years, B-mode sonographic patterns as well as colour Doppler sonographic patterns of atelectasis have been reviewed. In addition, contrast-enhanced sonography (CES) allows differentiation between compression atelectasis and obstructive atelectasis by different patterns of enhancement. Laboratory Studies 1. Pulmonary function testing in atelectasis of the lung usually shows a restrictive pattern. In some cases with associated bronchiectasis, a combined obstructive and restrictive pattern may be obtained. 2. On arterial blood gas analysis, atelectasis of a significant size may show hypoxaemia. However, despite hypoxaemia the PaCO2 level is usually normal or low as a result of the increased ventilation. Flexible Fiber-Optic Bronchoscopy Flexible fiber-optic bronchoscopy (FOB) can be a useful diagnostic and therapeutic procedure. 1. Bronchoscopy helps in evaluating the cause of bronchial obstruction. In addition, bronchoscopy helps in clearing mucous plugs when they cause bronchial obstruction. 2. Bronchoscopy has its limitations. Because only the sub segmental bronchi are visualised, a distal end bronchial lesion is not accessible through bronchoscope. 3. In an evaluation of middle lobe syndrome, bronchoscope may show an endobronchial aetiology (mucus plugging/ broncholithiasis/tumour), although the non-obstructive causes of the syndrome, such as inflammatory processes and defects in the bronchial anatomy and collateral ventilation may be missed. 4. During FOB, the washing, brushing and biopsy specimens of any obstructing mass should be examined for evidence of malignancy. Complications of Atelectasis Patients with atelectasis of lobe or segment of lung may have following complications: 1. Acute pneumonia 2. Bronchiectasis 3. Hypoxaemia and respiratory failure 4. Post-obstructive drowning of the lung 5. Sepsis 6. Pleural effusion and empyema MANAGEMENT OF ATELECTASIS Medical Care The treatment of atelectasis depends on the underlying aetiology. Treatment of acute atelectasis, including post-operative lung collapse, requires removal of the underlying cause. In patients with pleural effusion, the pleural aspiration should be done and investigated for biochemistry and cytological examination. 1788 Tuberculosis should be treated with anti-tubercular drugs. In

pneumothorax, intercostal tube drainage results in expansion of the lung. Immediate repositioning of the endotracheal tube will result in re-expansion of the lung in cases with inadvertent endotracheal tube of the right main bronchus. Large emphysematous bullae might require surgical resection. Chest physiotherapy and FOB might be helpful in patients with mucous plugging of the airways. If a foreign body is suspected to be the cause for obstructive atelectasis, therapeutic bronchoscopy for its removal is indicated. In case of endobronchial tumour, the obstruction can be relieved by surgery, radiation or chemotherapy. In selected patients, laser therapy or airway stenting may be considered. Non-pharmacologic therapies for improving cough and clearance of secretions from the airways include chest physiotherapy, including postural drainage, chest wall percussion and vibration, and a forced expiration technique (called huffing). For post-operative atelectasis, prevention is the best approach by a good perioperative care. Anaesthetic agents associated with postanaesthesia narcosis should be avoided; narcotics should be used sparingly because they depress the cough reflex. Early ambulation and use of incentive spirometry are important. Encourage the patient to cough and to breathe deeply. Postoperative atelectasis is treated with adequate oxygenation and if required, by intubation and mechanical ventilatory support. When these efforts are not successful within 24 hours, flexible FOB should be performed. In patients with chronic atelectasis, associated fibrosis, destruction and bronchiectasis can result in infection and haemoptysis. This can be prevented by regular chest physiotherapy and postural drainage, vaccines and antibiotics. Surgical care Chronic atelectasis with symptoms such as recurrent infections or significant haemoptysis is treated with segmental resection or lobectomy. PULMONARY FIBROSIS Pulmonary fibrosis describes the clinical end-point of a multiplicity of diverse pathological processes, ranging from infection to autoimmune diseases, most of which are of unknown aetiology but have characteristic features that allow them to be classified as distinct disease entities (Table 3). Clinical Presentation of Pulmonary Fibrosis Symptoms By far, the most common presenting complaint of a patient of pulmonary fibrosis is dyspnoea. Depending upon the underlying cause, it may be acute, as in infections, extrinsic allergic alveolitis; sub-acute as in Pneumocystis carinii pneumonia associated with human immunodeficiency virus (HIV); or chronic as in asbestosis, pulmonary sarcoidosis. Cough is a fairly common symptom, and a very non-specific initial finding. Cough can be disabling, particularly in idiopathic pulmonary fibrosis (IPF) and diseases that primarily affect airways, such as bronchiolitis, cryptogenic organising pneumonia and sarcoidosis, in which cases it is also associated with expectoration. Other less common symptoms include chest pain and haemoptysis.

Post-infections

Drug-induced

Toxins/Poisons/ Organic Dusts

Occupational and Environmental

Post-TB Post-viral mycoplasma Human immunodeficiency virus-related

Nitrofurantoin, Bleomycin, Sulfasalazine, Beta-blockers, Gold, Penicillamine, Amiodarone, Busulfan, Methotrexate, Bromocriptine, Carmustine, Cyclophosphamide, Ergots, Nitrosoureas

Oxygen, Chlorine, Fluorine, Nitrogen dioxide, Paraquat radiation-induced, Fungal spores Animal proteins

Asbestosis

Collagen Vascular Diseases

Vasculitides

Inherited Causes

Idiopathic Causes

Tuberous sclerosis Neurofibromatosis Ankylosing spondylitis Familial pulmonary fibrosis

Idiopathic pulmonary fibrosis Sarcoidosis Langerhan’s cell histiocytosis Lymphangioleiomyomatosis, Amyloidosis Hemosiderosis

Rheumatoid arthritis, Churg-Strauss syndrome Systemic lupus erythematosus Polyarteritis Nodosa Sjögren’s syndrome Wegener’s granulomatosis Systemic sclerosis

Silicosis/Berylliosis Progressive massive fibrosis

Atelectasis and Pulmonary Fibrosis

Table 3: Causes of Pulmonary Fibrosis

Table 4: Radiographic Pattern of Distribution of Pulmonary Opacities in Pulmonary Fibrosis Upper Zones

Mid Zones

Lower Zones

Pulmonary Koch’s Sarcoidosis Langerhan’s cell histiocytosis Silicosis Progressive massive fibrosis Extrinsic allergic alveolitis

Pulmonary oedema Idiopathic pulmonary fibrosis Alveolar proteinosis Asbestosis Pneumocystis jirovecii infection Collagen vascular diseases Tropical pulmonary eosinophilia Rheumatoid lung disease Primary Sjögren’s syndrome

Signs Most common findings are crackles. These are usually inspiratory, and occur not only in most patients of pulmonary fibrosis associated with idiopathic pulmonary fibrosis, but also in many other interstitial lung diseases. The crackles are usually audible at the lung bases initially. Gradually, as the disease progresses, crackles extend upto the lung apices. In bronchiectasis, crackles may be inspiratory as well as expiratory. Radiological Features Tables 4 and 5 summarise the radiological features of pulmonary fibrosis. Table 5: High Resolution Computed Tomography (HRCT) Features of Pulmonary Fibrosis Cystic Disease

Honey-combing

Ground-glass Opacities

Langerhan’s cell histiocytosis Lymphangioleiomyomatosis

Asbestosis Collagen vascular diseases Chronic hypersensitivity Pneumonitis Sarcoidosis Idiopathic pulmonary fibrosis (IPF) End-stage acute respiratory distress syndrome

IPF Alveolar proteinosis Radiation pneumonitis Sarcoidosis

Complications of Pulmonary Fibrosis Pulmonary fibrosis leads to the development of hypoxia, which in turn produces pulmonary arterial hypertension and right-

Generalised Miliary tuberculosis, cystic fibrosis, metastases, acute respiratory distress syndrome, drug reactions, microlithiasis, lymphangitis carcinomatosis

sided heart failure. Supplemental oxygen therapy may prove beneficial. Treatment of Pulmonary Fibrosis As stated earlier, pulmonary fibrosis is an end-stage process and optimal therapy is an area of intense research. Supportive care, physiotherapy, and pulmonary rehabilitation are essentially required for all the patients. Supplemental oxygen inhalation may prove helpful for hypoxaemic individuals. Preventive strategies like vaccination with influenza and pneumococcal vaccines are useful to combat infection with these pathogens and should not be overlooked. Adequate counselling of patients regarding avoidance of exposure to likely offending drugs, toxins, occupational or environmental agents also form an important part of the treatment of pulmonary fibrosis. Corticosteroids and immunosuppressive therapy may be useful in relevant situations. Lung transplantation can be considered in end-stage fibrosis with an unfavourable prognosis. RECOMMENDED READINGS 1.

Lawson WE, Loyd JE. The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease? Proc Am Thorac Soc Jun 2006; 3(4): 345-9.

2.

McCool FD, Rosen MJ. Nonpharmacologic airway clearance therapies: ACCP evidence-based clinical practice guidelines. Chest 2006; 129(1 Suppl): 250S-9S.

3.

Schindler MB. Treatment of atelectasis: where is the evidence? Crit Care 2005; 9: 341-2.

4.

Woodring JH, Reed JC. Types and mechanisms of pulmonary atelectasis. J Thorac Imaging 1996; 11: 92-108.

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23.19 INTRODUCTION Lung cancer is the most common cancer globally. During the past two decades, better understanding of the biology, use of systemic chemotherapy and development of biologic therapy for non-small cell lung cancer (NSCLC) has led to modest improvement in the quality of life and overall survival. Currently, adjuvant chemotherapy (4 cycles of platinum-based combination) is considered standard in completely resected NSCLC stage II and IIIA. Role of chemotherapy in resected stage IB NSCLC is not clear at present. Post-operative radiotherapy (PORT) is not indicated for stage I or II NSCLC, and remains controversial in resected stage IIIA (N2) disease. For advanced NSCLC, cisplatin-based doublets (two drugs) combination is preferred in patients with good performance status (ECOG,0- 1), whereas carboplatin-based combinations are preferred in patients with impaired organ functions (kidney, heart). Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. Patients who fail to primary therapy benefit with docetaxel or pemetrexate or erlotinib. A small subset of patients with advanced NSCLC benefit with EGFR inhibitors—tyrosine kinase inhibitors, e.g. geftinib and erlotinib, though effect generally lasts for months. Benefit is seen predominantly in never-smokers, female patients with adenocarcinoma histology and in those with presence of activating mutations in the EGFR-TK domain. Currently, it is not clear if EGFR inhibitors should be used upfront or after chemotherapy or if they can be used as adjuvant in patients with early stage NSCLC. Another biologic agent, Bevacizumab (vascular endothelial growth factor inhibitor), when used with chemotherapy has been found to improve outcome in selected patients with non-squamous cell advanced NSCLC. BENIGN TUMOURS OF TRACHEOBRONCHIAL TREE Benign tumours of tracheobronchial tree are rare and account for 0.2% of all the respiratory malignancies (Table 1). Clinical presentation includes symptoms of airway obstruction like cough, shortness of breath or wheezing. Because of these nonspecific symptoms, patients may be mistaken for asthma or obstructive lung disease and may receive oral corticosteroids, leading to delay in diagnosis. Some patients may also present with atelectasis and secondary pulmonary infection when tumour is detected incidentally. Haemoptysis can also be a presenting symptom. The chest radiographs may demonstrate collapse of a lobe or an entire lung due to complete obstruction or to hyperinflation of the lung peripheral to a bronchial tumour that causes a ball valve effect. Computed tomography of the chest may demonstrate a tracheal or bronchial mass but it may underestimate the extent of submucosal invasion. Fibre-optic bronchoscopy is useful in: (i) directly visualising the tumour and its extent; and (ii) to take biopsy samples to clinch the diagnosis. Malignant tumours 1790 require further investigations to rule out distant metastasis.

Benign and Malignant Tracheobronchial Tumours Lalit Kumar, MP Ram Prabhu

Table 1: Benign and Malignant Tumours of Tracheobronchial Tree Benign tumours of trachea and major bronchi Bronchial mucous adenomas Carcinoids Pleomorphic adenomas Malignant tumours of trachea and major bronchi Mucoepidermoid carcinoma Adenoid cyctic carcinoma Squamous cell carcinoma Bronchogenic carcinoma Small cell lung cancer Non-small cell lung cancer Squamous cell carcinoma Adenocarcinoma Large cell carcinoma Bronchoalveolar carcinoma Other types: adenosquamous type, etc.

Carcinoid tumours are of neuroendocrine origin, found in large bronchi. Histologically, they are composed of cuboidal cells with small and hyperchromatic nuclei arranged in organoid or ribbon-like pattern. On immunohistochemistry, these cells stain positive for neuroendocrine markers like chromogranin and synaptophysin. Typical carcinoids have low mitotic rate with no necrosis. These tumours rarely metastasise. Atypical carcinoids, on the other hand, have higher mitotic activity and necrosis, and have poorer prognosis.Two per cent of bronchial carcinoids secrete serotonin and cause classical features of carcinoid syndrome—diarrhoea, flushing and hypotension. Some of them cause Cushing’s syndrome by secreting ACTH. Treatment of benign tumours consists of segmental resection of trachea or bronchus with or without sleeve resection of corresponding lung parenchyma. Unresectable malignant tumours are managed with radiotherapy or local ablative measures like laser photocoagulation or cryotherapy, although treatment in such cases is mostly palliative. BRONCHOGENIC CARCINOMA Lung cancer is the most common malignancy worldwide in males and is also the leading cause of death due to cancer. Almost half of the cases occur in the developing countries. Incidence of lung cancer is declining in industrialized nations (like United States) due to smoking control measures; it continues to rise in developing countries. INDIAN SCENE In India, lung cancer is the most common cancer among males (ICMR, 2005). Data from urban and rural population-based cancer registries is shown in (Table 2). The Cancer Atlas Programme of ICMR has revealed high incidence of lung cancer in certain pockets in north-east India.The median age at diagnosis is lower in India (54 versus 68 years), with higher male to female ratio (4:1 versus 1.4:1). Only 12% of patients had stage I-II

Table 2: Age Adjusted Incidence Rates of Lung Cancer in Population-Based Cancer Registries Registry Aizwal District Mizoram State Imphal West District Mizoram State excluding Aizwal District Kamrup Urban District Delhi Bhopal Chennai Silchar Town Mumbai Bangalore Ahmedabad Dibrugarh District Sikkim State Barshi

Males

Females

39.3 24.9 19.2 17.0 14.8 13.8 12.3 11.2 10.4 8.9 8.5 5.5 5.4 5.2 1.9

42.2 24.7 16.5 14.5 5.1 3.2 0.8 3.0 1.4 3.2 2.8 1.0 2.7 6.2 0.9

Source : Consolidated report of the PBCRs 2001-2004.

Table 3: Lung Cancer: A Comparison Between Indian and Western Data

Age (median in years) M:F Smoking Stage IA IB IIA IIB IIIA IIIB IV Histologic type/Sub type Adenocarcinoma (bronchoalveolar) Squamous carcinoma Large cell carcinoma Small cell carcinoma Large cell neuroendocrine Others

Industrialised Nations

India

68 1.44:1 92 (male) 80 (female)

54 4:1 64

16.4 10.8 1.6 5.4 14.6 15.2 36.2

0.3 4.6 0.9 6.1 10.3 35.5 42.4

32 29 9 20 2 12

27 34 — 10 — 25

RISK FACTORS The various risk factors implicated in lung cancer are given in Table 4. Smoking Smoking is the most important risk factor for lung cancer especially for small cell lung cancer (SCLC) and squamous cell carcinoma.The relative risk of developing lung cancer is 30 times higher in smokers than in non-smokers. Only 5% to 10% of all patients with lung cancer are non-smokers. Tobacco smoke contains more than 300 chemicals, of which 40 are potent carcinogens. Nitrosoamines like nicotine-derived nitrosoamine ketone (NNK) and polycyclic aromatic hydrocarbons like benzo a pyrene can induce lung cancer in animal models similar to human lung cancer. Nicotine and inorganic metals like nickel, arsenic and chromium also act as carcinogens. The risk of lung cancer is directly related to the duration and intensity of smoking. Similarly, cessation of smoking is associated with decline in the risk of lung cancer.The relative risk

is 16 after 5 years of cessation compared to non-smoker, 8 after 10 years and 2 after 30 years. Passive smoking also increases the risk of lung cancer. Studies indicate that it may contribute to 25% of all lung cancers in non-smokers. Table 4: Risk Factors for Lung Cancer Smoking Industrial Carcinogens: accounts for up to 8% of lung cancer related deaths Radionuclides such as uranium, radon in miners, radon derivatives (especially small cell lung cancer) Asbestos, especially with heavy smoking; asbestos fibres include: actinolite,amosite,anthophyllite, chrysotile,crocidolite,and tremolite Silica Arsenic compounds: arsenic trioxide, arsenic pentoxide, arsenic acid and derivatives Organic compounds like polycyclic aromatic hydrocarbons (PAHs), diesel fumes Metals like nickel, chromium Fibrosis/Scars: Scars (scar carcinoma, cavitary lesions after tuberculosis) (cavitary carcinoma) Dietary Factors Genetic Predisposition Risk in relatives of lung cancer patients is increased by factor 2-4 Chromosomal Deletions and Mutations: 3p21 deletion, mutations of tumour suppressor gene p53, and Rb, altered oncogene expression (myc in small cell lung cancer; K-ras, Her2/neu in adenocarcinomas) Cytochrome P450 DNA repair genes like ERCC and XRCC In East Asia, 40% of lung cancer cases occur in never-smokers and are associated with increased incidence of EGFR mutations.

Benign and Malignant Tracheobronchial Tumours

compared to 36% and squamous cell carcinoma is the predominant histological subtype (Table 3).

Development of lung cancer is a multi-step process; initially there is epithelial metaplasia followed by dysplasia, carcinoma in situ and then invasive carcinoma. PATHOLOGY AND CLASSIFICATION The WHO histological classification of epithelial tumours of lung consists of 42 different histological varieties, but all these varieties can be grouped under two broad types: tumours originating from surface epithelium of bronchi or bronchioli, namely, non-small cell lung cancer and those arising from neuroectodermal cells/APUD (amine precursor uptake and decarboxylation), small cell lung cancer. Both these types differ in their cell of origin, histology, behaviour of growth and spread, natural course, staging and management. The non-small cell lung cancers (NSCLCs) can be further subdivided into following types based on histological features although they do not differ in staging and treatment. Squamous cell carcinoma was the most common type three decades ago; adenocarcinoma is currently the predominant type in industrialised nations. In India, squamous cell cancer is still the predominant histologic subtype (Table 3),there is marginal increase in the incidence of adenocarcinoma subtype. Squamous cell carcinomas typically arise from epithelium of proximal segmental bronchi,evolving through stages of squamous metaplasia,dysplasia, carcinoma in situ and invasive carcinoma and present as a hilar mass (Figure 1A ). Figure 1B shows the CT image of same patient Adenocarcinomas are typically located in the periphery of the 1791 lung and are less amenable to detection by sputum cytology or

Lung cancer is a heterogeneous disease at molecular level. This is evidenced by the fact that a small subset of patients with advanced disease benefit with EGFR inhibitors – tyrosine kinase inhibitors (TKIs), e.g. geftinib and erlotinib, though effect generally lasts for months. Benefit is seen predominantly in never-smokers, female patients with adenocarcinoma histology and in those with presence of activating mutations in the EGFR-TK domain.The two most common mutations in the TK domain, exon 19 deletions and L858R have been associated with best responses. Similarly, pemetrexate is a newer antifolate drug and is effective for patients with advanced NSCLC with non-squamous histology.

Figure 1A: Chest radiograph showing right hilar mass with raised diaphragm.

MODE OF SPREAD Lung cancer spreads locally by direct invasion of adjacent structures like chest wall, pleura, diaphragm, trachea, Oesophagus, and great vessels of mediastinum, pericardium and the heart. Lymphatic spread occurs to bronchopulmonary, mediastinal and subcarinal and then supraclavicular lymph nodes. Lower lobe lymphatics drain into posterior mediastinum and subcarinal nodes. Right upper lobe lymphatics drain towards the superior mediastinum and left upper lobe lymphatics drain into the anterior mediastinum as well as superior mediastinum. Distant metastasis occurs to bone, liver, adrenals and brain and to any site in the body by haematogenous dissemination. Metastasis can also occur to the same lobe or other lobes or contralateral lung. Rare sites like skin and subcutaneous tissue, breast, ovary, testis and thyroid have been reported.

Figure 1B: Computed tomography of the same patient with evidence of right hilar mass and pleural effusion.

bronchoscopy but more approachable for CT-guided needle biopsies. Fourteen different subtypes have been described. Bronchoalveolar carcinoma is special subtype of adenocarcinoma seen more commonly in non-smoking females of Asian origin.This is multi-focal, spreads along the airways (known as lepidic spread) before stromal and angiolymphatic invasion and can hamper with gas exchange at alveolar surface causing dyspnoea. Mucinous variety can be associated with copious mucinous expectoration. Special interest has developed in this variety due to high incidence of epidermal growth factor receptor (EGFR) mutations and response to targeted therapeutic agents like erlotinib and gefitinib.

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Large cell carcinomas comprise 15% of all lung cancers and present similar to adenocarcinomas as a peripheral lung nodule. Some of them show neuroendocrine differentiation and when associated with necrosis and high mitotic rate, are called large cell neuroendocrine carcinomas.

CLINICAL FEATURES Cough is the most common symptom followed by breathlessness, haemoptysis and chest pain. Breathlessness may occur due to endobronchial obstruction by tumour causing collapse of a lobe or whole lung or pleural effusion. Rarely, breathlessness may be due to lymphangitis carcinomatosis, a condition where lymphatics are infiltrated by tumour (Figure 2). Haemoptysis occurs more often in a central lesion. Rapid enlargement of tumour, especially SCLC, can cause obstruction of SVC resulting in facial puffiness, plethora and engorged veins over the neck and chest wall together known as superior vena cava syndrome. Pancoast tumour is a lesion arising from the apical region of the lung (Figures 3A and B). It may cause Horner’s syndrome due to involvement of sympathetic ganglia or its roots. Brachial plexus involvement may be seen. Systemic symptoms like weight loss and loss of appetite are common. Symptoms may also occur due to metastatic lesions like bone pain in skeletal metastasis, painful and tender hepatomegaly in liver metastasis. Seizures and features of raised intracranial tension like headache, vomiting and papilloedema can occur in brain metastasis. A unique constellation of symptoms can develop in lung cancer affecting the neuroendocrine system and skin caused by humoral substances released by tumour tissue, known as paraneoplastic syndromes. Clinical significance of paraneoplastic syndromes lies in the fact that they may precede cancer by months to years and may warn about occurrence.When they occur along with cancer, they may give a clue to underlying disease. Usually they resolve with treatment of the disease but some neurological syndromes may persist. Paraneoplastic syndromes are more commonly seen with SCLC but are also seen with NSCLC. The most common syndrome associated with SCLC is syndrome of inappropriate

Hypercalcaemia is more common in squamous cell type of NSCLC. It is caused by secretion of parathyroid hormone related peptide (PTHrP) although hypercalcaemia due to extensive bone metastasis has to be ruled out. Clubbing and hypertrophic osteoarthropathy can occur in NSCLC. Thromboembolic manifestations can also occur. Table 5 describes clinical features reported in major studies from India. Table 5: Clinical Presentation: Experience from India (%)

Figure 2: Computed tomography of the chest showing lymphangitis carcinomatosis.

PGI Chandigarh (%) Cough with expectoration 88 Chest pain 52.2 Loss of weight 90 Breathlessness Not reported Weakness 90 Haemoptysis 69 Fever 19.6 Anorexia 90 Hoarseness of voice 29. 9 Nausea and vomiting 6 Puffiness of face 19.8 Dysphagia 20.8 Others 30.5

AIIMS Other New Delhi Centres N=907 (%) (%) 83 (69.5) 78.9 88 83.9 91.4 37.2 68 88.8 28.5 — 10.5 (SVCO) — —

40-94.3 16-66.7 11.4-77 24-59 4-60 28-60 22-68.6 20.5-70 9-33 25.0 2.9-8.3 2.9-6 —

Benign and Malignant Tracheobronchial Tumours

syndrome is characterised by proximal muscle weakness which worsens with exercise. It can be differentiated from myasthenia gravis by electromyogram (EMG) and anti-cholinesterase antibodies. Peripheral neuropathy, limbic encephalitis and paraneoplastic cerebellar degeneration can occur in SCLC.

SVCO = Superior vena cava obstruction. Figure 3A: Chest radiograph showing advanced pancoast tumour with erosion of rib and body of vertebra.

Figure 3B: Computed tomography of the same patient showing first rib and vertebral involvement and apical mass.

secretion of anti-diuretic hormone (SIADH) resulting in hyponatraemia due to secretion of ADH by the tumour. Hyponatraemia is usually asymptomatic but can rarely cause neurological manifestations like seizures and altered mental status. Cushing’s syndrome due to secretion of ACTH or corticotropin releasing hormone (CRH) has also been reported and portends a poor prognosis. Lambert-Eaton myasthenic

INVESTIGATIONS Complete blood count and renal and liver function tests along with electrolytes are recommended in all cases. Chest radiograph may reveal large peripheral lung nodule or central obstructing lesion, collapse or pleural effusion (Figure 4). Mediastinal lymphadenopathy and sometimes diaphragmatic palsy or lymphangitis carcinomatosa can be made out. Central lung lesion (near hilum) is mostly seen in small cell or squamous cell cancer. Peripheral lung lesions (distant to hilum, nodular structures) are frequently large cell lung cancer or adenocarcinomas. Diffuse lung disease is usually alveolar carcinoma. Contrast-enhanced computed tomography (CECT) of chest and upper abdomen will pick up smaller lesions not visible on radiographs and also better define the anatomy of the lesion and its relation to mediastinal structures as well as lymphadenopathy . It also reveals metastasis to other lobes, opposite lung, liver, or adrenals (Figure 5). CT scan has a sensitivity of 60% and specificity of 80% to detect lung cancer. FDG-PET scans ([18F] Flouro-deoxyglucose-Positron emission tomography (FDG-PET scans) is useful in detecting mediastinal lymphadenopathy, visceral and bone metastasis. PET scan has higher sensitivity and specificity (70% and 80%, respectively) and high negative predictive value of 90%. Integrated PET-CT scans further improve sensitivity and specificity to 80% and 95%, respectively. MRI scans are not useful for diagnosis and staging but they may be useful in tumours invading spine, great vessels

1793

performed due to availability of non-invasive imaging (CT and PET-CT) and less invasive procedures. SOLITARY PULMONARY NODULE Solitary pulmonary nodule is defined as an asymptomatic lung lesion less than 6 cm in diameter with normal physical examination and normal blood counts and liver function tests (Figure 6). It can be benign or malignant. Age greater than 45 years, history of smoking and a doubling time of 30 to 400 days indicate a high probability of malignant lesion. Circular, crescentric or densely calcified lesions are more likely to be benign. Suspicious lesions should be further investigated and the rest should be kept under follow-up. CT-guided needle biopsy yields an accurate diagnosis in 85% to 90% of the cases in peripheral lung lesions. Open biopsy is done in more central lesions. FDG-PET scans are considerably sensitive and specific in identifying malignant solitary pulmonary nodule.

Figure 4: Chest radiograph showing mass lesion with evidence of cavity in squamous cell carcinoma.

Figure 6: Computed tomography of the chest showing speculated nodular lesion.

Figure 5: Computed tomography showing left adrenal metastasis.

or brachial plexus. MRI brain is superior to CT scan in detecting intracranial metastasis. Bone scan is used to detect skeletal metastasis. DIAGNOSIS Sputum cytology has a sensitivity of 65% in detecting lung cancer, especially in central lesions and with multiple sampling. Pleural fluid cytology helps in diagnosis in 60% to 70% of cases. CT-guided fine needle aspirate helps in diagnosing peripheral lesions with 95% yield. Sometimes, this technique is used to confirm solitary lesion in liver or adrenals. Fibreoptic bronchoscopy helps in visualising more central lesions and also to take biopsy or brush samples. Transbronchial aspirate of lung lesion or mediastinal lymph node can also be done. Video-assisted thoracoscopy (VAT) can be used in diagnosis, staging and interventional procedures like resection or mediastinal lymph node sampling. Mediastinoscopy is used to accurately stage the 1794 nodal disease. Thoracotomy and mediastinotomy are rarely

STAGING TNM staging is used to define the extent of disease spread. Recently, International Association for the study of Lung Cancer (IALC, 2009) has proposed revised TNM staging. In this new classification, T1 tumours (0 to 3 cm) have been sub- classified as T1a (3 cm) to T2a (3 to 5 cm) and T2b (5 to 7 cm) and T2 tumours exceeding 7 cm as T3. Satellite nodule in the same lobe (T4) is now classified as T3 and additional nodules in a different ipsilateral lobe (M1) as T4 and additional nodules in contralateral lung as M1a, pleural and pericardial dissemination (T4) as M1a and distant metastases have been reclassified as M1b in the new staging system (Table 6). TREATMENT Surgery remains the treatment of choice for patients with stage I and II disease where the lesion is resectable. In Stage IIIA, ipsilateral mediastinal nodes are resectable but generally have a poorer outcome and post-operative adjuvant chemotherapy and/or radiotherapy is required. Stage IIIB lung cancers are unresectable in view of invasion of mediastinal structures or contralateral lymph nodes and stage IV disease is incurable by surgery due to distant metastasis. Resectability and operability has to be determined in each individual patient before planning surgery. Resectability indicates whether the disease can be excised without any residual disease. Some stage IIIA lesions

Primary Tumour TX Tumour proven by presence of malignant cells in bronchopulmonary secretions but not visualised by imaging or bronchoscopy, or any tumour that cannot be assessed, as in pretreatment imaging T0 No evidence of tumour Tis Carcinoma in situ T1 Tumour 3 cm but 5cm but 7 cm or of any size with invasion of any of the following: chest wall (including superior sulcus tumour) , diaphragm, mediastinal pleura, parietal pericardium; or tumour in the main bronchus within 2 cm of the ( but not involving) the carina; or associated atelectasis or obstructive pneumonitis of the entire lung; or separate tumour nodule(s) in the same lobe T4 Tumour of any size with invasion of any of the following: mediastinum, heart, great vessels, trachea, oesophagus, vertebral body, carina; or separate tumour nodule(s) in a different lobe of the lung Regional Lymph Node Involvement Nx N0 N1 N2 N3

Regional lymph node status cannot be assessed No demonstrable metastasis to regional lymph nodes Metastasis to ipsilateral peribronchial and/or pulmonary or hilar nodes and intrapulmonary nodes (including direct extension) Ipsilateral mediastinal and/or subcarinal Contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular nodes

Metastasis Mx M0 M1 M1a

Distant metastasis cannot be assessed No distant metastasis Metastasis present Separate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural (or pericardial effusion) M1b Distant metastasis

modalities like spirometry with diffusion capacity, arterial blood gas analysis, echocardiography and ventilation-perfusion scans. If the post-operative predicted value of FEV1 or DLCO equals or exceeds 40% of predicted, this is considered to be associated with lesser peri-operative risk. Lobectomy, bilobectomy or pneumonectomy can be performed depending on the extent of the disease. Post-operative mortality rates range from 6% for pneumonectomy to less than 1% for smaller resections. Radiotherapy (RT) plays a role in locally advanced unresectable disease. External-beam radiotherapy from a linear accelerator is generally used after three dimensional CT planning. A dose of 60Gy to 66Gy is delivered to the primary lesion and 40 to 45Gy to the uninvolved lymph nodes over a period of 6 to 8 weeks when irradiated.Toxicity includes, acute complications like acute radiation pneumonitis (developing within 1 to 6 months of RT), acute oesophagitis and rarely pericarditis, myelitis and brachial plexopathy. Late complications include pulmonary fibrosis (20 mm Hg, with a pulmonary capillary wedge pressure (PCWP) or LV enddiastolic pressure 3 Wood units. It is very useful for excluding the elevated left heart pressure (measured as the PCWP) as a cause of right HF. However, it is an invasive procedure and its use cannot be recommended routinely. Cardiac Bio-Markers Natriuretic peptides are released by cardiac myocytes. B-type natriuretic peptide (BNP) and N-terminal BNP levels are elevated in patients with cor pulmonale secondary to RV stretch and may be dramatically elevated in acute PE. Given the high sensitivity of these peptides for moderate to severe PAH, their measurement is recommended.

Figure 3: Two-dimensional echocardiography showing enlargement of the right ventricle.

Doppler echocardiography is the best and most reliable method for non-invasive diagnosis of PAH. It allows estimation of the PAP by measuring the jet velocity of tricuspid regurgitation using continuous wave Doppler echocardiography. If sufficient lung hyperinflation prevents an adequate trans-thoracic examination, trans-oesophageal echocardiogram may be useful. Magnetic Resonance Imaging Magnetic resonance imaging (MRI) allows the measurement of volumes and blood flow in the thorax. It may be useful for assessing RV structure and function, particularly in patients who are difficult to image with echocardiography because of severe lung disease. However, its role as a routine diagnostic tool to diagnose PAH in patients with pulmonary diseases needs to be defined.

TREATMENT The primary treatment must be directed to the specific underlying pulmonary condition leading to cor pulmonale. This chapter focuses on the treatment of cor pulmonale secondary to COPD. General principles of medical treatment includes decreasing the work of breathing by assisting ventilation, use of bronchodilators, steroids as well as treatment of any underlying infection. In the management of chronic cor pulmonale, diet and lifestyle modifications play an important role. These include smoking cessation, salt restriction, and weight loss. Structured pulmonary rehabilitation programmes have been useful. Patients with severe PAH, especially if there is history of syncope, should avoid over-exertion. Blood transfusion is indicated in anaemic patients. Phlebotomy should be performed in patients with severe polycythaemia (haematocrit >65%). This results in reduction in PVR and PAP and improvement in exercise tolerance. Oxygen Therapy Long-term oxygen therapy (LTOT) has convincingly shown to improve the pulmonary haemodynamics in patients with COPD. 1801

Adequate oxygenation relieves pulmonary vasoconstriction and reduces PVR and RV after-load. The RV contractility is improved leading to an increase in its stroke volume and cardiac output. Renal vasoconstriction is also relieved, resulting in an increase in urinary sodium excretion. There is improvement in oxygen delivery to brain, heart, and other vital organs. Two landmark, prospective randomised trials evaluated the pulmonary haemodynamics in patients with COPD using LTOT. In the British Medical Research Council (MRC), oxygen administration for at least 15 hours a day prevented further rise in PAP. Similarly, in the USA, nocturnal oxygen therapy trial (NOTT ), administration of continuous oxygen resulted in favourable pulmonary haemodynamics and improved survival as compared to only nocturnal oxygen therapy. Further, the results of many small scale studies also support that the LTOT convincingly attenuates the progression of PAH. It may even reverse the PAH, however, the PAP seldom returns to normal. The longer the daily duration of oxygen therapy, the better are the pulmonary haemodynamics in these patients. Accordingly, continuous oxygen therapy is strongly recommended. However, it must be emphasised that at times acute administration of high concentration of oxygen to hypoxic COPD patients can adversely affect breathing, especially if there is hypercapnia.These patients need to be observed more closely in the initial phase of domiciliary oxygen therapy to ensure that the ventilatory drive is not being impaired. Today, three systems: gas cylinders, liquid oxygen systems, and oxygen concentrators are available for delivery of LTOT at home. Of these, the most attractive is the oxygen concentrator which extracts pure oxygen from the room air and provides a constant supply of oxygen. Recent advances in their designs have made these devices portable as these weigh less, easy to carry and store, and the oxygen supply lasts longer. Diuretics Diuretic therapy is the mainstay in the management of chronic cor pulmonale with excessive RV over-load. It alleviates dyspnoea, hepatic congestion, and peripheral oedema. It decompresses the RV by reducing the pre-load, reducing in the ventricle wall stress, and improved myocardial performance. Potentially, reduced shift of interventricular septum towards LV improves LV filling and systemic cardiac output. However, excessive volume depletion should be avoided, since significant contraction in the RV filling volume and pressure in the setting of PH may reduce cardiac output. Another potential complication of diuretic therapy is the development of metabolic

1802

alkalosis. This suppresses the ventilation and can result in worsening of hypercapnia. Digoxin It is of uncertain benefit in the management of cor pulmonale. Its effects on the RV are unclear. Clinical studies do not support its routine use in patients with cor pulmonale. If needed, it should be given in low doses and monitored carefully. It must also be emphasised that patients with COPD are particularly sensitive to its use. It can result in serious arrhythmias in the setting of hypoxia, acidosis, and electrolyte imbalance. Pulmonary Vasodilators These agents have been largely studied in the setting of primary PAH (idiopathic PAH) or PAH secondary to connective tissue disorders. No large scale studies or guidelines are available for their use in patients having PAH secondary to pulmonary diseases. Inhaled nitric oxide is more potent vasodilator than oxygen. However, if used alone, it worsens ventilation-perfusion imbalance. Also, the delivery of nitric oxide and the cost are potential obstacles for its use.The phosphodiesterase-5-inhibitors (sildenafil), prostacyclin and its analogues (epoprostenol) and endothelin receptor antagonist (bosentan) are specific pulmonary vasodilators and have been successfully used in idiopathic PAH, scleroderma and chronic pulmonary thromboembolic disease. It may be possible that in future, these drugs may be used synergistically with LTOT in patients with cor pulmonale secondary to pulmonary diseases. PROGNOSIS Before the widespread availability of LTOT, development of PAH in COPD patients doubled the mortality. However, even with LTOT, the 5-year survival is approximately 30% to 35% with mean PAP >25 mm Hg as compared 60% to 65% in those whose initial pressures are 40 mm Hg) suffer extremely poor prognosis with approximate 5-year survival of 15%. RECOMMENDED READINGS 1.

Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008; 32: 1371-85.

2.

De Marco T, Rapaport E. Cor pulmonale. In: Mason R, Broaddus V, Murray J, et al., editors. Murray and Nadel’s Textbook of Respiratory Medicine; 4th Ed. Philadelphia: Saunders; 2005:pp.1544-69.

3.

Han MK, McLaughlin VV, Criner GJ, et al. Pulmonary diseases and the heart. Circulation 2007; 116:2992-3005.

4.

Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54(1 Suppl):S43-54.

5.

Weitzenblum E. Chronic cor pulmonale. Heart 2003; 89:225-30.

24

Section

Rheumatology Section Editor: Rohini Handa 24.1 24.2 24.3 24.4 24.5 24.6 24.7 24.8 24.9 24.10 24.11 24.12 24.13 24.14 24.15 24.16 24.17

Basic Considerations of Rheumatology Rohini Handa Soft Tissue Rheumatism and Regional Rheumatic Pain Syndromes Ved Chaturvedi Low Backache C. Panchapakesa Rajendran, S. Rajeswari Osteoarthritis Siddharth Kumar Das Gout and Other Crystal Arthritides U.R.K. Rao Rheumatoid Arthritis A.N. Malaviya Spondarthritides Milind Y. Nadkar Sjögren’s Syndrome Uma Kumar Systemic Lupus Erythematosus V.R. Joshi Antiphospholipid Syndrome Vikas Agarwal Systemic Sclerosis R. Porkodi The Vasculitides Pradeep Bambery Mixed Connective Tissue Disease and Overlap Syndromes G. Narsimulu, Vara Prasad IR Inflammatory Muscle Diseases Alakendu Ghosh, Pradyot Sinhamahapatra Rheumatic Manifestations of Systemic Diseases Debashish Danda Miscellaneous Rheumatic Disorders Binoy J. Paul Emergencies in Rheumatology Lata S. Bichile, Vaibhav C. Chewoolkar

1804 1808 1813 1818 1822 1829 1844 1851 1853 1860 1863 1867 1876 1879 1883 1886 1891

24.1

Basic Considerations of Rheumatology

Musculoskeletal (MSK) complaints are frequently encountered in clinical practice. Pain is the most common presenting manifestation. Since a wide variety of conditions may give rise to MSK pains, a systematic approach is necessary to arrive at a diagnosis. Patient history is the single most important source of diagnostic information, followed by a careful physical examination. Laboratory investigations play a supplementary role, rather than primary role. Several MSK diseases resemble each other at the outset and a definitive diagnosis may not be possible at the first patient visit. A distinctive pattern may become discernible only over a period of observation. In such a situation, symptomatic treatment without rushing to give a specific label and close follow-up are quite appropriate. APPROACH TO A PATIENT WITH MUSCULOSKELETAL COMPLAINTS The three key points that need address are origin of pain, nature of disease, e.g. inflammatory or non-inflammatory, and pattern recognition. Origin of Pain (Articular or Non-Articular) The first task of the clinician who is confronted with MSK pains is to ascertain the exact source of pain by history and examination (Figure 1). Not all pains around a joint originate in the joint itself. Adjacent periarticular structures such as bone, ligament, tendon, bursa, or muscle may be responsible (Table 1). In general, articular pains tend to be diffuse and deep seated. In contrast, the pain of bursitis is characterised by localised point tenderness away from the joint line. Active (patient moves the joint himself/herself ) and passive (physician puts the patient’s joint through range of motion) movements also help in making this distinction on the bedside. Articular pain is aggravated by both active and

Figure 1: Approach to a patient with musculoskeletal pain. SpA = Spondarthritides; RA = Rheumatoid arthritis; TB = Tuberculosis; SLE = Systemic

1804 lupus erythematosus.

Rohini Handa passive movements in contradistinction to periarticular pain, which is more aggravated by active than passive movements. Mechanical symptoms like locking, instability or ‘giving way’ point to articular origin of pain. The clinician has also to be aware of the possibility of ‘referred pain’. For example, hip pain may be referred to the knee. Table 1: Identifying the Site of Musculoskeletal Pain Arthritis

Joint swelling and tenderness Pain often diffuse, deep seated Pain increases on both active and passive movements

Bursitis

Point tenderness over the anatomical site Pain more on active than passive movements

Tendinitis

Linear, tender swelling of tendon sheath Stretching the tendon induces pain Tendon rub may be palpable/audible

Enthesitis

Pain at tendon insertion site Characteristic feature of spondarthritides

Bone pains

Deep seated Tenderness can be elicited by pressing bones

Muscle pains

Diffuse, not well localised Tenderness on squeezing muscles

Fibromyalgia

Diffuse pain with characteristic tender points

Growing pains

Benign leg pains, typically bilateral, in children of 8-12 years age; usually a diagnosis of exclusion

Arthralgias should be differentiated from arthritis. Arthralgias are joint pains without obvious inflammation; whereas, arthritis is associated with demonstrable features of inflammation like joint swelling and tenderness. Raised temperature and visible redness are usually not seen in chronic arthritides like rheumatoid arthritis (RA) or spondarthritides (SpA). These are more a feature of conditions like acute gout or septic arthritis. Arthralgias are non-specific and seen in several non-MSK conditions, e.g. haematological diseases, post-viral fever, metabolic arthropathy like hypothyroidism, etc. A drug history may be important because some commonly used drugs like statins can cause MSK symptoms. Nature of Disease (Inflammatory or Non-Inflammatory?) One of the fundamental concepts in rheumatology is to differentiate inflammatory rheumatic diseases like RA, SpA, lupus, etc. from non-inflammatory disorders like osteoarthritis (OA) since the management is radically different. Inflamed joints stiffen or ‘gel’ after periods of inactivity and tend to loosen with use. In contrast, non-inflammatory or mechanical joint pain improves with rest and is typically associated with use related pain. Table 2 outlines the points that help in clinical differentiation. It has to be borne in mind that even patients with inflammatory joint disease can develop mechanical symptoms, for example, secondary OA of knees in a patient with RA.

Inflammatory rheumatic diseases Examples Morning stiffness Pain aggravation Spontaneous flares Acute phase reactants like ESR, CRP

Non-inflammatory rheumatic diseases

RA, SpA, SLE

OA, trauma, hypothyroidism > 30 minutes < 30 minutes On resting the joint On moving the joint Common Uncommon Increased Normal

RA = Rheumatoid arthritis; SpA = Spondarthritides; SLE = Systemic lupus erythematosus; ESR = Erythrocyte sedimentation rate; CRP = C-reactive protein.

Pattern Recognition Joint pains are a near universal feature of rheumatic or MSK diseases. However, other features like chronology, number/type/ sequence of joints affected, symmetry, presence or absence of fever, extra-articular involvement, etc. give rise to a distinctive pattern that helps in making a diagnosis (Table 3). For example, an inflammatory polyarthritis in a young woman that is associated with fever and malar rash is highly likely to be lupus. Similarly, an insidiously developing arthritis associated with Raynaud’s phenomenon and skin thickening and tightening suggests a diagnosis of systemic sclerosis (SSc). It is worthwhile to remember that on occasions, especially at disease onset, the symptoms and signs may not fit into any one pattern, when the term ‘undifferentiated’ arthritis is used. Over a period of time, the disease may resolve, evolve into a definitive entity or stay ‘undifferentiated’. It is because of this reason that management decisions in rheumatology are based on organ involvement rather than diagnostic labels. Often, features of two or more MSK diseases may be present in the same patient when the term ‘overlap syndrome’ is employed. The various features that aid pattern recognition are discussed below: Table 3: Pattern Recognition in Musculoskeletal Diseases Mode of onset Acute Insidious Duration Acute or self-limited Chronic Number of affected joints Monoarthritis Oligoarthritis Polyarthritis Distribution Symmetrical or asymmetrical Lower limbs versus upper limbs Small versus large joints Specific joints Extra-articular features Fever Mucocutaneous lesions Eye Nodules Sequence of involvement Intermittent Additive Migratory

Chronology The mode of onset and duration of symptoms help in differential diagnosis. Acute onset is seen with septic arthritis, reactive arthritis, viral arthritis, gout or trauma. On the other hand, conditions like RA, SpA and OA tend to be insidious in onset. Based upon duration, MSK complaints may be classified into acute (lasting 6 weeks). Patients with acute, self-limited conditions like viral arthritis may require only a limited evaluation and follow-up. However, patients with symptoms lasting >6 weeks need detailed evaluation. Other groups of patients who merit detailed evaluation irrespective of symptom duration are patients with prominent constitutional/ systemic symptoms, e.g. fever, weight loss etc., older patients and patients who exhibit multiple organ involvement.

Basic Considerations of Rheumatology

Table 2: Differentiating Inflammatory from Non-Inflammatory Rheumatic Diseases

Number of joints affected Arthritides are divided into monoarthritis (single joint involvement), oligoarthritis (affecting 2, 3 or 4 joints, also known as pauci-articular disease) and polyarthritis (affecting > 5 joints). The important conditions in each category are listed in Table 4. It is important to know the number of joints affected because it narrows down the diagnostic possibilities, and helps the clinician in embarking upon investigations in a planned manner. Involvement of a single joint should prompt the clinician to consider crystal arthropathy (like gout) or septic arthritis. A good rule of the thumb is to consider every case of monoarthritis as infection of the joint unless proven otherwise. Joint aspiration and synovial fluid analysis are mandatory. Overlooking septic arthritis is a serious error because delay in treatment rapidly results in joint destruction. Synovial fluid should be subjected to gross examination, total and differential leucocyte counts, Gram and Ziehl-Neelsen staining, culture, and crystal studies. Protein and sugar estimations in synovial fluid, unlike CSF or pleural/peritoneal fluids are of no value. Tests for mucin, clot and viscosity are no longer performed. Polymerase chain reaction (PCR) for Mycobacterium tuberculosis in synovial specimens can be associated with false positives and should never be interpreted in isolation from clinical findings. The normal synovial fluid has a cell count less than 200 WBCs/mm 3, mostly mononuclear. The cell count in non-inflammatory conditions like OA is less than 2000 WBCs/ mm3 while the count in inflammatory conditions like RA and gout is >2000 WBCs/ mm3. Septic arthritis is associated with very high counts in range Table 4: Differential Diagnosis Based on Number of Joints Affected Monoarthritis

Oligoarthritis

Polyarthritis

Septic arthritis

Gout

Rheumatoid arthritis

Tuberculous arthritis

Juvenile idiopathic arthritis (JIA)

Psoriatic arthropathy

Gout and other crystal deposition diseases

Psoriatic arthropathy

SLE Systemic sclerosis

Spondarthritides

Spondarthritides

Juvenile idiopathic arthritis Adult-onset Still’s disease Inflammatory bowel disease Gout (rarely)

Monoarticular presentation of polyarticular disease

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of 100,000/mm3 with >90% polymorphonuclear leucocytes. Synovial fluid crystal identification is the gold standard for diagnosis of gout and other crystal arthropathies. The SpA constitute the vast majority of oligoarthritides encountered in clinical practise. It is a big group of inter-related conditions where ankylosing spondylitis is the prototypic illness. Other disease entities in SpA include reactive arthritis (including Reiter’s syndrome), psoriatic arthropathy, arthritis associated with inflammatory bowel disease and undifferentiated SpA. Clinically SpA should be suspected whenever a young patient less than 40 years (males outnumber females) presents with inflammatory low back pain and asymmetrical, lower limb, large joint oligoarthritis, i.e. asymmetric involvement of hips, knees or ankles. While dealing with low backache (LBA), it is clinically helpful to differentiate between mechanical and inflammatory low backache. Mechanical causes comprise more than 90% cases of LBA. Inflammatory LBA, a typical feature of SpA, worsens after rest or prolonged sitting in the same posture, in contrast to mechanical causes like prolapsed intervertebral disc which improve on rest. Early morning stiffness, buttock ache, enthesitis, dactylitis, peripheral joint synovitis and eye involvement, if present, support the diagnosis of SpA. Sacroiliitis is the characteristic radiologic hallmark of SpA. HLA B27 is present in a varying proportion of patients with SpA depending on the underlying condition. However, HLA B27 can be present in healthy individuals also. The presence of HLA B27 does not mean SpA and conversely, the absence of HLA B27 does not rule out SpA. Gout presents most often as monoarthritis, less commonly as oligoarthritis and rarely as polyarthritis. JIA and psoriasis can cause both oligoarticular and polyarticular joint disease. Spondarthritides are characterised by inflammatory low back pain in addition to arthritis. Another clinical feature with discriminant value is sausage digit or dactylitis seen in reactive arthritis or psoriatic arthropathy. Herein, the entire digit is diffusely swollen. This is clinically a very important point of distinction from joint diseases like RA where only the joint gets swollen (fusiform or spindle-shaped swelling) and not the entire digit (Figures 2A and B). The term polyarthritis refers to involvement of more than four joints. It may be due to inflammatory causes like RA, SLE,

1806

psoriasis, systemic sclerosis (SSc), juvenile idiopathic arthritis (JIA), rheumatic fever (RF), adult-onset Still’s disease, etc. or noninflammatory causes like OA. Hand examination is crucial in patients with polyarthritis as explained below. Symmetry Symmetrical involvement refers to affliction of the same joints on right and left sides. Even in symmetrical involvement, mirror image symmetry is not required. To clarify things, involvement of right 4th, 5th and left 2nd metacarpophalangeal (MCP) joints is deemed symmetrical involvement of MCP joints. RA, systemic lupus erythematosus (SLE), SSc, and nodular OA of hands are typical examples of symmetric polyarthritis. Gout and SpA are typically asymmetric oligoarthritides. Psoriasis can cause either asymmetric oligoarthritis or symmetric polyarthritis. The most important practical point is that a clinician should hesitate to give a diagnosis of RA, if the disease is asymmetrical. UPPER LIMB VERSUS LOWER LIMB JOINT INVOLVEMENT This can provide a clue to the differential diagnosis. Joints of both upper and lower limbs are involved in RA, SLE and psoriasis. Predominant involvement of lower limbs is seen in gout, SpA and erythema nodosum, whereas, haemochromatosis preferentially affects joints of upper limbs. Type of Joints Affected Small versus large RA typically affects both small and large joints. In fact, inflammatory, symmetric polyarthritis of small joints of hands like MCP joints and proximal interphalangeal (PIP) joints, is a characteristic feature of RA. Similarly, psoriasis, lupus and SSc affect both small and large joints. In contrast, SpA affects large joints much more than smaller joints. Therefore, the typical pattern of joint involvement in SpA is asymmetric oligoarthritis of large joints of lower limbs. Thus, the pattern in RA and SpA is quite different and distinctive, permitting bedside recognition. Specific joints These can give a clue to the nature of arthritic illness, e.g. distal interphalangeal (DIP) joint involvement is characteristic of OA, while DIP joints are spared in RA. Other conditions which give rise to DIP joint involvement are psoriasis and SSc. Involvement

Figures 2A and B: (A) Dactylitis seen in reactive arthritis versus (B) fusiform swelling in rheumatoid arthritis.

Basic Considerations of Rheumatology

of the first carpometacarpal joint is typical of OA, while ankle and shoulder are rarely involved in primary OA. Spine Spinal involvement other than cervical spine is rare in RA. In contrast, inflammatory low back pain is a characteristic feature of SpA. Sequence or Pattern of Involvement The three common patterns of joint involvement are intermittent, additive, and migratory. Intermittent arthritis is episodic and the patient may be totally asymptomatic in between the episodes. Examples include gout, Behçet’s syndrome, Reiter’s syndrome, intermittent hydrarthrosis, and palindromic rheumatism. Additive arthritis is one where more and more joints are afflicted with time. This is seen with RA, SpA, psoriasis, OA, etc. Migratory polyarthritis refers to a pattern wherein pain and swelling in a specific joint starts rapidly and subsides in 24 to 36 hours; the arthritis then picks up new joints. The difference from additive pattern is that the previously involved joints in migratory pattern return to normal as new joints become involved, whereas in the former the joint involvement persists. Migratory pattern is seen in rheumatic fever, gonococcal arthritis, viral disease, sarcoidosis, and bacterial endocarditis. These patterns may not be seen in the classical form due to treatment received by the patient. Also, these patterns may coexist in the same patient. However, when one pattern dominates, it may suggest a particular diagnosis. One of the commonly overlooked diagnoses in India is juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis (JRA) or juvenile chronic arthritis (JCA), in children below the age of 16 years. There is a tendency to label all joint pains in children as rheumatic fever (RF) with undue reliance on one laboratory marker, that is, elevated ASO (anti-streptolysin O) titres. The joint pains in RF are migratory, affect large joints and tend to subside over 6-12 weeks, with or without treatment. The major brunt is borne by the heart. In contrast, the arthritis in JIA tends to be additive, persistent, and may involve small or large joints. The presence of deformities strongly militates against a diagnosis of RF, since the arthritis in RF is most often non-deforming. Extra-Articular Features Features that may be associated with joint involvement like fever, skin lesions, nodules, etc. play a role in differential diagnosis. Fever along with arthritis narrows down the diagnostic possibilities to SLE, systemic-onset JIA (Still’s disease), vasculitis, infective endocarditis, rheumatic fever and adult-onset Still’s disease. It is important to realise that although malaise is very common in RA, fever of moderate-to-high grade is not seen with RA and should necessitate a search for other causes. Mucosal or cutaneous lesions are seen in SLE, psoriasis, Behçet’s syndrome, reactive arthritis, SSc, erythema nodosum, vasculitides, gonococcal arthritis, etc. The malar rash of SLE is characteristic and can be appreciated even in dark skinned individuals. Gonococcal infection usually occurs in young, sexually active adults and the skin lesions comprise of a pustule with an erythematous base. Nail changes of psoriasis can easily be masked by nail paint in female patients. The type of eye involvement may also vary with different eye diseases. RA usually causes keratitis or scleritis in contrast to

Figures 3A and B: Arthritis with nodules.

uveitis seen in SpA. A detailed description of skin/eye manifestations of various rheumatic diseases is beyond the scope of this chapter. Conditions causing nodules in a patient with arthritis include RA, OA (Heberden and Bouchard nodes), tophaceous gout, rheumatic fever, multicentric reticulohistiocytosis, sarcoidosis, erythema nodosum, vasculitides, etc. (Figures 3A and B). However, the associated features make the pattern recognition possible. For example, carditis, migratory polyarthritis, erythema marginatum and chorea in RF hold the clue to diagnosis. Rheumatoid nodules are uncommon in Indian patients with RA when compared to Western patients. Similarly, nodular OA of hands is less often encountered in India as compared to Caucasians. CONCLUSION Rheumatology is predominantly a clinical subspecialty. Pattern recognition, based on detailed history and thorough physical examination, remains the cornerstone of the diagnostic approach to a patient with musculoskeletal complaints. A good history provides as much as 80% of diagnostic information, with the physical examination and investigations contributing only 15% and 5%, respectively. RECOMMENDED READING 1.

Handa R. Approach to a patient with arthritis- mono/oligoarthritis. National Medical Journal of India 1999; 12:121-2. One of the series of 5 articles by the author that provide the readers with a step by step, bedside approach to 1807 rheumatic complaints.

24.2

Soft Tissue Rheumatism and Regional Rheumatic Pain Syndromes

INTRODUCTION Soft tissue rheumatism refers to symptoms arising not from the joints themselves, but those that arise from the periarticular structures, such as ligaments, tendons, insertion of tendons at bony sites (entheses), tendon sheaths, bursae and muscles. STR may present clinically in two main forms: 1. Localised (regional) pain syndromes 2. Diffuse pain syndrome or fibromyalgia Regional rheumatic pain syndromes are a common presentation in general practice. Diagnosis of these pain syndromes is predominantly clinical and depends upon general awareness of these disorders and knowledge of anatomy, especially soft tissue structures. One important point which the author has learnt is to use two colour pens for marking the exact site of pain—red for swelling and blue for pain. The author terms this method as ‘Red Blue Marking Method’ for regional rheumatic pain syndromes which leads to better symptom localisation. It is more rewarding to do a thorough physical examination and use the simple marking methods than ordering unnecessary tests. The aetiopathogenesis of regional rheumatic pain syndromes is still unclear. Factors implicated include genetic, environmental, occupational, repetitive trauma, psychological, etc. The regional rheumatic pain syndromes are classified by the major anatomical structure involved (Table 1). Low backache has been dealt within a separate chapter. Table 1: Common Regional Rheumatic Pain Syndromes Shoulder Knee Rotator-cuff disorders Bursitis (pre; infra-patellar, Bicipital tendinitis anserine) Adhesive capsulitis (frozen shoulder) Baker’s cyst Osteochondritis dissecans Elbow region Traction apophysitis Olecranon bursitis Lateral epicondylitis (tennis elbow) Anterior knee pain syndrome Medial epicondylitis (golfer’s elbow) Patellar instability syndrome Ankle and foot Wrist Achilles tendinitis DeQuervain’s tenosynovitis Retrocalcaneal bursitis Carpal-tunnel syndrome Plantar fasciitis Trigger finger/thumb Bony deformities Dupuytren’s contracture Morton’s neuroma Hip Metatarsalgia Trochanteric bursitis Iliopsoas bursitis Ischial bursitis Meralgia paraesthetica

DISORDERS OF THE SHOULDER REGION Shoulder pain may have its origin in the glenohumeral joint, acromioclavicular joint or periarticular structures, or be referred from the cervical spine (felt at the supraspinatus region), thoracic outlet, subdiaphragmatic conditions (felt at the tip of the 1808 shoulder), or brachial plexus. Rotator cuff disorders (impingement

Ved Chaturvedi syndrome) are the most common cause of shoulder pain. The spectrum ranges from mild tendinitis of the rotator cuff, with or without inflammation of the adjacent subacromial bursa, to bicipital tendinitis, tears of the rotator cuff and secondary glenohumeral osteoarthritis. Trauma, unaccustomed activities, ageing, vascular compromise, etc. are contributory factors. Rotator Cuff Disorders The presentation of rotator-cuff lesions depends on the age of the patient. Young adults often present acutely after forceful activity like throwing or after trauma. In the middle-aged individuals, the onset is more gradual and history of repetitive or strenuous upper limb activity may be present. There may be no precipitating factors in the elderly patients. The patient typically experiences pain on active abduction, and sometimes when lowering the arm. Patients have difficulty in working overhead or lifting and reaching behind their back when dressing. Clinical examination reveals limitation of active movement by pain, and tenderness localised to the rotator cuff and greater tuberosity. The ‘supraspinatus’ or ‘empty can’ sign (pain on resisted elevation of the arm to 90° midway between abduction and forward flexion with the thumb pointing downwards in internal rotation) is often positive. Neer’s ‘impingement sign’ (one hand of the examiner forward flexing the patient’s arm while the other hand restricting scapular rotation) is positive; the patient develops pain in the overhead position near the end of full flexion. Rotator cuff tears can be partial or complete. Clinical features include shoulder pain on abduction, night pain, varying degrees of weakness of abduction and external rotation, local tenderness and loss of range of movement. The supraspinatus and impingement signs are usually positive: inability to actively maintain 90º of passive shoulder abduction. Magnetic resonance imaging and ultrasound are employed for diagnostic imaging. Initial management of rotator cuff tendinitis consists of rest, nonsteroidal anti-inflammatory drugs (NSAIDs), and physical treatments including heat application and range of movement exercises (early mobilisation of the shoulder is important in minimising the disability). If symptoms persist for more than 2 to 4 weeks, injection of a depot corticosteroid into the nearby subacromial bursa is often beneficial. Surgery is indicated for intractable pain and severe functional impairment. Bicipital Tendinitis Bicipital tendinitis is often related to chronic impingement of the bicipital tendon by the acromion. It usually occurs in association with rotator cuff tendinitis and glenohumeral instability. The pain is felt over the anterior aspect of the shoulder after radiating into the biceps muscles. It is increased by the overhead activities, shoulder extension and elbow flexion. Localised tenderness is present over the tendon in the

Subacromial Bursitis Chronic subacromial bursitis often occurs in association with rotator cuff tendinitis and chronic impingement. Primary subacromial bursitis due to trauma, infection, rheumatoid arthritis (RA), or other arthritic disorders is rare. Abduction is painful, and there is local tenderness and sometimes fluid distension of the bursa, which is visible just anterior to the acromion with the shoulder extended. Adhesive Capsulitis Adhesive capsulitis, also known as frozen shoulder capsulitis, or pericapsulitis, is characterised by progressive, global restriction of shoulder movements associated with pain and functional disability. A period of immobility of the shoulder is the most commonly identified predisposing factor. It is more common after the sixth decade and in females. The condition may also coexist with diabetes mellitus, hypothyroidism, lung carcinoma, myocardial infarction, cardiac surgery and shoulder trauma. Although adhesive capsulitis is often a self-limiting disorder, the extent and rate of recovery are variable. Dynamic sonography, demonstrating limitation of sliding movements of the supraspinatus tendon during abduction of the arm is diagnostic. Treatment of adhesive capsulitis consists of NSAIDs, physical therapy and corticosteroid injections into both the glenohumeral joint and subacromial bursa. Physiotherapy is important. Gentle range of movement exercises, beginning with pendulum exercises and wall climbing with the fingers, and finally active strengthening exercises, are required to restore joint mobility. Operative capsulotomy, with surgical release of the coracohumeral ligament and of subacromial adhesions, is occasionally beneficial in patients with chronic symptoms refractory to conservative treatment. DISORDERS OF THE ELBOW REGION Lateral epicondylitis (tennis elbow), medial epicondylitis (golfer’s elbow), and olecranon bursitis are the common soft tissue lesions at the elbow. Lateral Epicondylitis (Tennis Elbow) It usually afflicts the dominant arm in individuals aged 40 to 60 years. In actual practice less than 5% cases can be attributed to tennis playing. There are no specific precipitating factors for this condition, which results from inflammation of the soft tissues attaching to the lateral epicondyle, especially, extensor carpi radialis brevis tendon. Patients present with pain over the lateral epicondyle and the surrounding area. Grip may be impaired and routine activities like lifting weight, shaking hands may produce pain. Examination reveals tenderness over the lateral epicondyle. Another cardinal sign is increase in pain in resisting wrist dorsiflexion while the elbow is in extension. Symptoms may also be precipitated by extending the elbow with wrist palmar flexed. Physical modalities like heat or cold, NSAIDs and local corticosteroid injections are used for its management.

Some patients benefit by elbow splinting also. Refractory cases may need surgical intervention in the form of lateral release of the extensor tendon. Medial Epicondylitis (Golfer’s Elbow) This is much less common than tennis elbow and results from involvement of the common flexor tendons at the medial epicondyle. Pain over the medial side of elbow on resisted wrist flexion while the elbow is extended in a reliable sign. The management is similar to that of lateral epicondylitis. Olecranon Bursitis The subcutaneous olecranon bursa is a frequent site for traumatic, inflammatory, and septic bursitis. Inflammatory olecranon bursitis may be due to RA, psoriatic arthritis, gout or sepsis. Non-septic olecranon bursitis can result from repetitive, minor, or unnoticed trauma to the elbow. It is less disabling as pain is minimal. Local tenderness and swelling are present. Management involves aspiration, NSAIDs, and one or more injections of corticosteroid. DISORDERS OF THE WRIST AND HAND DeQuervain’s Tenosynovitis DeQuervain’s tenosynovitis of the abductor pollicis longus and extensor pollicis brevis is commonly due to repetitive occupational activity. It is common in females in the age group of 30 to 50 years. It may also occur in association with RA, psoriatic arthritis, and pregnancy, and during the post-partum period. Most patients complain of pain along the radial aspect of the wrist and at thumb base during pinch grip, grasping and other hand activities. Finklstein’s test is positive (the thumb is flexed into the palm and wrist deviated ulnarly resulting in pain over the radial side). Treatment consists of heat application, NSAIDs, and splinting.

Soft Tissue Rheumatism and Regional Rheumatic Pain Syndromes

bicipital groove. Bicipital tendon pain can be reproduced by resisted supination of the pronated forearm with the elbow 90º flexed, shoulder flexion against resistance.Treatment entails rest, NSAIDs, and physical modalities like hot packs, ultrasound, etc. Some cases require local corticosteroid injection into the tendon sheath parallel to the tendon fibres. Care should be taken to avoid direct injection into the tendon.

Trigger Finger or Thumb (Stenosing Digital Tenosynovitis) The pathological lesion is tenosynovitis of the flexor tendons of the finger or thumb, resulting in fibrosis localised to the annular pulley that overlies the metacarpophalangeal joint. A nodular thickening of the tendon often develops at the site of stenosis, that interferes with the normal gliding of the tendon, resulting in pain over the area of the pulley and ‘snapping’ or ‘triggering’, of the finger or thumb. Examination reveals tenderness over the area of the proximal pulley, and often limitation of digital flexion and extension. Management consists of heat application, exercises, NSAIDs and local steroid injections. Dupuytren’s Contracture This presents as nodular thickening and contraction of the palmar fascia which may lead to flexion contractures of the fingers. The ulnar side is commonly affected. Treatment involves physiotherapy and local steroid injections. DISORDERS OF THE HIP REGION It is important to differentiate pain arising from hip joints and adjacent structures from referred pain. Referred pain at the hip can be due to thoracolumbar spine disorders, peripheral vascular diseases and intra-abdominal pathology. The skin over the greater trochanter is innervated by T12 roots, while L1 supply the inguinal region and L2-4 supply the anterior aspect of thigh. Radiculopathies due to spine disorders can, therefore, 1809

mimic hip pain. However, in these illnesses there is no limitation of hip movements. Abdominal problems like inguinal or femoral hernias, ureteric stones, tuberculous abscess, retroperitoneal appendicitis and pelvic inflammatory diseases may also masquerade as hip arthritis. Careful clinical examination makes differentiation possible at the bedside. Thrombosis or aneurysm of aorta and its iliac branches can give rise to buttock, thigh or calf pain that may be confused with hip pain. Examination of peripheral pulses can be rewarding in such a situation. The common rheumatic pain syndromes around the hip include trochanteric bursitis, ischiogluteal bursitis and illopsoas bursitis. Trochanteric Bursitis Patients with trochanteric bursitis present with a deep, aching pain over the lateral upper thigh which is often intensified by walking but it may be worse at night, especially when the patient is lying on the affected side. The diagnosis is confirmed with palpation of the posterior aspect of the greater trochanter which elicits local tenderness in this area. Treatment includes rest and local injection of depot steroids.

to pain and associated local tenderness in this region. The typical presentation is that of an obese woman presenting with nocturnal pain, and rarely, a palpable mass on upper and medial aspect of tibia. Gastrocnemius-Semimembranous Bursitis (Baker’s Cyst) Any cause of synovitis in the knee can lead to leakage into the popliteal space when a communication exists between the gastrocnemius-semimembranous bursa. Symptoms consist of fullness and tightness in the popliteal space which increases with walking. A Baker’s cyst can be detected clinically by palpation of fullness in the medial-third of the popliteal fossa. Ultrasonography will establish the diagnosis in most of the cases (Figure 1). Baker’s cysts may dissect into the muscles of the calf, simulating thrombophlebitis. Rupture of a Baker’s cyst should be confirmed by Doppler ultrasound.

Ischiogluteal Bursitis Also called ‘weaver’s bottom’, it results from prolonged sitting on hard surface. The bursa lies over the ischeal tuberosity and helps gliding of the gluteus maximus muscle. The diagnosis is made by the characteristic history and by eliciting tenderness on palpation of the ischeal tuberosity with the patient lying supine with the hip flexed. Treatment consists of using a cushioning seat, NSAIDs, stretching exercises while lying on the cushion. A local depot steroid should be given cautiously due to adjoining sciatic nerve. Iliopsoas Bursitis The bursa lies over the anterior surface of the hip joint under the iliopsoas muscle and between the hip joint capsule. Typically, patients present with an inguinal mass which may be painful and may be associated with secondary femoral vein obstruction or femoral nerve compression. Intra-articular pathology of hip joint may be associated with the bursitis.

Figure 1: Ultrasound demonstrating Baker’s cyst.

DISORDERS OF THE KNEE REGION Knee pain is a common articular complaint. Non-arthritic conditions comprise a large proportion of knee complaints, particularly in younger age groups.

Treatment of an intact or ruptured Baker’s cyst includes depot steroid injection in knee. Due to close proximity of popliteal vessels, it is wise not to use posterior approach for direct aspiration of the Baker’s cyst.

Pre-Patellar Bursitis Pre-patellar bursitis presents as a painful, red swelling anterior to the kneecap and is seen most often in people who spend a lot of time kneeling. Active knee extension is usually quite painful although passive knee flexion is usually only minimally limited. Infection, gout and repeated trauma are usual factors.

Iliotibial Band Syndrome (Runner’s Knee) The iliotibial band is a fascial band connecting the ilium with the lateral tibia, connecting to the tensor fasciae lata and the gluteus maximus. Repetitive flexion and extension, particularly with high intensity running, can lead to inflammation of the iliotibial band or at its associated bursa overlying the lateral femoral condyle. Examination reveals tenderness localised to the lateral femoral condyle approximately 2 cm above the joint line, pain with weight bearing on the knee when flexed 30º to 40º. Treatment consists of rest, local heat, and depot corticosteroid.

Infra-Patellar Bursitis The deep infra-patellar bursa lies between the upper portion of the tibial tuberosity and patellar ligament and it is separated from the knee joint synovium by a fat pad. It presents as tenderness in the soft tissues of either side of the ligament just proximal to its insertion on the tibial tubercle. Anserine Bursitis The anserine bursa is located about 5 cm below the medial 1810 aspect of the knee. Anserine bursitis is a term loosely applied

Internal Derangements of Knee Internal derangements of the knee refer to disruption of the normal functioning of the ligaments and menisci usually due to significant, often athletic trauma. MRI and arthroscopy are helpful in diagnosis.

Chondromalacia patellae is a term which has been used synonymously with patellofemoral pain. It is most commonly described as poorly localised, anterior knee pain, frequently accompanied by the ‘grab’ sign (patients cover the entire front of the knee with the band when asked to identify the location of the discomfort). Pain frequently occurs after prolonged sitting with flexed knees, the so-called ‘theatre’ sign. Treatment modalities include avoidance of overuse, exercises, and antiinflammatory medications. DISORDERS OF THE FOOT The most common causes of heel pain are Achilles tendinitis, retrocalcaneal bursitis, and plantar fasciitis. Achilles tendinitis presents with gradual onset of pain with foot push off. Physical examination reveals tenderness and occasionally thickening of the tendon which can also be detected by ultrasonography (Figure 2). Retrocalcaneal bursitis is associated with posterior heel pain and may be associated with tender swelling on both sides of the insertion of the tendon. Localised pain with weight-bearing on the undersurface of the heel is the typical presentation. Spondyloarthopathy, trauma, gout and hypothyroidism are the few known causes. Treatment consists of a heel pad or cushion, rest, local heat, anti-inflammatory agents or in some cases local steroid injection. Plantar fasciitis is the most common cause of subcalcaneal heel pain. Patients usually complain of pain on the undersurface of heel on weight bearing, especially after a period of rest, e.g. on taking the first few steps on awakening in the morning. Localised tenderness may be elicited on the anteromedial part on calcaneum on its plantar surface. Radiographs are often normal. Plantar spurs, if seen, are often not the cause of the heel pain which is due to inflammation of the plantar fascia. Causes include repetitive overuse as in athletes, excessive standing and walking, improper

Figure 2: Ultrasound demonstrating Achilles tendinitis.

footwear with hard soles, and spondyloarthropathies. Treatment is by means of rest, hot fomentation, NSAIDs, soft footwear with heel cushions, ultrasound therapy, and sometimes local injection of corticosteroids. Metatarsalgia Metatarsalgia is the symptom of pain across the plantar surface of one or more metatarsophalangeal joints and may be due to diverse causes including callosities, flat-foot, arthritis, muscle imbalance, fat pad atrophy, Morton’s neuroma, hallux valgus or rigidus, tarsal tunnel syndrome, and arterial insufficiency. Tarsal tunnel syndrome most often refers to compression of the posterior tibial nerve as it courses around the medial malleolus. The typical presentation is with dysaesthesias involving the plantar aspect of the foot that is often more prominent at night. The diagnosis of tarsal tunnel syndrome may be confirmed by nerve conduction studies documenting delay in conduction of the posterior tibial nerve across the ankle. DIFFUSE PAIN SYNDROME AND FIBROMYALGIA Fibromyalgia is a clinical syndrome characterised by persistent, diffuse pain in the body. This is typically described by the patient as “pain all over the body” including joints, muscles and spine. However, there is no clinical discernible evidence of inflammation at any of these sites, and therefore, this condition is classified as soft tissue rheumatism. This is more commonly seen in young or middle-aged women and the pain is accompanied by a number of other symptoms including: fatigue, depressed mood, sleep disturbance, headaches and social isolation. Clinical examination reveals multiple, soft tissue tender points over bony prominences, muscles and tendons. The American College of Rheumatology (ACR) classification criteria in vogue required tenderness on pressure (tender points) in at least 11 of 18 specified sites and the presence of widespread pain for diagnosis. Widespread pain was defined

Soft Tissue Rheumatism and Regional Rheumatic Pain Syndromes

Patellofemoral Pain Syndrome

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as axial pain, left- and right-sided pain, and upper and lower segment pain. Recently, the American College of Rheumatology has proposed diagnostic criteria for fibromyalgia that do away with tender point examination and permit a symptom-based diagnosis. A patient satisfies diagnostic criteria for fibromyalgia if the following three conditions are met: 1. Widespread pain index (WPI) >7 and symptom severity (SS) scale score >5 or WPI 3-6 and SS scale score >9. 2. Symptoms have been present at a similar level for at least 3 months. 3. The patient does not have a disorder that would otherwise explain the pain. The WPI score ranges from 0 to 19 while the SS score ranges from 0 to 12. The successful management of fibromyalgia requires both non-pharmacological and pharmacological measures, with particular emphasis on patient education, in order to explain the nature of the disease and to highlight that joint or bone damage will not occur in this condition, unlike untreated inflammatory arthritis. A suitable programme of graded exercises can be very helpful in maintaining adequate mobility and improving functional capacity. Psychobehavioural management can also help and these include

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psychotherapy, hypnotherapy and relaxation response therapy, where available. The drugs that might be useful are analgesics and NSAIDs, tricyclic anti-depressants such as amitryptyline, fluoxetine, gabapentin and pregabalin. For one or two very troublesome tender points not responsive to analgesics or NSAIDs, a local steroid injection may often be helpful. CONCLUSION Regional rheumatic pain syndromes, despite being very common in clinical practice, are neither properly recognised nor adequately treated. There are usually no serologic markers or pathognomonic imaging findings. Awareness of the entity and a basic knowledge of regional rheumatic anatomy are sufficient to permit clinical recognition in the vast majority of the cases. Treatment is simple and comprises patient education, NSAIDs, physical modalities like heat, cold, ultrasound therapy, etc. and intralesional corticosteroids. RECOMMENDED READING 1.

Wolfe F, Clauw D, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010; 62: 600-1.

24.3

Low Backache C Panchapakesa Rajendran, S Rajeswari

INTRODUCTION Low back pain (LBP) is the most common rheumatic disorder accounting for 30% to 50% of rheumatic musculoskeletal complaints encountered by general practitioners. As an ailment, it is second only to the common cold with 70% to 80% of the population experiencing LBP at some point of time. Most often it is a self-limited illness and becomes chronic only in 5% of cases. LBP is the most common pain syndrome in industrial countries with the highest prevalence in persons aged 45 to 65 years. The incidence in the industrial sector in India is 11% in textile workers. ANATOMICAL CONSIDERATIONS The functional unit of the lumbar spine consists of two vertebral bodies and an intervertebral disc anteriorly and the facet joints posteriorly (Figures 1 and 2). The anterior portion is flexible and serves the functions of shock absorbency and weightbearing.The nucleus pulposus provides shock absorbency to the disc and the annulus fibrosus allows for the flexibility of the functional unit. The posterior portion of the unit protects the neural elements. It acts as a fulcrum and guides the movements for the functional unit.The lower lumbar discs need to bear a load of 1000 kg when stressed with pure compression forces. The posterior segment muscles and abdominal muscles help to dissipate these compression loads. The sacrum and iliac bones function as one unit. The lumbosacral angle also plays a role in determining the posture and degree of spinal curvature. The back is sensitive to 4 to 8 Hz vibrations and whole body vibration produce buckling and slipping of the lumbar discs and degeneration. AETIOLOGY Aetiologies of low backache are enumerated in Table 1. Clinical Features and Approach A detailed history of involved relevant systems, a good social history, and methodical clinical examination are essential for arriving at a diagnosis. LBP can present as acute or chronic pain (Table 2). Acute LBP is one where the duration is less than 1 month, subacute from 1 to 3 months, and chronic if the duration is more than 3 months or if pain occurs episodically within a 6 months period. Mechanical causes of low backache account for the majority (90%) of cases while systemic diseases account for only 10%. Acute LBP has a favourable natural history. Most episodes resolve in a few weeks. In one-third of patients, the LBP may last for a month. Chronic LBP of more than 3 months duration is seen only in a minority. Acute Low Back Pain It is important to rule out catastrophic conditions enumerated in Table 3 as they require emergency intervention. Certain ‘Red Flags’ (danger signs) of serious disease should be looked out for when dealing with acute LBP. These include history of trauma, fever, incontinence, unexplained weight loss,

Figure 1: Normal lumbar spinal canal.

Figure 2: Sagittal section of spine.

cancer, long-term steroid use, parenteral drug abuse, intense local pain, human immunodeficiency virus infection, thoracic pain, neurological symptoms, structural spinal deformity, inability to get into a comfortable position associated with a pattern of symptoms not compatible with benign mechanical disease, and lack of response to conservative measures. ‘Yellow Flags’ are signs which identify patients at risk for chronicity and disability. These include factors like age, physical 1813

fitness, abdominal muscle weakness, smoking, obesity, low educational level, high pain levels and disability, etc. psychosocial factors (like poor cognitive functioning, anxiety, stress, depression, distress, somatisation, etc.), and occupational factors (like manual material handling, bending and twisting, whole body vibration, poor work relationships, social support and job dissatisfaction). Table 1: Aetiologies of Low Backache Congenital Abnormal vertebral facets Sacralisation of L5 transverse process Spondylolysis or spondylolisthesis between L5 and S1 vertebrae (Figure 4) Acquired Inflammatory Infective Osteomyelitis, e.g. tuberculosis Discitis Epidural abscess Non-infective or rheumatologic Spondyloarthropathies (e.g. ankylosing spondylitis) Trauma to ligaments, muscles, vertebrae or annulus fibrosus with disc prolapse Vascular Abdominal aortic aneurysm dissection Epidural haematoma Haemoglobinopathies

Sciatica Pain radiating below the knee and down the leg and associated with mechanical impingement upon the nerve. A positive straight leg raising test (Figure 3) indicates a herniated intervertebral disc while a positive exercise stress test is in favour of lumbar canal stenosis. Anterior thigh pain Conditions like inguinal hernia, hip joint disease, diabetic mononeuropathy, renal calculi, abdominal aneurysm and retroperitoneal tumours have to be ruled out with appropriate investigations. Posterior thigh pain It may be due to back strain and referred pain due to damage of muscles in the lumbosacral spine or a high herniated disc (L3-L4 level). Clinical tests to distinguish inflammatory from mechanical back pain should be done (Table 4). Some special situations are summarised in Table 5.

Neoplastic Primary tumours of the spine, e.g. multiple myeloma Metastatic Degenerative Disc disease Facetal arthropathy Spinal canal stenosis Metabolic Osteoporotic vertebral fracture Paget’s disease Mechanical Poor posture aggravated by Obesity Pregnancy Over work

Figure 3: Straight leg raising test. The leg is raised 30° to 70° until radicular symptoms are elicited, when test is positive.

Referred Pain Abdominal viscera (renal, pancreas, posterior duodenal ulcer) Pelvic disorders (pelvic inflammatory disease) Soft Tissue Rheumatism Fibromyalgia Psychogenic/Malingering Miscellaneous Whole body vibration Computer-related

Chronic Low Back Pain Patients belonging to this category are those who have not responded to six weeks of conservative management. These patients can be divided into four groups based on the location and radiation of pain as described below: Localised low back pain Pain not radiating below the gluteal region forms the largest group in which inflammation, infections,tumour and degeneration 1814 have to be ruled out.

Figure 4: Spondylolisthesis at L5 level.

Category

Pathologic Entity

Superficial somatic Cellulitis (skin, subcutaneous tissue) Deep somatic Muscular strain

Radicular

Visceral referred

Nerve root pain

Psychogenic

Quality

Location

Onset and Duration

Aggrevating Alleviating Factors

Neurologic Deficit

Sharp

Well localised

Acute

Intensified by direct contact

None

Sharp

Diffuse

Acute or chronic Intensified with movement Multiple segments Chronic Diminished with rest

None

Low back

None

Arthritis Fracture Discogenic

Dull Boring Segmental

Spinal stenosis

Radiating, claudication, paraesthesia

Pancreas, intestine, prostate, endometriosis, abdominal aneurysm Diabetic femoral neuropathy

Deep, colicky, Segmental with boring, tearing radiation inside body

Burning paraesthesia, numbness Depression, conversion Variable reaction, malingering

Acute

Afferent Acute/chronic distribution of affected nerve root Acute/chronic

Radicular

Non-dermatomal Persistent

Aggravated by bending, sitting, Valsalva manoeuvre Aggravated by lumbar extension, walking, standing relieved by flexion, sitting Not affected by motion, walking, etc.

Intensified by sensory stimulation of the damaged nerve No consistent correlation

Table 3: Catastrophic Conditions Leading to Acute Low Back Pain

Table 5: Special Situations

Leaking or ruptured abdominal aneurysm Acute paraplegia due to central herniation of nucleus pulposus presenting as cauda equina syndrome Epidural haemorrhage Embolus Anterior spinal artery thrombosis Epidural abscess Spinal cord tumours

Work related Lifting/bending Childhood and adolescence Developmental anomalies Infections Malignancies Carrying heavy school bags Young adults Spondyloarthropathies Ligament injuries Prolapsed intravertebral discs Increased computer usage Pregnancy LBP Hyperlordosis Muscle stretching Pelvic instability Myofascial pain Middle-aged Degenerative Posterior facet arthropathy Elderly Osteoporosis + fracture Degenerative Malignancy

Table 4: Differences between Pain due to Inflammatory and Mechanical Causes Feature

Inflammatory Mechanical

Age of onset Sex Onset Effect of activity Effect of rest Radiation to legs Limitation of movements Neurologic symptoms and signs

20-40 years Male > female Subacute Relieves Aggravates + diffuse + in all directions Negative

Any age Equal Often acute Aggravates Improves + radicular/sclerotomal + only in some directions May be present

INVESTIGATIONS It needs to be emphasised that investigations play a minimal role in low back pain, especially acute LBA which has a tendency to spontaneous recovery. Investigations may be needed to rule in or rule out ‘red flag’ conditions. Over reliance on radiographs should be avoided. Evident radiographic abnormalities are often not responsible for back pain. Similarly in chronic LBP, imaging studies should only be obtained if results are likely to influence surgical or medical treatment. However, patients with history of trauma or pointers towards systemic disease need appropriate laboratory investigations and radiological work-up.

Low Backache

Table 2: Classification and Features of Low Back Pain

None

Present

None

Present

None

Laboratory Investigations The following laboratory abnormalities reflect a serious underlying pathology. High erythrocyte sedimentation rate, C-reactive protein and low haemoglobin occur in inflammation, malignancy and in systemic disorders. Elevated serum alkaline phosphatase is commonly seen in metastases, osteomalacia and Paget’s disease and elevated serum acid phosphatase or prostate-specific antigen in prostatic cancer. The ‘M’ band in 1815 serum electrophoretic pattern is seen in multiple myeloma.

Radiological Investigations The basic screening procedure is plain radiograph. Additional investigations include computed tomography (CT), magnetic resonance imaging (MRI), myelogram, bone scan, bone densitometry and single photon emission computed tomography (SPECT ). CT and MRI are of special value in evaluating the anatomical details (Figure 5). MRI is the modality of choice; however, the CT defines the bony architecture of the spinal canal better than MRI. Bone scan is a useful screening procedure for the diagnosis of inflammation, infection and secondaries. Bone densitometry is indicated when osteoporosis is considered. SPECT is performed when a bony abnormality is suspected. In discitis, the tracer uptake has a vertical orientation. In metastatic involvement, the area of increased uptake extends from the vertebral body into the pedicle. Fractures show linear horizontally oriented areas of increased uptake centered in the vertebral body and in the transverse process. Increased uptake centered about the disc space and also seen in and projecting beyond the surface of the vertebral body is noted in degenerative joint disease.

The investigations of choice for the catastrophies include an urgent CT or MRI for cauda equina compression and an angiogram for ruptured aortic aneurysm. TREATMENT There is no single form of therapy that is effective for all forms of back pain. Acute Low Back Pain Cauda equina compression and abdominal aneurysm require emergency surgery, decompression in the former and resuscitation in the latter. Once the above emergencies have been ruled out, acute LBP can be treated conservatively by controlled physical activity, which refers to two days of bed rest, preferably in the semi-fowler position with the knees and hips flexed. Progressive mobilisation and exercise should follow this as the patient’s pain improves. Don’t take back pain lying down is the present trend. Physical modalities employed for mechanical low back pain include interferential therapy (IFT), transcutaneous electrical nerve stimulation (TENS), dry and moist heat, microwave and ultrasound. Functional exercises which replicate function to maximise movement, stability and offer mechanical advantage, rather than traditional ones are advocated. Analgesics (like paracetamol, tramadol, etc.) or non-steroidal anti-inflammatory drugs (NSAIDs) are used for pain relief. Local injections of cortisone or local anaesthetics, narcotic analgesics for severe pain, and muscle relaxants are also used if needed. Back discipline (e.g. using a straight back support chair, standing on a broad base and flexing the knees while lifting weights) helps prevent recurrences. Chronic Low Back Pain Chronic LBP can be managed conservatively by the administration of analgesics, NSAIDs, muscle relaxants including tricyclic anti-depressants, and physical modalities like heat therapy. Early intervention in the form of spinal manipulation therapy and exercises may be more effective than bed rest and analgesics. The Mckenzie method is very effective for nonspecific spinal pain.

Figure 5: Clinical practice guidelines for diagnosis and treatment of low back pain (LBP).

In chronic LBP, the investigations vary depending upon the subgroups. For localised back pain, plain radiograph, CT or MRI be done. MRI differentiates metastatic spinal fractures from osteoporotic lesions. The investigation of choice for sciatica is MRI. Evaluation of anterior thigh pain includes radiographs for hip arthritis, CT with contrast in abdominal aneurysms, ultrasonogram for ureteric colic due to stone, intravenous urogram for evaluation of the urinary tract and MRI for retro-peritoneal tumours. Posterior thigh pain may need MRI or CT myelogram. Bone biopsy is indicated in rare situations when the diagnosis of the bone pathology is not clear.

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Smoking should be avoided; obesity should be checked; correct lifting techniques and proper posture maintenance while sitting and standing should be adopted. Exercises include pelvic tilt, knees to chest, hamstring stretch and partial curl to name a few. Psychiatric counselling is given when warranted. Cognitive behavioural therapy has been proved to be useful. If conservative management fails, local or epidural steroids are given. Surgery in the form of decompression or spinal fusion is indicated when the patient develops intractable pain, neurological symptoms or deficit due to disc disease, spinal canal stenosis and unstable vertebral articulation. Patients with persistent chronic LBP benefit from multidisciplinary pain clinics where psychosocial approaches by interdisciplinary specialists, including occupational and vocational therapy, ergonomics and biofeedback are utilized. Acupuncture and yoga have proved to be useful (Figure 6).

Low Backache

OUTCOME MEASURES The McGill pain questionnaire is the most commonly employed and its Indian modification in vernacular languages needs to be validated. The other common instruments used for chronic LBP are back specific function (Roland Morris Questionnaire), generic health status (SF-36), pain (Visual Analogue Pain Scale) (Figure 7), work disability and patient satisfaction. The Oswestry LBP Disability Index by Fairbank et al interprets ‘percentage of disability’ as 0% to 20%—minimal; 20% to 40%— moderate; 40% to 60%—severe; 60% to 80%—crippled and 80% to 100%—bed-bound (exaggerated symptoms).

Figure 7: Visual analogue pain scale.

SUMMARY Dealing with LBP, in general, can be arduous and taxing. Acute LBP is self-remitting in most patients as 90% improve within three months. Most back pains are mechanical in origin. Surgery for LBP is indicated only in 1% of those affected. Referrals to multidisciplinary comprehensive pain centers should be made, only after initial attempts at treatment fail. Chronic LBP may not be curable but can be surely made bearable. RECOMMENDED READINGS

Figure 6: Clinical practice guidelines for diagnosis and treatment of low back pain.

1.

Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: A joint clinical practice guidelines from the American College of Physicians and the American Pain Society. Ann Intern Med 2007; 147: 478-91.

2.

Koes BW, Van Tulder MW, Thomas S. Diagnosis and treatment of low back pain. British Medical Journal 2006; 332: 1430- 4.

3.

Tiwari RR, Pathak MC, Zodpey SP. Low Back Pain among Textile workers. Indian Journal of Occupational and Environmental Medicine 2003; 7: 1.

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24.4 INTRODUCTION Osteoarthritis (OA) is characterised by focal loss of cartilage with accompanying periarticular bone response in the form of subchondral bone sclerosis and attempted new bone formation by way of bony over-growths called osteophytes. OA involves all components of the joint, including bone, cartilage, meniscus and synovium. OA clinically presents as joint pain and crepitus in the elderly. EPIDEMIOLOGY OA is an important cause of disability and the second most common musculoskeletal problem in the world (30%) after back pain (50%). The reported prevalence of OA in rural India is 5.8%. The major risk factors associated with the knee joint OA are age, female sex, obesity, non-smoker, occupational knee bending, physical labour and chondrocalcinosis. Symptomatic and radiographic OA increases with age. The disease follows a more severe course in women with greater symptoms, more extensive involvement, and increased prevalence of knee and hand joint involvement. In contrast, men have an increased prevalence of hip OA in western countries. Obesity precedes OA and is not its secondary consequence. Weight reduction is shown to be an effective primary as well as secondary disease prevention strategy (5% reduction in weight decreases the risk for symptomatic OA by 50%). Indians have increased knee OA as compared to Western people. This could be related to excessive squatting in day-to-day activities, especially amongst women. Hip OA is comparatively uncommon in India. Joint trauma, malalignment, meniscectomy and quadriceps weakness are important risk factors. Vitamin D deficiency, possibly acting through production of quadriceps weakness or through undefined mechanisms, has been said to be associated with progression of OA.

Osteoarthritis Siddharth Kumar Das associated with primary OA of the hip or knee. Genetic basis of generalised OA is further strengthened by its association with human leucocyte antigen HLA A1, and B8, and α1 antitrypsin M2 phenotype. Genome wide scans suggest possibility of susceptibility to be linked to chromosome 2q in the IL-1 and IL-1Ra gene region. This cluster may harbour susceptibility for knee OA but not for hip OA. PATHOGENESIS Normal hyaline cartilage consists of chondrocytes (1% to 2%) embedded in extracellular matrix composed of water, type II collagen and proteoglycan. The chondrocyte secretes numerous inactive matrix metalloproteinases (MMPs) that include stromelysin, collagenase, gelatinase, etc. which can destroy the whole cartilage framework. These are activated by plasmin and activated stromelysin. Chondrocytes also release tissue plasminogen activator (tPA) that converts blood or chondrocyte-derived plasminogen to active plasmin. This cascade is modulated by tissue inhibitor of MMPs (TIMP) and plasminogen activation inhibitor (PAI). Interleukin-1(IL-1) plays a pivotal role in OA pathogenesis. It increases the synthesis and secretion of latent or inactive MMPs and tPA; suppresses proteoglycan synthesis and hence, the cartilage repair; decreases TIMP1 and PAI synthesis; and may be involved in proliferation of osteoblast-like cells leading to osteophyte formation. Matrix repair is stimulated by insulin-like growth factor (IGF-1), fibroblast growth factor (FGF) and transforming growth factor-β (TGF-β) which increase proteoglycan synthesis (Figure 1). In early stages there is matrix and cartilage degeneration on the one hand and active chondrocyte replication with enhanced biosynthesis on the other hand. This leads to a state of homeostasis, known as compensated OA, in which both repair and degeneration are balanced. After a few years, the reparative process is exhausted resulting in progressive OA.

Chondrocalcinosis imparts a small risk, independent of age, for the development of knee OA. Chondrocalcinosis was thought to be rare in India. Although no epidemiological data is available, our recent experience suggests that it is not uncommon. Crystals are not proved to be causative but are intimately linked to the development/progression of OA. Evidences for the genetic basis of OA are increasing. Heberden’s nodes have been shown to be clustered in families with a dominant inheritance. Twin studies show 65% concordance for developing OA. Certain familial forms of OA associated with spondyloepiphyseal dysplasias are linked to a point mutation in the gene coding for type II collagen (COL2A1). An endemic variety of secondary OA has been reported from Western Karnataka (Handigodu disease) that in all probability is due to a spondyloepiphyseal dysplasia occurring in a particular community. No specific genetic abnormality has been found so far. Hand joint OA is being linked to HFE gene mutations. 1818 However, the common HFE variants C282Y and H63D are not

Figure 1: An overview of probable degradative mechanisms involved in OA and possible sites of action of drugs for osteoarthritis.

Previously, OA was considered to be an inherently noninflammatory disorder. However, about 25% patients of OA of

The cartilage is devoid of nerve endings. Hence, the pain in OA is believed to originate from the capsule, synovium, periosteum, subchondral bone, ligaments, muscles, etc.

Nodal Generalised OA (GOA) Nodal generalised OA is seen 10 times more often in middleelderly women. It is characterised by Heberden’s nodes (bony enlargement of distal IP joint), Bouchard’s nodes (bony enlargement at proximal IP joints) and familial clustering (Figure 2).

Osteoarthritis

the knee present with clinical evidence of inflammation that may be secondary to release of IL-1.

MORPHOLOGY Earliest identifiable changes are loss of proteoglycans and decreased metachromasia in cartilage. There is focal loss of cartilage, associated with reactive proliferation of chondrocytes to form clusters. Progression of these changes leads to breach of surface integrity, fissures, pitting, flaking of cartilage and development of vertical clefts (fibrillations).These fissures deepen and may expose the subchondral bone, which becomes ivory-like due to thickening and vascularisation (eburnation). Associated bone growth in subchondral region leads to sclerosis,while growth in joint margin leads to the formation of osteophytes. NATURAL HISTORY The course of OA is highly variable, with radiological progression seen in one-third to two-third of patients. Improvement is rare. Symptoms may progress, improve, or may even be arrested spontaneously and do not correlate well with radiographic progression. CLINICAL FEATURES Pain in or around the involved joints is the cardinal symptom. Usually it starts insidiously as intermittent, localised, deep ache, often aggravated by joint use and relieved by rest, in an asymmetric fashion and then becoming symmetric. The pain becomes persistent and in advanced cases night pain may be very disturbing. Knee joint involvement is typically associated with pain on descending or ascending stairs, squatting for toilet, climbing into autorickshaws, rickshaws, buses, etc. There may sometimes be locking or buckling of knee joint. Hip involvement causes problems of gait and pain in the groin or medial part of thigh. Stiffness in joints on first awakening (morning stiffness) in OA usually lasts 5 to 30 minutes (average 20 minutes). Stiffness occurring after periods of rest or inactivity (gelling) is frequent and lasts for a few minutes. Functional impairment in OA is variable and depends on associated muscle wasting, weakness, and on radiological severity of the disease. Signs of OA include bony swelling, crepitus (sensation of bone rubbing against bone on movement), restricted movement, deformity of joint, muscle weakness and muscle wasting. Commonly involved joints in OA are the knee, the hand joints (distal interphalangeal, first carpometacarpal and proximal interphalangeal joints) and spinal apophyseal joints, while hip, acromioclavicular, and sternoclavicular involvement is uncommon. The carpal joints, the elbow, ankle, glenohumeral and the intertarsal joints are rarely involved in OA. A bowleg deformity is seen in over 50% of patients with knee OA. Signs of local inflammation like knee joint effusion may be seen in some patients. SUBSETS OF OSTEOARTHRITIS OA for convenience can be categorised into four major subsets, though subsets may overlap with each other.

Figure 2: Bouchard and Heberden nodes.

Erosive OA It is characterised by involvement of the interphalangeal joints of the hands often with florid inflammation and erosive changes that lead to deformities and ankylosis. A small proportion (15%) may evolve into seropositive rheumatoid arthritis (RA). Isolated Knee Joint OA It is the most common form of OA where knee may be the only joint involved. It is usually starts unilaterally in the beginning but becomes bilateral over a period of time. Obesity, female gender and knee bending are the important risk factors. It may involve predominantly medial femorotibial, lateral femorotibial or patellofemoral compartment.The involvement of patellofemoral component is tested by eliciting pain when patella is compressed against femur on active extension of knee (Shrug test). Spinal OA Apophyseal joint involvement is the only true form of OA of spine. Pain in bending backwards is the typical physical sign of such involvement. Intervertebral disc degeneration with osteophyte formation (Figure 3) is considered an integral part of OA. It is common in the lumbar (lumbar spondylosis) and the cervical (cervical spondylosis) regions, the sites of maximum spinal motion. It gives rise to local pain and/or radicular pain. Diffuse idiopathic skeletal hyperostosis (DISH) comprises of flowing calcification along the anterior longitudinal ligaments and disc margins. DISH and OPLL (ossification of posterior longitudinal ligament) are considered to be variant forms of OA. INVESTIGATIONS The earliest feature is joint space narrowing, which in the knee is best demonstrated in weight-bearing radiographs (Figures 4A and B). Osteophytes are the hallmark of the disease. Subchondral bone sclerosis, subchondral cysts, deformity, loose bodies and calcification [linear due to calcium pyrophosphate dihydrate (CPPD) deposition, spotty due to hydroxyapatite deposition] are the other changes.

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DIAGNOSIS The diagnosis of OA is clinicoradiological. It is well known that early OA may not show radiological changes, while only 50% to 60% of patients with OA by radiograph are clinically symptomatic. Erosive form of OA is particularly difficult to differentiate from RA. A positive rheumatoid factor (RF) and an elevated erythrocyte sedimentation rate help in diagnosing RA. Patients having mixed disease further complicate the picture. OA changes may follow joint damage due to RA. It must be remembered that joints actively involved in RA seldom show osteophytes. The elderly may demonstrate RF positivity even in the absence of RA. Therefore, elderly patients with a positive RF, isolated knee pain and crepitus without hand joint involvement are more likely to have OA rather than RA.

Figure 3: Lumbar spondylosis.

Computed tomography is useful in assessing the axial joints. Ultrasound is useful in assessing changes in periarticular structures, like Baker’s cysts. Bone marrow oedema, cartilage defects, meniscal tears, osteophytes, subchondral cysts, sclerosis, synovitis and synovial effusions may be seen on magnetic resonance imaging (MRI). MRI and Scintiscan (Tc99m biphosphonate) are, however, not recommended for routine clinical use. Synovial fluid cell count is less than 2000/mm3 with mononuclear cell predominance. Synovial fluid may show the presence of crystals in 30% to 70% patients, commonly seen are CPPD. However, hydroxyapatite (HA) or basic calcium phosphate (BCP) crystals may also be detectable.

MANAGEMENT The treatment of OA is aimed at minimising pain, optimising function and reducing disability using a combination of nonpharmacological, pharmacological and surgical therapies. Non-Pharmacological Management Patient education and joint protection measures like avoidance of poor posture and limitation of excess joint loading are important. Day-to-day activities may need alteration (e.g. change of toilet seat from the Indian style to Western style; avoiding weight loading movements of the joints, (e.g. avoidance of squatting, sitting on low chairs, sofas, floor and climbing stairs, etc.). Weight reduction is important in obese patients. When the disease is relatively quiescent, low intensity weightbearing activity is safe and beneficial for muscle strength, mobility and a sense of well-being. But when the disease is

Figures 4A and B: Showing osteoarthritis of the right knee with: space reduction in medial compartment (A); chondrocalcinosis seen on lateral view of knee joint (B).

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Application of superficial heat on periarticular tissue by hot packs and paraffin baths alleviates pain, relieves muscle spasm and decreases joint stiffness. Deep heat by ultrasound and diathermy may damage cartilage and should be avoided. Heat increases inflammation, hence, ice packs are more helpful for acutely inflamed knee or bursae. Pharmacological Management Analgesics and nonsteroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat the both pain and inflammation in OA. Their use is limited by their gastric and renal toxicity, especially in the elderly. Some studies have shown acetaminophen (paracetamol) 1 g 3 to 4 times a day (maximum 4 g per day) to be equally effective as other NSAIDs in OA with the advantage of fewer gastric side effects. NSAIDs like aspirin and indomethacin which have been implicated in cartilage degeneration are best avoided in OA. Newer selective cyclooxygenase-II (COX-2) inhibitors like meloxicam, celecoxib, etoricoxib, etc. have been shown to be chondroneutral and equally effective with fewer NSAIDs-related side effects. Capsaicin cream on topical application gives relief from pain and tenderness by depleting substance P in sensory nerve endings and may be used. Absorption of locally applied NSAIDs may be erratic but may have a strong psychological value. Chondroitin and glucosamine Chondroitin and glucosamine are nutraceutical agents whose use and effectiveness have been debated with conflicting reports in the literature. Glucosamine sulphate is given in doses of 1500 mg per day and chondroitin 1200 mg per day. They may provide symptomatic benefit in some patients with knee OA. It is unclear whether they have a disease modifying role. The sulphate salt of glucosamine marketed by one pharmaceutical company only has been shown to be consistently effective in OA and also been shown to provide disease modification. However, the hydrochloride salt has never been shown to benefit patients. Diacerein Diacerein in doses of 50 mg twice daily with meals is being used in OA. Diacerein has a small, consistent benefit in improvement of pain. It is believed to be an inhibitor of IL-1. Intra-articular treatments Intra-articular steroids are employed in patients with knee OA who have effusion. Since repeated steroid injections may lead to more cartilage damage, it is recommended that the same joint should not be injected more than 3 times a year. The

incidence of joint infection following intra-articular steroids is low. Visco-supplementation with intra-articular hyaluronan injection is a promising therapy, providing symptomatic relief to about 60% to 70% patients with knee OA especially those without effusion. Hyaluronan is given as 3 to 5 (depending on molecular weight) intra-articular injections at weekly intervals. Local reaction may occur in up to 8% patients. Considering that IL-1 is an important cytokine for the development and progression of OA, anakinra has been used intra-articularly. Early studies have shown that its use is safe but a single injection with a half-life of a few hours is not effective in reducing the pain.

Osteoarthritis

active with significant pain and inflammation, patients should not overstress with exercise. Quadriceps strengthening exercises are important. Supportive devices are often an adjunct to other modalities. Devices like canes, crutches, orthotic shoes and knee braces when used properly, lead to pain relief with improved function. A ¼ inch lateral heel raise or shoe insert is frequently helpful in varus deformity of knees.

Colchicine One centre from India has reported that patients presenting with significant inflammation with demonstrable CPPD crystals in joint fluid have better symptomatic relief when treated with colchicine. Even in patients not presenting with inflammation, colchicine produces significant symptomatic relief. Colchicine is used in a dose of 0.5 mg twice daily. Other modalities Tetracyclines chelate metals and thus inactivate MMPs. Since MMPs are important in the degradative pathway, doxycycline has been used for the management of OA. Chondrocyte transplants directly or in scaffolds, have been shown to regenerate near-normal hyaline cartilage and may be useful for small lesions of the cartilage but are not currently routinely recommended for the treatment of OA. Surgical Management Joint replacement must be considered in any patient presenting with end-stage joint disease with pain not responding to conventional treatment. Total knee replacement is opted by patients who are older and have weakness, more difficulty in getting up, more problems in climbing stairs and impaired extension of knee. Total hip and knee joint replacement have improved the quality of life and decreased the morbidity due to OA. Most series report excellent long-term results in over 90% of patients undergoing joint replacements. Other surgical therapies available for OA are loose body removal, osteotomy, arthrodesis, arthroplasty, synovectomy, debridement, etc. with varying grades of efficacies. PREVENTION Weight reduction is the only known method of reducing the risk of symptomatic OA. Lifestyle changes, like less squatting and less stair climbing, are likely to help. Some of the therapies described for OA possibly reduce the progression of OA, and hence, are more likely to be beneficial for prevention rather than for treatment. However, one has to realise that if prevention of OA is to be attempted the effort has to start in twenties and thirties, as we know that the seeds of OA are sown early. RECOMMENDED READINGS 1.

Cochrane Database Syst Rev 2005; (2): CD002946.

2.

Doherty M. Clinical feature and subset characterisation. In: Doherty M, editor. OA, London Wolfe; 1994: pp 61-83.

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24.5

Gout and Other Crystal Arthritides URK Rao

Many crystals are associated with articular syndromes (Table 1). In practice, only monosodium urate monohydrate (MSU), calcium pyrophosphate dihydrate (CPPD), and calcium hydroxyapatite (BCP) are commonly encountered. Table 1: Crystal Associated Arthritides Crystal

Clinical features

Monosodium urate (MSU)

Acute/chronic gouty arthritis, tophi, renal calculi

Calcium pyrophosphate dihydrate (CPPD)

Acute pseudogout, chronic inflammatory or degenerative arthritis; chondrocalcinosis Calcific periarthritis, acute/chronic inflammatory or destructive arthritis, soft-tissue calcinosis

Basic calcium phosphate hydroxyapatite (BCP) Calcium oxalate aluminium phosphate

Acute arthritis in patients on renal dialysis

Cholesterol

Chronic synovial effusions in RA/OA

Cysteine/cystine

Acute arthritis

Charcot-Leyden (lysophospholipase)

Synovial fluid and tissue deposition, with eosinophilia

Xanthine

Acute arthritis (rare), renal calculi

GOUT Gout is an inflammatory response to the MSU crystals formed secondary to hyperuricaemia.The major clinical manifestations are acute synovitis, chronic erosive and deforming arthritis, tophi, nephrolithiasis, and interstitial nephritis.The epidemiology of hyperuricaemia is different from that of gout. Mean uric acid (urate) concentrations are age and sex related. Prepubertally, in males the mean concentration is around 3.5 mg/dl, with a steep rise to 5.2 mg/dl at puberty. In females, the mean concentration is up to 4.7 mg/dl with rise only after menopause. Hyperuricaemia is defined as a serum or plasma urate concentration greater than 7.0 mg/dl in males and 6.0 mg/dl in females. Gout is seen in only one-tenth of patients of hyperuricaemia. The incidence of gout varies in population from 0.2 to 3.5 per 1000, with an overall prevalence of 2-26 per 1000. Gout is found to have increased prevalence in recent years. It is rare in children and premenopausal females. The peak age of onset in males is between 40 and 50 years. Pathogenesis of Urate Crystal-Induced Inflammation Uric acid is a weak acid, present mainly as urate, the ionised form in physiologic fluids. At concentrations greater than 6.8 mg/dl, urate can crystallise as MSU in and around joints. MSU crystals are released into the joint cavity, activate synovial lining cells, recruit and activate mastocytes and peripheral blood monocytes. At the cellular level, inflammation induced by urate crystals is brought by innate immune engagement of the crystals by plasma membrane receptors including toll-like 1822 receptors (2 and 4). In turn, they produce various cytokines such

as interleukins (e.g. IL-1, IL-8) and chemokines leading to endothelial cell activation. Neutrophils are recruited into the joint cavity, leading to MSU crystal phagocytosis and cell activation. Auto-limitation of active inflammation is brought out by macrophages, neutrophil necrosis and apoptosis. Risk Factors Serum uric acid concentration is the single-most important determinant of the risk of developing gout. With normal renal function, its blood concentration depends mainly on the breakdown of nuclear proteins and dietary purine load (Figure 1). Provocative factors include alcohol, dietary excesses, surgery, trauma, sepsis, stress, starvation, dehydration and drugs like diuretics, pyrazinamide and aspirin.

Figure 1: Body uric acid pool.

Classification Hyperuricaemia and gout may be classified as primary and secondary (Table 2). Increased production of uric acid as a cause of gout is seen in only 10-15% of subjects (over-producers) and in 80-90%, uric acid excretion is impaired (under-secretors). Clinical Features Gout can occur in four phases. Asymptomatic hyperuricaemia Hyperuricaemia may be an incidental finding and may never lead to gout. Conversely, serum uric acid levels may not be elevated during acute gouty arthritis. This is because ACTH released in response to stress is uricosuric. Generally, asymptomatic hyperuricaemia needs close observation with no active treatment. However, growing epidemiological and experimental evidence indicates that asymptomatic hyperuricaemia is capable of directly promoting hypertension and vascular disease. Severe over-production of urate, as may occur with cytotoxic chemotherapy, is associated with high risk of acute renal failure and requires intervention. Acute gouty arthritis The big toe (first metatarsophalangeal joint) is the classic site for gout. One-third of patients may get their first attack at another site such as the in-step of the foot, ankle, knee, or hand joints. Sydenham’s classic description lists the important clinical characteristics used to diagnose a typical attack. The attack is

Gout and Other Crystal Arthritides

acute, it starts in the night, the joint and surrounding tissues are swollen, hot, red, shiny and extremely painful. There is a mild fever with chills. Left untreated, the attack will start to improve in a week or two. The skin over the joint may subsequently desquamate. Atypical manifestations include tenosynovitis, bursitis, cellulitis or mild pain and discomfort without swelling, lasting a day or two. Acute gout in one joint may provoke migratory attacks affecting other joints over subsequent days (cluster attacks). Pauci or polyarticular gout attacks are more common in women, especially with diuretic use. Table 2: Causes of Hyperuricaemia Primary hyperuricaemia Increased uric acid production Idiopathic (10%) Specific enzyme defects Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency Increased phosphoribosyl pyrophosphate (PRPP) synthetase activity Decreased uric acid excretion Idiopathic (90%) Secondary hyperuricaemia Increased uric acid production Increased purine synthesis de novo-specific enzyme defects Complete HGPRT deficiency Glucose 6-phosphatase deficiency (type I) Increased turnover of preformed purines Myeloproliferative disorders, e.g. polycythaemia vera, granulocytic leukaemias Lymphoproliferative disorders, e.g. lymphomas, myelomas Others—Macroglobulinaemia (Waldenstrom’s) Carcinomatosis Chronic haemolytic anaemia Gaucher’s disease Exfoliative psoriasis

Figure 2: Gouty arthritis affecting toes in a 45-year-old male. A tophus can be seen over the base of left great toe.

Decreased uric acid excretion Renal, e.g. chronic kidney disease, nephrogenic diabetes insipidus Increased levels of organic acids, e.g. exercise, starvation, ketoacidosis and alcohol drugs, e.g. diuretics, low-dose aspirin, pyrazinamide, cyclosporine, ethambutol Other medical disorders, e.g. hyperparathyroidism, myxoedema, Down’s syndrome, lead nephropathy, sarcoidosis

Intercritical gout After the first attack of gout, the second episode may never occur or occurs after several years. However, in most of the patients, the next few episodes occur within one year. The frequency of attacks and number of sites involved gradually increase with time. Chronic gout (tophaceous gout) Development of chronic tophaceous gout depends on uncontrolled hyperuricaemia of long duration, usually more than 10. But tophi or chronic polyarthritis may occur as early as 3 years or as late as 40 years after the first acute attack. Tophi appear as firm, nodular or fusiform swellings. In inflamed tophi, the overlying skin may be erythematous. In ulcerated tophi, white chalky material, the urate crystals, may exude. The common locations of tophi are the great toe, feet (Figure 2), hand joints (Figure 3) and olecranon. Tophi of helix of the ear, though classic is uncommon. The gout in elderly patients, especially women, may present differently compared to typical gout occurring in middle-aged men (Table 3).

Figure 3: Gouty arthritis affecting fingers in a 45-year-old male.

Table 3: Typical Gout versus Elderly-Onset Gout Feature

Typical Gout

Elderly-Onset Gout

Age of onset Peak in mid 40s

Over 65

Sex

M=F

M>F

Presentation Acute monoarthritis; lower extremity (base of greater toe, instep of the foot)

Polyarticular upper and lower extremity (finger involvement more common than typical gout)

Tophi

Several years of attack

May occur early

Associated features

Obesity, hyperuricaemia, Renal insufficiency, hypertension, alcohol diuretic use abuse

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RENAL DISEASE After gouty arthritis, renal disease is the most frequent complication of hyperuricaemia. Urate nephropathy is attributed to the disposition of MSU crystals in the renal interstitial tissue. Other manifestations include acute uric acid nephropathy or uric acid calculi. Calcium oxalate renal stones occur more commonly in patients with hyperuricaemia or gout than in normouricaemic subjects. Renal failure accounts for 10-25% of deaths of gouty patients. Co-existent hypertension may be more important than urate in the pathogenesis of renal failure. It should be remembered that hyperuricaemia may be seen secondary to chronic renal failure without gout. Obesity, hypertension and hyperuricaemia are important associated disorders. A negative association exists between gout and rheumatoid arthritis (RA) and gout and systemic lupus erythematosus. Investigations The synovial fluid is turbid with greatly elevated neutrophils. The synovial fluid should ideally be examined under polarised light. Urate crystals are needle-shaped, generally 5-25 µm in length, intracellular or extracellular in location and negatively birefringent (Figure 4). Urate crystals can also be demonstrated in gouty tophi. Figure 5: Radiograph of right foot with soft tissue swelling and erosions with over-hanging edges at first MTP joint.

classic attacks, other conditions to consider are psoriatic arthritis, reactive arthritis, osteoarthritis, traumatic arthritis, pseudogout and palindromic rheumatism. Chronic tophaceous gout and polyarticular gouty arthritis are often mistaken for rheumatoid arthritis.

Figure 4: Negatively birefringent needle-shaped monosodium urate crystals.

Hyperuricaemia is confirmed if two or more fasting serum uric acid levels are elevated. Over-producer status can be determined by more than 700 mg in 24 hours urinary urate on a normal diet, or by a single urine sample with increased uric acid/creatinine ratio (normal 10 to 11 mg/dl requires treatment) and the presence of risk factors. Urate lowering drugs are not indicated after just a single attack of gout but should be considered after a second or third attack. Allopurinol is instituted 10 to 15 days after resolution of inflammation by NSAIDs or colchicine.

Anti-hyperuricaemic therapy is usually given indefinitely. Figure 7 shows the line of action for treatment of gout. Acute gout Drug therapy should be initiated as early as possible. When used within the first few hours of an attack, NSAIDs or colchicine give a good response. Though indomethacin is widely used, other NSAIDs like diclofenac, naproxen, etoricoxib, piroxicam, etc. can also be used. Intra-articular steroid therapy terminates the gouty attack. This form of therapy is useful in a situation where NSAIDs cannot be given in adequate doses or are ineffective. Oral steroids may be indicated in severe acute attacks but the response is variable and rebound attacks may occur on their withdrawal. 1825

Figure 7: Therapeutic algorithm to reduce the elevated serum uric acid in gout.

Recurrent attacks of gout Colchicine in low doses (0.5 mg twice daily) is used prophylactically to prevent recurrent attacks. Tophaceous gout In treating tophaceous gout, it is mandatory to lower plasma urate concentration to such a degree (6/10 is needed for classification of a patient as having definite RA)‡

Rheumatoid Arthritis

Table 2: The 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis*

Joint involvement§ 1 large joint¶

0

2-10 large joints

1

1-3 small joints (with or without involvement of large joints)#

2

4-10 small joints (with or without involvement of large joints) 3 >10 joints (at least 1 small joint)**

5

Serology (at least 1 test result is needed for classification)†† Negative RF and negative ACPA

0

Low-positive RF or low-positive ACPA

2

High-positive RF or high-positive ACPA

3

Acute-phase reactants (at least 1 test result is needed for classification)‡‡ Normal CRP and normal ESR

0

Abnormal CRP or abnormal ESR

1

Figure 5: Typical physical findings of moderate swellings in the metacarpophalangeal and proximal interphalangeal joints in a patient with established RA.

Duration of symptoms§§ < 6 weeks

0

> 6 weeks

1

*The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA. †Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted. ‡Although patients with a score of 3 times the ULN for the laboratory and assay. Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored as low-positive for RF. ACPA = anti-citrullinated protein antibody. ‡‡Normal/abnormal is determined by local laboratory standards. CRP = C-reactive protein; ESR = erythrocyte sedimentation rate. §§Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g. pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.

Figure 7: The ‘Swan-neck’ deformity of the fingers in a patient with late RA.

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Figure 8: The Boutonnière deformity in the finger joints; ulnar deviation (at MCP joints) is also seen.

Figure 9: The ‘Z’ deformity in the right thumb; also note ‘swan-neck’ deformities in some of the fingers.

Figures 11A to C: Typical deformities in the forefeet in RA.

Extra-Articular Features These include: Rheumatoid nodules These are firm nontender subcutaneous that tend to develop over pressure areas of the body most common being elbows and extensor surface of the proximal forearm (Figure 12). Other sites for rheumatoid nodules are Achilles tendon, fingers, occipital region on the scalp, and ischial tuberosities. Studies on RA from India have reported very low prevalence of rheumatoid nodules (~3%) that are very often unilateral. Eye

Figure 10: Late RA with advanced subluxation of the metacarpophalangeal joints with ulnar deviation and wrists with wasting of the small muscles of the hands. Note the ‘squaring’-deformity of the left wrist and swan-neck deformity 1834 of the left little finger.

Involvement of the lacrimal glands causes dryness in the eyes (keratoconjunctivitis sicca). Redness, pain, gritty feeling and excess mucous collection in epicanthus on getting up in the morning are the usual complaints. Usually there is associated parotid and minor salivary gland involvement causing dryness of mouth. Scleritis and episcleritis are the other less common

Rheumatoid Arthritis

Figure 12: Rheumatoid nodules: on olecranon processes, forearms, adjacent to small finger joints.

complications of RA. In episcleritis, the eye becomes red and, in contrast to conjunctivitis, results in no discharge other than tearing in response to the gritty discomfort. Scleritis causes severe ocular pain and a dark red discolouration. No discharge is present. When severe, scleritis can cause resorption of the sclera down to the uveal layer, a complication called scleromalacia perforans that may cause vision loss.

difficult to distinguish from those caused by the disease itself. As a practical rule lung disease due to active RA that has been suboptimally treated is much more common than drug induced

Skin There is no specific lesion of RA. The so-called ‘senile’ purpura resulting from skin atrophy and capillary fragility in patients inappropriately treated with long-term glucocorticoids is common. Palmer erythema and Raynaud’s phenomenon may be seen. RA vasculitis usually manifests with nail fold infarcts or palpable purpura, most commonly seen on the lower leg. A severe form of vasculitis is a deep, erosive, ulcerated scarring lesion seen on the lower legs called pyoderma gangrenosum (Figure 13). It is indicative of severe disease that has not been well controlled. Severe systemic vasculitis, a dreaded complication of RA, is rarely seen now mainly because of early and effective treatment. Lung Pleuritis is the most common manifestation but in the majority it is subclinical. Interstitial pneumonia and fibrosis of non-specific class is more common in RA (as against scleroderma where the usual type interstitial lung disease is seen) (Figure 14). There is increasing dyspnoea associated with fine, diffuse, dry basal crepitations. Radiographs show a diffuse reticular (interstitial) or reticulonodular pattern in both lung fields often described as ‘ground-glass’ appearance; these can progress to a honeycomb appearance on plain radiographs and a characteristic lattice network seen on high-resolution CT scans. Less common but serious lung lesions in RA including nodules in the lung (Figure 15) (they may cavitate), bronchiolitis obliterans with organising pneumonia disease, arteritis with pulmonary hypertension and a rare small airways disease. Another important consideration is that methotrexate (MTX) and leflunomide (LEF), important drugs for treatment of RA, may also cause lung disease that may be

Figure 13: Pyoderma gangrenosum on the lower leg.

1835

standing RA may cause nephrotic syndrome. Subtle subclinical heart involvement is not uncommon and includes pericarditis (rarely may cause symptomatic pericardial effusion or, even tamponade), myocarditis, endocarditis, valvular disease and conduction defects. Much more important, however, is systemic inflammation-related premature atherosclerosis leading to coronary artery disease and myocardial infarction in young. Other clinical problems Osteopoenia and osteoporosis is common and may lead to increased fracture risk. Risk of infection is also increased by approximately 1.5 to 2 times of the matched normal controls. Cancer risk, especially haematological malignancies, is 2 to 3 times higher in RA that is not related to its treatment.

Figure 14: Interstitial lung disease in RA.

Unusual Patterns or RA Variants These include ‘elderly-onset-RA’ or EORA and arthritis robustus (details available in the web version). Syndrome of Early Undifferentiated Polyarthritis If the duration of symptoms is less than 6 weeks, RA cannot be diagnosed with certainty. 30% to 40% of such patients may go in spontaneous remission never evolving into RA. Therefore, it has been called undifferentiated polyarthritis syndrome (UPS). ACR defines three categories of RA disease duration: early disease (24 months, late RA). Early disease has been further subdivided by disease duration of 10 years) it would be prudent to get proper retinal examination done for HCQ retinal toxicity. Other reported adverse effects include abdominal discomfort, nausea, lose motions, skin rash, tinnitus, headache and myopathy. It crosses placenta, therefore, with risk of foetal abnormalities. Sulphasalazine (SSZ) It was the first drug to be specifically designed by Svartz (1942) for the treatment of RA. Approximately 45% of patients would have beneficial effect at the end of 6 months. It is a popular drug for mild-to-moderate early disease and, like HCQ is the most popular DMARD to be used in combination with MTX and HCQ therapy. It is generally well tolerated but, gastrointestinal disturbance and intolerance, allergic skin rash, reversible reduction in sperm count are not uncommon. Less commonly

Table 4: Disease Modifying Anti-Rheumatic Drugs (DMARDs): Standard DMARDs and Biological DMARDs Synthetic small molecules empirically found to be effective in the treatment of RA (Standard DMARDs)

Mechanism-based molecules produced biotechnologically for targeted modification of biological response (Biological DMARDs)

DMARDs presently used widely

DMARDs not widely used now

α (iTNF-α α): Inhibitors of tumour necrosis factor-α Infliximab, etanercept, adalimumab*, certolizumab pegol*

Organic-gold compounds D-Penicillamine Chloroquine Cytotoxic drugs: azathioprine, cyclophosphamide, chlorambucil, others

B-cell depletion therapies Rituximab Others:Tocilizumab (inhibitor of IL-6), abatacept (co-stimulation blocker), large number of other molecules in the ‘pipeline’

DMARDs presently used sparingly

Low-dose methotrexate Minocycline (LD-MTX) Cyclosporine Sulphasalazine Others: tacrolimus Hydroxychloroquine Leflunomide *Not released in India at the time of writing.

1839

cytopoenias and liver function abnormalities may be seen. A rare manifestation is drug-induced lupus. Methotrexate (MTX) It was developed several decades ago as an anti-cancer drug that works as a potent inhibitor of dihydrofolate reductase (DHFR), a critical enzyme in folate metabolism. The dose of MTX required for its cytotoxic-antiproliferative action in the treatment of malignancies is, however, high; usually >1gm/m2 (average person measures 1.73 m2). Therefore, therapeutically, the MTX dose required to treat malignancies has been designated ‘HD-MTX’. It is of note that the rheumatologists use several folds less MTX dose than that used in oncology; mostly in the range of 7.5 to 15 mg once weekly. Only in recent days dose in the range of up to 15 mg/m2 or 25 mg/wk (maximum of 30 mg/wk) has been recommended. The therapeutic dose of MTX used is rheumatological conditions is, therefore, called LD-MTX. It would appear that HD-MTX and LD-MTX are, for all practical purposes, two different drugs with different modes of action and different indications of use in clinical medicine (details on web version). LD-MTX in RA LD-MTX is now considered the ‘anchor drug’ among DMARDs. The beneficial effects become visible within weeks. MTX is used in RA as a monotherapy as well as the cornerstone in any DMARD combination, including those with biologicals. It has a convenient weekly dose schedule; it is inexpensive and better tolerated than most other DMARDs with high ‘retention rate’ over long periods of time. LD-MTX can be administered orally or by subcutaneous injections. Oral weekly dosing is convenient but, above 15 mg/week dose, a switch over to subcutaneous route improves gastrointestinal tolerability and bioavailability. Conventionally, the initial dose is 7.5 mg weekly that is escalated every two weeks to a maximum of up to 30 mg weekly dose to achieve maximum disease control. More recently, it has been recommended that in patients with no risk factors (see below) LD-MTX treatment could be initiated at the dose of 15 mg/week orally, escalating with 5 mg/month to a maximum of 25-30 mg/ week with a switch to subcutaneous administration in the case of an insufficient response. However, patients with very active polyarticular disease and markers of bad prognosis will benefit from starting with parenteral administration. The dose may be successfully reduced to once in two weeks in patients with stable remission for a long-time. LD-MTX has also been shown to reduce radiological progression of disease. Common Adverse Effects and Monitoring of LD-MTX Treatment Toxicity monitoring is simple and inexpensive and only includes blood counts, liver enzymes (AST, ALT), and renal status (serum creatinine). Commonly seen adverse effects, albeit minimal, include gastrointestinal intolerance, stomatitis, hair loss and liver function abnormalities. At the recommended doses bone marrow suppression is rare. Folic acid or folinic acid supplementation reduces the frequency of liver function test abnormalities, stomatitis and marrow suppression. Folic acid supplementation is at the dose of 1 mg daily or 5 mg weekly on the next day of the MTX dose. Switching to subcutaneous injections is another way of offsetting GI intolerance. Mucositis can be easily controlled with folinic acid supplementation 1840

(usually 50% of the MTX dose) given 12 hours after the LD-MTX dose. MTX is teratogenic, therefore, needs to be discontinued for at least 10-12 weeks before the patient tries for pregnancy. Rare adverse effects (~1%) include interstitial pulmonary inflammation and fibrosis that would necessitate discontinuation of the drug. However, the earlier debate related to MTX-induced lung and liver fibrosis has slowly died down as this does not appear to be a great risk. Most vaccinations work well and not suppressed with LD- MTX. Leflunomide (LEF) It suppresses the de novo synthesis of pyrimidine (uridine and cytidine) nucleotides by inhibiting dihydroorotate dehydrogenase. It is given orally once a day at the dose of 10 or 20 mg. Adverse effects include diarrhoea, liver toxicity (transaminitis), leukopenia and potential to raise blood pressure. It is potentially teratogenic and normally should not be prescribed in women in reproductive age unless strict contraception is ensured. Table 5 gives details of commonly used standard DMARDs. Biological DMARDs These are genetically engineered biotechnologically produced version of natural molecules that specifically target pathogenic mediators of joint inflammation and damage. There are two main categories of biologicals namely monoclonal antibodies (suffix ‘mab’) and, fusion proteins (suffix ‘cept’). They are highly effective in controlling disease activity, and halting/reversing disease progression and damage (Table 5). The major drawback is cost. Glucocorticoids (GC) Besides their anti-inflammatory action they have been shown to retard disease progression and joint damage in RA. Unfortunately, because of serious systemic long-term adverse effects GC use in RA remains limited to only a few situations: (i) Depot-preparations for intra-articular or intra-lesional administrations to control localised disease flares such as in a single (or a few) joint(s) or para-articular lesions such as tenosynovitis, carpal tunnel syndrome others. The commonly used preparations are depot-methylprednisolone, depottriamcinolone-acetonide and depot-triamcinolonehexacetonide (the last one not available in South-East Asia); (ii) Depot-methylprednisolone given as intramuscular injections at weekly intervals for a few weeks at the initiation of DMARD treatment as ‘bridge-therapy’, to control inflammation and pain during the period it takes for slow-acting DMARDs to start their action; (iii) Large-dose intravenous bolus given on 2 or 3 consecutive days for ‘debulking’ of severe disease at the initiation of treatment or uncontrolled disease flare during the follow-up; (iv) As one of the drugs in a step-down combinationDMARD strategy with a moderate dose that is tapered off over the next several weeks; (v) For treating some of the more serious complications of RA, e.g. vasculitis, eye and pulmonary involvement, serositis; (vi) To prevent nausea, vomiting and gastrointestinal intolerance often seen with MTX dose of 20 mg/ week or more. A small to moderate dose of GC given about 1530 minutes before the MTX dose once-a-week may relieve this problem. Prolonged continuous daily use of GC in RA is not recommended especially in our country where metabolic syndrome is a major problem in the population. An important

Standard DMARD

Route/ Schedule

Clinically Important Adverse Effects

Screening

Low-dose methotrexate

Oral/subcutaneous weekly

GI intolerance, mucositis, transient transaminitis

Renal and liver status, Complete blood counts, liver blood counts, hepatitis B and C enzymes, serum creatinine 2-3 monthly.

Hydroxychloroquine

Daily oral dose

GI intolerance, skin rash, skin hyperpigmentation Prolonged therapy with dose >6 mg/kg may rarely cause retinopathy

In patients > 50 years of age taking drug for several years, yearly eye examination for retinal toxicity

—

Sulphasalazine

Daily in divided dose

GI intolerance, skin rash, rarely granulocytopaenia

Complete blood count, liver status and G6PD deficiency

Complete blood count, liver enzymes 2-3 monthly

Leflunomide

Single daily dose

Diarrhoea, skin rash, alopecia, transaminitis, granulocytopaenia

Complete blood count, liver enzymes, renal function, hepatitis B and C

Complete blood count, liver enzymes, serum creatinine, 2-3 monthly

Biological DMARD

Dose/route

Clinically important adverse effects

Screening

Monitoring

Infliximab

IV infusion over 4-6 hours, usually 3 monthly infusions

Flare of latent tuberculosis, other infections, autoimmune phenomenon, psoriatic lesions, increased chances of malignancy?

For latent tuberculosis, infections

For tuberculosis, infections

Etanercept

50 mg weekly subcutaneous injections

Local injection reactions; infections; flare of latent tuberculosis

-do-

-do-

Rituximab

IV infusion cycles of 1 gm slow IV infusion × 2 at 15 day interval; to be repeated 6 monthly

Allergic reactions during infusions, infections, multifocal leucoencephalopathy

Infections, hepatitis B and C screening

Infections

Abatacept

1 gm as slow IV infusion every 15 days × 3; Subsequent doses 4 weekly

Infections

-do-

-do-

Tocilizumab

8 mg/kg body weight, given as slow IV infusion, every month

Infections, deterioration in lipid profile, especially blood triglyceride levels

-do-, lipid profile

-do-, lipid profile

point to remember is that, when used over prolonged periods, there is no safe dose of GC. Even at very low doses (20 active joints); extra-articular disease (e.g. presence of rheumatoid nodules, secondary Sjögren’s syndrome, RA vasculitis, Felty’s syndrome, and RA lung disease); high ESR and high levels of CRP; high titres of RF and ACPA; bone oedema or erosions on imaging; and presence of certain genetic markers (HLA-DR4 SE, other single nucleotide polymorphism). Therapeutic armamentarium consists of standard and biological DMARDs, 1841

Figure 18: An overview of treatment strategy for RA.

judicious use of GC and adjunct and supportive treatment. An overview of treatment strategy for RA is given in Figure 18. Use of Standard (Non-Biological) DMARDs Based upon the variables mentioned above patients are treated according to the algorithm given in Figures 19A to C. DMARDs are used as monotherapy, as duel-DMARD combination or as triple-DMARD combination therapy. Often these are combined with systemic GC mainly at the initiation of treatment as ‘bridge’ therapy or for ‘debulking’ or during disease flares (see under ‘glucocorticoids’-above). As a general rule, adequate doses of standard DMARDs should be given for adequate periods of time to achieve satisfactory response. Only if the satisfactory response is not achieved after such a trial of standard DMARDs, biologicals are considered as a therapeutic option. Traditionally 6 to 12 weeks of maximally tolerated doses are given to evaluate the efficacy of a certain DMARD/DMARD combinations. If low-disease activity state or remission is not achieved by the end of that period it could be considered an ‘unsatisfactory response’ and the treatment is modified accordingly. Use of Biological DMARDs At the time of writing the drugs approved and available in India 1842 included specific inhibitors of TNF-α namely the chimeric

monoclonal antibody infliximab (fully humanised adalimumab not yet released in India) and fusion protein etanercept. Monoclonal antibody against CD20 positive B cells called rituximab, co-stimulation blocking fusion protein CTLA4-Ig called abatacept, and monoclonal antibody against IL-6 called tocilizumab are also available. Present day recommendation of these highly expensive drugs is in patients who do not achieve satisfactory disease control with standard DMARDs within a reasonable period of time. Under certain circumstances they could also be recommended in patients at a much earlier stage if several features of poor prognosis are present and the cost and insurance coverage is not a limiting factor. The algorithm for the use of biological DMARDs in RA is given in Figures 20A to C. Treatment of Complications of RA and Co-Morbidities Treatment of RA requires much more than just the stringent control of disease activity. Thus, sicca features require appropriate moisturising eye drops, control of eye infections and some drugs (e.g. pilocarpine) to enhance tear production. Frequent sips of water help preventing complications in the mouth-mucosal infections, sores; stringent oral hygiene is necessary to prevent dental problems in such patients. GC and cytotoxic drugs may be required for interstitial lung. Commonly seen co-morbidities in RA include diabetes

Rheumatoid Arthritis

Figures 19A to C: Algorithm for the treatment of RA with standard non-biological disease modifying drugs (DMARDs). Early RA = RA < 6 months duration; Low DA= low disease activity as defined by DAS28 value < 3.2; Mod-HI DA = Moderate/high disease activity defined by DAS28 value > 3.2; Features of PP = Features of poor prognosis [include functional limitation (defined by using any standard measurement scales, e.g. ‘modified-Health Assessment Questionnaire’ or validated variations of this scale), extra-articular manifestations (e.g. presence of rheumatoid nodules, secondary Sjögren’s syndrome, RA vasculitis, Felty’s syndrome, and RA lung disease), rheumatoid factor positivity (in significant titres), positive anti-cyclic citrullinated peptide antibodies (in significant titres), or bony erosions by radiography]; LD-MTX = low-dose methotrexate (up to 30 mg/week, the dose used in rheumatology in contrast to high-dose methotrexate used in oncology practice); LEF = leflunomide; SSZ = sulphasalazine; HCQ = hydroxychloroquine; ‘+’ sign indicates recommended use of these drugs in combination. Established RA = disease duration of 6 to 24 months; the sign ‘↓ ’ indicates ‘If failure to respond’; Late RA = disease duration > 2 years. Courtesy: Based upon recommendations of the American College of Rheumatology (ACR) for the use of non-biologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis, 2008; Saag KG et al, Arthritis Care & Research, 2008; 59(6): 762-84.

Figures 20A to C: Algorithm for the treatment of RA with biological disease modifying drugs (DMARDs). Abbreviations used are the same as in Figure 18; Anti-TNF = Inhibitors of tumour necrosis factor- α. Courtesy: Based upon recommendations of the American College of Rheumatology (ACR) for the use of non-biologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis, 2008; Saag KG et al, Arthritis Care & Research, 2008; 59(6): 762-84]. Note: Till the time of writing tocilizumab was not approved by Federal Drug Administration (FDA), USA, therefore, not mentioned in ACR recommendations, available and approved for use in India.

mellitus, hyperlipidaemia, hypertension, cardiovascular disease and thyroid disease. These need appropriate treatment.

RECOMMENDED READINGS

The Role of Physical Medicine and Surgery in the Treatment of RA

2.

These include physical therapy exercises, use of different physical modalities for pain relief, help in maintaining muscle mass, full range of joint movements and preventing deformities. Additionally, the use of different appliances for simplifying and assisting in daily chores are available. Surgeons specialising in soft-tissue surgery and bone-and-joint surgeons play very important role in the management of RA especially in advanced disease.

1.

3.

4.

Firestein GS, Harris ED, Jr Genovese MC. Rheumatoid Arthritis. In: Firestein GS, Budd RC, Harris ED, Jr., McInnes IB, Ruddy S, Sergent JS. Kelley’s Textbook of Rheumatology; 8th Ed. Philadelphia: WB Saunders; 2009: pp 1035-1144. Luqmani R, Hennell S, Estrach C, Basher D, Birrell F, Bosworth A, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (after the first 2 years). Rheumatology (Oxford) 2009; 48: 436-9. Malaviya A. Approach to the patient with polyarthritis. In: Rao URK, Mahendranath KM, Misra R, Gupta SJ, Handa R, Mahajan A. ed. Manual of Rheumatology; 3rd Ed. Mumbai: Indian Rheumatology Association Publisher; 2009: pp 11-20. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in 1843 rheumatoid arthritis. Arthritis Care & Res 2008; 59: 762-84.

24.7 Spondarthritides or spondyloarthritides (SpA) are a family of related inflammatory diseases which include ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis and spondylitis, enteropathic arthritis and spondylitis, juvenileonset spondyloarthritis, and undifferentiated spondyloarthritis (Table 1). These disorders are also referred as seronegative spondyloarthropathy (SSA) as these are negative for rheumatoid factor (RF). Table 1: Spondyloarthropathies Ankylosing spondylitis Reiter’s syndrome or reactive arthritis Arthropathy of inflammatory bowel disease (Crohn’s disease, ulcerative colitis) Psoriatic arthritis Undifferentiated spondyloarthropathies Juvenile chronic arthritis and juvenile-onset ankylosing spondylitis

These disorders share certain clinical features and genetic associations: predilection for male sex, asymmetric lower limb large joint arthritis, sacroiliitis, enthesitis (inflammation of the ligamentous attachments to the bones), uveitis, dactylitis, absence of rheumatoid factor and a strong association with human leucocyte antigen (HLA)-B27. The European Spondyloarthropathy Study Group (ESSG) has provided classification criterion to have uniformity among patients (Table 2). The sensitivity and specificity of ESSG criteria is 87%. The comparison between different members in this group is given in Table 3. Table 2: European Spondyloarthropathy Study Group Classification Criteria for Spondyloarthropathies Inflammatory spinal pain OR Synovitis (asymmetric, predominantly in lower limbs) AND Any one of the following (sensitivity, 77%; specificity, 89%) Positive family history Psoriasis Inflammatory bowel disease Alternate buttock pain Enthesopathy Adding sacroiliitis (sensitivity, 86%; specificity, 87%)

ANKYLOSING SPONDYLITIS Ankylosing spondylitis (AS) is an inflammatory condition. Predominant clinical feature of AS is inflammatory backache followed by stiffness of the spine. The diagnosis of AS in most clinical trials is based on the modified New York (1984) criteria (Table 4). In the past radiographic sacroiliitis was an important pre-requisite to diagnose AS. However, magnetic resonance 1844 imaging (MRI) has now made it possible to make an earlier diagnosis. This has been incorporated in the newly developed

Spondarthritides Milind Y Nadkar Assessment of Spondylo Arthritis International Society (ASAS) SpA criteria (Table 5). Table 3: Features of Spondarthritides Characteristics

AS

ReA/

PsA

USpA Age of onset (years) Type of onset Male: Female Sacroiliitis or spondylitis Peripheral arthritis HLA-B27 (whites) Eye involvement Cardiac involvement Skin or nail involvement Role of infectious agents as triggers

5 RBC/HPF) or leucocyturia (>5 WBC/ HPF) are uncommon presentations and need exclusion of other causes. Renal disease is usually preceded by high antidsDNA antibody titres and low C3, C4 levels. The biochemical correlates of lupus nephritis (LN) are elevated serum creatinine and low albumin. LN in Indians tends to be severe. Renal biopsy, though not essential for the diagnosis, is useful to

Neurological Neuropsychiatric lupus (NSL) is the second serious manifestation of SLE, being associated with significant morbidity and mortality. Its pathogenesis is not clear. Vasculopathy, thrombosis and antibody induced cell damage or dysfunction are thought to play a role. Manifestations are diverse. Headache including migraine and subtle cognitive dysfunction are common. Other psychiatric manifestations include anxiety, acute confusional state and psychosis. Convulsions, focal motor and sensory deficits (stroke, movement disorders, cranial neuropathies, paraplegia), cerebritis, peripheral neuropathies and autonomic dysfunction are other manifestations. Myelopathy, meningitis, and chorea are rare. Primary neuropsychiatric diseases, infection, steroid psychosis, and metabolic disorders are important differential diagnoses. CSF examination, CT, MRI and PET scan are of variable diagnostic value.

Systemic Lupus Erythematosus

assess severity, nature, and reversibility or otherwise of renal involvement. WHO classification of LN is being replaced by histologic classification of lupus nephritis as per the International Society of Nephrology/Renal Pathology Society (ISN/ RPS) 2003 (Table 5). Diffuse proliferative glomerulonephritis (class IV) is the most common histologic type). Untreated nephritis results in chronic renal failure.

Cardiovascular Pericarditis, the most common cardiac manifestation, is often silent. Large pericardial effusion, cardiac tamponade, and constrictive pericarditis are rare. Myocarditis may present as unexplained tachycardia, heart failure, arrhythmia or heartblock. Mitral and aortic valve involvement can be clinically significant. With the availability of echocardiogram, LibmanSacks endocarditis, the classical cardiac manifestation of SLE, is diagnosed more frequently. It is often associated with antiphospholipid antibodies. The risk of infective endocarditis is increased. Coronary arteritis is rare. Accelerated atherosclerosis is an important late complication and a major cause of premature death. Traditional risk factors apart, SLE itself and corticosteroid use are independent risk factors for premature atherosclerosis. Pulmonary Pleurisy and pleural effusion are the most common pulmonary manifestations. Lupus pneumonitis, alveolar haemorrhage, and pulmonary arterial hypertension, though rare, are lifethreatening manifestations. Lupus pneumonitis needs to be differentiated from infective pneumonia. Interstitial lung disease is sometimes encountered. Pulmonary tuberculosis may complicate immunosuppressive therapy. Shrinking lung syndrome is a rare manifestation. Pulmonary embolism is associated with APS. Haematological Anaemia of chronic inflammation is common. Concomitant iron deficiency may be present. Coombs’ positive anaemia is sometimes the initial manifestation of SLE. Leucopaenia and lymphopaenia are characteristic and correlate with disease activity. Cytopaenias are most commonly due to peripheral destruction and not due to marrow suppression which is often secondary to medications. Thrombocytopaenia may be due to 1855

Table 4: Histologic Class, Clinical Presentation, Prognosis and Treatment of Lupus Nephritis Histologic Type

WHO Class

Frequency (%)

Proteinuria (%)

Nephrotic Syndrome (%)

Azotaemia Death (%) (%)

Uraemic Death (%)

Treatment

Normal

I

70%); * not possible as per Chapel Hill definition.

infiltrates, nodules, cavities, mass lesions, ‘abscesses’, areas of consolidation and haemorrhage. Clinical features comprise of cough, chest pain, expectoration, haemoptysis and respiratory failure. Large pleural effusions are uncommon. Cavitating nodules are highly suggestive of vasculitis. Metastases and disseminated infection need to be excluded. Heart Pericardial and myocardial involvement is commonly seen at necropsy but is rarely of great clinical significance. Coronary arteritis leading to significant ischaemic injury is associated with Kawasaki’s disease and classic polyarteritis nodosa. Gastrointestinal Tract Gastrointestinal manifestations are caused by bowel ischaemia. Symptoms range from mild abdominal angina to those of perforation and peritonitis. The later carry a grave prognosis. In a patient with established vasculitis and in those with an obscure multisystem disease, abdominal pain, emesis, intestinal obstruction and bleeding are important ‘red flags’ that warrant immediate investigation and treatment. Haemobilia and hepatic infarction especially in polyarteritis nodosa (PAN), splenic infarcts, pancreatitis, and a syndrome resembling inflammatory bowel disease have been reported. Kidneys Renal lesions due to vasculitis are diverse. Large vessel disease results in ischaemia and renovascular hypertension. Medium vessel involvement leads to infarction and haematomas within and around the kidney while small vessel disease is associated with glomerulonephritis. This can vary from mild, focal or segmental disease to rapidly progressive, crescentic involvement leading to significant, often life-threatening, renal failure. Glomerular lesions may show immune complex deposition or could be pauci-immune as in the ANCA associated vasculitides. In patients with suspected vasculitis, proteinuria, microscopic haematuria and active urinary sediment, in the absence of infection, should start alarm bells ringing for urgent management.

1870

Reproductive Organs Testicular infarction, presenting like torsion, is common in medium vessel vasculitis like PAN. Penile ulcers on the glans

and shaft are uncommon but reported. These, and scrotal ulcers are, however, frequently seen in Behçet’s syndrome. Nervous System Mononeuritis multiplex and polyneuritis cranialis are the most important ‘red flags’ suggesting a vasculitic process. Diffuse brain dysfunction is possible consequent to metabolic disturbances like renal and respiratory failure or sepsis. CLINICAL SUSPICION Acute progressive palpable purpura, ulcerating nodules and plaques, skin infarction or necrosis, and impending gangrene of unidentifiable cause, all suggest systemic vasculitis which must be investigated (Tables 8 and 9) and treated expeditiously (Table 10).These lesions are an important warning to physicians at the onset and relapse of SNV. In patients without skin involvement, diagnosing SNV can be difficult. A high index of suspicion is essential to link apparently unrelated, seemingly unimportant and unexplained manifestations together. Chronic unresolving sinusitis, obstinate otitis media, recurrent or poorly responsive scleritis, severe constitutional symptoms without specific laboratory abnormalities, pulmonary ‘tubercular’ infiltrates unresponsive to adequate antitubercular drug therapy, non-resolving pneumonia despite adequate antibiotic therapy, abdominal angina in a young person, unexplained gastrointestinal bleeding, failure to recover from a ‘successful’ appendectomy, testicular ‘torsion’ in a young hypertensive, unexplained haematuria, and all the ‘red flags’ mentioned above should prompt the question ‘Could this be a systemic vasculitis?’(Table 11). If more than one system is involved, (e.g. otitis media in a patient with ‘pulmonary TB’, abdominal pain and mononeuritis multiplex in a young hypertensive) it is easy to answer in the affirmative. However, even when only one system is involved, a less than optimal response to standard therapy should be enough to start investigating along these lines. In desperately ill patients with an unexplained, rapidly progressive, systemic disease, it is justifiable to initiate life-saving treatment after eliminating sepsis.

Table 8: Essential Investigation for Patients with Suspected Systemic Vasculitis Haematology Biochemistry

Urine Microbial Serology Imaging Histology

Hb, TLC, DLC, platelet count, ESR (preferably Westergren method) Renal and hepatic function, serum albumin, globulin, alk. Phosphatase, CRP (quantitative) or other acute phase reactants* Protein, microscopy and culture Blood culture, cultures for fungi* ANCA, RF, ANA, hepatitis B and C, cryoglobulins, GBM* Chest radiograph, CT of head, chest and abdomen*, angiogram*, echocardiogram Biopsy from involved area essential to confirm diagnosis

*Denotes tests that may be indicted in some, but not for all, patients.

Routine Systemic inflammation, the hallmark of SNV, can be established by an elevated ESR, leucocytosis, thrombocytosis, normocytic, normochromic anaemia, hypoalbuminaemia, hyperglobulinaemia and elevated acute phase reactants like CRP. Urine analysis and microscopy help establishing renal involvement. Appropriate culture to exclude infection must be done. Serology Serologic tests help in distinguishing between primary and secondary vasculitis. Rheumatoid factor (RF) is frequently positive in patients with vasculitis. High titres are, however, a hallmark of systemic rheumatoid vasculitis. Anti-nuclear antibodies (ANA) are present in high titres in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s syndrome (SS) and other overlap syndromes. When these conditions are responsible for vasculitis, a positive ANA, contributes significantly to the correct diagnosis. Positive tests for Hepatitis B and Hepatitis C virus help in the diagnosis of classic polyarteritis nodosa (cPAN) and cryoglobulinaemic vasculitis due to essential mixed cryoglobulinaemia (EMC). Anti-glomerular basement membrane (GBM) antibodies, in patients with the pulmonary renal syndrome, indicate Goodpasture’s syndrome. ANCA Anti-neutrophil cytoplasmic antibodies (ANCA) have added a new dimension to the study, understanding and classification of the vasculitides (Table 9). Serum with ANCA produce three basic patterns at indirect immunofluorescence (IIF). The classic cytoplasmic, or C-ANCA, shows central, coarse, dense, granular fluorescence. Perinuclear, or P-ANCA, shows perinuclear fluorescence and atypical ANCA shows a mixed pattern. The antibody specificities and clinical correlation of each pattern are listed in Table 9. ANCA testing, using IIF and ELISA, is essential in the investigation of all patients with presumed vasculitis. While ANCA is positive in high titres during the acute phase of the ANCA associated vasculitides, there is poor correlation between titres and clinical disease activity.

Table 9: Anti-neutrophil Cytoplasmic Antibodies (ANCA). Indications, Methods, Patterns, Antigens, Associations and Interpretation Indications for testing Suspected systemic necrotising vasculitis Pulmonary renal syndromes Sub-glottic stenosis and tracheobronchial pathology Retro-orbital, nasal, paranasal sinus related mass/destruction Scleritis, scleromalacia, limbal inflammation, recurrent/ unresponsive Methods used Indirect immunofluorescence (IIF) using unstimulated, ethanol fixed human neutrophils for pattern ELISA for antibody specificity Patterns and antigens C-ANCA coarse granular central fluorescence linked to antiserine proteinase 3(PR3). P-ANCA perinuclear linked to anti-myeloperoxidase (MPO), lactoferrin, cathepsin G, elastase, defensins, azurocidin, BPI (bactericidal permeability increasing protein), lysozyme, etc. All neutophilic granular proteins with antimicrobial functions. Associations C-ANCA (anti-PR3), WG (> 90% in active disease), MPA (about 10% in active disease), CSS (50-60% in active disease) P-ANCA, (anti-MPO), MPA (70-90% in active disease), WG (< 10% in active disease) P-ANCA and indeterminate staining ANCA, (non-MPO), inflammatory rheumatic diseases, RA, Felty’s syndrome, SLE, juvenile arthritis, systemic sclerosis, inflammatory bowel disease, autoimmune hepatitis, crescentic glomerulonephritis, sepsis, infective endocarditis, malaria, tuberculosis, Hansen’s disease, onchocercosis, bronchiectasis, cystic fibrosis, druginduced vasculitis, lung cancer and other neoplasia Interpretation C-ANCA with anti-PR3 in the clinical setting of WG is highly suggestive of WG C-ANCA with anti-PR3 is positive in only the rare patient with MPA P-ANCA with anti-MPO in the clinical setting of MPA is highly suggestive of MPA P-ANCA, non-MPO, is not diagnostic of any condition P-ANCA, anti-lactoferrin and anti-elastase in the appropriate setting support drug-induced vasculitis P-ANCA anti-cathepsin G and anti-lactoferrin in the appropriate setting support inflammatory bowel disease

The Vasculitides

INVESTIGATION Investigations are listed in Table 8.

Imaging Clinical diversity precludes the development of a radiologic protocol suitable for all patients. A chest radiograph is essential and may show a variety of lesions. Nodular cavitating infiltrates are characteristic of WG. On serial examinations, they may also migrate. Unresolving or rapidly progressive consolidation during adequate antitubercular or antibiotic therapy, also suggests a vasculitis. Pulmonary haemorrhage (WG, MPA) manifests as a rapidly enlarging parenchymal lesion. Angiography, CT, MRI and PET scans help with diagnosis, delineation of disease extent, identification of a biopsy site and monitoring response to therapy. Patients with large vessel vasculitis like Takayasu’s need angiography to define the extent of disease, classify it and identify areas for intervention like angioplasty and stent insertion. Angiography may show the pathognomonic visceral aneurysms in PAN. 1871

Histology Histologic proof of vasculitis remains the gold standard. Every possible attempt should be made to identify and biopsy the involved tissue (Figure 1). Skin lesions are an obvious first choice. However, it must be emphasised that the same histologic findings may be observed in patients with benign cutaneous vasculitis and SNV. If the kidneys are involved, renal biopsy is often helpful. While it is usually not possible to distinguish between WG and MPA based on renal glomerular histology alone, granulomatous inflammation, is present, supports WG. In the presence of mononeuritis multiplex, a sural nerve biopsy may reveal vasculitis of the vasa nervosum. Similarly, mucosa of the sinuses and nose may be sampled if the area is involved. Biopsy from these sites is limited by the size of the sample that can be safely taken and many pieces may be needed to establish the diagnosis. Vasculitis is often a patchy process and may be completely missed in a small biopsy. Open lung biopsy is a safe and highly rewarding procedure in patients with obscure lung shadows. As relatively large samples can be taken, they provide excellent material for diagnosis. Differential Diagnosis The vasculitides have many mimics (Table 5). Their treatment is different hence, they need to be excluded. Decision to Treat While patients with benign cutaneous or a slowly progressive disease allow time for histologic confirmation, seriously ill patients do not. As these patients carry a high mortality risk, institution of therapy is of paramount importance. The five factor clinical score is an excellent simple objective measure of the gravity of the clinical situation. In patients with SNV, the presence of renal failure, proteinuria more than 1 gm/24 hours, gastrointestinal involvement, CNS manifestations or cardiomyopathy are each accorded a score of one. Over 2 years, patients with a total score

of 0 had a mortality of 12%, those with 1, 26% and those with 2, 46%. Clearly, patients with visceral disease should receive prompt and aggressive treatment, frequently on empirical grounds. Infections are also common in such patients, before, during and after immunosuppressive therapy. Frequently, the two are inseparable and need to be treated simultaneously. The vasculitides and their mimics are frequent among patients presenting to the emergency departments. Diagnosis is delayed at survival peril. Table 10 lists the problems that must raise the question of a possible vasculitis in this group. TREATMENT (TABLE 11) Vasculitis caused by infection should be treated with the appropriate antimicrobial agents and surgical intervention. Results are good if instituted early. Benign cutaneous vasculitic conditions generally respond well to low dose steroids, antihistaminics to suppress itching, dapsone and exposure of ulcerated areas to ultraviolet light.The occasional unresponsive patient may be helped with azathioprine or methotrexate. It is very unusual for isolated cutaneous vasculitis to require aggressive immunosuppressive therapy. Patients with SNV mandate the use of high dose corticosteroids, cytotoxic and other immunosuppressive agents (Table 10). The NIH protocol, the first successful treatment plan for these conditions, commenced with oral prednisolone (1 mg/kg/day) and cyclophosphamide (CYC) (2-3 mg/kg/day). Steroids were tapered off and stopped within 6 months, but CYC continued in the same dose for a year after remission was attained. Thereafter, it was tapered gradually.This treatment revolutionised the management of these conditions. Before its development, 5-year survival for SNV like WG was less than 5% to 7%. With treatment, it increased to 75% to 85%. Problems related to treatment, like haemorrhagic cystitis and bladder cancer due to CYC, marrow toxicity, a high relapse rate after withdrawal, and infection gradually emerged. The search for an ideal regimen has, thus, continued.

Table 10: Emergency Medicine, Presentations to the Emergency Department, Symptoms and Signs

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Presentation

Organ/System Involved

Manifestations

Very acute

Lungs Airways Kidneys Urinary/genital tract Nervous system GI Tract Heart Liver and biliary tract

Pulmonar y haemorrhage, respiratory failure, anaemia, increased DLCO, bronchopneumonia Stridor due to tracheomalacia Acute, rapidly progressive renal failure, haematuria, infarction, accelerated hypertension Haematoma, ureteric obstruction, bladder neck obstruction, testicular infarction Mononeuritis multiplex, polyneuritis cranialis, infarction, stroke, retinal ischaemia Perforation and peritonitis, intestinal ischaemia, occasionally bleeding Acute coronary syndrome Infarction, haemobilia, pancreatitis

Acute

Lungs Kidneys Urinary/genital tract Nervous system GI Tract

Pulmonary nodules and infiltrates, consolidation, compromised airway Loin pain, haematuria, worsening renal function, proteinuria with active sediment Testicular pain, hydronephrosis, perirenal haematoma Focal neurologic defect Abdominal angina

Indolent with acute exacerbation

The patient

With polymyalgia rheumatica, red eye, chronic sinusitis, worsening or miraculously improved asthma,oral ulceration, new onset hypertension, fever, arthralgia, non-specific skin rash, with recent onset palpable purpura and other systemic features in permutations and combinations beg the question, ‘Is this a vasculitis?’

Distribution

Progression

Involvement

Investigation

Eliminate

Initiate Therapy With

Therapy for Poor Response

Cutaneous

Slow

Skin alone

All listed + biopsy

All mimics

Steroids

Azathioprine, Methotrexate, Dapsone, Cyclophosphamide

Systemic

Slow

Skin, joints, polymyalgia ENT

All listed + biopsy

Steroids + Methotrexate

Azathioprine, Cyclophosphamide, Mycophenolate mofetil

Systemic

Slow initially, with acceleration

Above + Kidney, CNS GI tract, heart, lungs liver, spleen

All listed + biopsy if possible

All mimics especially chronic infections All mimics especially Infections and tumours

Azathioprine, Mycophenolate mofetil, Cyclosporin, biologic therapy

Systemic

Rapid

As above + Lung haemorrhage, rapidly progressive renal failure, focal CNS defect, Multiple organ/ system involvement, GI perforation

As much as possible

There is a place for empirical therapy Steroids + Cyclophosphamide ± Plasmapheresis Empirical high dose IV methylprednisolone + IV Cyclophosphamide ± Plasmapheresis and Antibiotics (if infection not clearly eliminated), ventilation, dialysis, ICU measures with monitoring of fluid therapy, electrolytes and organ/ system support Surgery (as indicated)

Currently, the use of intermittent ‘pulse’ CYC (750 mg/m2) has gained ground. It is used every 2 to 3 weeks initially for 2 to 3 doses and then every 4 weeks till six ‘pulses’ have been administered. With steroids, this treatment is very successful in inducing a remission.This form of therapy also results in lower infection rates and a far lower cumulative dose of CYC to achieve remission. This should lead to reduced rates of secondary malignancy. Once remission is achieved, recent trials have established that they can be maintained using azathioprine or methotrexate. Some forms of vasculitis have been shown to respond very well to specific interventions. Temporal arteritis is very responsive to corticosteroids. Infusions of immunoglobulins are very useful for Kawasaki’s disease, while Behçet’s disease responds to colchicine, azathioprine, cyclosporine and thalidomide. Patients with cryoglobulinaemia and hepatitis B related classic PAN respond well to plasmapheresis to achieve initial control and subsequently to antiviral drugs. Several patients, however, do not respond to conventional therapy described above. Alternate regimens incorporating mycophenolate mofetil, deoxyspergualine, and several monoclonal antibodies have been tried with variable success. Patients with vasculitis, on treatment, need to be carefully monitored for side effects and complications of these toxic regimes. Those on CYC should be encouraged to drink plenty of water to avoid cystitis, and possibly cancer. Further treatment depends on the demonstration of relapse. All patients with vasculitis and specially those with the life-

Infection

The Vasculitides

Table 11: Management of Vasculitis with Risk and Extent Stratification (* = very rarely used)

Addition of another drug like azathioprine may help some. Anti TNF therapy may be helpful. Rituximab has helped (Other useful agents are listed in text)

threatening SNV need to be closely followed, preferably with objective systems of record keeping. The Birmingham Vasculitis Activity score is one such instrument that permits, on a single page, a comprehensive record of each clinic visit with a numerical expression of both improvement and deterioration. IMPORTANT INDIVIDUAL VASCULITIDES Large Vessel Vasculitis Takayasu’s arteritis Takayasu’s arteritis (TA) is relatively common in India while temporal arteritis is extremely rare. TA affects young people who present with symptoms and signs of ischaemia involving the ocular, cerebral, renovascular, cardiopulmonary, limb, and splanchnic circulation in various permutations and combinations. The disease is classified according to the angiographic pattern of aortic involvement. Very few patients present with acute vascular inflammation. Most of them present with established stenotic or rarely, aneurysmal lesions. The common clinical findings are absent pulses, asymmetric blood pressure measurements and vascular bruits. If present, tenderness over the involved vessels, specially the carotids (carotidynia) is an important sign of active disease. Treatment with immunosuppressive regimens suppresses active inflammation but has only marginal effect on vessel patency. Patients with critical stenosis require angioplasty with stent insertion or surgical revascularisation 1873 for relief from ischaemia.

Temporal arteritis Giant cell arteritis (GCA) is a disease of older people characterised by headache, polymyalgia rheumatica, and a distended, tortuous, thickened and sometimes tender temporal artery. Jaw claudication is an important symptom and blinding serious retinal ischaemia develops in several patients. The ESR is often over 100 mm and ultrasonography of the artery is helpful in identifying areas of involvement. The disease usually responds very well to corticosteroids alone. Medium and Small Vessel Vasculitis Polyarteritis nodosa Polyarteritis nodosa (PAN) is a disease of protean manifestation with involvement of several organ systems. There is a close association between hepatitis B virus infection and PAN, and it was also the first vasculitis which was successfully treated with antiviral drug therapy. Patients usually have a nondescript febrile illness with loss of weight and other constitutional symptoms. However, most patients develop additional features like hypertension, mono or polyneuropathy, testicular pain, myalgia, and muscle weakness and renal insufficiency. Some patients will develop signs and symptoms of intestinal obstruction/perforation, renal, hepatic and splenic infarction. Investigations are usually not very specific but angiography may demonstrate the almost pathognomonic microaneurysms. Only an occasional patient is ANCA positive. Treatment has made a great difference to the outcome. When no effective treatment was offered, the median survival was three months. Today, with the appropriate use of steroids and cytotoxic drugs, five years survival has increased to over 80%. Classic PAN is often a ‘one shot’ illness and relapses are less frequently observed than in other SNVs. Churg-Strauss syndrome This entity is also called allergic angiitis and granulomatosis. The dominant feature is asthma and eosinophilia. The asthma may be long standing or of relatively recent origin. At the start of the vasculitic phase, most patients complain of severe worsening and unresponsiveness of previously controlled asthma. However, in some patients asthma may almost vanish at the time vasculitis develops. Cardiac and skin involvement is common in this disorder. Histology reveals vasculitis and an extravascular eosinophilic granuloma. Significant renal involvement is rare compared to other systemic vasculitides. Most patients respond adequately to corticosteroids but a few may require cytotoxic drug therapy. Wegener’s granulomatosis This entity shows very wide clinical variations. It is compatible with several years of survival at one end of its clinical spectrum and death within days at the other. The upper airways, lungs and kidneys are the most commonly involved areas; however, no organ system is consistently spared.

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Patients may present with severe ocular inflammation including scleritis, uveitis, corneal ulceration, dacryocystitis, lid ulcers and proptosis. Ear involvement includes severe unresponsive otitis media, perforation of the drum, bleeding and deafness. Nasal manifestations include extensive crusting, discharge, bleeding, perforation of the septum and a saddle nose deformity. Pulmonary manifestations include cough, sputum production,

haemoptysis and pulmonary haemorrhage. The chest radiograph may show infiltrates, nodules, cavities or consolidation. Renal involvement is in the form of pauciimmune focal, segmental or crescentic glomerulonephritis with or without renal failure. In many patients, WG starts as an indolent, locally confined, inflammatory disease.This,‘granulomatous’ phase may last from weeks to several years before the aggressive ‘vasculitic’ phase supervenes. In patients from northern European origin, a prolonged indolent phase enables the diagnosis to be made while the disease is confined to a single area. In India, however, it appears that this phase is abbreviated. Well over half of our patients presented with established widespread systemic involvement. The clinical similarity with pulmonary tuberculosis has often delayed consideration of WG. A very large number of the patients with WG in India had, and continued to receive antitubercular drug therapy in spite of continued clinical deterioration. There are a few pointers that may help to distinguish between these two. Ocular, ear, paranasal sinus, and nose involvement as well as vasculitic skin involvement and renal insufficiency are very uncommon in patients with tuberculosis. The presence of any of these features should raise suspicion and a diagnosis of WG should be considered. Radiologically, the infiltrates in TB are usually apical and the cavities are in the upper zone. However, in WG, infiltrates and cavities are more in the middle and lower zones of the lung. The demonstration of C-ANCA is useful however, rare patients with TB are P-ANCA positive so, the testing must be done carefully. WG is treated with a combination of steroid and cytotoxic drugs for variable duration depending upon the response. Given the possible complications of the disease and its treatment, such patients should be treated in a specialised unit with adequate experience. Untreated WG had a mean survival of a few months. Renal failure, apart from pulmonary haemorrhage and widespread vasculitis are the usual causes of death in the first year. Later, destructive pulmonary disease and respiratory failure become more important. With adequate therapy more than 90% of patients should achieve a clinical remission. Systemic rheumatoid vasculitis This complication develops in patients with longstanding seropositive rheumatoid arthritis and carries a poor prognosis. The usual manifestations include new or worsened constitutional symptoms, cutaneous leucocytoclastic vasculitis and mononeuritis multiplex. Treatment should include steroids and cytotoxic drugs. Small Vessel Vasculitis Microscopic polyangiitis This disorder was initially considered to be a variant of PAN. It has now come to be recognised as an independent entity with closer similarity to WG. While its renal manifestations and alveolar haemorrhage are very similar to WG, its other manifestations, including involvement of the skin, the nerves, and GI tract resemble PAN. Serologically, 90% of patients are PANCA positive. There are no granulomata seen at histology.

Henoch-Schönlein purpura This condition predominantly affects children and young adults. The typical presentation includes palpable purpuric skin lesions, GI tract involvement with bleeding, arthralgia and glomerulonephritis. In most instances, it is a self-limiting condition and does not require treatment. However, the presence of severe bowel involvement and other atypical features like focal neurologic deficit, pulmonary haemorrhage and rapidly progressive renal failure warrant steroid and/or cytotoxic drug therapy even though their efficacy has not yet been established in a clinical trial. These complications are more frequently observed in adult patients. Cutaneous leucocytoclastic vasculitis Vasculitis confined to the skin producing infarcts, nodules, ulcers and very occasionally, gangrene is common. These patients should be investigated for the presence of systemic disease and if found negative can be treated with low doses of steroids and immunomodulating agents like dapsone. Behçet’s syndrome This vasculitic disease entity has a pronounced geographical distribution, from Turkey to Japan via Iran and also the northern part of India. It affects young people and is more virulent in males. The dominant clinical manifestations are of painful oral and genital ulcers, a variety of skin lesions, severe, vision threatening ocular inflammation, arthralgia, focal CNS dysfunction, aseptic meningitis, colonic ulceration, aneurysms and venous thrombosis. There is a strong association with HLA B51 and it is the leading cause of blindness in Japan. The course is relapsing and remitting. However, the intensity wanes with advancing age. A variety of agents have been found to be useful including steroids, cytotoxic drugs, cyclosporine, thalidomide, colchicine, antibiotics and anti-TNF therapy.

Kawasaki’s disease This, predominantly childhood, vasculitis has a strong affinity for the coronary arteries. Most patients are under 5 years of age. Fever, conjunctival congestion, inflamed oral mucosa, cervical non-suppurative lymphadenopathy and cutaneous manifestations are the major features. Immunoglobulins have been found to be very effective in treating this condition. Followup echocardiograms may reveal the development of coronary aneurysms.

The Vasculitides

The dominant clinical features are due to a pauci-immune glomerulonephritis. Other features include pulmonary haemorrhage, cutaneous vasculitis, mononeuritis, joint pains, hypertension, GI tract involvement and occasionally CNS involvement. The disease responds to immunosuppressive treatment protocols useful for WG.

Cogan’s syndrome Is a rare disease of young adults characterised by non-syphilitic interstitial keratitis, recurrent symptoms like Meniere’s disease and large vessel vasculitis, frequently involving the aorta and its major branches. Other features include joint pain, fever, abdominal pain, intestinal bleeding, hepatosplenomegaly and lymphadenopathy. While ocular involvement may respond to topical steroids, ear involvement requires systemic treatment. Vasculitis requires aggressive immunosuppressive therapy as outlined above. Primary angiitis of the central nervous system It is a rare disorder characterised by focal, or occasionally diffuse, neurologic involvement, MRI abnormalities and characteristic angiographic appearances without any other systemic features. Biopsy reveals a granulomatous angiitis in many patients. Treatment with steroids and cyclophosphamide is successful if the diagnosis is made early. THE CHALLENGE Thinking that a vasculitis could be responsible for the patient’s problems is the biggest hurdle we need to cross. Treatment is very rewarding but entails hard work. Due to the multisystem nature of these disorders, the development of a multi-disciplinary team greatly facilitates patient management. RECOMMENDED READING 1.

The Vasculitides, Section 11 in Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH (editors), Rheumatology; 3rd Ed. Mosby; 2003: pp 1583-715.

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24.13

Mixed Connective Tissue Disease and Overlap Syndromes G Narsimulu, Vara Prasad IR

DEFINITION Mixed connective tissue disease (MCTD) is a disease characterised by combination of clinical features of systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis (PM), and rheumatoid arthritis (RA). MCTD is considered as a distinct clinical entity because of the presence of very high anti-U1RNP antibody. A few authorities consider MCTD as a subset of SLE or scleroderma. EPIDEMIOLOGY The prevalence is four times less than that of SLE indicating an overall prevalence of 10/100,000. The peak onset of the disease is in the second and third decade, but it can occur in children and elderly also. The female to male ratio is 9:1. IMMUNOPATHOLOGY U1nRNP is a subunit of spliceosomes. Spliceosomes are complex nuclear particles involved in the processing of premessenger RNA into mature spliced RNA. Two subunits of spliceosomes are antigenic targets in autoimmunity. These are: 1. Small nuclear ribonucleoprotein particles (snRNPs). 2. Heterogenous nuclear RNP (hnRNP). The snRNP contains small RNAs that are complexed with proteins. These RNAs contain a high content of uridine and are, therefore, called U RNAs. Five different types of URNAs are defined on the basis of immunoprecipitation (U1, U2, U4, U5, and U6). Autoantibodies to these complexes are mainly directed to the protein components. Antibodies directed exclusively against U1 subunit are known as antiU1RNP antibodies. They precipitate three proteins with molecular weight of 68000, 33000, and 22000. The clinical correlates of MCTD appear to be most closely associated with antibodies to the 68 kD and the 33000 proteins of the U1 RNP complex. A proposed model of RNP self antigen-driven autoimmunity is shown in Figure 1. The characteristic lesions in the involved organs are intensive obliterative proliferative vascular lesions in large, medium and small vessels with less inflammatory infiltrates. There is increased synthesis of type III collagen leading to abnormal type I to type III ratio, unlike scleroderma where the ratio is maintained. CLINICAL FEATURES The various features of the connective tissue disorders making up MCTD develop over many months or years. The presenting symptoms are Raynaud’s phenomenon, puffy hands, arthralgia, myalgia and fatigue. The fingers as well as the entire hand may become puffy. SKIN AND MUCOUS MEMBRANE Skin manifestations include Raynaud’s phenomenon, sclerodactyly, skin tightening, photosensitivity, malar rash, and 1876 the rash of dermatomyositis and panniculitis. Sclerodermal

Figure 1: Model of RNP self antigen-driven autoimmunity. Self antigen (including 68kD and U1-RNP) triggers both the innate and adaptive arms of the immune system and breaks immunologic tolerance. Activation of B cells and dendritic cells leads to autoantibody production and also activate T cells leading to tissue damage.

changes are usually limited to the distal extremities and sometimes the face but spare the trunk. Telangiectasia and calcinosis may also occur. Other lesions include oral uclerations, sicca symptoms, orogenital ulceration, livedo vasculitis, and nasal septal perforation. Joints Joint pains, stiffness and non-erosive peripheral arthritis are common. Joint involvement in MCTD is more common and more severe than seen in SLE. Deformities can occur but joint erosions are uncommon. Muscle Myalgia is a common symptom. Myositis also occurs frequently, but most often without significant demonstrable weakness, electromyographic changes or muscle enzyme elevation. Sometimes, it may present as inflammatory myositis with antiU1RNP antibody without other features of MCTD. Lung About 85% of patients have pulmonary involvement, which is often asymptomatic. Low diffusion capacity for carbon monoxide may be the only abnormality. Pleurisy commonly occurs, but is seldom associated with large pleural effusion. Interstitial lung disease (ILD) also is well described in MCTD. HRCT is a sensitive tool to determine the presence of ILD in MCTD. Pulmonary hypertension is the most common cause of death in MCTD. Pulmonary arterial hypertension (PAH) is usually caused by a bland intimal proliferation and medial hypertrophy of pulmonary arterioles. PAH may also be due to coexistent antiphospholipid (APL) antibodies.

Mixed Connective Tissue Disease and Overlap Syndromes

Heart All three layers of heart can be involved in MCTD. Pericarditis may occur in 10% to 30% of cases. Myocardial involvement also is described. ECG changes are seen in 20% cases. Arrhythmias, conduction disturbances and mitral valve prolapse also can occur. Gastrointestinal System Gastrointestinal involvement is seen in about 70% patients. The most common manifestations are oesophageal dysmotility, lower oesophageal sphincter laxity, and gastrooesophageal reflux. Abdominal pain, malabsorption syndrome, and chronic active hepatitis also are described. Pseudodiverticula along the antimesenteric border of colon can occur like in scleroderma. Kidney Approximately 25% of patients develop renal disease. Membranous glomerulonephritis is the most common. It is usually mild, but can cause nephrotic syndrome. Diffuse proliferative glomerulonephritis (DPGN) is unusual in MCTD. This is believed to be due to the protective role played by the high titers of anti-U1RNP. Renal crisis secondary to malignant renovascular hypertension is seen in a few patients. Central Nervous System Central nervous system (CNS) involvement is rare in MCTD. Trigeminal neuropathy is the most common problem encountered. Vascular headache, aseptic meningitis, peripheral neuropathy, transverse myelitis and sensorineural hearing loss also are described. Fever Fever may be prominent feature, can present as pyrexia of unknown origin. Fever may be traced to co-existent myositis, aseptic meningitis, serositis, lymphadenopathy or intercurrent infection. Haematology Anaemia of chronic inflammation is seen in 75% of patients. Other abnormalities noted are positive Coombs’ test, leucopaenia, thrombocytopaenia, thrombotic thrombocytopaenic purpura and red cell aplasia. LABORATORY FINDINGS The diagnosis of MCTD depends on the demonstration of antiU1RNP antibody in high titres. Antinuclear antibody positivity is seen in 100% of patients in high titre with coarse speckled pattern. This finding should prompt the measurement of antibodies to U1RNP, Sm, Ro and La. Anti U1RNP antibodies by haemagglutination test titre > 1:1600 is characteristic feature of MCTD. The absence of anti-Sm antibodies and anti-DNA antibodies in a patient seropositive for anti U1RNP is an important finding discriminating MCTD from SLE. Other investigations show features common to connective tissue diseases in general. The most frequent haematological findings are leucopaenia, thrombocytopaenia and a high ESR. Serum immunoglobulins may be extremely high, with IgG concentrations reaching more than 40 g/l in some patients. In contrast to SLE, in MCTD the complement concentrations are usually normal or high. Rheumatoid factors are increased in approximately 70% of patients.

Figure 2: Indirect immunofluorescence on Hep-2 cells with a patient’s serum containing anti-U1-RNP antibody. This shows speckled nuclear staining, with characteristic sparing of the nucleoli and negative staining of the chromosomes of the cell in early metaphase.

DIAGNOSIS The diagnosis of MCTD is clinicoserologic. The two diagnostic criteria for MCTD that are widely employed are Alarcon-Segovia’s Criteria and Kahn’s Criteria. Alarcon-Segovia’s Criteria (a) Serologic criteria: High titre anti RNP (b) Clinical Criteria: Swollen hands, synovitis, myositis, raynaud’s phenomenon, acrosclerosis MCTD present if criteria A accompanied by 3 or more clinical criteria, one of which should be synovitis/myositis. Kahn’s Criteria (a) Serologic criteria: High titre antiRNP >1:1600 with speckled ANA (b) Clinical criteria: Swollen fingers, Synovitis, Myositis, Raynaud’s phenomenon MCTD present if criteria A is accompanied by Raynaud’s phenomenon and two or more of the three remaining clinical criteria. When myalagia replaces myositis in diagnostic criteria sensitivity increased to 81.3% from 62.5% with no change in specificity. PROGNOSIS The course of MCTD is unpredictable. In most of the patients it has a benign course. It is the major organ involvement that dictates the morbidity and mortality in an individual case. MANAGEMENT There is no specific treatment for MCTD. The treatment depends on the pattern of clinical involvement (Table 1).

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Pulmonary hypertension being the most common cause of death, patients should be evaluated at regular intervals for its development. It should be suspected in patients with increasing breathlessness. Echocardiogram is the most useful screening test. A definitive diagnosis requires cardiac catheterisation showing a mean resting pulmonary arterial pressure more than 25 mmHg at rest. Table 1: Guidelines for Managing MCTD Problem

Treatment

Raynaud’s phenomenon Use gloves, keep warm, prevent finger trauma, stop smoking, avoid beta blockers Drugs: Nifedipine, Prazosin, bosentan Arthralgia/Arthritis NSAID’s, hydroxychloroquine, methotrexate Myositis Acute severe: high dose Prednisone 60 to 100 mg/day Chronic, low grade: low dose Prednisone 10 to 30 mg/day methotrexate or IVIG Pleurisy/Pericarditis NSAIDs, low dose Prednisone 10 to 30 mg/ day Myocarditis Steroids + monthly cyclophosphamide, avoiddigoxin Nephrotic syndrome Steroids + monthly IV cyclophosphamide/ daily/oral cyclophosphamide + ACE inhibitors + low dose aspirin and Dipyridamole to prevent thrombotic complications Aseptic meningitis High dose steroids Dysphagia Proton pump inhibitors and prokinetic drugs (mosapride, domperidone) Digital gangrene Anticoagulation, local chemical sympathectomy, endothelin receptor antagonist therapy

Analgesics and nonsteroidal anti-inflammatory drugs alone may be needed in one-third cases. Manifestations like aseptic

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meningitis, myositis, pleurisy, pericarditis and myocarditis usually respond to corticosteroids. Gloves and calcium channel blockers are useful in Raynaud’s phenomenon. Arthritis and cutaneous manifestations respond well to antimalarial agents such as hydroxychloroquine. High dose steroids are indicated for the treatment of severe systemic disease such as vasculitis myositis, or interstitial lung disease. IV gammaglobulin or danazol can be tried in patients with steroid-resistant thrombocytopaenia, refractory myositis and haemolytic anaemia. Unless contraindicated, all patients should take supplementary calcium and vitamin D. Immunosuppressive drugs may be useful for induction of remission or for their corticosteroid sparing effects. The commonly used agents are azathioprine, cyclophosphamide and methotrexate. OVERLAP SYNDROMES Overlap syndromes occur when patients meet criteria for the diagnosis of more than one connective tissue disease. Raynaud’s phenomenon, arthritis, and sclerodactyly are usually found in most of the overlap syndromes. For example, a patient with SLE who develops erosive arthritis in a distribution similar to RA, is labelled an overlap of RA and SLE. Usually one syndrome gradually takes on the features of another. Sometimes, the features of both diseases may occur concurrently. Sjögren’s syndrome commonly overlaps with RA, SLE, Systemic sclerosis, PM, primary biliary cirrhosis, etc. MCTD is a serologic subset of overlap syndrome characterised by the presence of antibodies to U1RNP. Other overlap syndromes include SLE with polymyositis in 4% to 16% of cases, SLE with RA (positive rheumatoid factor, nodules and erosive arthritis) known as ‘rhupus’. Scleroderma can be associated with myositis and limited scleroderma with primary biliary cirrhosis (Raynold’s Syndrome). The management of overlap syndromes is dictated by individual organ involvement and not by diagnostic labels. For example, the arthritis of SLE, RA or scleroderma is treated in a more or less similar fashion.

24.14

Inflammatory Muscle Diseases Alakendu Ghosh, Pradyot Sinhamahapatra

INTRODUCTION The idiopathic inflammatory myopathies (IIM) are a heterogenous group of acquired muscle disorders, presenting with muscle weakness, increased serum muscle enzymes, abnormal myogram and inflammatory changes in muscle histology. The three major entities in IIM are: polymyositis (PM), dermatomyositis (DM) and inclusion-body myositis. In all age groups, DM is the most common and PM is the least common. Inclusion-body myositis is the most common myopathy above the age of 50. CLASSIFICATION The classification is summarised in Table 1. Table 1: Classification of Idiopathic Inflammatory Myopathies (IIM) 1.

Primary idiopathic polymyositis

2.

Primary idiopathic dermatomyositis

3.

Polymyositis or dermatomyositis with malignancy

4.

Juvenile dermatomyositis (or polymyositis)

5.

Polymyositis or dermatomyositis associated with other connective tissue diseases

6.

Inclusion body myositis

7.

Rare forms of idiopathic myositis: Granulomatous myositis, eosinophilic myositis, focal myositis, orbital myositis, etc.

CLINICAL MANIFESTATIONS PM is a subacute myopathy that evolves over weeks to months and presents with proximal muscle weakness. It affects adults, but rarely also children. The patient presents with painless weakness of the proximal muscles of limbs, trunk and neck flexors over few months (55%), and sometime acute or subacute painful proximal weakness (30%). There may be some constitutional features. Uncommonly, the patient may present with a more indolent course over years, myalgia alone, or a rash alone in DM. Facial and bulbar weakness are rare and ocular weakness is not a feature of idiopathic PM. However, dysphagia due to oropharyngeal weakness occurs in one-third, and signifies poor prognosis. DM is associated with characteristic cutaneous rash that accompanies muscle weakness (Figure 1). These skin manifestations include: (i) typical ‘heliotrope’ rash, which is a violaceous discolouration around the eyelids, may be oedematous, accompanied by an erythematous rash on the face (ii) Gottron’s papules, which are erythematous scaly lesions on the hands, over bony prominences like the knuckles at the metacarpophalangeal and interphalangeal joints; (iii) the erythematous rash on the face, neck, and anterior chest (in many patients in a ‘V’ sign) or back and shoulders (Shawl sign), lateral

Figure 1: Dermatomyositis with skin rash.

thighs (Holster’ sign); and (iv) dilated capillary loops at the base of the finger nails. DM affects both children and adults and women more than men. Juvenile DM may present with calcification. Calcinosis is associated with increased morbidity (Figure 2). Inclusion body myositis (IBM) occurs over the age of 50 years and is more common in men. It usually affects proximal as well as distal muscles and can be asymmetric. Muscle atrophy and swallowing difficulty are prominent in IBM. Facial and extraocular muscles are never affected. Neck extensor muscles may be involved causing head drop. Myalgia is uncommon occurring in 30% of patients. IIM may be associated with a number of extramuscular clinical manifestations like fatigue, malaise, weight loss and low-grade fever. Pulmonary involvement in IIM is due to weakness of the thoracic muscles or interstitial lung disease (ILD) (around 40%) or aspiration pneumonia due to pharyngeal weakness. Cardiac involvement in IIM may include atrioventricular conduction disturbances and myocarditis/pericarditis. Joint contractures occur mostly in dermatomyositis. The patients can have dysphagia, or reflux. Gastrointestinal ulcerations due to vasculitis and infection are common in children with dermatomyositis. Inflammatory myopathies can have association with malignancies in some organs like ovaries, gastrointestinal tract, nasopharyngeal, lung, breast, non-Hodgkin’s lymphoma (NHL) specially in elderly people. The malignancy may be during antecedent, or subsequent to myositis onset. 1879

Figure 2: Juvenile dermatomyositis (JDM) with calcinosis.

DIAGNOSIS The clinical diagnosis of PM and DM is confirmed by three laboratory investigations: (i) serum muscle enzyme concentration, (ii) typical electromyography, and (iii) muscle biopsy histology. In addition, magnetic resonance imaging (MRI), MR spectroscopy can help localisation of extent and autoantibody testing helps in the evaluation. Autoantibodies like antisynthetase or anti-SRP (signal recognition particles) are found in 20% of patients. Jo-1 antibodies predicted the persistent use of drugs. Antinuclear antibodies (ANA) may be positive in 50% to 80% and rheumatoid factor in 20% of patients (Table 2). Age appropriate screening for malignancy (thorough clinical examination, colonoscopy, mammography, chest computed tomography (CT), abdominal with pelvic CT, stool occult blood, prostate specfic antigens (PSA), serum CA125, CA19-9) is recommended, especially in elderly patients with dermatomyositis, high erythrocyte sedimentation rate (ESR), and/or in presence of cutaneous necrosis on the trunk, cutaneous leucocytoclastic vasculitis, evidence of capillary damage in muscle biopsy. The most sensitive muscle enzyme assay is creatinine kinase (CK), which is increased up to 50 times the normal upper limit in active disease. CK increases before clinical weakness and falls before clinical improvement. However, CK can be normal in some patients with active DM and late stages of polymyositis. CK levels are normal in corticosteroid induced myopathy. CK may be increased in a number of conditions (Table 3). PM/DM may be associated with other connective disease usually termed as overlap syndrome. DM develops in up to 12% of patients with systemic sclerosis, PM in 5% to 8% of lupus 1880 patients.

Table 2: Clinical Profiles of IIM Based on Autoantibodies Myositis specific antibodies

Clinical features

1.

Antisynthetase

2.

3.

Anti-signal recognition particle (SRP) Anti-Mi 2

4.

Anti-MAS

PM/DM features, with acute onset muscle weakness; associated with fever, Raynaud’s phenomenon, ‘mechanic’s’ hand, interstitial lung disease (Antisynthetase syndrome) (Jo1 with mainly PM features and other antibodies with mainly DM features) PM features, with very acute onset and severe muscle weakness; cardiac involvement; poor response to treatment; high mortality DM features, with acute onset; associated with ‘V’ sign and ‘shawl’ design, cuticular overgrowth at fingers; good response to treatment PM features; acute onset; association with alcoholic rhabdomyolysis; good response to treatment

Myositis associated Clinical features antibodies 5. 6. 7. 8.

Anti-Ku and anti-PM-Scl Anti-KJ

Associated with a PM and scleroderma overlap clinical picture Associated with PM features, Raynaud’s phenomenon and interstitial lung disease Anti-U1-RNP Associated with PM/DM overlap syndrome Anti-Ro/SSA and Associated with DM/PM features and an anti-La/SSB overlap clinical situation with SLE or Sjögren’s syndrome.

Needle electromyography can be helpful for detecting an active myopathic process, recognising that the process is consistent with IIM and excluding other neuropathies and some myopathies. The most common findings are low amplitude, short duration, polyphasic potentials. However, the

Following strenuous and/ or prolonged exercise: An important, but often forgotten cause of an isolated elevation of CK

Muscle trauma: Injury Following EMG Needle stick Surgery

Muscle diseases (other than IIM): Infections: Viral, bacterial, protozoal or fungal Idiopathic: associated with other connective tissue disorders Dystrophies Metabolic Myocardial infarction Rhabdomyolysis

characteristic triad is: (a) myopathic potentials, (b) fibrillations, positive sharp waves, increased insertional activity, and (c) complex repetitive discharges. Typical electromyographic features may not be present in 10% of patients. The muscle biopsy is the gold standard and can provide definitive evidence for diagnosing IIM, but at the same time, most common cause of misdiagnosis due to erroneous interpretations. Biopsy should be performed on the side opposite to the electromyogram (EMG) study to avoid needle artifact. MRI might help localising the extent of muscle involvement. In PM multifocal endomysial CD8+ lymphocytic infiltration in histologically healthy muscle fibre is found. In DM, the inflammation is predominantly perimysial and perivascular infiltration by CD4+ lymphocytes. Skin biopsy findings are not specific for DM, and are not routinely required, but exclude other skin conditions that can have similar clinical appearances.

Drugs: Toxic myopathy Causing myositis: D penicillamine Direct elevation by reducing the excretion of CK: barbiturates, morphine, diazepam

Endocrine/ Metabolic: Hypothyroid Hypokalaemia Ketoacidosis or hyperosmolar state Renal failure Diabetic nephritic syndrome

Others: CNS disease; cerebral ischaemia, head injury, psychosis, delirium tremens Tumours: gastrointestinal, bronchial Pneumococcal sepsis

Inflammatory Muscle Diseases

Table 3: Causes of Elevated CK Levels other than IIM

Table 4: Summary of Diagnosis of PM/DM Symmetrical proximal muscle weakness developing over weeks/ months Elevated serum muscle enzymes: Creatine kinase (CK), aldolase Abnormal electromyography: Myopathic potentials (short duration, low amplitude, polyphasic), fibrillation, positive sharp waves, insertional activity, complex repetitive discharges Abnormal muscle biopsy: Multifocal endomysial mononuclear cell infiltration, degeneration and regeneration Skin manifestations of dermatomyositis: Gottron’s papules, Gottron’s sign, Heliotrope rash

than a reduction of CK levels should be the clinical parameter that denotes response to therapy (Figure 3). Prednisolone is the first line drug. The initial dose of prednisolone is 1 to 2 mg/kg/d (60-100 mg/day) for 4 to 8 weeks (variable) and then tapered gradually as muscle strength

Differential Diagnosis Other causes of proximal muscle pain and weakness must be excluded. These are endocrine (hypothyroidism, hyperthyroidism, osteomalacia, Cushing’s syndrome—usually steroid induced, Addison’s disease) and metabolic causes (hypokalaemia) plus rare causes like muscle enzyme defects. Infectious myositis (viral- HIV, picornavirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), rubella, influenza; bacterial- pyomyositis, Lyme, tuberculosis, parasitic- Toxoplasma, Trichinella, etc.) needs exclusion. Drugs like statins, fibrates, zidovudine, penicillamine, colchicine, hydroxychloroquine, cyclosporine and alcohol, cocaine are also important causes of muscle pain and weakness. It is important to note: (i) to exclude PM in suspected muscular dystrophy where the history is short – CK, EMG, and muscle biopsy would help; (ii) to diagnose overlap of PM with another disease like rheumatoid, lupus where assessment of muscle power is difficult because of pain – CK, muscle biopsy helps; (iii) to exclude polymyalgia rheumatica in cases with significant pain, especially in elderly with high ESR; (iv) patients with muscle pain and weakness due to endocrine and metabolic myopathies—clinical suspicion is a must. A summary of diagnosis is given in Table 4. TREATMENT Very few controlled trials are available. The goals of therapy are to improve the ability to carry out activities of daily living by increasing muscle strength and control the extramuscular manifestations of IIM. Improvement in muscle strength rather

Figure 3: Treatment algorithm for PM/DM. Notes: Physical therapy to maintain muscle strength is important at all stages MTX = Methotrexate; AZA = Azathioprine 1. IV Pulse if ther is alveolitis, dysphagia or myocarditis 2. Is severe disease, IVIg may be added at this stage

1881

improves (reduce dose by 10% every two weeks) over 2 to 3 months, to a maintenance dose of around 0.25 to 0.5 mg/kg per day. Pulsed intravenous methyl prednosolone (15 mg/kg/ d, max 1g) is used in severe cases especially with alveolitis, severe dysphagia, or myocarditis. Prevention and monitoring for steroid induced side effects is mandatory. Calcium and bisphosphonate supplementation should be given as necessary. Most patients will respond to this therapy, but some will require additional immunosuppressive drugs. Increasingly, immunosuppressives are being used along with corticosteroids from begining. Selection of an immu-nosuppressive drug remains empirical and depends on personal experience of treating physician. Azathioprine is given orally in a dose of 2 to 3 mg/kg/day tapered to 1 mg per kg per day once steroid is tapered to 15 mg per day. It can take 4 to 6 months to work. The maintenance dosage is 50 mg per day. Methotrexate is given orally in a dose of 7.5 to 25 mg weekly. This usually acts more rapidly. As dosage increases, taper off steroid dose. Concomitant folic acid minimises side effects of methotrexate. Patients need to be monitored regularly with blood counts, serum creatinine and alanine aminotransferase (ALT ). Cyclosporine has also been found to be beneficial and is used in a dose of 3 to 5 mg/kg/day. Mycophenolate mofetil is emerging as a promising and well-tolerated drug and is used in a dose of 2 gm/day. Cyclo-phosphamide, given intravenously every 3 to 4 weeks has shown mixed results, but may be of particular benefit for patients with active ILD. Rituximab has been tried in refractory cases. Antimalarials are used for skin lesions in DM. Intravenous immunoglobulin (IVIg) has been shown to be beneficial in improving muscle strength acutely. It is used as a

1882

single intravenous infusion of 2 gm/kg. Plasmapheresis was not found to be helpful in a double blind placebo-controlled study. Lack of improvement of muscle power may be due to relapse or activity (accompanied by rise in CK) or steroid myopathy (CK normal). Neck flexor strength would be unchanged in patients developing steroid myopathy. Muscle power may not recover fully in all subjects. If other features suggest inactive disease, drugs may be reduced. COURSE AND PROGNOSIS Disease related death occurred in at least 10% of patients, 20% remained in remission and were off drugs whereas 80% had polycyclic course. DM infrequently relapses, but usually respond to therapy. PM patients have frequent relapses, but recover with less strength after each bout. Patients with IBM and polymyositis with anti-SRP antibody have the poorest prognosis. Older patients, and those with associated malignancy, delayed treatment, and cardiorespiratory complications have poor survival. RECOMMENDED READINGS 1. 2. 3.

Bronner IM, Vander Meulen MFG. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis 2006; 65: 1456-61. Dalakas MC. Immunotherapy of myositis: issues, concerns and future prospects. Nat Rev Rheumatol 2010; 6: 129-37. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003; 362: 971-82.

Web Resources 1. 2.

International Myositis Assessment and Clinical Studies Group https://dirapps.niehs.nih.gov/imacs/index.cfm The Myositis Association http://www.myositis.org

24.15 INTRODUCTION Forty per cent of all human beings suffer from some musculoskeletal symptoms during their life time and one-third have a true musculoskeletal disorder. However, at times musculoskeletal symptoms and signs are manifestations of nonrheumatic systemic diseases. Lack of awareness can lead to erroneous or delayed diagnosis of primary illness. Hereditary, inflammatory, infective, neoplastic, metabolic, nutritional, drugrelated and psychogenic diseases can present with rheumatic complaints (Table 1). Some of the common systemic conditions with rheumatic manifestations are discussed below. DIABETES MELLITUS It can cause rheumatic manifestations as direct, indirect or associated features. Calcaneal Osteolysis One of the most common rheumatic symptoms in diabetics is foot pain due to calcaneal osteolysis. Neuropathic Joint (Charcot Joint) Unlike syphilis in the past, diabetes is now the most common cause of neuropathic joint, the most damaged and deranged joint, one can imagine. It can affect any weight-bearing joint like knees and ankles, but small joints can also be affected. Clinical clues include significant sensory deficit and pain which is far less than what one might expect from the degree of radiologic damage. Osteomyelitis is an important differential diagnosis. Rotator Cuff Disease Restricted abduction of shoulders due to degenerative process causing supraspinatus tendonitis, bicipital tendonitis, and subacromial bursitis is fairly common in diabetics, often loosely termed as ‘periarthritis’. Diffuse Idiopathic Skeletal Hyperostosis (DISH) Also called as Forestier’s disease, it is seen in elderly women with diabetes mellitus with back pain. Radiographs reveal exuberant, bridging osteophytosis in spine which superficially resembles ankylosing spondylitis (AS). However, there is no sacroiliitis in DISH in contrast to AS where sacroiliitis is the characteristic feature. DISH is a degenerative condition. It is not specific for diabetes and may be seen even in absence of diabetes mellitus. Crystal Arthritis Both gout and pseudogout are found with higher prevalence in diabetics, when compared to non-diabetics. Gout typically afflicts the big toe while pseudogout usually affects large joints with intermittent inflammatory arthritis, mimicking a septic arthritis but without leaving much residual damage. Radiographs in pseudogout may show chondrocalcinosis at various places: triangular ligament calcification of hands or calcifications of intervertebral space, pubic symphysis or knee joint cartilage. Synovial fluid examination under polarising

Rheumatic Manifestations of Systemic Diseases Debashish Danda microscope can clinch the diagnosis. Gouty fluid is likely to show needle-shaped intracellular negatively birefringent crystals of monosodium urate (MSU), whereas calcium pyrophosphate dihydrate (CPPD) crystals of pseudogout are blunt, rhomboidshaped and positively birefringent. Septic Arthritis Diabetes is one of the most common conditions associated with septic arthritis and septic bursitis. Joint aspiration and synovial fluid examination by Gram stain and culture are important. Staphylococcus aureus and Gram-negative organisms are the usual causative agents. Septic arthritis requires prolonged and aggressive antibiotic treatment with joint lavage. Delay can lead to joint destruction and contractures. Diabetic Cheiroarthropathy (Prayer Sign or Namaste Sign) Myxomatous deposition around small joints of hands, tendons and ligaments leads to this complication causing limited joint mobility (LJM). In one series, LJM was diagnosed in 42.9% of type 1 and 37.3% of type 2 diabetic patients. Abnormally thick skin was detected in 31.4% of type 1 and 33.7% of type 2 diabetic patients. Skin abnormalities were observed mainly in patients with LJM. There was a high prevalence of hand flexor tendon abnormalities (18.6%). Decreased range of shoulder and hip mobility and flexor tendon abnormalities were significantly more common in patients with LJM. Other Musculoskeletal Features in Diabetes Complex regional pain syndrome (CRPS) or shoulder-hand syndrome or reflex sympathetic dystrophy is often found in diabetics. Other musculoskeletal features include carpal tunnel syndrome, Dupuytren’s contracture, sclerodactyly and scleroderma-like skin changes, tendency for early osteoporosis with tendency to fracture vertebra or neck of femur. HAEMATOLOGICAL MALIGNANCIES Haematological malignancies can cause arthropathy by direct infiltration, immune complex-mediated inflammatory arthropathy, haemarthrosis due to low platelets and altered clotting mechanisms, septic arthritis or hyperuricaemia-related gouty type arthritis. They are, therefore, notorious masqueraders leading to delayed diagnosis, especially in children. The clue is pain and tenderness out of proportion to findings in the joints, associated low haemoglobin, low platelets, and at times, abnormal white cell counts (high or low) or morphology. Bone marrow examination can be confirmatory. Metaphyseal radiolucent bars in radiographs are a clue for leukaemic arthropathy. Multiple myeloma (predominantly kappa light chain) and primary amyloidosis (lambda light chain predominant myeloma) can present with features exactly like rheumatoid arthritis including subcutaneous nodules, arthritis and carpaltunnel syndrome.‘Shoulder pad’ sign, macroglossia or lytic lesions on radiographs should arouse suspicion of multiple myeloma. 1883

Table 1: Rheumatic Manifestations of Systemic Diseases Hereditary diseases with rheumatic manifestations Heritable collagen diseases, e.g. benign hypermobile joint syndrome, osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan’s syndrome, pseudoxanthoma elasticum, cutis laxa, Stickler’s syndrome, spondyloepiphyseal dysplasia, Alport’s syndrome, etc. Inborn errors of metabolism, e.g. homocysteinuria, alkaptonuria, Menke’s kinky hair syndrome, mucopolysaccharidoses, Fabry’s disease Storage diseases, e.g. Haemochromatosis, Wilson’s disease Primary immunodeficiency diseases, e.g. DiGeorge’s syndrome, Brutton’s agammaglobulinaemia, IgA deficiency, common variable immunodeficiency, hyper IgM syndrome, complement deficiency disorders Bone and joint dysplasia, e.g. osteochondrodysplasia, spondyloepiphyseal dysplasia, hypophosphatasia Inflammatory disorders with rheumatic manifestations* RA Primary Sjögren’s syndrome SLE Overlap syndromes Vasculitic disorders Infective conditions with rheumatic manifestations Viral : Hepatitis B, hepatitis C, HIV, parvovirus, Epstein-Barr virus, cytomegalovirus, rubella, coxsackie, echovirus, O’nyongnyong, chikungunya and dengue Bacterial : Septic arthritis, infective endocarditis, melioidosis, brucellosis, Mycobacterial TB, atypical mycobacteria, leprosy Parasitic : Guinea worm arthritis, trichinosis causing myositis, filariasis, schistosomiasis, and amoebiasis causing arthralgia Fungal : Sporotrichosis Neoplastic diseases with rheumatic manifestations Haematological : Leukaemias, lymphomas, myelomas Solid tumours : Renal cell carcinoma, pancreatic carcinoma Metastatic process Primary amyloidosis Metabolic diseases with rheumatic manifestations Diabetes mellitus Hypothyroidism Hyperthyroidism Hypoparathyroidism Hyperparathyroidism Acromegaly Cushing’s syndrome Renal tubular acidosis Paget’s disease Nutritional diseases with rheumatic manifestations Osteomalacia Rickets Drug or treatment related Serum sickness like process following vaccination, drugs Drug-induced lupus (INH, phenytoin, D-penicillamine, biological agents like TNF-blockers) Drug-induced vasculitis (propylthiouracil and leukotriene inhibitors monteleukast/zafirleukast-induced Churg-Strauss syndrome) Hyperuricaemia with drugs (Pyrazinamide) Myositis/myopathy (statins, zidovudine, penicillamine, steroid) Haemodialysis Psychogenic diseases with rheumatic manifestations Chronic pain syndromes (controversial) *The diagnosis can often be made without difficulty because joint pains are frequently the presenting feature. Other diseases where musculoskeletal involvement is evident include sarcoidosis, inflammatory bowel disease, coeliac disease and psoriasis.

The classical triad comprises of bone pain, anaemia and renal failure. Bone marrow examination, electrophoresis for ‘M’ band and serum immunoglobulin levels confirm the diagnosis. There may be higher levels of the pathogenic isotype of immunoglobulins and suppression of the other isotypes, e.g. in IgA meloma, IgA will be high and IgG, IgM and other isotypes may be low in quantity. Hairy cell leukaemia can present with polyarteritis nodosa-like vasculitis. Some lymphomas can produce dermatomyositislike presentations, as paraneoplastic manifestation. Other presentations include erythromelalgia in myeloproliferative 1884 diseases presenting as red, swollen, warm, stout, and puffy

fingers and toes; and cryoglobulinaemic vasculitis in plasma cell dyscrasias, etc. Rheumatic associations of myelodysplastic syndromes include polyarteritis nodosa type systemic vasculitis and polymyalgia rheumatica. SOLID MALIGNANCIES Lung cancers causing hypertrophic osteoarthropathy (triad of clubbing, polyarthritis or polyarthralgia and widening of wrists and ankles), panniculitis in pancreatic carcinoma, dermatomyositis/polymyositis in carcinoma of stomach, ovary and several adenocarcinomas are well known entities. Jaccoud’s arthritis is described in lung malignancies while scleroderma-like process

Rheumatic manifestations suggesting a hidden cancer include rapid onset of an unusual inflammatory arthritis, clubbing or diffuse bone pains in a patient 50 years of age or older, chronic unexplained vasculitis, refractory fasciitis, Raynaud’s phenomena unresponsive to vasodilator therapy, rapidly progressive digital gangrene or Lambert-Eaton myasthenic syndrome. Paraneoplastic rheumatological syndromes may coincide, follow or antedate the diagnosis of cancer, or herald its recurrence. The clinical course generally parallels that of the primary tumour, and treatment of the underlying malignancy often results in regression of the rheumatic disorder. Awareness that cancer can cause certain non-metastatic symptoms is important for early diagnosis and treatment of an occult neoplasm. Management consists of control of the underlying cancer and symptomatic treatment of the rheumatic syndrome with nonsteroidal anti-inflammatory drugs. CHIKUNGUNYA ARTHRITIS Chikungunya fever is associated with severe arthralgias, myalgias and skin rash. The fever usually lasts a few days. However, the rheumatic complaints can be crippling. The viral polyarthropathy frequently involves the small joints of the hand, wrist and ankles and may also involve other larger joints such as knees and shoulders. The pain may be severe enough to immobilise the patient and interfere with activities of daily living. Rheumatological manifestations are less severe in children in this infection. The arthralgias can persist for weeks to months. Treatment is mainly symptomatic. MYCOBACTERIAL INFECTIONS Tuberculosis (TB) usually presents as chronic inflammatory monoarthritis of large joints. Atypical mycobacteria and at times tuberculosis can present with polyarticular large and small joint disease with significant tenosynovitis, associated bursitis and discharging sinuses, similar to fungal arthropathies. Mycobacteria-related rheumatic manifestations are often classified into four different categories: 1. Direct musculoskeletal involvement of M. tuberculosis, including spondylitis, osteomyelitis, septic arthritis, and tenosynovitis. 2. M. tuberculosis infection complicating rheumatologic diseases such as rheumatoid arthritis after therapy with tumour necrosis factor-alpha inhibitors. 3. Anti-mycobacterial drug-induced rheumatologic syndromes such as pyrazinamide and ethambutol-induced hyperuricaemia, quinolone-induced tendinopathy, druginduced lupus with INH. 4. Reactive immunologic phenomena in mycobacterial infection, such as Poncet’s arthritis, erythema nodosum, etc.

Poncet’s arthritis is a form of reactive arthritis in tuberculosis. It is a sterile arthritis of large or small joints, usually short lasting and non-deforming, thought to be due to hypersensitivity to mycobacterial antigens. It was originally seen after intravesical instillation of BCG vaccine for bladder malignancies. It is more common with extrapulmonary TB, rather than in pulmonary TB. Usually, symptomatic treatment with NSAIDs suffices most of the time. Erythema nodosum seen in the setting of TB can be confused with sarcoidosis. Mantoux test in such a case may be helpful. LEPROSY AND LEPRA REACTION Striking rheumatological manifestations can be seen in leprosy and lepra reactions. Type 2 lepra reaction is a type 3 immune response, i.e. immune complex- mediated process similar to SLE. Therefore, it is not surprising to find lupus-like presentations in these patients. They may even present with dermatomyositis, overlap connective tissue disease and medium vessel vasculitispolyarteritis nodosa-like process. Infiltration of ear lobule and infiltrated appearance of face, depressed bridge of nose, nerve thickening and madarosis can be the clues in a suspected case. In a case of mononeuritis multiplex presenting as foot drop, wrist drop, cranial nerve palsy, one must suspect leprosy if diabetes is ruled out. The other differential diagnosis includes classic polyarteritis nodosa. Seven quadrant slit-skin smear is a good test; the other test is nerve biopsy with appropriate acidfast staining for M. leprae.

Rheumatic Manifestations of Systemic Diseases

may be seen in adenocarcinomas and carcinoid tumours. Solid tumours and tumours of mesenchymal origin can also give rise to oncogenic osteomalacia presenting as out of proportion bony pain and tenderness. Renal cell carcinoma is another malignancy which causes myriad of rheumatological manifestations including arthritis, vasculitis, etc. due to production of proinflammatory cytokines by this tumour. Carcinomatous polyarthritis is a special entity mostly associated with explosive onset, asymmetric, large joint polyarthritis often sparing the upper limbs. This can occur even with haematological malignancies, not necessarily with carcinomas alone.

HIV Table 2 shows rheumatic manifestations of HIV. A host of autoantibodies are also described in HIV infection namely: anticardiolipin, anti-beta-2 GPI, anti-DNA, anti-small nuclear ribonucleoproteins (snRNP), anti-thyroglobulin, anti-thyroid peroxidase, anti-myosin and anti-erythropoietin antibodies. The clinical correlation of autoantibodies in HIV-infected patients with clinical autoimmune disease is yet to be established. With the upsurge of HAART (highly active antiretroviral treatment), the incidence of autoimmune diseases in HIV-infected patients is increasing, especially after immune reconstitution syndrome. Table 2: Rheumatic Manifestations of HIV Increased incidence of reactive arthritis due to possible several gastrointestinal infections Aggressive psoriatic arthritis Sjögren’s-like disease called diffuse interstitial lymphocytosis syndrome (DILS)* Septic arthritis Pyomyositis and polymyositis Systemic lupus erythematosus Anti-phospholipid syndrome Vasculitis *Presents as prominent parotid and lacrimal gland enlargements. This differs from Sjögren’s by the presence of CD8-positive lymphocytes infiltration rather than CD4 cells seen in Sjögren’s syndrome.

RECOMMENDED READINGS 1.

Mohan A. Chikungunya fever: clinical manifestations and management. Ind J Med Res 2006; 124: 471-4.

2.

Schon L, Easley MC. Charcot neuroarthropathies of the foot and ankle. Clin 1885 Orthop 1998; 349: 116-31.

24.16

Miscellaneous Rheumatic Disorders

This chapter deals with a group of unrelated disorders like heritable connective tissue disorders, relapsing polychondritis, Charcot’s arthropathy, hypertrophic osteoarthropathy and pigmented villonodular synovitis. HERITABLE CONNECTIVE TISSUE DISORDERS Heritable diseases of connective tissues are a diverse group of disorders characterised by abnormalities in the musculoskeletal tissues including cartilage, bone, tendon, ligament, muscles and skin.They are further classified into disorders primarily affecting the cartilage and bone (skeletal dysplasias) and diffuse disorders that have a more profound effect on the connective tissues like Ehler-Danlos syndrome (EDS), Marfan’s syndrome and other disorders manifested by abnormal extracellular matrix molecules. Skeletal Dysplasias (Osteochondrodysplasias) These are a group of developmental disorders of the chondral and osseous tissues that are often accompanied by short stature. They include defects of tubular and flat bones or of the axial skeleton, disorganised development of cartilaginous and fibrous component and idiopathic osteolysis. The most important varieties of skeletal dysplasias are osteogenesis imperfecta, chondrodystrophies like achondroplasia and spondyloepiphyseal dysplasias (Table 1).

Binoy J Paul In addition to fracture susceptibility there is marked osteoporosis secondary to osseous matrix abnormality. The skeletal abnormalities varies with the type (Table 2). OI is associated with variable non-osseous features like blue sclera, dentinogenesis imperfecta, deafness, pectoral deformities, mitral valve prolapse and growth retardation. The diagnosis of OI can be usually made clearly on clinical and radiological basis. Treatment with bisphosphonates or calcitonin may be beneficial to prevent vertebral compression than long bone fractures and to delay the development of scoliosis. These drugs also reduce the bone pain. Long-term management requires expert physical therapy or orthopaedic surgery. Table 2: Classification of Osteogenesis Imperfecta Type Inheritance

Sclera

Deafness

Skeletal abnormalities

I

Autosomal dominant

Blue

50%

Mild to moderate bone fragility No deformities Mild to moderate short stature

II

Autosomal dominant or recessive

Blue

No

III

Autosomal dominant or recessive

Variable

Common

Extreme fragility of connective tissue Congenital fractures Soft large cranium Micromelia, Beaded ribs Lethal in the perinatal period Progressive deformity of bone Very short stature Relative microcephaly Triangular facies Dentinogenesis imperfecta

IV

Autosomal dominant

Normal

Uncommon Variable short stature Mild to moderate bone deformities Dentinogenesis imperfecta Moderate joint hyperextensibility

Table 1: Heritable Diseases of Connective Tissues Skeletal dysplasias Osteogenesis imperfecta Chondrodystrophies, e.g. Achondroplasia Spondyloepiphyseal dysplasias Kniest dysplasia Morquio’s disease Hereditary multiple exostoses Diastrophic dysplasia Idiopathic osteolysis Diffuse heritable diseases Ehler-Danlos syndrome Marfan’s syndrome Pseudoxanthoma elasticum William’s syndrome Benign joint hypermobility syndrome

Osteogenesis imperfecta (OI) It is a genetic syndrome of abnormal bone matrix with secondary osteoporosis. OI is one of the most common heritable disorder of connective tissue. It is inherited as autosomal recessive or autosomal dominant manner depending on the disease subtype. It is associated with abnormalities of structure or synthesis of Type I collagen (Table 2). The severity of the disease ranges from a slight increase in 1886 susceptibility to bone fractures to forms that are lethal in utero.

Chondrodystrophies Chondrodystrophies are a large and strikingly heterogenous group of heritable skeletal dysplasias with abnormal proportion of limbs, trunk and/or skull and often associated with short stature.

Achondroplasia Achondroplasia is the most common skeletal dysplasia, which is due to mutation in the gene expressing the fibroblast growth factor receptor 3 (FGFR3). The distinguishing features are present at birth, although the diagnosis is seldom made at that time. The head is large with frontal bossing, midface hypoplasia and prognathism. There is rhizomelic shortening of arms and legs, increased lumbar lordosis, bowing of the legs, overgrowth of fibula and a trident shaped hand with short broad phalanges. Radiographs show a very small sacrosciatic notch of pelvis, changes in the epiphysis of distal femur and constriction at the base of the skull. Adult life may be shortened if there is spinal canal stenosis causing spinal cord compression. Otherwise most of these persons live a healthy productive and independent life. Limb lengthening involving bilateral femoral and tibial distraction osteotomies may add up to 12 inches to the adult height. The procedures are best done in the second decade. Spondyloepiphyseal dysplasias Spondyloepiphyseal dysplasias (SEDs) constitute a group of closely related disorders characterised by short stature and a disproportionately short trunk. Infants with the most severe forms of SEDs are obviously dwarfed at birth. Many other less severely affected patients may not present until later in life and their symptoms can be easily confused with those of osteoarthritis. They present with short stature and symmetric joint pain caused by epiphyseal changes. There are two types of spondyloepiphyseal dysplasias Congenita and Tarda (Table 3). Radiographic features include flattening and/or sclerosis of epiphyses of long bones. There will be flattening of the vertebral bodies also. Table 3: Spondyloepiphyseal Dysplasias Type

Onset

Inheritance

Associated features

Congenita

Birth

Autosomal Dominant

Short limbs Equino varus feet Myopia, retinal detachment

Tarda

Late childhood

X-linked recessive

Moderately short stature Platyspondyly Onset of pain in the hip and back at the age of about 10 yrs Progressive joint deformities

DIFFUSE HERITABLE CONNECTIVE TISSUE DISORDERS Ehler-Danlos Syndrome (EDS) EDS is a genetic syndrome affecting primarily joints, skin and blood vessel all. It consists of a heterogenous group of generalised connective tissue disorders associated with multiple modes of inheritance and associated with abnormalities of types I, III, V collagen or fibronectin, enzyme deficiencies or abnormalities of copper metabolism.

There are around 10 types of EDS. The genetic inheritance and incidence varies with the type. 1. Type 1 EDS is the gravis form. Patients have velvety and hyperextensible skin, marked joint extensibility, cigarette paper scars and easy bruising. 2. Type II EDS (mitis) has a less severe presentation of type I with associated premature degenerative arthritis. 3. In Type III EDS joints are hypermobile with repeated joint dislocations and degenerative arthritis. 4. Type IV (Vascular EDS) is the severest form associated with lethal complications like rupture of arterial wall, colon or pregnant uterus. There is a characteristic facies with large eyes and thin nose and lips. Patients have marked bruisability, an aged skin appearance on hands and feet and joint hypermobility limited to the small joints of hands. Type I to IV are having autosomal dominant inheritance. 5. Type V EDS is clinicaly similar to Type II but the mode of inheritance is X-linked. 6. Type VI EDS is having autosomal recessive inheritance with soft extensible skin, scoliosis, ocular fragility and hypermobile joints. 7. Type VII EDS presents predominantly with joint symptoms beginning with congenital dislocation of hips usually bilateral and continuing with striking joint laxity and multiple dislocations. There may be moderate short stature and mild skin bruising and extensibility. 8. Type VIII EDS is associated with generalised periodontitis in addition to skin and joint hyperlaxity. 9. Type IX EDS has bladder diverticula and rupture, soft lax skin associated with bony occipital horns. 10. Type X EDS is associated with abnormal platelet aggregation in addition to mild joint hypermobility and easy bruising.

Miscellaneous Rheumatic Disorders

Some chondrodystrophies are associated with an abnormality of Type II collagen. However, in most chondrodystrophies the abnormality of extracellular matrix is unknown.

Management of EDS is mainly conservative. Joint hypermobility generally decreases with age. Sports that hyperextend and otherwise stress the joints should be discouraged in childhood. Joint surgery may be performed for pain, instability or poor range of motion. Skin fragility in EDS necessitates particular attention to closure in even minor surgical procedures. Sutures should be more closely spaced and left in place for a longer period than normal. In Type IV EDS, patient should be asked to report to the physician for all appropriate vascular and visceral symptoms for prompt evaluation. If pregnancy is attempted, elective caesarean section through lower uterine segment is essential to prevent uterine rupture or vaginal tears. Marfan’s Syndrome (MS) Marfan’s syndrome was the first heritable connective tissue disorder to be described which has an autosomal dominant inheritance. There is no racial or geographic influence on incidence with an approximate prevalence of one per 20,000. Aetiopathogenesis Classic Marfan’s syndrome is caused by mutation in fibrillin-1 (FBN-1) gene. Fibrillin is a glycoprotein abundant in aortic tunica media, ciliary zonules, skin and periosteum. 1887

Clinical features Musculoskeletal features include stature greater than 95 percentile and limbs disproportionately long for trunk size (arachnodactyly), scoliosis, pectus excavatum or carinatum, high arched palate, flat feet and marked laxity of joints. Ocular features include non progressive upward subluxation of lens and myopia. Cardiovascular manifestations include mitral valve prolapse and dilatation of ascending aorta which lead to mitral or aortic regurgitation. Ghent nosology (Table 4) helps in the diagnosis of Marfan’s syndrome. Table 4: Ghent Nosology of Marfan’s Syndrome

occur in some of these patients. Mitral valve prolapse and spontaneous pneumothorax are rare manifestations. BJHS patients also display Marfanoid habitus increased skin stretchiness and other manifestations overlapping with other heritable diffuse connective tissue diseases. Brighton’s criteria will help to make a diagnosis of hypermobility syndrome (Tables 5 and 6). Table 5: Brighton Hypermobility Score – Nine Points No.

The ability to

Right

Left

1.

Passively dorsiflex the 5th metacarpophalangeal joint to >90°

1

1

Skeletal system (four or more of )

Ocular system

2.

Oppose the thumb to volar aspect of the ipsilateral forearm

1

1

Pectus carinatum Pectus excavatum Span to height >1.05 Wrist and thumb sign Scoliosis >20o Elbow extension 10o

1

1

4.

Hyperextend the knee to >10o

1

1

5.

Place the hands flat on the floor without bending the knee

1

Total

9

For index case: Diagnosis requires major criteria in at least two different organ systems and involvement of a third organ. For a relative of index case: Major criterion in one organ system and involvement of a second organ system.

Management Management of Marfan’s syndrome is multidisciplinary including periodic ophthalmology, orthopaedics, cardiovascular and rheumatology evaluation. Surgical intervention may be needed when scoliosis exceeds 45o. Cardiovascular care includes periodic ECG and echocardiographic evaluation for aortic root dilatation.Treatment with β-blockers decreases the rate of aortic root dilation and increases survival. Aortic surgeries for aneurysms, valve regurgitation using composite graft to replace both ascending aorta and aortic valve has markedly increased the survival in these patients. Pregnancy is better avoided in women with Marfan’s syndrome having moderate aortic dilatation. Benign Joint Hypermobility Syndrome Benign joint hypermobility syndrome (BJHS) is a common disorder which is strongly heritable. It is characterised by the development of symptoms in otherwise healthy individuals with hypermobile joints. Some of the workers regard it as being the same as Ehler-Danlos syndrome Type III (EDS-Hypermobility type). It is three times more common in females and exhibits a dominant inheritance with variable penetrance. Clinical features Trivial strain or injury to the joints, ligaments, tendons or enthesis can cause pain, swelling in these patients. Recurrent joint instability or subluxation could be the initial symptoms in some patients. Secondary osteoarthritic/spondylotic changes in the peripheral or spinal joints can occur later in life. Extra-articular features include soft silky skin, hiatus hernia, 1888 rectal prolapse, uterine prolapse and varicose veins which can

Table 6: The 1998 Brighton Revised Diagnostic Criteria for the Benign Joint Hypermobility Syndrome (BJHS) Major criteria A Brighton score of 4/9 or greater (either currently or historically) Arthralgia for longer than 3 months in 4 or more joints Minor criteria A Brighton score of 1, 2 or 3 out of 9 (0,1, 2 or 3 if aged 50+) Arthralgia in one to three joints or back pain or spondylosis; spondylolysis or spondylolisthesis Dislocation in more than one joint or in one joint on more than one occasion Three or more soft tissue lesions Marfanoid habitus Skin striae, hyperextensibility, thin skin or abnormal scarring Eye signs, drooping eye lids, myopia or antimongoloid slant Varicose vein, hernia, uterine/rectal prolapse BJHS is diagnosed in the presence of two major criteria or one major and two minor criteria or four minor criteria. Two minor criteria will suffice if there is an affected 1st degree relative. Major criteria one and two are mutually exclusive.

Management Simple analgesics or anti-inflammatory drugs are useful in pain and soft tissue injuries. The widespread chronic pain can be treated with serotonergic and noradrenergic agents. Physiotherapeutic approaches include building up of muscles responsible for joint and core stability, avoiding harmful postures and mobilising techniques to restore the normal tensile strength of lax tissues. Relapsing Polychondritis Relapsing polychondritis (RP) is a rare autoimmune disease of unknown aetiology with episodic but potentially progressive inflammatory manifestations, primarily involving cartilaginous structures of the ear, nose, eyes, airways and joints. It affects people of 40–60 years age group with equal frequency in both sexes. Over 30% of the cases are associated with an existing autoimmune or haematological disease (Table 7).

Table 8: Diagnostic Criteria for Relapsing Polychondritis

Rheumatoid arthritis Systemic lupus erythematosus Scleroderma Sjörgen’s syndrome Seronegative spondyloarthritis Wegner’s granulomatosis Polyarteritis nodosa Churg-Strauss vasculitis Behçet’s disease Myelodysplastic syndromes Lymphoma Inflammatory bowel disease Primary biliary cirrhosis

Major Criteria Proven inflammatory episode involving auricular cartilage Proven inflammatory episode involving nasal cartilage Proven inflammatory episode involving laryngo tracheal cartilage

Pathogenesis Autoimmune reaction of unknown aetiology stimulates the release of degenerative enzymes causing cartilage destruction. The cartilage matrix is initially infiltrated with mainly mononuclear and occasionally plasma cells and later leads to fibrosis and calcification. Clinical features Auricular chondritis is the key manifestation and is rarely absent in the course of the disease. Acute episodes manifest with pain, tenderness, swelling, warmth and marked redness affecting helix, antihelix or tragus sparing the soft lobule which lacks cartilage. Attacks resolve spontaneously within days but relapses invariably, leading to induration of pinna, drooping or cauliflower ear. Nasal conduits are far less obvious resulting in nasal pain tenderness mild swelling or redness and can cause saddle nose deformity. Laryngeal, tracheal and bronchial conduits can lead to hoarseness of voice, stridor, cough or expiratory dyspnoea. Costal chondritis provokes localised parietal pain and rarely results in depression of anterior chest wall. Joint manifestations vary from arthralgia to oligo or polyarthritis which can be acute and migratory or chronic nonerosive and non-deforming variety. Peripheral arthropathy is usually asymmetric and mainly affects the wrists, metacarpophalangeal and proximal interphalangeal joints, elbows, knees and ankles. Vestibular dysfunction, hearing impairment, conjunctivitis, uveitis, keratitis, episcleritis, ascending aortic aneurysm, glomerulonephritis, cutaneous or CNS vasculitis can also occur. Diagnosis Although the diagnosis of RP is relatively easy many conditions can mimic the initial changes or the associated disease may confuse the clinical picture. An empirical diagnostic criterion has been evolved (Table 8). Investigations Elevation of acute phase reactants occur during acute flares, tests for rheumatoid factor or ANA can be positive. Histological examination of the affected cartilage is suggestive of the diagnosis when it shows the association of degenerative changes with the presence of inflammatory cell infiltrates especially CD4+ lymphocytes, macrophages and polymorphonuclear cells. Loss of basophilic staining of the matrix is also seen reflecting the proteoglycan depletion.

Minor Criteria Ocular inflammation (Conjunctivitis, keratitis, episcleritis, uveitis) Hearing loss Vestibular dysfunction Seronegative inflammatory arthritis. When two major criteria or one major and two minor criteria are present diagnosis is confirmed.

Miscellaneous Rheumatic Disorders

Table 7: Conditions Associated with Relapsing Polychondritis

Treatment Systemic treatment is empirical and should depend on the clinical manifestation, disease activity and severity. In mild auricular or nasal chondritis and arthritis nonsteroidal antiinflammatory drugs (NSAIDS), colchicine, dapsone or low dose prednisolone can be used. Methylprednisolone ‘pulses’ (1gm/ day for 3 days) are useful in frank respiratory flares, recent sensory neural deafness or systemic vasculitis. Immunosuppression with methotrexate (0.3mg/kg/week) or cyclophosphamide (50-150 mg/day) in addition to steroids is used in severe resistant cases. Local steroids (eye drops, intra articular injections or inhaled steroids) are useful in ophthalmic articular or airway diseases. Airway obstruction or stenosis may need tracheostomy or stents. Neuropathic Arthropathy (Charcot’s Joint ) Neuropathic joint disease (Charcot’s joint) is a progressive destructive joint disease associated with sensory loss. The common causes are diabetes mellitus, leprosy, tabes dorsalis, syringomyelia, hereditary sensory neuropathies, amyloidosis and spinal cord trauma. Clinical features The distribution of the joint involvement depends on the underlying neuropathy as shown in Table 9. The onset of neuropathic arthropathy is usually gradual. The joint will be swollen and warm. Because, there is relatively little pain, patient often do not seek medical consultation until progressive deterioration has occurred. Arthralgia is well documented in 50% of patients though the symptoms are usually less than expected from the degree of joint destruction. Table 9: Joint Involvement in Neuropathic Arthropathy Disease

Site of involvement

Diabetes mellitus

Metatarsophalangeal, tarsometatarsal, intertarsal joints Tarsal, tarsometatarsal joints Shoulder, elbow, wrist Knee, ankle, intertarsal Metatarsophalangeal joint Knee, hip, ankle Knee, ankle

Leprosy Syringomyelia Hereditary sensory neuropathy Tabes dorsalis Amyloidosis

Investigations Plain radiography in early stages shows joint effusion periosteal calcification or minimal subluxation. Subsequently 1889

fragmentation of articular surface occurs leading to complete joint disorganisation. This is associated with prominent periosteal new bone formation. Osteocartilaginous bodies of synovial origin and fragments from articular surface lead to a great deal of osseous debris inside the joint. Osteosclerosis and osteophytosis are very prominent radiological features. Synovial fluid may be serous, sero-sanguinous and lipid crystals secondary to subchondral bone lesions may be seen. Treatment The management of Charcot’s joint consists of joint immobilisation and rest for stabilisation of the joint. Weight bearing may be avoided and orthotic devices like plaster cast crutches stabilising splints or braces are used as required to permit limited mobilisation.The treatment of basic neurological disease usually does not prove beneficent to the joint. Recently bisphosphonates like pamidronate have been used successfully to halt the underlying bone resorption in neuropathic arthropathy. Hypertrophic Osteoarthropathy Hypertrophic osteoarthropathy (HOA) is a syndrome characterised by abnormal proliferation of the skin and osseous tissues at the distal part of extremities, clinically manifesting as clubbing, periostosis of tubular bones and synovial effusions. HOA is classified as primary or secondary and the latter having very diverse aetiologies as shown in Table 10. There is now evidence to sustain the belief that clubbing and HOA represent different stages of same disease process. In majority of cases the finger deformity is the first manifestation and as the syndrome progresses periostosis becomes evident. Table 10: Classification of Hypertrophic Osteoarthropathy Primary (Patchy dermoperiostosis) Secondary Pulmonary Bronchogenic carcinoma, lung abscess, emphysema, Bronchiectasis Pulmonary fibrosis, Mesothelioma of pleura, arteriovenous fistula Cardiovascular Congenital cyanotic heart disease, bacterial endocarditis, Aortic aneurysm, Eisenmenger’s syndrome Hepatic Cirrhosis, hepatoma Intestinal Inflammatory bowel diseases, oesopharyngeal or colonic carcinoma Miscellaneous Graves’ disease, thymoma, thalassemia, connective tissue diseases

1890

Clinical features Primary HOA (Patchy dermoperiostosis) is an autosomal dominant condition characterised by insidious development of clubbing with cylindrical thickening of forearm and legs. Recurrent mildly symptomatic joint effusions may be accompanied. Facial features may be thickened and furrowed with nasolabial fold and a corrugated scalp known as ‘Leonine’ facies. Skin may show excessive sweating and a ‘greasy’ feel. Other features include gynaecomastia, acne vulgaris, striae and cranial suture defects. Investigations ESR may be elevated with increase in serum alkaline phosphatase (due to considerable new bone formation). Synovial fluid is characteristically non-inflammatory. Radiological examination shows periosteal new bone formation often seen in the tibia, radius, ulna, fibula and femur. The coarse layered appearance is most evident along the diaphysis. Radionucleotide bone scan and MRI are more sensitive in detecting periosteal reaction earlier than plain radiography. Treatment For patients with painful osteoarthropathy, NSAIDs are effective in alleviating pain. Treatment of the underlying disease results in dramatic regression of all features of secondary HOA. Vagal block and vagotomy are also helpful in symptomatic relief. Pigmented Villonodular Synovitis Pigmented villonodular synovitis (PVNS) is a benign proliferation of the synovial tissue that usually presents as an indolent progressive monoarthritis or tenosynovitis. The disease usually affects young adults. The synovium has a brownish colour and has numerous large fingers like villi. The proliferated synovium grows into the subsynovial tissue and invades the adjacent cartilage and bone. Patients often present with insidious onset of pain and swelling of the affected joint, most often the knee rarely hip or ankle. Radiographs show joint space reduction, erosions and subchondral cysts. Joint fluid can be brown or black in colour. Treatment consists of total synovectomy followed by irradiation of the joint. RECOMMENDED READINGS 1.

Lindsley CB, Petty RE, Hall JG. Primary disorders of bone and connective tissues. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Text Book of Paediatric Rheumatology; 5th Ed. Elsevier Saunders; 2005.

2.

Marini J. Heritable connective tissue disorders. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH. Rheumatology; 4th Ed. Mosby Publishers; 2007.

24.17 INTRODUCTION Rheumatological emergencies do occur in a considerable number of patients. The first presentation itself can be an emergency. Presentation may vary depending on the underlying disease process. If the underlying disease is already known, approach towards diagnosis is easier as compared to cases presenting for the first time. EMERGENCIES IN RHEUMATOID ARTHRITIS (RA) Septic Arthritis Septic arthritis is caused by pyogenic bacteria. The infection spreads through the bloodstream, or through surgery, an injection, or injury. The causative organism is usually Staphylococcus or Streptococcus. In adults, gonococci and mycobacteria may be the causative agent. Intravenous drug users and immunocompromised are more likely to have septic arthritis caused by gram-negative bacteria. Symptoms are, severe pain and swelling in the affected joint (Figure 1). Chills and fever are also common. Septic arthritis in the hip may be experienced as pain in the groin area that becomes much worse if the patient tries to walk. Synovial fluid should be tested for TLC, which is usually high, and for bacteria and other organisms. A culture of blood and synovial fluid should also be done and radiographs obtained to assess any joint damage. Antibiotics should be started and should be continued for at least six weeks. Draining the fluid from the infected joints may be required. Surgical drainage is reserved for septic arthritis of the hip, as that site is inaccessible for repeated fluid removal. Splinting can

Figure 1: Septic arthritis of the knee joint.

Emergencies in Rheumatology Lata S Bichile, Vaibhav C Chewoolkar relieve pain. After a period of rest, gentle exercise to prevent stiffness should be started. Recovery is usually good, although many patients will develop osteoarthritis or deformity. Atlantoaxial Dislocation Atlantoaxial subluxation is a well-recognised complication of RA. Anterior subluxation is most common, but vertical subluxation of the dens may also occur. Symptoms include paraesthesia, numbness, and muscular weakness. In severe cases this can result in spastic paralysis, paraplegia, tetraplegia, sensory loss and also loss of bladder control, faecal incontinence, and syncope. Physical examination may reveal upper motorneuron weakness, hyper reflexia, and a positive Babinski’s sign. Immediate immobilisation should be done. Magnetic resonance imaging (MRI) is valuable for the assessment of spinal cord damage. A single horizontal or vertical spinal dislocation without significant neurologic features requires no surgical intervention. A neck collar may suffice and, if necessary, nonsteroidal anti-inflammatory drugs (NSAIDs) and simple neck traction. Neurologic symptoms and signs of cord compression is a strong indication for neurosurgery. Different surgical techniques are now being developed which allow removal of the odontoid peg and/or fusion without the need for long periods of immobilisation. Rheumatoid Heart Disease Pericarditis and rheumatoid valve involvement occurs in seropositive patients with subcutaneous nodules. This usually involves the mitral and aortic valve. Rheumatoid aortic valve disease may be haemodynamically significant and it can be rapidly progressive simulating aortic cusp rupture. Pericarditis occurs in 30% to 50% of patients. Rapidly progressive effusive pericarditis is associated with high morbidity. Pericarditis resolves as the rheumatoid disease is controlled. Symptomatic patients generally respond to NSAIDs. Occasionally, glucocorticoids are required if the symptoms are severe. Heart failure will require diuretics and inotropic agents. Cardiac tamponade will require therapeutic aspiration. Valve replacement may be indicated in patients with severe or progressive valvular stenosis or regurgitation. Acute Upper Airway Obstruction Cricoarytenoid arthritis can occur in RA. Rheumatoid nodules can develop within the larynx and trachea and can erode through local structures. If large, the nodules can cause dyspnoea, due to obstruction of the larynx, especially during acute infections. Symptoms may range from dysphonia to frank aspiration and even acute airway compromise. Indirect laryngoscopy in the acute phase reveals erythema and swelling of the arytenoid mucosa. Operative direct laryngoscopy is the standard for definitive diagnosis of cricoarytenoid joint fixation. High resolution computed tomography (HRCT) is the investigation of choice in assessing cricoarytenoid involvement. 1891

Management consists of tracheostomy for an acute obstruction. Medical treatment includes corticosteroids at the earliest. Periarticular local steroid injections have helped in ameliorating acute joint dysfunction. EMERGENCIES IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Acute Transverse Myelitis It presents as a rapidly progressive motor, sensory and autonomic dysfunction. The risk increases in the presence of antiphospholipid antibodies (APLA) syndrome. The pathogenesis of acute transverse myelitis may be related to a vascular thrombosis, or to a direct interaction between antiphospholipid antibodies and membrane phospholipids at the spinal cord level. Clinical presentation is with sudden onset of leg weakness or sensory loss and/or bowel or bladder dysfunction. Evolution of the neurodeficit is complete by 1 to 2 days. Thoracic spinal cord is most commonly involved followed by lumbar and cervical. Cerebrovascular Accident Vasculitis, local thrombosis or artery-to-artery emboli sometimes manifests with clinical stroke syndromes (Figure 2). Emboli can occur as a result of Libman-Sacks endocarditis which produces sterile vegetations on the heart valves. Strokes may be secondary to treatment of SLE, as steroids can cause atherosclerotic changes. Evidence of disease activity in other organs is helpful. Important is to evaluate cerebrospinal fluid (CSF) to rule out infection. CSF abnormalities, such as elevated cell count, elevated protein, or reduced glucose, may be present in one-third of the patients. Low levels of C4 and other complement components have also been detected in the CSF. MRI appears to be superior to conventional computed tomography (CT). Nuclear magnetic resonance (NMR) spectroscopy may provide better demonstration of brain lesions.

who are HLA-B27 positive. Uveitis may also be seen in other spondyloarthropathies including reactive arthritis, undifferentiated spondyloarthropathy and psoriatic arthritis. Presentation is usually acute and unilateral, with a painful red eye,photophobia, increased lacrimation, and blurred vision. The involvement is usually anterior, rarely involving posterior elements. The iris is oedematous and discoloured. Pupil may become irregular if posterior synechiae form.There is copious exudate in the anterior chamber of the eye, which can be seen on slit-lamp examination. In most cases topical therapy with corticosteroid eye drops and mydriatics is all that is required.The eye may need to be protected from the light to ensure comfort during the period of pupillary dilatation. Administration of steroids orally, intravenously or by intraocular injection is required when local treatment fails to relieve the inflammation. Inadequate treatment may lead to adhesions and secondary glaucoma. EMERGENCIES IN VASCULITIDES Alveolar Haemorrhage and Pulmonary Renal Syndrome (PRS) Alveolar haemorrhage is a medical emergency and occasionally is the initial presenting manifestation. Pulmonary-renal syndrome is diffuse alveolar haemorrhage and glomerulonephritis occurring simultaneously. Haemoptysis is the most classic finding in combination with peripheral oedema and haematuria or other signs of glomerulonephritis. Bleeding is from low-pressure vessels but it is rarely massive. Haemoglobin levels can drop dramatically. Pulmonary infiltrates may be diffuse or patchy, and usually are perihilar, sparing the apices (Figure 3). The renal pathology is small-vessel vasculitis resulting in a form of focal proliferative glomerulonephritis. Goodpasture’s syndrome is the prototype cause, but Wegener’s granulomatosis, microscopic polyangiitis, and, less commonly, other vasculitides can also cause pulmonary renal syndrome.

Figure 2: MRI showing venous infarcts in SLE.

Corticosteroids are the most important class of drugs available. Methylprednisolone (0.5 to 1g per day) intravenously for 3 to 5 days followed by oral prednisolone 1 mg/kg should be employed. Intravenous cyclophosphamide (0.5 to 1 g) has also been reported to be effective in serious forms of central nervous system manifestations. With APLA, anticoagulation is necessary. For progressive unresponsive disease, plasmapheresis or intravenous immunoglobulin may be considered. Usual therapies for seizures should also be employed. EMERGENCIES IN SPONDYLOARTHROPATHIES Uveitis Uveitis is the most common extra-articular manifestation 1892 in ankylosing spondylitis. The incidence is higher in individuals

Figure 3: X-ray chest of a patient with pulmonary haemorrhage in Polyarteritis nodosa.

Initial testing includes urinalysis for evidence of haematuria and red cell casts (suggesting glomerulonephritis). Diffusion

Ultrasonography demonstrates oedematous bowel loops. Gastroscopy and colonoscopy can show signs of ischaemia and ulceration. Common CT findings include dilated bowel, focal or diffuse bowel-wall thickening, abnormal bowel-wall enhancement, mesenteric oedema, engorgement of mesenteric vessels and ascites.Vascular thromboembolism and aneurysms that involve fairly large vessels can also be demonstrated by conventional or CT angiography (Figure 4).

Emergencies in Rheumatology

capacity of carbon monoxide (DLCO) may be increased. Bronchoscopy is important to exclude infection and to document the presence of blood when there is no haemoptysis. Hemosiderin-laden macrophages provide proof that bleeding has occurred within the lung. Serum antibody testing may help distinguish some causes, such as antiglomerular basement membrane antibodies in Goodpasture’s syndrome, antinuclear antibodies (ANA), and anti-deoxyribonucleic acid antibodies in SLE, anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase-3 (PR3-ANCA) in Wegener’s granulomatosis, perinuclear ANCA (p-ANCA) in microscopic polyangiitis. Definitive diagnosis requires lung biopsy and/or renal biopsy. Standard therapy includes pulse intravenous methylprednisolone (500 to 1000 mg once a day for 3 to 5 days). Mechanical ventilation with high positive end expiratory pressure may be required. As life-threatening features subside, the dose can then be reduced to 1 mg/kg, prednisone tapered gradually over the next 12 weeks. Cyclophosphamide should be added at a dose of 0.5 to 1 g/m2 administered intravenously as a monthly pulse or 1 to 2 mg/kg per day orally. Maintenance therapy includes low-dose corticosteroids coupled with cytotoxic agents. Visual Impairment in Giant Cell Arteritis (GCA) Permanent visual loss is one of the most dreaded manifestations of GCA. Visual disturbances have been described in 25% to 50% of cases, although the incidence of visual loss is much lower, about 6% to 10% in most series. Blindness might be partial or complete. Other visual symptoms include transient or permanent diplopia or ptosis. Loss of vision in GCA is caused by inflammation in the arteries supplying the optic nerve head or retina. Involvement of the second eye can occur. On early fundoscopy, the optic disc is pale and swollen whereas the retina appears almost normal. Within 4 to 6 weeks, the optic disc becomes atrophic, with a chalky appearance. The retina will appear greyish, swollen and a contrasting red zone, ‘cherry red spot’, can be seen in the macula. Acute phase reactants like erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) are commonly elevated. Often there is normocytic normochromic anaemia. Colour doppler ultrasonography may show a dark ‘halo’ around the lumen of temporal arteries, stenoses or occlusion may also be found. Temporal artery biopsy, however, remains the gold standard. Oral steroids are commonly used but intravenous methylprednisolone can be used for severe cases. The treatment is initiated at 1 mg/kg per day of prednisolone for 4 to 6 weeks followed by taper of 5 mg every 1 to 2 weeks while monitoring clinical symptoms and ESR or CRP. Azathioprine has been shown to exert a modest corticosteroid-sparing effect. There has been a value of methotrexate in corticosteroid-resistant cases. Acute Mesenteric Vasculitis Abdominal pain caused by bowel ischaemia secondary to mesenteric vasculitis is an uncommon complication of systemic vasculitis. Bowel ischaemia can lead to perforation and haemorrhage, and has a high mortality. The onset may be acute and severe (e.g.mesenteric infarction) or chronic due to mesenteric ischaemia. Chronic mesenteric ischaemia may be manifested by a variety of symptoms including abdominal pain after eating (‘intestinal angina’), weight loss, nausea, vomiting and diarrhoea.

Figure 4: Coeliac angiography with superior mesenteric artery cannulation revealing aneurysm at porta hepatis in a patient with Polyarteritis nodosa.

Aggressive anti-inflammatory immunosuppressive treatment should be initiated. The treatment of choice is high-dose intravenous infusions of methylprednisolone or an equivalent agent. Use of heparin is a double edged sword and its use is to be decided on individual basis. In non responding patients and with severe haemodynamic compromise, surgical management is required. Mononeuritis Multiplex The onset may be sudden, with pain and paresthesias radiating in the distribution of a peripheral nerve, followed in hours or days by a motor deficit of the same peripheral nerve. This may progress asymmetrically to involve other peripheral nerves and produce a mononeuritis multiplex or a multiple mono-neuropathy. All sensory modalities and motor functions may be affected. Nerve conduction studies should be done at the earliest. Confirmation is by nerve biopsy. Small arteries in the epineurium are affected. Changes include fibrinoid necrosis in acute lesions to intimal proliferation and perivascular fibrosis in more chronic lesions. Methylprednisolone 500 to 1000 mg intravenously for 3 to 5 days should be used to obtain a rapid response followed by oral corticosteroids. Other immunosuppressives like cyclophosphamide, azathioprine, methotrexate, cyclosporine and Mycophenolate mofetil can also be used. Plasmapheresis and IVIG are reserved for fulminant cases. EMERGENCIES IN SYSTEMIC SCLEROSIS Scleroderma Renal Crisis Scleroderma renal crisis is characterised by sudden onset of accelerated hypertension, rapidly progressive renal 1893

insufficiency, microangiopathic haemolysis, and consumptive thrombocytopaenia. Markedly elevated plasma renin activity and dramatically rising creatinine is found in most cases. Renal crisis must be considered in any patient with scleroderma whose blood pressure rises even mildly above previous recordings. Vasospasm occurring on pre-existing renal arteriolar disease is thought to cause excessive renin release. The subsequent effects of angiotensin II induce further renal cortical ischaemia and fixed loss of cortical blood flow and necrosis. Vascular injury in the form of intimal disruption, fibrin deposition and microangiopathic haemolysis is the sequel. Corticosteroid therapy has been postulated as an associated factor. Anaemia and thrombocytopaenia occurs, blood smears demonstrating fragmented red cells, followed by increase of fibrin degradation products and reticulocytosis. Urine analysis typically reveals protein and red cells. Aggressive treatment improves outcome. Angiotensin converting enzyme (ACE) inhibitors should be used. When maximum doses of ACE inhibitors do not control the blood pressure, calcium channel blockers or vasodilators can be used, as needed. Dialysis may be necessary. ACE inhibitors should be continued since there may be delayed recovery of renal function. Renal transplantation can be done successfully. EMERGENCIES IN INFLAMMATORY MYOPATHIES Respiratory Muscle Weakness Significant respiratory muscle weakness may develop in patients with polymyositis or dermatomyositis. Both inspiratory and expiratory muscles may be affected, including the diaphragm. Bulbar weakness results in hoarseness or dysphonia, dysphagia with regurgitation of liquids. Pharyngeal and tongue involvement increases the risk of aspiration. Muscle biopsy should be performed in all cases to confirm the diagnosis. Arterial blood gases will show hypoxia with carbon dioxide retention. Chest radiograph should be done to exclude infection. A simple bedside investigation includes periodic single breath count. Increasing hypoxia, neck muscle weakness (Figure 5), falling single breath count, paradoxical breathing is an indication of impending respiratory failure and need for mechanical ventilation. Patient should be started on intravenous Methylprednisolone (1g per day) for 3 to 5 days followed by oral prednisolone 1mg/kg per day. IVIG or plasmapheresis has been successfully used for severe nonresponding disease. Biological agents like rituximab have been showed to be useful in a few case reports. Outcome is usually good with most patients regaining power to normal. Cardiac Disease Signs of cardiac involvement in PM and DM may be found in more than 70% cases. It is commonly asymptomatic, but can contribute to mortality. The activity of the cardiac disease may be independent of the myositis. The major manifestations include conduction disturbances, arrhythmias, and myocarditis. Less common is congestive heart failure due to myocarditis or fibrous replacement of the myocardium. Symptomatic pericarditis is rare. Although electrocardiographic abnormalities are frequent, most are minor non-specific ST-T wave changes. The MB fraction of 1894

Figure 5: Neck muscle weakness in a patient with polymyositis.

creatine kinase is frequently elevated. Treatment includes diuretics for cardiac failure. Dopamine or dobutamine should be added as per clinical requirement. ACE inhibitors should be used as these agents are known to prevent maladaptive remodelling. CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME Catastrophic antiphospholipid syndrome is a life-threatening complication where multiple thromboses of medium and small arteries in three or more organs can occur over a few days. This is discussed elsewhere. CONCLUSION Spectrum of emergencies varies from patient to patient. Superimposed infections, disease flares and adverse reaction to drugs can contribute to morbidity and mortality. A thorough knowledge, appropriate investigations and rapid, accurate treatment of rheumatological emergencies should favourably influence morbidity and outcome. RECOMMENDED READINGS 1.

Martens PB, Ho G Jr. Septic arthritis in adults: clinical features, outcome, and intensive care requirements. J Intensive Care Med 1995; 10: 246-52.

2.

Rosenbaum R. Neuromuscular complications of connective tissue diseases. Muscle Nerve 2001; 24: 154-69.

3.

Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43: 2437-44.

4.

Teener JW, Raps EC. Life-threatening complications of autoimmune disease: evaluation and treatment of respiratory failure in neuromuscular disease. Rheum Dis Clin North Am 1997; 23: 277-92.

Section

25

Nutrition Section Editor: S.V. Madhu 25.1 Nutrition—Basic Considerations S.V. Madhu

1896

25.2 Assessment of Nutritional Status Prema Ramachandran

1900

25.3 Protein Energy Malnutrition Piyush Gupta

1904

25.4 Water Soluble Vitamins Milind Y. Nadkar

1909

25.5 Fat Soluble Vitamins Ghan Shyam Pangtey

1913

25.6 Minerals, Trace Elements and Antioxidants M. Raghunath, D. Sreeramulu

1917

25.7 Food Allergy and Food Intolerance U.V. Mani

1922

25.8 Eating Disorders Anupam Prakash

1924

25.9 Enteral and Parenteral Nutrition Varsha

1927

25.1 INTRODUCTION The word nutrition comes from the Latin word nutrire, to suckle or feed—the primary act of suckling so characteristic of the process of nutrition. Nutrition by definition is the process of nourishment while nutrient is the substance that provides nourishment. Humans not only need nutrients for their nourishment but they also need it in sufficient amount. Nutrients are classified as macronutrient or micronutrient based on daily requirement. Macronutrients include carbohydrates, proteins, fats and minerals like calcium, phosphorus, sodium, chloride, potassium, sulphur and magnesium. Vitamins and minerals that are required in amount less than 100 mg per day constitute micronutrients. Nutrients that cannot be synthesised in body are called essential. While carbohydrates, fats and proteins mainly provide energy and help in tissue building and maintenance, vitamins and minerals mainly support metabolism. Hence, a person must consume a balanced diet to provide all the nutrients in proper measure, known as requirements. A requirement is defined as the lowest continuing intake of a nutrient that will maintain a defined level of nutrition in an individual. GENERAL PRINCIPLES OF DIETARY RECOMMENDATIONS Dietary standards are basically the average daily amounts of essential nutrients required to meet the physiological needs of practically all healthy persons in a group with specified characteristics. It is estimated on the basis of available scientific knowledge. These standard values are together called dietary reference intake (DRI). These include estimated average requirement (EAR), recommended daily allowance (RDA), adequate intake (AI) and tolerable upper intake level (UL). A nutrient has either EAR and an RDA, or an AI. When an EAR for the nutrient cannot be determined (and therefore, neither can the RDA), then an AI is set for the nutrient. Dietary Reference Intakes Estimated average requirement (EAR): Average daily nutrient intake level estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group. Recommended dietary allowance (RDA): Average daily nutrient intake level sufficient to meet the nutrient requirement of nearly all (97% to 98%) healthy individuals in a particular life stage and gender group. Adequate intake (AI): A recommended average daily nutrient intake level based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate, used when an RDA cannot be determined. Tolerable upper intake level: Highest average of daily nutrient intake level likely to pose no risk of adverse health effects to 1896

Nutrition—Basic Considerations SV Madhu almost all individuals in the general population. As intake increases above the upper intake level, the potential risk of adverse effects increases. RDA AND ITS IMPORTANCE RDA is estimated by first evaluating the EAR for an absorbed nutrient by healthy individual’s representative of a sex and age group. An amount is then added as a safety factor which is to compensate for the individual variation and bioavailability of nutrients in commonly consumed foods. When the standard deviation (SD) of the EAR is available and the requirement of the nutrient follows Gaussian distribution, the RDA is calculated as: RDA = EAR + 2SDEAR In cases where SD is not available, a coefficient of variation of 12.5% is assumed and RDA is 25% (+ 2SD) higher than the mean requirement. Adult men and women differ in their nutrient requirements to a small degree but requirement in the latter group alters significantly during pregnancy and lactation. RDA should be such that it allows maximal rate of growth, prevents biochemical and clinical abnormalities, allows for saturation of enzymes and co-factors, accounts for obligatory losses and builds up the stores. They meet the requirements only when all other nutrients are also provided in optimal amounts. For example, giving fat soluble vitamins according to RDA in the presence of very low fat content food will lead to vitamin deficiency despite being given at RDA levels. However, it must be recognised that RDA is not meant to be used as standard to determine whether or not a given individual requirement has been met, since it is a level above the requirement of most individuals in a given population. RDA for Indians The first attempt towards defining the dietary allowances for Indians was made by the Nutrition Advisory Committee of the Indian Research Fund Association [now Indian Council of Medical Research (ICMR)] in 1944. The ICMR constituted an Expert Group in 2008 to revise and update the nutrient requirements and dietary allowances for the Indian population. This is the Sixth Expert Group constituted by the ICMR. The last Group was constituted in 1988. The committee was guided by the newer developments that are published in FAO/World Health Organisation (WHO)/UNU reports and background information generated by research and surveys in India. Since RDA is the average daily dietary intakes sufficient to meet the nutrient requirement of nearly all healthy individuals, it is necessary to take into account the factors that influence the metabolism of food nutrients. These are: (i) the bioavailability, and (ii) the individual variability.

The energy expended includes the expenditure at rest (basal metabolic rate), physical activity and thermogenesis (specific dynamic action of foods). Pregnancy and Lactation Extra energy is required during pregnancy and lactation for the growing foetus and infant, respectively. According to the recent ICMR recommendations, the additional intake of energy is changed to 350 Kcal/day during second and third trimesters of pregnancy, 600 Kcal/day for the first 6 months of lactation and 520 Kcal/day in next 6 months. DIETARY SOURCES OF ENERGY Carbohydrates, fats and proteins constitute the sources of energy. Each gram of carbohydrate and protein gives 4 Kcal each while a gram of fat gives 9 Kcal of energy. These three energy sources are to be balanced such that the person receives enough protein for tissue building and maintenance, and sufficient carbohydrate and fat to fulfil the energy requirement. Carbohydrates Carbohydrates account for the major part of energy requirement. They are basically made of either simple sugars or complex sugars. Recent scientific evidence considers the unhealthy role of simple sugars. Hence, it is recommended that simple sugars should not account for more than 10% of total energy. A wide range of carbohydrate (55% to 75%) intake should be from whole grains and legumes, vegetables and fruits. Proteins The dietary proteins are essential to provide amino acids for the synthesis of body proteins, both structural proteins and biologically active enzymes and other biologically important nitrogenous compounds in the body. Adequate dietary protein is essential during growth in children. In the adult, it is essential for the synthesis of new proteins to replace those, which are being broken down. Additional proteins are also required during pregnancy and lactation for the growing foetus and infant. There are eight essential amino acids (EAA) that are considered essential as they cannot be synthesised in the body. They need to be provided in proper proportions and in adequate quantities to synthesise tissue proteins in the body. In a diet, proteins are to be provided in proper quantity as well as proper quality. The quality of protein depends on its ability to supply the required amounts of essential amino acids. Animal proteins are generally considered to be of better quality. Egg protein is used as a reference against which the other proteins are compared. Vegetable proteins lack one or the other EAA, such as lysine or methionine. Lysine is the limiting amino acid in most

cereals while methionine in the pulses. The biological quality of a mixture of vegetable proteins based on cereals and pulses is only 65% as compared to 100% of egg protein. The safe level of intake in terms of dietary protein is 1.0 g/kg body weight per day. Additional protein requirements of 15 g per day during pregnancy and 25 g per day during 0-6 months of lactation have been recommended. Fats Fats being concentrated forms of energy, both optimum and safe intakes need to be mentioned while recommending fats. Source of the fat in diet can be from visible sources or from invisible sources. Visible sources include vegetable oils or animal. A substantial amount of fat is present in cereals, pulses and vegetables which form the invisible fat.

Nutrition—Basic Considerations

ENERGY REQUIREMENT The energy requirement of an individual has been defined by WHO in 1985 as “the level of energy intake from food that balances energy expenditure when the individual has a body size and composition and level of physical activity, consistent with long-term good health, also allowing for maintenance of economically essential and socially desirable activity. In children, and pregnant and lactating women, it includes the energy needs to be associated with the deposition of tissues or secretion of milk at rates consistent with good health”.

Like amino acids, there are fatty acids that are essential for body and are called essential fatty acids (EFAs). Generally referred as polyunsaturated fatty acids (PUFAs), they include linolic and alpha-linolenic acid. The minimum amount of fat that should be taken by average Indian adult is 20% of total energy (TE); 10% from visible sources and 10% from invisible sources. However, the fat intake should not exceed 30% of TE. Of these saturated fatty acids should not exceed 10% of TE. 10% of TE should be from PUFA. The remainder should be from monounsaturated fatty acid (MUFA). Dietary Fibre Dietary fibre which forms an indigestible and important component of plant foods were never considered as source of energy. Some dietary fibres undergo fermentation in the colon and yield short chain fatty acids. These are used as source of energy by the colonic cells and by the liver. Up to 2.6 Kcal of energy is derived from a gram of fermentable foods and no energy from non-fermentable fibre. Normally, 70% of fibres are fermentable. Hence, energy conversion factor for fibre is taken as 2.0 kcal/g. The intake of 40 g/2000 kcal may be rationalised in different groups based on recommended energy intake. MALNUTRITION A decade ago, in India, malnutrition meant mostly undernutrition. But India now being a country in developmental transition, has come to face the other burden of malnutrition, namely overnutrition. With 10% rural adults and 20% urban adults suffering from overnutrition, India is in nutritional transition as well. Pre-transition undernutrition and posttransition overnutrition are together leading to an emerging double burden of malnutrition. Undernutrition Undernutrition has improved compared to post-independence time substantially but the improvement has slowed down with very little improvement in last few years. Though severe clinical forms of protein-energy malnutrition (PEM) and other nutrient deficiencies are reduced to major extent, there are still subclinical forms of deficiencies that are persisting. Around 36% of women and 34% of men are still having body mass index (BMI) below normal. More than 50% women (particularly pregnant women) and children suffer from iron deficiency anaemia (IDA). The fight against undernutrition is becoming more and more difficult because for every frank case of nutrition deficiency,

1897

there are dozens of others suffering from subclinical malnutrition who are missed. Factors causing undernutrition It is necessary to look into the factors that are responsible for undernutrition in order to fight against it. Factors like Illiteracy and low socioeconomic status were responsible for undernutrition in post-independence India, the same factors are still playing the main role 60 years after independence. Women, especially pregnant women and children are the vulnerable risk groups. Rural areas have more percentage compared to urban, almost double in case of adults according to National Family Health Survey-3 (NFHS-3). In case of children, higher birth order and the nutritional status of mother are also important risk factors. Over that, the never ending cycle of undernutrition leading to infections, which in turn leads to undernutrition, makes the problem more complicated. Protein Energy Malnutrition (PEM) Despite various government schemes undernutrition is still a major problem in our country. Among children less than 3 years, there are 45% who are stunted, 23% who are underweight and 40% who are wasted. The problem is more in rural, uneducated and low socioeconomic households. Despite the efforts of various organisations, the problem still persists because of lack of awareness and motivation. Even among adults 36% of women and 34% of men are underweight. With the problem involving well more than one-third of Indian population it will have negative impact on the health and development of the country. Macromineral Deficiency Among the macrominerals calcium (Ca2+) deficiency has been the main concern. Other macrominerals are sufficient in the diet and do not cause any deficiency. Although intakes according to previous ICMR (1988) survey have been successful to reduce fracture rates, it has resulted in compromises in stature and restriction in the function of the skeletal system. Human body has the ability to adapt to different levels of intakes of Ca2+ and maintain a positive Ca 2+ balance even at 400 mg per day. This prompted earlier committee to fix 400 mg per day as RDA. Despite more than 50% of the adult population obtaining the RDA level of 400 mg per day, there is evidence of widespread Ca2+ depletion as indicated by bone density measurements, particularly in women after repeated pregnancies and lactation. These observations lead to new RDA of 600 mg per day. Micronutrient Deficiency Even though micronutrients are required in small amounts, they are essential in various body functions. Hence, even slight deficiency can present profoundly. Moreover, many of these are present in lesser amounts in diet and are easily altered by various cooking practices. Among minerals iodine and iron deficiencies are important public health problems. Iodine deficiency is the single greatest cause of mental retardation both worldwide and in India. Also iodine deficiency disorders (IDDs) are one of the most important micronutrient deficiency disorders of public health significance in India. Environmental factors and goitrogens in food are the 1898 two main factors responsible for deficiency. A study conducted

by National Institute of Nutrition (NIN) and Director-General of Health Services (DGHS) in 2003, in 40 districts, revealed that the overall prevalence of total goitre registered a significant decline from 14% to 69% during 1984-94 to 2% to 40% in 2003, especially in the Northeastern regions after universal iodisation. But with focus now on whole spectrum of IDD, 263 out of 324 districts surveyed by DGHS have been labeled as endemic. Iodine deficiency has ceased to be a disease of high altitudes. Also living on the sea coast does not guarantee iodine sufficiency, as significant pockets of iodine deficiency have been reported from the coastal regions too. According to NFHS-3 only half of the children below 5 years live in household using iodised salt, same as reported during NFHS-2. A lack of iodine in the diet can lead to IDD, which can cause miscarriages, stillbirths, brain disorders, and retarded psychomotor development, speech and hearing impairments, and depleted levels of energy in children. Iodised salt effectively will account for only half of RDA and so the food practises should be altered to avoid goitrogens in the food. Hopefully the ban on un-iodised salt by the Government of India (in 2006) will improve the scenario in coming years. Iron is the other micromineral that poses a public health burden. Around 70% of children, 55% of women and 24% of men are anaemic according to NFHS-3. In a study conducted in slum children, 75% of anaemia responded to iron and 22% to vitamin B12. The situation has actually worsened in children and women compared to NFHS-2 despite various government schemes. Widespread zinc (Zn) deficiency has been thought as a possible cause for growth failure and morbidity in children according to some available data. But lack of supportive evidence of lowered blood Zn levels and other causes that can manifest as the symptoms assumed to be due to Zn deficiency makes it difficult to attribute them to Zn deficiency specifically. Vitamin deficiencies are also significant. Although there has been a significant reduction in severe clinical forms of vitaminA deficiency, it is still a public health problem with 40% to 60% children in developing countries showing inadequate biochemical status of vitamin A. Only 25% of below 3 years children received vitamin A supplementation in last 6 months. Very low intakes, poor bioavailability of pro-vitamin A from the predominantly vegetarian diet and recurrent infections are thought to be the main reasons for widespread prevalence of vitamin A deficiency. While the severe forms of bone disease are no longer prevalent in children now, growing urbanisation, reduced physical activity and low exposure to sunlight has contributed to a spurt of vitamin D deficiency ( VDD) as evidenced from low circulating vitamin D levels. Among water soluble vitamins thiamine, riboflavin, folic acid and B 12 deficiencies are important concern. According to National Nutrition Monitoring Bureau (NNMB), 40% households meet RDA of thiamine and only 13% do so for riboflavin. According to various studies, it is estimated that the B12 deficiency involve up to 30% to 40% of Indian population. OVERNUTRITION With increased usage of unhealthy processed foods, decreased usage of time tested traditional diets and increased sedentary lifestyles; India is fast approaching other developing countries

who are malnourished, i.e. both under-nourished and overnourished, does not vary too much across various states or in urban and rural population. The reason being, as the percentage of under-nourished are decreasing, there is an increase in number of adults who are overweight.

Though clear-cut nationwide data are not available on childhood obesity, it is estimated that around 25% of urban children are obese. This is to be taken seriously as these children carry a significant risk of developing diabetes, hypertension, metabolic syndrome and coronary heart disease (CHD) in the future as they grow into adulthood. The percentage of adults,

1.

Dietary Reference Intakes: Applications in Dietary Assessment. Washington, National Academy Press; 2000.

2.

International Institute for Population Sciences (IIPS) and Macro International. National Family Health Survey (NFHS-3), 2005-6: India: Volume I. Mumbai: IIPS; 2007.

3.

Nutrient Requirements and Recommended Dietary Allowances for Indians. A Report of the Expert Group of the ICMR. Hyderabad: NIN; 2009.

Hence, the planning to correct undernutrition has to consider even the possible problem of overnutrition in future. Unless correct measures are taken regarding proper balanced diet, India might become obesity capital as well apart from already being diabetes mellitus capital. RECOMMENDED READINGS

Nutrition—Basic Considerations

which are becoming more obese. According to NFHS-3, around 9% of adult men and 13% of adult women are overweight. Even rural areas are not behind with 10% of adult population of rural area being overweight. Obesity is becoming a substantial problem among several groups of women in India, particularly women living in urban areas, who are well educated, and those from households with a high standard of living. Approximately 25% in each of these groups have a BMI of 25 or more. Indians already being at risk for obesity and diabetes due to their ethnicity, the rising trend of over nourishment might put more burden compared to what it could do in other developing or developed countries.

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25.2 INTRODUCTION It is well known that nutritional status is an important determinant of health and modifier of course and outcome of diseases. Nutritional status is normal when the food and nutrient intake of the person is sufficient to meet the requirements for normal physical activity, and physiological requirements for growth and development. Balanced diet and adequate physical activity promote normal nutritional and health status and protect against illnesses due to lack or excess of nutrient intake. Appropriate nutritional care during illness can reduce the severity, shorten the duration of illness, hospitalisation and convalescence. Therefore, assessment of nutritional status of the individual seeking health care should be incorporated as a part of promoting good health as well as clinical management of illness. Health care seekers are becoming increasingly aware of the importance of nutrition and collect information from individuals about: (i) nutritional status; (ii) appropriate and sustainable diets and lifestyle that will prevent illnesses and protect and promote health; and (iii) dietary management during illness that will provide symptomatic relief and promote rapid recovery. Undergraduates and postgraduates should have the necessary knowledge and skills for assessment of nutritional status and providing appropriate nutrition advise to the individuals, families and communities for prevention and management of under- and overnutrition and nutrition care during illness and convalescence. PARAMETERS FOR ASSESSMENT OF NUTRITIONAL STATUS Major parameters used for assessment of nutritional status are:  Dietary intake – Food frequency method – 24-hour recall  Physical activity pattern  Clinical assessment of nutritional deficiency signs  Anthropometric assessment of nutritional status  Body composition studies using various techniques  Biochemical assessment. Assessment of Dietary Intake Dietary intake of individuals, families and communities vary depending upon their socioeconomic status, dietary habits and customs. Information of nutrient intake will help in identifying factors responsible for under- and overnutrition and micronutrient deficiencies which could have contributed to illness. Illness may modify the dietary intake and aggravate nutritional deficiencies. 1900

Food frequency questionnaire provides a relatively rapid and easy method of assessing food consumption of the individual,

Assessment of Nutritional Status Prema Ramachandran including meal and dietary patterns, specific foods avoided or preferred. Food frequency questionnaire will not give any idea about the quantities in which the food stuffs are consumed which is an important determinant of deficiency or excess. Diet history using 24-hour recall is an excellent tool to obtain information on the family cooking patterns, intra-family distribution of food and individual’s dietary intake. Diet survey using 24-hour dietary recall should not be done on the day following holidays or festival or fast days because dietary intake on these days will not be representative. Single day 24-hour dietary recall cannot be taken as accurate representation of dietary intake of the individual but if repeated over time may provide useful information whether nutrition counselling has resulted in on dietary modifications of the individual. Available data from diet surveys in India indicate that Indian diets remain predominantly cereal-pulse based. Dietary intake in poor segments especially in children and adolescents are below the requirement; as a result undernutrition rates are high. Low intake of vegetables and fruits, poor bioavailability of iron, and lack of universal use of iodised salts are responsible for micronutrient deficiencies being major public health problems even today. Even segments of population with no economic constraints, do not consume diversified balanced diets with adequate intakes of fruits and vegetables, animal/dairy products. In some urban affluent segments there is an increase in consumption of junk food, rich in carbohydrates and fat, resulting in rapid increase in obesity in these groups. Assessment of dietary intake and appropriate advise is important for maintenance of optimal health and combating over- and undernutrition. Physical Activity Pattern Physical activity pattern is emerging as an important determinant of nutritional status both in urban and rural areas. Earlier majority of men and women in rural and urban areas were moderately active. However, increasing access to mechanised transport, access to water and fuel in the vicinity of the house hold and increasing mechanisation of the occupational activities have resulted in a steep decline in physical activity. This in turn has resulted in substantial reduction in energy requirements of the individual. Steep reduction in physical activity and relatively unchanged energy intake have been identified as the major factors responsible for rising obesity rates in urban and rural populations. In some urban affluent groups, increased intake of energy dense junk food and sedentary lifestyle are emerging as major factors associated with overnutrition. Nutrition surveys carried-out by the National Nutrition Monitoring Bureau (NNMB) has shown that by mid nineties there had been a steep reduction in physical activity not only in urban but also in rural areas (Table 1). Health education

Table 1: Physical Activity Pattern in Rural Adults Based Upon NNMB Survey 1994-95 Activity status

Sedentary Moderate Heavy Pooled

Men

Women

Total

No.

%

No.

%

No.

%

1349 2650 48 4047

33.3 65.5 1.2 100.0

2765 1632 14 4411

62.7 37.0 0.3 100.0

4114 4282 62 8458

48.6 50.6 0.8 100.0

NNMB = National Nutrition Monitoring Bureau.

Clinical Assessment of Nutritional Status In the last century, clinical assessment of nutritional deficiency signs was a very important component of assessment of nutritional status. However, with improvement in dietary intake and better access to health care, there has been a steep decline in the prevalence of clinical signs of deficiencies. Pellagra, scurvy, keratomalacia are no longer seen. Even in tertiary hospitals, kwashiorkor, and marasmus are rarely seen. Glossitis, angular stomatitis (suggestive of vitamin B complex deficiency), Bitot’s spots (vitamin A deficiency) are seen in less than 1% of children and adults. There has been a steep decline in goitre even in the erstwhile goitre belt. Even though clinical forms of macro- and micronutrient deficiencies have become uncommon, subclinical biochemical deficiencies continue to be common. It is a matter of concern that unlike all other nutritional deficiencies, there has not been any change in the prevalence of anaemia. Clinical signs of anaemia are non-specific (easy fatiguability, pallor, oedema feet) and do not revert soon after therapy, e.g. spoon shaped nails. It is not possible to clinically assess severity of anaemia and response to iron therapy; so estimation of of haemoglobin by cyanmethaemoglobin method is the best method for diagnosis of anaemia and assessing response to therapy. Majority of Indians irrespective of age, sex and socioeconomic status are iron deficient and anaemic; in view of this whenever any person seeks health care for any reason, they should be screened for anaemia and appropriate treatment provided for all anaemic persons. Anthropometric Assessment Anthropometric assessment is one of the most widely used methods for assessment of nutritional status both at the community level and for the individuals because of the relative ease and reproducibility of measurements, availability of standards based on normal population for comparison and demonstrated association between abnormal measurements and clinical illnesses. In the past when undernutrition was the major problem, weight and height were the most widely used measurements for the assessment of nutritional status. Height is the index that reflects the cumulative impact of past undernutrition. Weight is the index that reflects partly the cumulative impact of past undernutrition (because stunting is

associated with lower body weight) and partly current nutritional status [low body mass index (BMI) for the current height is associated with lower body weight]. With the emergence of dual nutrition burden, BMI (weight in kg/height in m2) has been increasingly used for the detection of both under- and overnutrition, especially in developing countries where stunting is common. In children BMI varies with age; World Health Organisation (WHO) has published the standards for BMI for age from 0 to 5 years in 2006 and 5+ to 18 years in 2007 and recommended that BMI for age which takes current height, weight and age into account and assesses current energy deficit or excess, should be used for the assessment of nutritional status, detection of both under- and overnutrition in children. India has accepted the WHO standards (2006 and 2007) for height, weight and BMI for age for assessment of under- and overnutrition in infants, children and adolescents. For adults, BMI has long been used as an indicator for both overand undernutrition.

Assessment of Nutritional Status

about exercise to become a part of daily routine to promote muscle and bone health and prevent development of adiposity in all age groups is critical for prevention of overnutrition and associated health hazards. As and when any person seeks health care, the opportunity should be utilised to assess nutritional status and physical activity and advise appropriate lifestyle modifications.

Measurement of length/height In infants and children who cannot stand erect recumbent length is measured using either a stadiometer or an infantometer (Figure 1). In the past, height was measured using anthropometry rod or stadiometer. In recent years when almost all health care institutions have a vertical wall and good cement flooring, there is a greater tendency to use simple wall mounted tape instruments to measure height in children and adults in hospital settings. The instrument is hung on the wall exactly two meters from the floor. To measure height accurately, the person is made to stand erect with back of heels, knees, buttocks, shoulder and head touching the wall. The head is to be positioned in Frankfurt plane (lower margin of the orbital fossa in the horizontal line with the external auditory meatus) and the horizontal limb of the instrument is brought down, so that it lies on the top of the head. The reading at the horizontal red mark on the tape is the height of the person.

Figure 1: Measuring length in infants.

Height is an excellent indicator of cumulative past undernutrition; serial height measurements in children can indicate whether they are growing according to their trajectory or deviating from it. Data from national surveys of India indicate that average height in men and women are about 160 cm and 150 cm, respectively and about 11% of women have height below 145 cm. Low birth length, stunting in childhood (nearly half of the pre-school children are stunted) and adolescence are major factors responsible for the low adult height in Indians.

1901

Measurement of weight During the last century accurate beam balances were used for measurement of weight in clinical settings. These balances were heavy and could not be shifted readily from one place to another. With the advent of electronic balances, it has became possible to measure weight with 100 g accuracy using a battery operated, relatively inexpensive, light and readily portable balances (Figure 2). In the past when undernutrition was the most common nutritional problem in the country, weight was the most widely used measurement for assessment of nutritional status in adults and children because it provided some insight into past and current energy deficiency. Underweight individuals are more prone for infections and infections can result in further deterioration in body weight. Nutritional support during illness and convalescence can limit and reverse the weight loss associated with illnesses. Data from national surveys indicate that mean weight in men and women are 45 and 53 kg, respectively. It is estimated that about half the children and a third of adult men and women are underweight in Indian population.

women are overnourished (Figure 3). India has entered the dual nutrition burden era; all practising physicians should assess the current nutritional status using BMI and provide appropriate advise regarding dietary intake and physical activity to all persons seeking health care.

Figure 3: Nutritional status of children and adults-NFHS 3.

Waist circumference With the emergence of non-communicable diseases as an important cause of morbidity in our country, it has become very important to measure waist circumference as an index of central adiposity. This correlates very well with insulin resistance and is a good indicator of the risk of diabetes and cardiovascular diseases. It is measured as the smallest circumference mid way between iliac crest and lower end of rib cage in standing position and at end of expiration. Waist measurements of 90 cm or above in males and 80 cm and above in females indicate central obesity in Asian Indians.

Figure 2: Measuring weight on an electronic weighing machine.

Computation of BMI With the emergence of dual nutrition burden it has become essential to assess current energy deficiency and excess; BMI which provides this information has been increasingly used for assessment of nutritional status. Low BMI is associated with increased susceptibility to infections; high BMI is associated with increased risk of cardiovascular diseases. Earlier the computation of BMI was considered difficult in clinical settings; however, with the ready availability of calculators (even in mobile phones), it has become very easy to compute BMI. In adults, cut-off points used are less than 18.5 for undernutrition and more than 25 for overnutrition. In children BMI varies with age; WHO’s BMI for age chart can be used to assess whether the child is undernourished or over-nourished. Data from NFHS-3 indicate that if BMI is used as the indictor for the assessment of nutritional status, about 17% of pre-school children and a third of men and women are under-nourished; about 2% of pre-school children and 9% of men and 13% of 1902

Assessment of Body Composition The Indians have higher body fat for a given BMI as compared to Caucasians; higher adiposity in Indians begins in infancy and childhood. Both amount and distribution of the adipose tissue have been shown to influence the risk of cardiovascular diseases; therefore, increasing attention being paid to fat mass and its distribution. Earlier circumferential measurements (mid arm circumference, waist and hip circumferences and waist/hip ratio) and measurement of fat fold thickness (triceps, biceps, supra-iliac and subscapular fat folds measured using Harpenden’s calipers) were commonly used for the assessment of fat mass and its distribution. Fat fold measurement requires a trained and skilled person; this has come in the way of widespread use of this relatively simple technique. In recent years, bioelectrical impendence measurement has been widely used in clinical settings for the assessment of total fat. Fat mass estimation by bioelectrical impedance assessment (BIA) when combined with the measurement of mid arm, waist and hip circumference can be used to differentiate overall, truncal and abdominal obesity. Epidemiological studies have explored the relative risk of diabetes and cardiovascular diseases with overall adiposity, truncal adiposity and abdominal adiposity, and also as between subcutaneous, intraperitoneal and retroperitonal fat accumulation in abdominal adiposity. Available data suggest

Biochemical Assessment of Nutritional Status Ideal biochemical test should be non-invasive, easy to carryout, specific, sensitive and preferably inexpensive. Such ideal tests are very few. In the development of any disease associated with deficiency or excess of nutrients, it is logical to expect that biochemical changes precede clinical manifestations. Biochemical tests can, therefore, expected to provide early warning of impending clinical problems. Biochemical tests in blood and urine can help diagnosis of the deficiency at the subclinical stage and confirm the clinical diagnosis. It has been reported that biochemical evidence of many vitamins and minerals have been seen in nearly half the apparently normal children and adults. It may not always be possible to get good correlations between biochemical tests, dietary intake and clinical parameters because of the wide range of normal biochemical values, varied rates of change of biochemical parameters, clinical deficiency and functional impairment. Inspite of these inherent limitations, biochemical tests have been widely used for the assessment of subclinical macro- and micronutrient deficiencies and excesses and risk of or confirmation of clinical problems. While isolated single biochemical estimation may not be of much use in the assessment of nutritional status, well chosen tests combined with dietary history, physical activity patterns and clinical examination findings provide complete information on nutritional status of the individual. Commonly used biochemical tests for the assessment of nutritional status and associated disease risks are dealt with in the respective chapters. CONCLUSION India is currently in the midst of socioeconomic, demographic, lifestyle, nutritional and health transition. Undernutrition continues to affect large segments of the population and is associated with increased risk of morbidity due to infections; simultaneously obesity and associated risk of non-

communicable diseases are emerging as important public health problems, especially, among affluent segments of the society. Data from India also indicate that undernutrition in early life, followed by increased energy intake and sedentary lifestyle predispose to overnutrition and risk of non-communicable diseases during adult life. Physicians and programme managers have to play a critical role in combating the dual nutrition and disease burden and enable the country to achieve rapid improvement in health and nutritional status of the population through: (i) assessment of nutritional status of the community through appropriate screening; (ii) appropriate nutrition and lifestyle counselling for health promotion and health protection; and (iii) promoting synergy between health and nutrition services.

Assessment of Nutritional Status

that abdominal adiposity is a part of metabolic syndrome which is associated with increased risk of both type 2 diabetes and cardiovascular disease risk.

Assessment of nutritional status is an important component of both public health interventions and care of individuals seeking health care. Ideally nutritional assessment should be carried out periodically in all individuals and more often during vulnerable segments of population such as children, adolescents, pregnant and lactating women and elderly citizens. Our population and the health systems is still not geared to such routine periodic assessment and appropriate counselling for health promotion and early detection and effective management of nutritional deficiencies and excesses before clinical problems arise. In view of this, assessment of nutritional status should be carried out as and when there is an opportunity—as a part of community based nutrition surveys—and when any person seeks health care. Once assessment is done appropriate advice should be given depending upon their nutritional status. RECOMMENDED READINGS 1.

Bamji’s MS, Prahlad RN, Vinodini R. Text Book of Human Nutrition; 2nd Ed., New Delhi: Oxford and IBH Publishing Co., Pvt Ltd; 2003.

2.

National Family Health Survey (NFHS-3): http://mohfw.nic.in/nfhsindia.org/ india3.html.

3.

Ramachandran P. Nutrition transition in India 1947-2007. www.wcd.nic.in //publications/reports.

4.

WHO multicentre growth reference standards 2006. www.who.int/entity/ childgrowth/mgrs/fnu/en/index.html.

1903

25.3 INTRODUCTION Adequate food and nutritions are essential for proper growth and physical development to ensure optimal work capacity, normal reproductive performance, adequate immune mechanism, and resistance to infections. Inadequate diet may produce several forms of malnutrition in children, the most important being the protein-energy malnutrition (PEM). Acute undernutrition results in wasting and occurs when food consumption is suddenly and severely reduced. Chronic undernutrition occurs when long-term food consumption is insufficient to meet the energy requirements on a daily basis for daily energy expenditure. It is usually assessed in terms of body measurements: in adults – thinness; in children – stunting. More than one-fourth of children under five years of age worldwide (about 150 million) are underweight while about one-third (182 million) are stunted. Geographically, more than 70% of PEM children live in Asia, 26% in Africa and 4% in Latin America and the Caribbean. The prevalence of stunting has fallen in developing countries from 47% in 1980 to 30% in 200607, although progress has been uneven according to regions. One key target of the United Nations Millennium Development Goals is to reduce the prevalence of underweight among children younger than 5 years by half between 1990 and 2015. However, worldwide, underweight prevalence is projected to

1904

Protein Energy Malnutrition Piyush Gupta decline from 27% in 1990 to 18% in 2015. The Asian data on overall prevalence of PEM is shown in Table 1. Table 1: Prevalence of Childhood Malnutrition Country

Per cent of infants born with low birth weight

Per cent of children under five years suffering from malnutrition Underweight Moderate Severe Wasting Stunted growth

Afghanistan Bangladesh Bhutan China India Maldives Myanmar Nepal Pakistan Sri Lanka World

– 22 15 2 28 22 15 21 19 22 14

39 46 19 7 46 30 35 45 38 29 25

12 – 3 – – 7 8 10 13 – –

7 16 3 – 19 13 9 12 13 14 11

54 36 40 11 38 25 34 43 37 14 28

Source: UNICEF, State of the World’s Children 2009, data not available for the space left.

According to National Family Health Survey-3 (NFHS-3) (200506) report, 43% of children under five years of age were underweight, and almost half (48%) were stunted (Figure 1).

Figure 1: Nutritional status of children under five years of age in India according to National Family Health Survey-3.

Nutritional Status of Adults Data on nutritional status of adults are determined by body mass index (BMI), which is expressed as follows: BMI = Weight (Kg)/Height (m2) A cut-off point of BMI of 18.5 is used to define thinness or acute undernutrition and a BMI of 25 or above indicates overweight or obesity. However, there is a strong justification for using BMI cut-offs of 23 for defining overweight in Indian population. At any given BMI, Asians have higher body fat percentage as compared to other ethnic groups. Table 2 presents the nutritional indicators of adults in India. More than one-third (36%) of women have a BMI below 18.5, indicating a high prevalence of malnutrition. Table 2: Nutritional Status of Indian Adults (15-49 Years of Age)* Nutritional status

BMI

Per cent females

Prevalence males

Obese >30 Overweight 25–29.9 Normal 18.5–24.9 Mildly thin 17–18.4 Moderately/severely thin 14 yr) Females (>14 yr) Pregnancy Lactation

400-500 300-600 900 600-700 750-770 1200-1300

5 5 5-15 5-15 5 5

4-5 6-11 15 11-15 15 19

2-2.5 30-60 75-120 75-90 75-90 75-90

Note: *as retinol acid equivalent. 1RAE = 1 µg retinol, 12 µg β carotene; ** As calciferol. 1 µg calciferol = 40 IU vitamin D. Source: Adapted from Food and Nutrition Board, Institute of Medicine-National Academy of Sciences: Dietary Reference Intake, 2002. National Academy Press, Washington, DC.

Vitamin A Metabolism Food derived from animals provide compound (retinyl esters) that are easily converted in intestine to retinol. Food derived from plants provides carotenoids, some of which may have vitamin A activity. There are more than 600 carotenoids in nature; β carotene is the most prevalent carotenoid with vitamin A activity, which can be split into intestine and liver to retinol. The β carotene absorption and conversion is less efficient than retinoids. The 12 µg of β carotene is equivalent to 1 µg of retinol. The retinol binding protein (RBP) is the special transport protein which binds to retinol in blood and transports it to the appropriate cells that have specific protein receptors for their binding. Vitamin A Biological Role The major role of vitamin A in body includes:  Supporting growth and reproduction 

Promoting vision



Maintenance and growth of epithelial cells of skin and mucous membrane



Antioxidant.

The vitamin A retinol has the major role in transport of vitamin A and in supporting growth and reproduction. In men retinol participates in sperm development and in women it supports normal foetal development. Retinol also has major role in the normal growth and remodelling of bones. The retinal plays two major roles in normal vision. Firstly, it is required for maintenance of crystal clarity of cornea and secondly it participates in the conversion of light energy into nerve impulse in the retina. The rhodopsin pigment present in retina 1913

is composed of a molecule of retinal and a protein opsin. When light strikes the retina the rhodopsin pigment gets bleached and retinal shifts from cis to trans configuration. This trans retinal cannot bind to opsin leading to change in membrane potential of opsin and activation of electrical impulse, which transmits it to nerve cell and later to brain. Much of trans retinal is converted back to active cis form but small amount of it gets converted to irreversible retinoic acid which has to be replaced with dietary intake. Retinoic acid-vitamin A has important role in promotion of cell differentiation and protein synthesis leading to normal development of epithelial cells of skin and mucous membrane integrity. Sources of Vitamin A The vitamin A recommendations are expressed in retinol activity equivalent (RAE). One RAE equals to1 µg of retinol; 12 µg of β carotene; 3.33 IU of vitamin A. Previously the vitamin A recommendations were used to be given in international units (IUs) but it is now expressed in µg and the same will be used in this chapter. Table 2 summarises the estimated mean requirements for vitamin A and the recommended safe intakes, taking into account the age and sex differences in mean body weights. Preformed vitamin A is found almost exclusively in animal products, such as human milk, glandular meats, liver and fish liver oils, egg yolk, whole milk, and other dairy products. Preformed vitamin A is also used to fortify processed foods, which may include sugar, cereals, condiments, fats and oils. Provitamin A carotenoids are found in green leafy vegetables (e.g. spinach, amaranth and young leaves from various sources), yellow vegetables (e.g. pumpkins, squash, and carrots), and yellow and orange non-citrus fruits (e.g. mangoes, papayas). Foods containing pro-vitamin A carotenoids tend to have less biologically available vitamin A but are more affordable than animal products. It is mainly for this reason that carotenoids provide most of the vitamin A activity in the diets of economically deprived populations. Vitamin A Deficiency (VAD) Vitamin A deficiency is a major health problem of developing countries. World Health Organisation (WHO) estimates that more than 100 million children’s have some degree of deficiency. In a recent study from India, the prevalence of Bitot’s spots and night blindness in schoolchildren was found to be around 5%, while prevalence of night blindness in pregnant females was found to be as high as 20% in few centres. The ocular manifestation due to VAD is known as xerophthalmia. The night blindness is the earliest manifestation of the VAD in which there is lack of vitamin A in back of eye (retina), in later stages of xerophthalmia there may be total blindness due to involvement of front of eye (cornea). The corneal involvement starts with dryness and hardening (xerosis) and later followed by softening, ulceration and necrosis (keratomalacia).

1914

The normal range of serum vitamin A (retinol) is between 30100 µg/dL. The other methods used to diagnose normal levels are blood spot retinol, tests for dark adaptation and liver biopsy to estimate the vitamin A reservoir. The serum level below

20 µg/dL is regarded as VAD. The clinical and subclinical infections can lower serum levels of vitamin A, on an average by as much as 25%, independently of vitamin A intake. Management of Vitamin A Deficiency Any stage of xerophthalmia should be treated with three 60 mg of vitamin A soft gel capsule given on day 0, day 1 and day 14. The dose should be half (30 μg) for the children’s in the age group of 6 to 11 months. Pregnant mothers with deficiency should be a treated with 7.5 mg per week for 3 months. Patients with malabsorption should be treated with 15 mg per day of water soluble vitamin A and this should be followed by maintenance dose according to serum retinol levels. Prophylactic vitamin A dose of 60 mg every 6 months is recommended in high-risk individuals and similarly children’s suffering from measles should be given two capsules of 60 mg for two consecutive days. Vitamin A Toxicity Routine consumption of large amounts of vitamin A over a period of time can result in toxic symptoms, including liver damage, bone abnormalities and joint pain, alopecia, headaches, vomiting and skin desquamation. Hypervitaminosis A appears to be due to abnormal transport and distribution of vitamin A and retinoids caused by overloading of the plasma transport mechanisms. Very high single dose can also cause transient acute toxic symptoms that may include bulging fontanelles in infants; headaches in older children and adults; and vomiting, diarrhoea, loss of appetite and irritability in all age groups. VITAMIN D Vitamin D (calciferol) is the only vitamin which can be synthesised in human body. It is required to maintain normal blood levels of calcium and phosphate, which are in turn needed for the normal mineralisation of bone, muscle contraction, nerve conduction, and general cellular function in all cells of the body. Vitamin D achieves this after its conversion to the active form 1,25-dihydroxyvitamin D [1,25(OH)2D], or calcitriol. This active form regulates the transcription of a number of vitamin Ddependent genes which code for calcium-transporting proteins and bone matrix proteins. Metabolism of Vitamin D Vitamin D, a seco-steroid, can either be made in the skin from the cholesterol like precursor (7-dehydrocholesterol) by exposure to sunlight or can be provided pre-formed in the diet. The version made in the skin is referred to as vitamin D3 or cholecalciferol whereas the dietary form known as vitamin D2 or ergocalciferol (Figure 1). The vitamin D is also known as a prohormone because it can be synthesised in human body and acts like a hormone at distant target cells. The vitamin D 3 is metabolised first in the liver to 25hydroxyvitamin D (calcidiol) and subsequently in the kidneys to1,25(OH) 2D (calcitriol) to produce a biologically active hormone. The calcitriol and other vitamin D metabolites are complexed to vitamin D-binding protein (globulin) in the blood. Calcitriol is believed to act on intracellular receptors similar to steroid hormones. Recently there has been rising interest in the discovery of vitamin D receptors in more than 20 different cells of the body

vitamin D deficiency should be investigated and treated first before vitamin D and calcium correction. In patient with chronic renal insufficiency or 1α-hydroxylation defect the treatment should be with 0.25-0.5 µg/day of calcitriol [1, 25(OH)2D3]. Patients with intact vitamin D hydroxylation should be treated with 60,000 IU of cholecalciferol sachet/week for 4 to 12 weeks followed by maintenance therapy of once monthly sachet or 800 IU daily. In patients with fat malabsorption intramuscular vitamin D should be used in the dose of 2.4 lac IU/6 months.

Fat Soluble Vitamins

which includes brain, bone marrow cells, skin, lymphocytes, etc. The exact role of these receptors is still unknown but it is speculated that this may have some important functions of immunomodulation and cell differentiation.

Vitamin D Toxicity The safety margin of vitamin D is very large and the toxicity is only seen at very large doses in the range of 40,000 IU/day. It may lead to hypercalcaemia and hypercalciuria, leading to nephrolithiasis if urinary calcium rises >250 mg/24 hour.

Figure 1: Synthesis of vitamin D in humans.

Sources of Vitamin D The most efficient and physiologically relevant endogenous synthesis of vitamin D is from the skin. This is maximum in the world, in a broad band around the equator. Approximately 30 minutes of adequate exposure of arms and face to sunlight can provide the daily adequate requirement of an individual. However, skin synthesis of vitamin D is negatively influenced by the following factors: latitudes >42° N or >42° S, winter months, thinned skin of elderly, dark pigmented skin (Asian and Africans), clothing and sunscreens use. It is reported that in winter months, persons living in latitudes higher than 42° have zero vitamin D synthesis. Vitamin D recommendation is usually given in international unit (IU) and the conversion used is 1IU = 0.025 µg cholecalciferol. The RDA for vitamin D is given in Table 2. The food sources rich in vitamin D are fortified dairy products, fortified margarine, fish oils and egg yolk. Vitamin D Deficiency Vitamin D deficiencies is widely prevalent in India and in recent studies up to 90% of Indians are found to be having hypovitaminosis D, which may be due to dark skin complexion, poor sun exposure, vegetarian food habits and lack of vitamin D in food fortification programme. The vitamin D acts on intestinal cells to increase calcium absorption from gut, therefore, in its deficiency serum ionised calcium level decreases leading to rickets in children’s and osteomalacia in adults. Optimal vitamin D level of 25(OH) D is >25 ng/mL (37 nmoL/L) but the level at which the parathyroid hormone (PTH) increases and bone density decreases is 2 ppm) is a major public health problem than the fluoride deficiency. About 25 million Indians spread in 15 states of India are suffering from flurosis. Among them Nalgonda, Nellore and Prakasam districts of Andhra Pradesh and Patiala district of Punjab are badly affected. In humans, the only clear effect of inadequate fluoride intake is an increased risk of dental caries (tooth decay) for individuals of all ages. The incidence of dental caries in children is observed to be high in areas where the fluoride content of drinking water is less than 0.5 ppm. Fluoride toxicity is 1919

observed where the drinking water contains excessive amounts of fluoride (>3 ppm). This leads to osteoporosis and osteosclerosis with brittle bones, the condition being called fluorosis, which is more dangerous than dental caries. In these cases hypercalcification of the bone of the spine, pelvis and limbs occurs. In addition, the ligaments of spine become calcified, producing a ‘poker back’. Neurological disturbances were observed secondary to changes in the vertebral column. Such persons are crippled and cannot perform simple daily tasks, such as bending, squatting, etc. as the joints become stiff. Fluoride toxicity can be prevented only by removing fluorides from drinking water supplies by treatment with activated carbon or by some other suitable adsorbents.

damage of lipids, proteins and DNA resulting in cell injury. Excess free radical production underlies the pathogenesis of diseases like atherosclerosis, carcinogenesis, diabetes, cataract and accelerated ageing.

Molybdenum Molybdenum is one of the essential trace elements.

Sources of Free Radical Oxidative damage can be brought about by free radicals generated from endogenous as well as exogenous sources. Some common endogenous sources are: 1. Mitochondria, 2. Electron transport, 3. Defense-phagocytes, 4. Membrane oxidases, and 5. Catecholamines. The exogenous sources of free radicals are: 1. Alcohol, 2. Chemicals, carcinogens, 3. Pollutants, 4. Radiation, 5. Smoking (tobacco), and 6. Stress.

Molybdenum functions as co-factor for some enzymes in humans, any disturbance of molybdenum co-factor metabolism can disrupt the function of all molybdoenzymes. These disorders result from recessive traits, for those individuals who inherit two copies of the abnormal gene (one from each parent) develop the disease. The symptoms of isolated sulfite oxidase deficiency and molybdenum co-factor deficiency are identical and usually include severe brain damage, which appears due to the loss of sulfite oxidase activity. Normally the average diets provide adequate amounts of molybdenum to humans and deficiency is rare. The major food sources of the trace elements, their deficiency symptoms and recommended daily allowances are given in Table 3.

Types of Free Radicals Superoxide Hydrogen peroxide Hydroxy radical Nitric oxide Lipid radicals Lipidperoxyl radicals Thiyl radicals Protein radicals

O2 – H 2O 2 HO NO L LO2 RS P

Radiation

→ H2 + H+ + OH– + H2O2 3H2O⎯⎯⎯⎯ Physiological Relevance of Free Radicals If the free radical production in our body is specially uncontrolled as happens under the conditions of alcoholism, over eating and smoking, the ROS/free radicals damage many of our biological systems.

Table 3: Summary of Trace Elements (Food Sources, Effect of Deficiency and RDA) S. No.

Trace element

Major food source

Deficiency symptoms

RDA

1.

Iron

Green leafy vegetables, pulses, jaggery, poultry, fish and egg yolks

20 to 40 mg

2. 3.

Iodine Zinc

Shell fish, sea weeds and sea fish Whole grains and sea food

4. 5. 6. 7. 8.

Selenium Copper Molybdenum Fluoride Cobalt

Whole grains Shell fish, nuts and legumes Legumes, grains and nuts Water, sea foods and tea Curd/milk, Dietary Source of vit B12

Iron deficiency anaemia, impairment of learning in children and in adults impairment of work capacity Goitre, Mental retardation Growth retardation, Delayed genital maturation Muscle weakness and fatigue High blood pressure fragile bones Amino acid intolerance and reduced fertility Dental caries, skeletal fluorosis Wasting disease observed in animals

ANTIOXIDANTS FREE RADICALS Production and Physiological Relevance Electrons are normally present in pairs. In the course of metabolism several atoms or groups of atoms are generated in the body, which have unpaired electrons, which are called free radicals. They usually seek electrons from other atoms to become paired electrons and thus stabilise their structure. Free radicals can react with proteins, nucleic acids, lipids and other molecules and alter their structure. In turn they attack other molecules due to their powerful oxidative nature and results in tissue damage. An imbalance between free radical generation and radical scavenging systems in the living organism causes oxidative stress which ends up in generation of reactive oxygen 1920 species (ROS) and RNS. It has been implicated in tissue damage,

150 to 200 µg 10 to 15 mg 50 to 100 µg 1 to 1.4 mg 75 to 250 µg 1 ppm No RDA necessary

Age related diseases are believed mainly to be the after effects of free radicals. In aged people the defects in secretary glands, eye sight and memory are partly due to the onslaught of free radicals and partly due to metabolic defects/nutrition, etc. ANTIOXIDANTS To defend against damage from free radicals and ROS, humans and other living organisms have developed powerful and complex antioxidant system. Antioxidants are diverse group of molecules that protect key biological sites from oxidative damage. They are either produced in the body (endogenous) or derived from the diet (exogenous). The endogenous antioxidant defense systems of the body are essentially of two types: enzymatic and non-enzymatic.

The following are the various defense systems in vivo against oxidative damage. Enzymatic antioxidants Superoxide dismutase (CuZnSOD present in Cytosol, Mn SOD in mitochondria and SOD in extracellular space), Catalase, Glutathione peroxidase (GSHPx), Glutathione reductase, etc. are the common antioxidant enzymes in the body. These are preventive antioxidants which suppress free radical formation as follows: 1. Non-radical decomposition of hydroperoxides and H2O2 S. No. Antioxidant i. Catalase ii. Glutathione peroxidase (cellular) iii. Glutathione peroxidase (Plasma) iv. Phospholipid hydroperoxides Glutathione peroxidase v. Peroxidase vi.

Glutathione S transferase

Mechanism Decomposition of H2O2 Decomposition of H2O2 and Free fatty acid hydroperoxides Decomposition of H2O2 and phospholipid hydroperoxides Decomposition of phospholipids and hydroperoxides Decomposition of H2O2 and lipid peroxides Decomposes lipid hydroperoxides

2. Antioxidants that sequester metals by chelation S.No. Metal Chelaters Mechanism i. Transferrin, Lactoferrin Sequestration of iron ii. Heptoglobin Sequestration of haemoglobin iii. Hemopexin Stabilisation of haem iv. Ceruloplasmin, albumin Stabilisation of copper 3. Antioxidants that quench active oxygen species: Superoxide dismutase-dismutates superoxides where as carotenoids, vitamin E, etc. Quenches singlet oxygen. 4. De novo enzymes: These enzymes repair the damage and reconstitute membranes, e.g. Lipase, protease, DNA repair enzymes and transferases. 5. Adaptation enzymes: These enzymes are generated at appropriate antioxidant enzymes and transfer them to the right site at the right time in right concentration. Non-enzymatic antioxidants Ascorbic acid, β-carotene, α-tocopherol, glutathione, selenium, lycopene, uric acid, bilirubin, flavonoids and other chemical antioxidants, etc. constitute some of the non-enzymatic antioxidants. These are radical scavenging antioxidants which scavenge radicals to inhibit chain initiation and break chain propagation, e.g. Hydrophilic ones among them are vitamin C,

Uric acid, bilirubin and albumin, etc. whereas vitamin E, Ubiquinol, carotenoids and flovonoids constitute lipophylic antioxidants. Phenolic antioxidants These are another group of antioxidants commonly present in plant foods. A large number of phytochemicals exert antioxidant activity and are known as non-nutritional antioxidants. These natural antioxidants are present mostly in plant foods as polyphenolic compounds (Phenolic compounds made up of multiple phenol rings). These phenols, especially those with multiple phenolic groups, are found to be better antioxidants than the well-known antioxidant vitamins. There are more than 5,000 individual phenolic compounds (flavonoids, monophenols and polyphenols) identified till date and more are expected to exist in nature. Major classes of phytochemicals are given in Table 4.

Minerals, Trace Elements and Antioxidants

Different Types of Antioxidant Systems The living organisms are endowed with a battery of antioxidant systems which defend the organism against oxidative stress due to various endogenous and exogenous sources. The balance between oxidative stress/antioxidant defense systems of the body, determine to a great extent the susceptibility of the organism to free radical/ROS induced tissue damage and associated diseases. Biological antioxidant is ‘any substance that when present at low concentrations compared to those of an oxidisable substrate significantly delays or prevents the oxidation of that substrate’.

Table 4: Major Classes of Phytochemicals with Antioxidant Activity S. No.

Major Classes of Phytochemicals

Compounds

1. 2. 3. 4.

Carotenoids Bioflavonoids Phytosterols Tannins

5. 6. 7. 8.

Chlorophylls Terpenoids Allylic Compounds Indoles

Lycopene, lutein, astaxanthin Genistein, diadzein, quercetin Sitosterol,Stigmasterol, oryzanol Catechins and other polyphenol compounds Chlorophyll A and chlorophyllin Iimonin and limonene Diallyl sulfide and disulfide Indele-3-carbinol

Recent evidence strongly suggests that eating plenty of antioxidant – rich plant foods may reduce the risk of chronic diseases. It is hypothesised that phytochemicals present in plant foods exert beneficial effects by combating oxidative stress in the body through maintaining a balance between oxidants and antioxidants. Polyphenols can act chemically as antioxidants due to their extensive conjugated π-electron system, which allows ready donation of electrons or hydrogen atoms from the hydroxyl moieties to free radicals, which causes antioxidant activity. Polyphenols are low molecular weight compounds found in commonly consumed plant foods, e.g.fruits, green leafy vegetables (GLVs), vegetables, nuts and oil seeds, etc. They are important to plants wherein they acts as antioxidants, enzyme regulators and precursors of toxic substances. Since different antioxidants work in different ways and in different places in the body, it is important to eat a variety of foods to get various antioxidants. Judicious selection and consumption of plant foods rich in polyphenoilc antioxidants could therefore be of great help in modulating the oxidative stress and associated diseases in the population. RECOMMENDED READINGS 1.

Handbook of Food and Nutrition. M Swaminathan. The Bangalore Printing and Publishing Co., Ltd., Bangalore; 2010.

2.

Textbook of Biochemistry (For Medical Students). DM Vasudevan and S Sreekumari; 5th Ed. Jaypee Brothers Medical Publishers (P) Ltd., New Delhi; 2008.

3.

Textbook of Human Nutrition. Mahtab S Bamji, Kamala Krishna Swamy and GNV Brahmam (editors); 3rd Ed, Oxford and IBH Publishing Co. Pvt. Ltd. New Delhi; 2009.

1921

25.7

Food Allergy and Food Intolerance

The importance of food comprising of macro, micro and other health promoting nutrients required for the growth and development of human life from conception to senescence is well known since the time immemorial. Extensive studies on the physicochemical and nutritional aspects of foods have also brought out various deleterious effects of some foods and food components in causing various health problems. Allergy is one of the side-effects of immunity develops under some conditions. There are several different types of allergies, some of which can occur in any person, and others that occur only in persons who have a specific allergic tendency. FOOD ALLERGY Food allergy is recognised as a common worldwide problem and, like other atopic disorders, its incidence seems to be increasing. Any abnormal clinical response associated with ingestion of a food or food additive is generally termed as food allergy. These adverse reactions can be further classified as food allergy and food intolerance depending on the type of mechanism involved. Food allergy refers to an abnormal immunologic response to a food that occurs in a susceptible host. Food allergy can be IgE-mediated, mixed IgE and cellmediated. Epidemiology The prevalence of food allergy is highest in infants and toddlers. Cow’s milk allergy is experienced by 2.5% of infants and up to 8% of children less than three years of age. The prevalence of food allergy decreases slightly with age, affecting almost 4% of the general population. Aetiology The diverse clinical manifestations of food allergy result in part from different immune mechanisms, target organ responses, and characteristics of triggering proteins. Conceptually, it is useful to categorise the immune mechanisms according to three general types—IgE antibody-dependent diseases (triggered by multiple foods, raw fruits and vegetables), cellmediated disorders without detectable IgE antibodies (triggered by egg, milk, wheat and soy) and disorders with mixed IgE and non-IgE mechanisms (triggered by wheat, lactose, fructose and some food additives). The development of allergy frequently starts in early childhood with initial eczema, followed by the subsequent sequential development of food allergy, allergic rhinitis, and asthma—the so-called ‘atopic march’. Allergic diseases are also an example of geneenvironment interactions. Clinical Features Allergic reactions to foods generally occur within a few minutes to one hour after eating the offending food which range from mild discomfort to severe life-threatening reactions. Symptoms 1922 can last for days or even weeks. The specific symptoms and

UV Mani severity of an allergic reaction are affected by the amount of the allergen consumed and the sensitivity of the allergic person. Diagnosis The evaluation of a patient with a possible allergic food reaction begins through clinical history and a complete physical examination to consider a potentially broad differential diagnosis between food-induced allergic clinical disorders and other gastrointestinal diseases, such as food intolerance (toxic and pharmacological effects or metabolic disorders), infections (viral, bacterial and parasitic), coeliac disease, inflammatory bowel diseases, bowel ischaemia, gall bladder disease, pancreatic insufficiency, and gastrointestinal neoplasms. Management Once a food allergy is diagnosed, strict elimination of the offending food allergen from the diet and avoidance of any contact with the food by ingestion, skin contact, inhalation, or injection is necessary. Thus, the primary therapy for food allergy is to avoid the causal food. Clinical tolerance develops to most food allergens over time, except for peanuts, nuts and seafood. Periodic re-introduction of food allergens under physician supervision is warranted to determine whether clinical tolerance has developed or not. There is a relationship between the decrease in serum food-specific IgE concentrations and the likelihood of developing tolerance. A greater decrease in serum food specific IgE levels over a shorter period of time might be indicative of a greater likelihood of developing tolerance. Prevention Approaches to delay or prevent allergy through dietary manipulation have been considered. Some studies suggest a beneficial role for exclusive breastfeeding of infants at highrisk for atopic diseases in the first 3 to 12 months of life and avoidance of supplementation with cow’s milk or soy formulas in favour of hypoallergenic formulas if breastfeeding is not possible. Maternally ingested food can pass in immunologically intact form into breast milk and might induce reactions in infants. No conclusive studies indicate that manipulation of mother’s diet during pregnancy or breastfeeding or the restriction of allergenic food from the infant’s diet will prevent the development of food allergy whereas the introduction of solid can be delayed until 6 months of age and major allergens, such as peanuts, nuts and seafood, be introduced after 3 years of age till the child develops its own immunity. Supplementation of antioxidant vitamins and minerals showed some good results in prevention of food allergy. It is postulated that an allergic response to antigen challenge, including inflammatory cell infiltration, results in the generation and release of reactive oxygen species. These oxygen free radicals lead to bronchoconstriction, increased mucus secretion and microvascular leakage.

(phenylketonuria and favism). Food intolerance can also be psychological in origin if the symptoms are triggered by emotional responses to the food in question.

FOOD INTOLERANCE Food intolerance (FI) reactions comprises of metabolic, pharmacologic, and gastrointestinal responses to foods or food compounds. It is a negative reaction, often delayed to a food, beverage, food additives or compounds present in the foods which produce symptoms in one or more organs and systems. In most cases, food intolerance is not associated with the production of IgE antibodies whereas food allergy does. Therefore, food intolerance is generally not life-threatening.

Clinical Features Symptoms of food intolerance vary greatly and can be similar to the symptoms of food allergy. Food intolerance symptoms usually begin within half an hour after consuming the food in question, but sometimes the symptoms may appear even after 48 hours. Food intolerance can present with symptoms affecting the skin, respiratory tract, gastrointestinal tract (GIT) either individually or in combination. On the skin, there may be skin rashes, urticaria (hives), angioedema, dermatitis and eczema. Respiratory tract symptoms can include nasal congestion, sinusitis, pharyngeal irritation, asthma and an unproductive cough. GIT symptoms include mouth ulcers, abdominal cramp, nausea, gas, intermittent diarrhoea, constipation and irritable bowel syndrome. Estimates of prevalence of food intolerance vary widely from 2% to over 20% of the population.

Aetiology The various organic chemicals present in a wide variety of foods, both of animal and vegetable origin, food additives, (colouring and flavouring agents) preservatives, (monosodium glutamate) and many food chemicals have been identified as the causative agents. A deficiency in digestive enzymes can also cause some types of food intolerance. Lactose intolerance is a result of the body not producing sufficient lactase to digest the lactose in milk, dairy foods, such as cheese. Another carbohydrate intolerance caused by enzyme deficiency is hereditary fructose intolerance. Coeliac disease is an autoimmune disorder caused by an immune response to the protein gluten found in many foods (wheat, rye, barley and to some extent oat) which results in gluten intolerance and can lead to temporary lactose intolerance also. The most widely distributed naturally occurring food chemical capable of provoking reactions is salicylate although tartrazine and benzoic acid are well recognised in susceptible individuals. Benzoate and salicylate occur naturally in many different foods, including fruits, vegetables, spices, herbs, nuts, tea, wines, and coffee, besides salicylates being present in pharmacological source such as aspirin and nonsteroidal anti-inflammatory drugs. Other chemicals which commonly cause reaction and crossreactivity include amines (banana, chocolate, cheese, tomato, etc.) nitrates and sulphites (in processed food) and some chemicals involved in aroma and flavour. Since the threshold levels vary in individuals, the consumption of large quantity of a single causative factor or many causative factors in a small quantity will result in FI of different degrees. FI can also occur as a secondary manifestation to an in-born error of metabolism

Food Allergy and Food Intolerance

Thus, by carefully analysing the causes and further by eliminating those causative agents, it is possible to overcome and control this disorder.

Diagnosis and Management The easiest test for food intolerance is to remove the food from the diet and see if symptoms improve and disappear. If the symptoms appear on re-introduction of the food, presence of FI is confirmed. Lactose intolerance can be tested more thoroughly using a lactose intolerance test, a hydrogen breath test and stool acidity test. Food intolerance can be managed simply by eliminating the causal food from the diet. It is also useful to avoid foods with additives which may cause FI. If the sensitive food chemicals are identified, an appropriate diet can be prescribed excluding those food chemicals with the help of a dietician. The treatment involves consumption of gluten free diet. Among the cereals, only rice, corn and possibly oats can be used. It is not advisable to eat pasta, salad dressing and some margarine because they contain wheat or wheat extractsand also drinking beer should be avoided. RECOMMENDED READINGS 1.

Lee LA, Burks AW. Food allergies: prevalence, molecular characterisation, and treatment/prevention strategies. Ann Rev Nutr 2006; 26: 539-65.

2.

Mahan LK, Escott-Stump S. Krause’s Food and Nutrition Therapy; 12th Ed. St. Louis: Saunders-Elsevier; 2008: pp 739-60.

3.

Sicherer SH, Sampson HA. Food allergy: recent advances in pathophysiology and treatment. Ann Rev Med 2009; 60: 261-77.

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25.8 INTRODUCTION AND EPIDEMIOLOGY Eating disorders are characterised by a severe and persistent disturbance in eating behaviour that causes psychosocial and sometimes, physical impairment. Anorexia nervosa (AN) and bulimia nervosa (BN), the two distinct forms of eating disorders, are 10 times common in females and the prevalence of the two disorders among females is respectively, 0.5% to 1% and 1% to 3%. The onset of the AN is observed in mid-adolescence and for the latter BN in late adolescence to early adulthood. Eating disorder ‘not otherwise specified’ (NOS) is observed usually in middle-aged, and the female sex predilection is absent and is observed in obese individuals. Eating disorder NOS is the most common eating disorder encountered in clinical settings constituting about half of adult outpatient eating-disordered population, with patients of bulimia nervosa constituting about a third, and the rest being cases of anorexia nervosa. In inpatient settings, the great majority of cases are either underweight forms of eating disorder NOS or anorexia nervosa. Since eating disorders were originally identified, the relationship between obsession with food and that with body weight has been consistently debated. It is also important to understand the particular way in which people with eating disorders perceive their bodies in the presence of other people. Two notions are fundamentally important:‘body-self’ and ‘bodyfor-others’. The ‘body self’ is understood as the basis of self consciousness and inter subjectivity. ‘Body-for-others’ means how one experiences one’s own body when someone else is looking at it and the subject body thus becomes conscious of being a body-object for others. Apart from a combination of psychological, biological and cultural risk factors; genetic factors also contribute to the risk of development of eating disorders. The exact aetiology hitherto remains unknown.

Anupam Prakash shape and weight. This has been described in different ways and is often expressed as strong desire to be thin combined with an intense fear of weight gain and fatness. 2. The active maintenance of an unduly low body weight; this is commonly defined as maintaining a body weight less than 85% of that expected or a body mass index (BMI) of 17.5 or less. 3. Amenorrhoea, in post-pubertal females not on oral contraceptive; this criterion is proposed to be removed in DSM V. For a diagnosis of BN, the following three features need to be present: 1. Over evaluation of body shape and weight, as in AN. 2. Recurrent binge eating: A ‘binge’ is an episode of eating during which an objectively large amount of food is eaten for the circumstances and there is an accompanying sense of loss of control. 3. Extreme weight-control behaviour, such as recurrent selfinduced vomiting, regular laxative misuse, or marked dietary restriction. In addition, the diagnostic criteria for AN should not be met. This ensures that the two diagnosis are mutually exclusive. Hence, the BMI becomes a distinguishing feature between the two. There are no positive criteria for the diagnosis of eating disorder NOS. Instead, this diagnosis is reserved for eating disorders of clinical severity that do not meet the diagnostic criteria of AN or BN. However, under the rubric of eating disorder NOS, DSM IV lists ‘binge eating disorder’ (BED). It is proposed that BED should be recognised as a specific eating disorder in DSM V.

CLASSIFICATION AND DIAGNOSTIC CRITERIA Psychiatric diagnosis are categorised by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV). Eating disorders are an extremely heterogenous diagnostic category. DSM IV recognises two eating disorders in adults, AN and BN; and a residual category-eating disorder not otherwise specified (EDNOS).

CLINICAL FEATURES Eating disorders share a common psychopathology, the over evaluation of the importance of body shape and weight, and their control. For people with eating disorders, self worth is dependent largely, or even exclusively, on their shape and weight and their ability to control them. The salient features of various eating disorders are outlined in Table 1.

Two subtypes each for AN and BN have been identified, depending upon the method adopted by the patients to control their weight: restricting type (AN-r) and binge-/purging (AN-p) for AN and purging/non-purging type for BN.

Anorexia Nervosa (AN) Patients become underweight, either because of persistent and severe restriction of both the amount and the type of food that they eat, or because of adopting a driven form of exercising. Anorexia nervosa patients typically value the sense of control that they derive from undereating. A subgroup of anorexia nervosa patients practice self-induced vomiting, laxative and/ or diuretic misuse, especially those who experience episodes of loss of control over eating. Interestingly, the amount of food

The diagnosis of AN is made in the presence of the following features:

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Eating Disorders

1. The over evaluation of body shape and weight; that is, judging self worth largely, or even exclusively, in terms of

A hierarchical relationship in order of severity has been proposed: (a) AN and behaviourally similar disorders — most severe (b) BN and behaviourally similar disorders (c) BED and behaviourally similar disorders (d) Eating disorder NOS — least severe

Eating Disorders

eaten during these ‘binges’ is often not objectively large; hence, they are described as ‘subjective binges’. Many other psychopathological features tend to be present and include depressed and labile mood, anxiety features, irritability, impaired concentration, loss of libido, obsessions to a varied extent and social withdrawal. Table 1: Salient Clinical Features of Eating Disorders Anorexia Nervosa

Bulimia Nervosa

Binge-Eating Disorder

Eating Disorder NOS

Age of onset Sex predilection BMI (kg/m2) Menstruation Restrictive eating

13 to 25 years Female (10:1) 25 Normal —

25 to 50 years None Normal to high Normal —

Binge-eating

May be seen in 25% to 50%

Criterion for diagnosis

Variable

Suicidal ideation Mortality

Yes Approx. 5% per decade

Rare Low to nil

Intermittent, absent compensatory behaviour — —

Physical characteristics

Physical overactivity, lanugo hair on trunk and limbs, oedema, azotaemia, anaemia, leucopaenia, sialadenosis, delayed gastric emptying, constipation, hypoglycaemia hypokalaemia, hypomagnesaemia, metabolic alkalosis, osteopaenia, hypotension, bradycardia, acrocyanosis

Less common. Hypokalaemia, hyponatraemia, hypomagnesaemia, metabolic alkalosis, dental caries, enamel erosion, sialadenosis, azotaemia, arrhythmias

Bulimia Nervosa It resembles BN, both in terms of eating habits and methods of weight control, but the distinguishing feature is that attempts to restrict food intake are regularly disrupted by episodes of (objective) binge eating. These episodes are often followed by compensatory self-induced vomiting or laxative misuse, although there is also a subgroup of patients who do not purge (non-purging BN). Due to this combination of under eating and over eating, the weight of most patients with BN tends to be unremarkable and is within the healthy range (BMI = 20–25 Kg/m2). Features of depression and anxiety are prominent in these patients. Rarely, these patients can engage in self harm and/or substance and alcohol abuse. Physical complaints are much less common, although electrolyte disturbance may occur in those who vomit or take laxatives or diuretics frequently. Binge-Eating Disorder (BED) This disorder refers to a clinical picture characterised by recurrent binge eating in the absence of the extreme weightcontrol behaviour seen in AN and BN. In fact, BED is rather different from AN and BN, and from the many presentations relegated to eating disorder NOS. Those affected tend to be middle-aged rather than adolescents or young adults, the marked preponderance of females is absent, and the state commonly co-occurs with obesity. Patients of BED invariably have a BMI >25 Kg/H2 (are overweight or obese). Furthermore, in marked contrast to AN and BN, BED tends to be intermittent rather than continuous with many individuals reporting sustained periods when they are free from binge-eating.

Complications related to obesity, limited ability to lose weight

— — —

MANAGEMENT Anorexia Nervosa (AN) The primary management is restoration of weight to at least 90% of the normal. However, this is greatly resisted by the patients and consequently is accompanied by frustration. Therefore, counselling of the patient is imperative. Patients with suicidal ideations and with serious medical complications need to be admitted. Otherwise outpatient counselling sessions providing behavioural therapy and interpersonal psychotherapy along with requisite nutritional advice can be provided. Family-based therapy can be used for adolescents. Behaviour therapy focuses on gaining control and changing unwanted behaviours. Drug therapy, including psychotropic drugs, is not found to be useful in AN. However, selective serotonergic reuptake inhibitors may be useful for treating comorbid anxiety or depression. The prognosis is good in the short-term, but long-term outlook is variable. One-fifth make a full recovery and one-fifth remain chronically ill, while the remaining have recurrent episodes of anorexia. Mortality from suicide or physical complications is reported at the rate of 5% per decade. Bulimia Nervosa (BN) Cognitive behavioural therapy is the treatment of choice. Cognitive behavioural therapy is a short-term, i.e. 4 to 6 months psychological treatment and produces symptomatic remission in 25% to 50% of patients. Interpersonal therapy is also beneficial. Fluoxetine or other selective serotonergic reuptake inhibitors can be used for bulimia symptoms and the latter can 1925

also benefit co-morbid symptoms. BN patients can be treated on outpatient basis and usually do not require admission. The prognosis is far better than AN patients and mortality is unusual. Eating Disorder Not Otherwise Specified and Binge-Eating Disorder Group or individual cognitive behavioural therapy has been found to be beneficial. Sibutramine or orlistat was being used for weight loss and selective serotonergic reuptake inhibitors for co-morbid depression or anxiety. Sibutramine has been banned and recent reports of orlistat causing hepatotoxicity have made its use controversial at the moment. CONCLUSION Eating disorders are severe psychological illnesses and are associated with significant physical and psychological

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disturbances in turn compromising the quality of life. It is important to realise that eating disorders form a spectrum of disorders across different age groups and varying body proportions. It is imperative to be aware of these disorders to make an early diagnosis and provide multidisciplinary therapy for restoration of health in these patients. RECOMMENDED READINGS 1.

Fairburn CG, Cooper Z. Eating disorders, DSM-5 and clinical reality. Br J Psychiatry 2011; 198: 8-10.

2.

Murphy R, Straebler S, Cooper Z, et al. Cognitive behavioural therapy for eating disorders. Psychiatr Clin North Am 2010; 33: 611-27.

3.

Sim LA, McAlpine DE, Grothe KB, et al. Identification and treatment of eating disorders in the primary care setting. Mayo Clin Proc 2010; 85: 746-51.

4.

Walsh BT, Sysko R. Broad categories for the diagnosis of eating disorders (BCD-ED): an alternative system for classification. Int J Eat Disord 2009; 42: 754.

25.9 INTRODUCTION Clinical nutrition can significantly improve patient care in hospitals. Until antibiotics were developed the combination of poor nutrition and infection contributed to the significantly high morbidity and mortality associated with many hospital admissions, particularly for patients needing surgical operations. Since infections can be largely overcome, the dangers of poor nutrition to malnourished patients, with serious illnesses remains highlighted. So much more needs to be done and must be done both in the assessment and management of suboptimal nutrition in hospitals. “Sick patients do not oblige their doctors by separating‘metabolic’ from ‘tissue pathology’ states.The whole problem must be solved together, not in sections” (Francis D Moore, 1959). Definition of ‘Critical illness’, in itself indicates the depth and magnitude of what the Francis Moore statement wishes to convey – its primarily a metabolic response to injury, and is secondary to a wide range of conditions, such as trauma, burns, systemic infection (sepsis), severe head injury, sterile inflammatory processes, etc. Needless to state the macronutrients and the micronutrients permutations and combinations would work out an astronomical figure when one begins fitting the puzzle of a perfect prescription for a sick individual.There are no shortcuts and the vista is yet unchartered for evidence-based documentation on the formulations that would work well not only in just prolonging life, but also to support healing with resultant good quality of life. If this were the basis for formulating nutrition support, it should work well. It is on this that Nutritional Support (NS) was started and has grown in popularity and it is now a multibillion dollar-a-year industry. This growth was and is still spurred by the assumption that such an intervention would improve patient outcome. The reasons of this multinational support are outlined in Table 1. Table 1: The Basis of this Wide Acceptance of NS (Parenteral NS ENS – PNS) Rests on 5 Lines of ‘Reasoning’ 1. Any living organism, when deprived of nutrient intake for a long enough period, will die. 2. An individual with a given disease who is also malnourished has a poorer prognosis than does one with the same disease but who is not malnourished (Studley’s observation). 3. NS improves measured parameters of malnutrition (especially such things as body weight or nitrogen balance). 4. Retrospective or prospective (with or without nonrandomised control groups) reports allegedly demonstrate therapeutic efficacy. 5. Doing something is better than doing nothing.

Translating knowledge into practice is always difficult clinical exercise. It seems appropriate that every hospital will have organised and effective clinical nutrition service, since there is a quantum leap in the concept that has not kept pace with the formulations of products. The original concept was “The Classic

Enteral and Parenteral Nutrition Varsha Approach to Nutrition Support” that centered on maintenance of Body Cell Mass (BCM) and Nitrogen Balance (NB) and its measurements to assess the effectiveness of NS. It must if not totally, be replaced to accommodate the more advanced concept of The Contemporary Approach to Nutritional Support that recognises the multi-factorial nature of illness: such as alteration of the stress response, administration of tissuespecific nutrients [arginine, glutamine, etc.]; stimulation or administration of growth factors is the GOALS of NS. Hence, the immediate translation of this new concept in understanding the importance of nutrition to critically ill patients (Table 2), would mean maintenance of organ function and immune status and improvement in clinical outcome more important than maintenance of BCM or NB. NS is currently in a dynamic phase fostered by knowledge from molecular biology, and it equates to ‘improves the efficiency and effectiveness of NS’. Table 2: Importance of Nutrition to Critically Ill Patients Goals for nutrition support – to meet the demands of accelerated energy and nitrogen flux as progressive protein-energy malnutrition (PEM) appears to increase morbidity and mortality 1. Early detection and correction of pre-existing malnutrition 2. Prevention of progressive PEM 3. Optimisation of the patient’s metabolic state (including provision of fluid and electrolytes) 4. Reduction of morbidity, and 5. Reduction of subsequent duration of recovery.

Prospective randomised and double blind studies on the efficacy on NS in malnourished patients with curable or reversible disorders are unethical given the present state of knowledge and experience. NS is indicated in the following patients: 1. A previously well-nourished patient with actual or expected complications or with ‘stress’, e.g. infections, polytrauma. 2. A previously well-nourished patient who has not consumed sufficient oral nutrition for 5 to 7 days prior to admission. 3. A patient found to be malnourished on admission. The information is pertaining to the existing scenario and one must begin by looking at the learning objectives that govern nutritional support’s two arms: enteral nutrition (EN) and parenteral nutrition (PN) and their access devices, formulations, implementation, complications and management. The introduction of chemically defined foods led on to the development of parenteral feeding, which has such life-saving potential for many seriously ill patients. However, EN is physiological and is superior to PN in terms of cost, reduced complications, ease of maintenance, efficacy of nutritional repletion, and maintenance of organ function. Providing even ‘token’ EN diminishes gut mucosal atrophy and maintains gut integrity thereby preventing translocation of bacteria and toxins from the gut into the circulation. It is this translocation that results 1927

in the ‘Stress Syndrome’. Peristalsis is NOT necessary for absorption of nutrients from the ileum. If access into jejunum is achieved, nutrients can be infused in the absence of bowel sounds, immediately after laparotomy and with ‘ileus’ Nasogastric suction (as in the management of stress-induced gastritis, gastric atony, etc.) is not a contraindication for distal feeding into the jejunum. INDICATIONS FOR NUTRITIONAL SUPPORT The key biochemical concept to remember in critical care is that stressed starvation is not the same as simple starvation. In the former, hypermetabolism (increase in resting energy expenditure) and hypercatabolism (loss of lean tissue, negative nitrogen balance) occur due to hormonal changes. Counter regulatory (or ‘anti-insulin’ hormones) such as catecholamines cortisol and glucagons are all elevated. While circulating insulin levels are also elevated as there is a relative insulin-resistance. Unless an attempt is made to decrease this ‘autocannibalism’, loss of protein results in death.

human gut is capable of absorbing complex moieties just as well. A disadvantage of elemental diets is their high carbohydrate content. Modular changes in EN (i.e. specific addition of protein, fat or carbohydrate as needed to standard commercially available formulae) are required for optimal National Status (NS). Formulae enriched with glutamine (to preserve gut integrity), fibre (to improve tolerance and to stimulate gut mucosa by virtue of degradation to short chain fatty acids) and omega-3 fatty acids with RNA (to stimulate immunity) are commercially available but their superiority in nutritional repletion has not been convincingly proven. Appropriate formula selection is important and an integral component of successful enteral tube feeding.First modern enteral formulas were homemade from blenderized foods diluted enough to pass through a feeding tube. The inherent problems were: difficulty with consistency and lack of nutrient standardisation.

Enteral Infusates/Formulations

Modern enteral formulas have evolved over these years (Table 4) and designed to meet patient nutrient requirements in a specified volume of formula. The basis of this evolution, however, has been the understanding of the patient’s digestive and absorptive capacity that influences the selection of formula composition, e.g. one must be aware of the following facts: 1. Gastric atony associated with sepsis may limit the use of direct intragastric feedings. 2. Limiting enteral feeding is advised in haemodynamically unstable patients because of reduced splanchnic blood flow. 3. Gastric feeding should be carefully monitored to avoid high gastric residuals and pulmonary aspiration.

Commonly classified as elemental or non-elemental. The elemental diets are said to be better tolerated. However, the

The different categories of enteral formulations are given in Table 4.

Guidelines for protein, carbohydrate, and fat are the same for EN and PN. Besides this, the route of delivery is equally an important integral factor in outcome. An algorithm delineated (Table 3) with respect to determining the appropriate route of delivery. ENTERAL NUTRITION Access Oral, nasogastric, nasojejunal, gastrostomy or Jejunostomy (needle catheter or tube).

Table 3: Determining Route of Nutrition Support TPN Yes ↓ TPN

Intestinal obstruction - bowel use X ? No ↓ Paralytic ileus? Yes ↓ No ↓ TPN Pancreatitis ? Yes ↓ No ↓ ↓

Pancreatitis severe? – Pancreatic pseudocyst – Pancreatic ascites – Pancreatic haemorrhage – Pancreatic infection – Pancreatic phlegmon – Severe pain ? Yes ↓ No ↓ TPN EN

Intractable vomiting? Yes ↓ No ↓ TPN Diarrhoea ? Stool output > 1 litre? Yes ↓ No ↓ TPN EN

Enterocutaneous fistula ? Yes ↓ No ↓ - Oesophagus Severe short - Stomach bowel syndrome - Duodenum < 100 cm jejunum - Proximal jejunum? Or 150 cm ileum? Yes ↓ No ↓ Yes ↓ No ↓ EN distal to fistula TPN TPN EN

Table 4: Enteral Formulations: Categories Type

Comment

Polymeric diets Monomeric diets

Whole protein nitrogen source, for use in patients with normal or near normal GI function Predigested nutrients; most have a low fat content or a high percentage of medium chain triglycerides for use in patients with severely impaired GI function Polymeric diets containing source of fibre; diets reportedly beneficial for prevention/ treatment of altered bowel function in enterally fed patients Formulas designed for feeding patients with specific disease states – now available for patients with respiratory disease, diabetes, renal failure, hepatic failure, and immune compromise, well-designed clinical trials may or may not be available

Fibre containing Disease specific 1928

Developing Enteral Formulary Criteria used for selecting EN products included on the enteral formulary are depicted in Tables 5A to D and Table 6. Table 5A: Carbohydrate (CHO) Source and Quality Generally provided using combination of: Hydrolysed cornstarch Maltodextrins Corn syrup solids, and/or Sucrose Form of carbohydrate (CHO) Influences osmolality, sweetness and digestibility of the enteral product – Monosaccharides; Oligosaccharides 2-8 units; Polysaccharides >8 units Most CHO except Lactose, easily digested, absorbed by the small bowel CHO content of formulas ranges from approx. 40% to 90% of total caloric content Symptoms of CHO intolerance range from abdominal discomfort to flatulence and diarrhoea Table 5B: Protein Source and Quality Amount ranges from 4% to 32% of total calories Low protein (20%) – in increased nitrogen requirements – e.g. trauma, burns, etc. Commercial formulas Intact protein Protein hydrolysates Crystalline amino acids

Table 5D: Electrolyte, Mineral Content, and Vitamin Content (Volume Necessary to Supply RDA) Most enteral products meet 100% of RDA at a given volume of formula (excluding renal and hepatic formulas) However, RDAs do not reflect needs during critical illness or severe hypermetabolism – hence manufacturers adopt different reference standards Of current interest – relationship between β-carotene and immune function - β-carotene may increase cytotoxicity of natural killer cells, enhance immune response, and increase levels of T-helper cells Presently six enteral products contain β-carotene

Enteral and Parenteral Nutrition

Mode of Infusions: Bolus, Cyclic, Continuous With respect to bolus mode, though there are disadvantages it is physiological mode of feeding. Continuous feeding is unphysiological as glucose stimulates release of insulin, which in turn decreases lipid mobilisation. In cyclic feeding, either the infusion is interrupted for 4 to 6 hours each day or a glucose-free solution with decreased amount of intracellular ions (K, Mg, and P) is infused. Better nutritional repletion and a decrease in liverenzyme elevation occurs. However, managing fluid balance and glucohomeostasis in an ICU patient is difficult with cyclic feeding.

Developing Enteral Formulary: Conclusions I. Appropriate formula selection requires knowledge about  The nutrient requirements of specific patient populations  Awareness about the potential effects of formulas on gastrointestinal, metabolic and immunologic functions. II.

Critical evaluation of formula composition to ensure efficacy and safety of product use: Formulas developed for particular disease states or clinical conditions – supported by well-designed clinical trials.

III. Enteral nutrition products: Market significant >80 products. IV. Choices include: – Formulas with peptides, fibre and β-carotene – Formulas, disease specific – Formulas designed to improve immune function V. Can current standard formulations be improved? 1. Are specific nutrients being given in excessive amounts, i.e. chromium and manganese? 2. Is there still too much contamination with toxic minerals, i.e. aluminum? 3. Are there nutrients and non-nutritional factors present in foods that will be beneficial if added to purified formulas?

Table 5C: Fat Source and Quality FAT: Essential fatty acids (EFAs) Fat provides an isotonic, concentrated energy source Fat content of ENF ranges from 50% of total calories Fat sources in enteral products – soy, corn – more frequently used, safflower and sunflower oils; canola oil, beef fat, refined marine fish oil – less frequently used, medium-chain triglycerides (MCT’s), and structured lipids Many products contain fats that do not provide adequate quantities of both linoleic (w-6 – 1-2% total calories) and linolenic (w-3 – 0.20.3% total calories) acid FAT: Medium chain triglyceride (MCT) Quickly hydrolysed intraluminally, increased levels of intake may increase the luminal osmotic concentration and cause abdominal distension and diarrhoea Metabolised in the liver – ingestion of high levels contraindicated in cirrhosis – may induce a situation similar to hepatic encephalopathy MCTs ketogenic – not be given to hyperosmolar diabetic syndrome patients 1929

Table 6: Physical Characteristics of Enteral Formulations (EFs) Osmolality Enteral products range in osmolality from 270 mOsm/kg to approximately 700 mOsm/kg - as a general rule, do not worry about diets whose osmolalities are 350-450 mOsm/kg water or less, except when fed directly into the duodenum or jejunum Osmolality may affect patient tolerance to a particular formula – hypo- and hyperosmolar feedings delay gastric emptying Hyperosmolar formulas may increase intraluminal osmotic concentration and create GI intolerance - the importance of hypertonicity in causing diarrhoea has probably been overestimated If the osmotic load relative to free water exceeds the ability of the kidney to concentrate, an osmotic diuresis results, leading to dehydration Nutrient Density (ND) 1.

2.

Calorie-Nutrient Density – may affect tolerance of tube feeding by its effect on gastric emptying a.

The greater the ND (kcal/mL) the slower the emptying rate into the duodenum

b.

Tolerance of a particular formula – fat, most powerful inhibitors of gastric motility – high intakes or rapid infusion into the duodenum – a significant delay in gastric emptying

c.

A consideration when initiating enteral feedings, especially in GI tract compromised patients – not used for an extended period or have mucosal disease/damage

Introduce nutrients gradually in a diluted or low-calorie formula – not to exceed the capability of the intestinal enzymes to hydrolyze the nutrients Approximate water content of EFs based on caloric density Caloric density (kcal/mL formula)

Water content (kcal/H20/1000 mL formula)

Water content (%)

1.0 -1.2 1.5 2.0

800-860 760-780 690-710

80-86 76-78 69-71

pH Solutions with a pH of less than 3.5 reduce gastric motility Not a major concern with most commercial formulas Residue

1930

PN Formulation Components 1. Energy substrates – carbohydrate and lipids 2. Protein 3. Electrolytes 4. Vitamins 5. Trace elements 6. Water Various combinations of these components are incorporated into the regimen for IV administration based on the patient’s individual needs and clinical limitations. Parenteral feeding imposes increased risks, major expense, and a serious handicap. Current clinical data on commercially available parenteral nutrition solutions – not embraced the new approaches (Tables 7A to F). Several amino acid solutions with varying concentrations with or without added electrolytes and major minerals are available. Dextrose solutions vary in concentration from 10% to 70%. A trained pharmacist usually does mixing. Fat emulsions are available as 10% or 20% solutions. The convenience and safety of 3-in-1 admixtures have made this popular. All components of PN are mixed in one high-volume bag and provided to the patient.While there are theoretical reasons to provide branchedchain amino acid-enriched infusates to stressed patients; the costeffectiveness of its routine use has not been demonstrated. PN Formulation Conclusions 1. Parenteral feeding imposes increased risks, major expense, and a serious handicap. 2. Current clinical data on commercially available parenteral nutrition solutions – not embraced the new approaches. Table 7A: Energy Substrates – Protein Crystalline amino acids – 4.0 kcal/g Amino acids: Standard – provide EAA and Non-EAA Standard amino acid (STD AA) formulations, based on egg protein – the workhorse for providing nutrients during the formative years of parenteral nutrition – this approach sought to provide nutrients for total-body nitrogen utilisation Table 7B: Energy Substrates – Carbohydrate

1.

Many formulas contain little or no residue

2.

May be advantageous in the management of specific gastrointestinal disorders (e.g. bowel fistula or enteritis)

Dextrose – hydrated – 3.4 kcal/g – multiple concentrations range from 2.5% to 70%

3.

Low-residue diets may cause constipation in some patients

Dextrose – acidic – pH range 3.5 to 6.5 – osmolarity vary depending on concentration

Complications 1. Aspiration pneumonitis. 2. Diarrhoea (due to hypoalbuminaemia, antibiotics, organisms). The use of intravenous albumin to improve tolerance to EN is controversial.

Higher concentrations of dextrose (>10%) reserved for administration via a central vein due to propensity to cause thrombophlebitis in peripheral veins

PARENTERAL NUTRITION (PN) Access Peripheral IV cannulae or central (single or multiluminal) catheters. Catheter insertion and care should follow established protocols.

Dextrose solutions 70% = 2.38 kcal/mL 50% = 1.70 kcal/mL 40% = 1.36 kcal/mL 30% = 1.02 kcal/mL

Sugar alcohol glycerol – less frequently used – 4.3 kcal/g – protein sparing – ?induces less insulin response than dextrose-based regimens

Table 7E: Electrolytes

10% - 1.1 kcal/mL

Standard daily ranges include:

20% - 2.0 kcal/mL

Sodium (Na) and Potassium (K) : 1-2 mEq/kg + replacement of losses

30% - 3.0 kcal/mL – not for direct administration

Calcium (Ca)

: 10-15 mEq

Soyabean oil or 50:50 mix of safflower and soyabean – other components of lipid emulsions – egg yolk phospholipid (emulsifier) – glycerin (to render formulation isotonic) – vitamin K and sodium hydroxide to adjust the final pH (range 6.0-9.0)

Magnesium (Mg)

: 8-20 mEq

Phosphate (P)

: 20-40 mmoL

Metabolic fate of lipid emulsions – issue of concern – lipids are not completely oxidised – during stress increased re-esterification of FFA into triglycerides and deposition into storage tissues and large amounts of lipid emulsion at rapid infusion rates result in compromised function of granulocytes, leucocytes, neutrophils, and phagocytes and decreased T-helper: T-suppressor cell ratios Hence, accepted method for Tx – provide 500 ml of a 10% IV fat emulsion 2 to 3 times weekly The practice of providing fat in 3-in-1 solutions (i.e. fat- CHO-protein) or total nutrient admixtures (TNAs) standard Long-chain IV fat emulsions – for Tx of EFAD and as parenteral caloric source, provides a dense caloric source with minimal fluid volume to the patient For clinical situations requiring 4 to 7 kcals/kg/d fat emulsions be prescribed and administered

Acetate and chloride – no specific ranges for intake – adjusted as needed to maintain acid-base balance Electrolytes available in salt forms Na and K – chloride, acetate, and phosphate Ca – chloride, gluconate, glycepatate Mg – sulphate, chloride Generally gluconate salt of Ca and sulphate salt of Mg preferred forms of cations – less likely to produce physicochemical incompatibilities Trace Elements Adults, paediatrics, neonates – with or without electrolytes commonly used in PN Zinc (Zn), Copper (Cu), Chromium (Cr), Manganese (Mn), Selenium (Se) Other Trace Elements (TE)? may be included Molybdenum (Mo), Iodine (I), Iron (Fe – available only as a single-entity product)

A baseline serum triglyceride level should be obtained and triglycerides monitored biweekly

Table 7F: Volume Aspects

Table 7D: Vitamins

Sterile water for injection – used to provide necessary fluid and volume to the PN feeding formulations

Single entity products and combinations of both fat-soluble and water-soluble vitamins Multivitamin for adults – typically include vitamins A, D, E, C (ascorbic acid), B1 (thiamin), B2 (riboflavin), niacin, folic acid, B6 (pyridoxine), pantothenic acid, biotin, B12 (cyanocobalamin). Vitamin K (if ordered) – added to the PN formulation separately or administered subcutaneously Pediatric formulations – pediatric doses of the same as listed above + vitamin K

Critically ill patient presents a challenge in fluid management TPN + other IV fluids given for concurrent medical problems – i.e. antibiotic, cardiac and pulmonary therapy. To minimise fluid overload, considerations be given to using concentrated solutions to provide nonprotein kilocalories and protein

MONITORING OF NUTRITIONAL SUPPORT Nutritional Monitoring

Vitamins marketed as single entry injectible products include all of the above except biotin, pantothenic acid, riboflavin, vitamin A and vitamin E

Weight gain, serum total protein and albumin levels, and nitrogen balance, total lymphocyte count.

Carnitine necessary for proper transport and metabolism of fatty acids – IV form of L-carnitine available

Fluid Status Monitoring

Complications 1. Catheter malfunction and sepsis; 2. Electrolyte and mineral deficiency; and 3. Glucose intolerance. Warning: Do Not Overfeed! hypophosphataemia and hypokalaemia can occur with lethal results during the ‘refeeding syndrome’. Developments in PN 1. Medium-chain triglycerides (MCT) containing formulas since it is carnitine-independent for transportation into mitochondria. 2. Glutamine-enriched formulas, as glutamine is vital for gut environment. 3. Carnitine and RNA enriched formulas, as these are implicated in enhancement of immune function. 4. Hormones supplementation (e.g. human growth hormone) that promote positive nutritional status.

Enteral and Parenteral Nutrition

Table 7C: Energy Substrates – Lipid – Emulsion – Energy and EFA

A negative balance during repletion is common due to mobilisation of intracellular water. In EN, the amount of free water in infusions is only 75% to 85% of the total volume. Biochemical Monitoring 1. Acid-base and electrolyte status, 2. Glucose levels, 3. Renal functions (BUN, Creatinine), 4. Liver functions (Bilirubin, enzymes) 5. Major mineral status (Calcium, Phosphorus, Magnesium) and 6. Serum triglycerides. Haematologic Monitoring Complete blood count, coagulation functions (prothrombin time). Functional Monitoring Sensorium, improvement in ventilatory muscle function. Frequency of Monitoring Each of the monitoring parameters listed above could be on a frequency that is hourly, daily or weekly basis on the degree 1931 and level of stability to be attained.

MISCELLANEOUS Highly-Related Issues Ethics Philosophies about NS in seriously ill patients should be discussed with the patient’s family. Ethics committees help to protect and guide the intensivist. Prolonging useful life is different from delaying death. Team approach For optimal, safe and cost-effective PN and EN, a well-trained team is necessary. CURRENT STATUS AND PROBLEMS Currently those involved in providing special oral, enteral (tube) and/or parenteral nutrition can have a good degree of satisfaction in achievements in nutrition support. However, this satisfaction be tempered by the recognition that particularly with regard to not only parenteral nutrition but also in some respects to enteral feeding, there are unresolved issues of varying degrees of clinical importance. Good survival outcomes, e.g.: 



1932

In pregnant women who are dependent on long-term parenteral nutrition, there is improved outcome of the very low-birth infant. Improved nutritional status of patients with a variety of serious malabsorption states including long-term survival



and a good quality of life for those with severe short-bowel syndromes. Improved survival and outcome of acutely ill patients with severe trauma, burns, and infections.

Providing NS to ICU patients, when indicated, is as important as haemodynamic, respiratory, and pharmacologic support. Delay in initiating and maintaining effective NS is lethal. No patient is ‘too sick’ to receive NS! However, appropriate protective randomised controlled trials (PRCTs) to evaluate the role of NS in the ICU is needed. Some NS (i.e. PNS) may actually have established harm. “Thy food shall be thy remedy” Hippocrates (400 BC) – May Be Wrong. It is what we think we know already that often prevents us from learning. Claude Bernard ...Miles to go before?! Success. RECOMMENDED READINGS 1.

Alpers DH, Stenson WF, Bier DM. Manual of Nutritional Therapeutics; 3rd Ed., A Little Brown Spiral Manual; 1995.

2.

Gottschlich MM, Stronts EP, Hutchins A. In: Rombeu JL, Rollendelli R eds. Enteral and Tube Feeding; 3rd Ed. WB Saunders; 1997.

3.

Heimburger DC, Ard JD. Handbook of Clinical Nutrition; 4th Ed., MOSBY An imprint of Elsevier; 2008.

4.

JAPEN Guidelines 2009. American Society for Parenteral and Enteral Nutrition.

5.

Rombeau JL, Caldwell MD. Clinical Nutrition – Parenteral Nutrition; 2nd ed., WB Saunders Co; 1993.

6.

Scheppach W. Addition of fiber to liquid formula diets: the pros and cons. J Parenteral Enteral Nutrition (JAPEN) 1990; 14: 204-9.

Section

26

Poisoning and Toxicology Section Editor: N.P. Singh 26.1

Poisoning—Basic Considerations and Epidemiology N.P. Singh, Gurleen Kaur

1934

26.2

Aluminium Phosphide Poisoning S.N. Chugh

1936

26.3

Organophosphorous Poisoning Surjit Singh

1939

26.4

Corrosive Poisoning Rakesh Kochhar

1941

26.5

Alcohol Poisoning Pritam Gupta, Ankur Gupta

1944

26.6

Plant Poisoning D.K.S. Subrahmanyam

1947

26.7

Drug Overdose Nusrat Shafiq

1950

26.8

Snake Bite Poisoning H.S. Bawaskar

1955

26.9

Scorpion Sting H.S. Bawaskar

1960

26.10 Fluorosis D. Raja Reddy

1965

26.11 Lathyrism U.K. Misra, J. Kalita

1970

26.12 Epidemic Dropsy Navneet Sharma

1972

26.13 Heavy Metal Poisoning Praveen Aggarwal

1974

26.14 Miscellaneous Poisoning Subhash Varma, Vikas Suri

1983

26.1

Poisoning—Basic Considerations and Epidemiology

INTRODUCTION The past 3 to 4 decades have seen a remarkable change in incidence and type of poisoning. A number of new compounds have been added to the list of potentially poisonous materials. Poisoning is the fourth most common cause of mortality in rural India, with childhood poisoning constituting 2.1% of total paediatric admissions and 1.2% of total deaths in this population. Acute poisonings are on the rise in many countries and similar trends have been observed in India as well. In spite of the fact that acute poisoning cases are second only to road traffic accidents in numbers, this is often a neglected health problem compounded with the problem of difficult diagnosis in poisoning cases. It is important to realise that poisonings are largely preventable and majority of poisoning cases die within 1 to 6 hours of exposure to poison. Therefore, it is imperative to have a sound knowledge in the subject of poisoning. In simple terms, a ‘poison’ is any substance that produces toxic effects to the human body. Hence, even drug overdose will be treated as poisoning. EPIDEMIOLOGY The exact incidence of poisoning in India remains uncertain but 1 to 1.5 million cases occur every year, of which 50,000 succumb to it. There is an increasing trend of poisoning with increase in age up to the third decade following which it declines, peak incidence being in 20 to 30 years of age group and rare cases occurring after 65 years of age. Half of the poisonings in India are suicidal, followed by accidental poisonings which are about one-fourth in proportion and homicidal poisonings contribute much less. Both suicidal and homicidal cases of poisoning are more common in India than in the Western countries, because of the ease with which poisons can be obtained from any market. Males are affected more than the females and most victims are recorded from the medium to low socioeconomic group primarily from rural areas. Most cases are literate and married people outnumber unmarried cases. Aluminium phosphide is the commonest poisoning agent reported from rural areas while organophosphorous agents are the commonest reported from other areas. Therapeutic drugs are responsible for only a minor proportion followed by food poisoning cases. Among the paediatric population, nonmedicinal compounds are the largest contributors, of which kerosene alone is responsible for the majority of cases. APPROACH While dealing with a case of poisoning, it is important to consider the following important facts: 1. Identification of the poison a. From the history/circumstantial evidence b. Signs and symptoms of the case 2. Entertain alternative differential diagnosis a. Differentiate from illnesses which can mimic poisonings 1934 3. Identify comorbidities

NP Singh, Gurleen Kaur 4. Offer treatment a. Stabilise patient’s vitals b. Removal of unabsorbed poison c. Use of antidote d. Enhance removal of poison from body e. Supportive management 5. Offer psychiatric counselling, especially for suicidal cases HISTORY AND EXAMINATION A proper history may be elusive because these patients may not be conscious or cooperative. However, an attempt should be made to ascertain the nature of poison, the quantity consumed, mode of exposure, the time of exposure and if there was any vomiting subsequently, which resulted in spontaneous expulsion of the ingested poison. A clinician should always suspect poisoning if there is any sudden unexplained unpredictable illness in a preceding healthy individual, specially if he/she is young or in transit (at railway stations or bus stations, drugging of innocent passengers with stupefying agents is common). A history of recent consumption of an unknown drink/food item from an unverified source, depression or acute stress, presence of insecticide box or pill box near the patient; are suggestive of poisoning. In cases of poisonings, medical management needs to be provided promptly, resuscitative measures may need to be instituted in comatose or unconscious patients (see chapter on Cardiopulmonary Resuscitation). The first assessment of the patient’s clinical condition is very important since it provides the baseline which can be used for subsequent assessments and also outlines the need for instituting emergency measures. After assessment of sensorium and vital signs and need for their management, a quick but thorough physical examination is essential. Absence of any focal deficits and just depression of sensorium without any parasympathetic or sympathetic symptoms could result from a cerebral depressant/sedative. Pupillary signs and signs of cholinergic or anticholinergic stimulation may help aid the diagnosis and in the institution of proper management. Miosis is observed in poisonings with organophosphates/carbamates, narcotics, barbiturates, phenothiazines, clonidine, phencyclidine; while mydriasis is seen with atropine, LSD, MAO inhibitors, nicotine, amphetamines, anti-histamines, tricyclic antidepressants. Skin colour can also be helpful at times – a cherry-red colour seen in carbon monoxide poisoning and cyanosis in absence of hypoxia indicates methaemoglobinaemia. Perioral corrosive burns and intraoral ulcerations and congestion suggest attempts at corrosive ingestion. Odour of the poison may be evident from the clothes or skin, and breath odour can be helpful in cases of ethanol or aluminium phosphide poisoning. Colour of the urine can indicate jaundice resulting from hepatic toxicity or black colour may result from intravascular haemolytic reactions.

Removal of Unabsorbed Poison It is important that whatever poison has not yet gained entry into the human body should be immediately removed. Clothes need to be removed in cases of organophosphorous poisonings, wherein the poison might have spilled on the clothes since these poisons can gain entry though the skin as well. In cases of poisoning with gas (carbonmonoxide poisoning), patient should be removed from the room and brought to fresh air. Skin and eyes should be thoroughly washed in cases of corrosive burns. Gastric lavage is one of the most effective methods to remove the unabsorbed ingested poison, if performed within 2 to 5 hours of ingestion, but is contraindicated in corrosive and kerosene poisonings. Induction of emesis is not advocated as it is not an effective method and, moreover, it can result in aspiration, induce convulsions and there exists a danger of the poison being pushed in to the small bowel from the stomach and getting easily absorbed. Use of Antidotes By definition, antidotes are agents which counteract the effects of poisons. Specific antidotes to all poisons are not known and hence nonspecific antidotes along with supportive therapy are provided in most cases. Activated charcoal acts mechanically by absorbing and retaining within its pores organic and also, to a less degree, mineral poisons. Activated charcoal 50 gm per dose can be repeated 4-hourly and can be given with a cathartic agent like sorbitol. Potassium permanganate, because of its oxidising properties, is a nonspecific chemical antidote and a dilute solution of 1:2000 is commonly used for gastric lavage in opium poisoning. Specific antidotes like atropine is a physiological antidote for organophosphorous insecticide poisoning, naloxone for morphine poisoning, BAL (Dimercaprol) for chelating arsenic or mercury, calcium sodium edentate for lead poisoning, Desferrioxamine for iron poisoning, D-penicillamine for other heavy metal poisonings (lead, gold, mercury and copper). Enhance Removal of Poison from Body Adequate hydration is one of the foremost steps since most toxins/poisons are excreted by the kidneys. Adequate hydration helps maintain the blood pressure which in turn maintains proper perfusion of the kidneys and also aids renal excretion of the poison. Overhydration should be avoided if patient has underlying heart disease, severe anaemia, incipient heart failure or pre-existing renal failure. Forced diuresis can be employed by using frusemide and/or mannitol infusions. Forced acid diuresis is useful for amphetamine poisoning, while alkaline diuresis is beneficial for aspirin and barbiturate poisoning. Urinary alkalinisation is done by administration of IV sodium bicarbonate (1 litre of a 1.26% solution over 3 hours). Intravenous potassium supplementation is necessary to ensure the production of an alkaline urine. Urinary acidification is achieved by giving ammonium chloride 4 gm every 2 hours through Ryle’s tube. Dialysis Support Small molecules that are free in the plasma (i.e. not protein bound) are removed by haemodialysis by diffusion down

a concentration gradient from the plasma to the dialysate. This way, toxins of molecular mass up to 2000 D can pass unhindered through all dialysis membranes; the cut-off for high-flux membranes is above 10,000 D. Clearance is enhanced by increasing the blood flow rate and also the ultrafiltration rate. Haemodialysis is, however, ineffective if the poisons or toxins are lipid-soluble or significantly protein-bound. Haemodialysis can be employed for several poisons like barbiturates, theophylline, lithium, bromides, salicylates, digitalis and methanol. Haemofiltration generates convective transport of solute through the membrane and allows high flux up to a molecular mass of 40,000 D. Since most poisons have molecular weights of less than 1,000 D, haemofiltration usually does not offer any particular advantage over haemodialysis but is occasionally required for large molecules like metal chelating complexes (desferrioxamine and sodium ethylenediamine tetraacetic acid) and aminoglycosides. Haemoperfusion is more suitable in scenarios of poisonings vis-a-vis haemodialysis since it does not depend upon the ability of poison to cross a selectively permeable membrane. Peritoneal dialysis is relatively inefficient compared to haemodialysis or haemofiltration as it achieves low mass transfer of solute and at a slower pace. However, it can be employed when haemodialysis is not rapidly available or is contraindicated.

Poisoning—Basic Considerations and Epidemiology

MANAGEMENT Apart from the routine investigations vomitus, urine, gastric lavage samples and suspected skin scrapings should be preserved for toxicological screening.

Exchange transfusion also has a role for poisoning cases complicated by massive haemolysis, as in sodium chlorate poisoning, wherein it will remove not only the poison but also red cell fragments and free haemoglobin. It can also be employed for hydrogen sulphide poisoning which is complicated by methaemoglobinaemia and sulphaemoglobinaemia. Supportive Management In many cases of poisonings, the agent may not be discernible and often a specific antidote does not exist. In these circumstances, the mainstay of management is supportive care supplanted by prevention and prompt treatment of complications. Common complications which may need to be managed include pain, arrhythmias, hypotension, electrolyte disturbances, seizures, coma, respiratory failure, hepatic failure, and acute renal failure. CONCLUSION Poisoning is a major problem in India. It can be suicidal, homicidal or accidental. Early, aggressive and planned approach is important. Try to identify, detoxify (removal of unabsorbed poison, use of antidotes or by haemofiltration/haemodialysis) maintain vitals, provide effective CPR required and once improved psychological assessment and support is a must, specially in suicidal poisoning. Legal aspects must, be kept in mind. RECOMMENDED READINGS 1.

Olson KR. Activated charcoal for acute poisoning: one toxicologist’s journey. J Med Toxicol 2010; 6: 190-8.

2.

Grover A, Singh NP, Guleria R. Pocket Book of Poisoning; 1st Ed. Pushpanjali Medical Publications Pvt. Ltd. Delhi; 2007.

3.

Dadeja H and Feehally J. Poisoning and drug overdose. Comprehensive Clinical Nephrology, Vol 2; 3rd Ed. In: Feehally J, Floege J and Johnson J. 1935 2007. pp 1155-64.

26.2

Aluminium Phosphide Poisoning

INTRODUCTION Aluminium phosphide (AIP), a solid fumigant pesticide is widely used in India for grain preservation at homes and in warehouses. It protects the stored grain from pests, insects and rodents by liberating toxic phosphine (PH3) gas after coming in contact with moisture. It is available in the form tablets, each weighing 3 g and packets, each weighing 10 g, packed in containers (Figures 1A to C). Each tablet/packet contains 56% of AIP and 44% of ammonium carbonate [(NH4)2 CO3] as active ingredients; is able to liberate PH3 by one-third of its weight. Phosphine, being a gas, diffuses uniformly throughout the grains and the residues such as phosphite and hypophosphite of aluminium are left in the packet/grains which are nontoxic. The poisoning is generally suicidal, rarely homicidal and occasionally accidental (children) and is common in younger age groups.

SN Chugh mitochondrial release of hydrogen peroxide (H 2O 2) and generation of oxygen free radicals by phosphine (PH3). Free radicals seem to play a role in the initiation and propagation of cell damage, in addition to the direct toxic effects of phosphine. CLINICAL TOXICITY The toxic dose of oral AIP compound is 500 mg/70 kg in humans. Toxicity occurs either due to suicidal ingestion of AIP or inhalation of liberated PH3 from fumigated grains. Phosphine is widely absorbed and distributed in the tissues. It is also known that AIP is absorbed as such and possibly deposited in liver leading to slow release of PH3 which may be responsible for extended poisoning in humans. The signs and symptoms of acute, moderate-to-severe ingestional poisoning appear within 45 minutes to one hour. The organs involved include gastrointestinal tract, heart, lungs, liver, kidneys and the brain. The clinical manifestations are depicted in Table 1. Inhalational toxicity is invariably accidental; occurs in persons sleeping in warehouses where stored grains are fumigated with AIP. An exposure to high PH3 concentration leads to shock or cardiovascular collapse but a lower concentration produces pulmonary oedema. However, the lower concentration (7.5 mg/m3) may cause cough, dyspnoea and mild respiratory failure. Table 1: Symptoms and Signs of Moderate-to-severe Aluminium Phosphide Poisoning System

Figures 1A to C: Available packagings of celphos. (A) Tube containing tablets of celphos; (B) Small pack containing 10 packets of celphos weighing 10 g each, and (C) Large container having 50 packets of celphos weighing 10 g each.

MODE OF ACTION OF PHOSPHINE Its toxic effects are due to the liberation of PH3 in the stomach after ingestion of AIP. Inhalation toxicity (inhalation of PH3) is uncommon and primarily involves lungs. The other gases liberated in addition to PH3 include ammonia and CO2 which provide an inert media for PH3 to act: AIP + 3HCI → AICI3 + PH3↑ AIP + 3H2O (moisture) → AI(OH)3 + PH3↑ (NH4)2CO3 + H2O→2NH3 ↑+ CO2 ↑+ 2H2O The exact mode of action of PH3 is not known. It has been claimed to inhibit cytochrome c oxidase, a respiratory chain enzyme, similar to cyanide. Some workers have claimed 1936 inhibition of mitochondrial catalase enzyme, extra-

Common

Gastrointestinal Nausea, vomiting, tract epigastric discomfort, retrosternal burning Cardiovascular Hypotension or shock tachycardia myocarditis arrhythmias Respiratory Cough, dyspnoea, rhonchi, crackles, foul breath Hepatobiliary —

Renal — Central nervous Anxiety, apprehension, system irritability, disturbances in consciousness

Uncommon/Rare Diarrhoea

Bradycardia pericarditis congestive heart failure Type 1 and type 2 respiratory failure Jaundice, hepatomegaly, raised transaminases, hepatic failure Acute renal failure Drowsiness and coma

INVESTIGATIONS 1. Complete haemogram 2. Blood biochemistry, e.g. urea, sugar, creatinine, transaminases, bilirubin, electrolytes, etc. 3. Electrocardiogram (ECG) for arrhythmias, myocarditis and conduction defects. 4. Chest radiograph (posteroanterior view) for acute respiratory distress syndrome (ARDS), aspiration pneumonia, etc.

There may be hypoxaemia (PaO2 distal) Areflexia Respiratory failure Death

87 99 27 39 52 14 86 52 37 33

DELAYED NEUROPATHY Some organophosphates, particularly triorthocresyl phosphate (TOCP) and tricresyl phosphate (TCP) produce what is called delayed neuropathy. On ingestion, they do not produce significant cholinergic crisis but 7 to 20 days later lead to a pure motor axonal neuropathy with wrist and foot drop. It is probably due to depression of a different type of esterase (neuropathy target esterase) in the nervous system. This form of toxicity has 1939

been seen occasionally in small epidemics in India due to adulteration of cooking oil with TOCP. However, with presently used organophosphates such as chlorpyriphos, it is uncommon. LABORATORY DIAGNOSIS The diagnosis can be made from history of ingestion or mucocutaneus exposure, clinical features and laboratory evaluation of plasma cholinesterase (PChE) and red cell acetyl cholinesterase (Red Cell AchE) activity inhibition. The depressed cholinesterase activity confirms the diagnosis of OP poisoning and it continues to remain depressed for 4 to 7 weeks. Though red cell AChE is more specific, PChE assay is easy and more widely available. Prolonged QTc interval, elevated ST segment, inverted T waves and prolonged PR interval are often observed electrocardiographic (ECG) findings. Torsade de pointes and complete heart block have also been reported. MANAGEMENT The initial management involves maintaining a clear airway and intubation might be necessary in case of respiratory distress. Assessment of vitals should be done and undertake resuscitation if necessary. The rest of management includes removal of OPCs from skin and gastrointestinal tract, administration of activated charcoal, atropine or glycopyrrolate, oximes and some newer compounds in addition to ventilatory support which they may require. Washing the skin with soap and water after removal of clothing is essential if there has been an accidental exposure, e.g. during agricultural spray. Care should be taken by health workers to protect themselves by using gloves, aprons, eye protection, etc., as they run the risk of getting poisoned by contact. In case of ingestion, emesis should not be induced as it can lead to complications like aspiration pneumonia, diarrhoea, paralytic ileus. There is no evidence at present that it helps in outcome and can lead to complications like lung aspiration, laryngeal spasm, oesophageal perforation and hypoxia. In India, as suicide is still an offence, gastric lavage is being carried-out routinely for medicolegal reasons to collect lavage sample. As it becomes necessary in our country, due to legal reasons, it should preferably be carried-out using wide bore nasogastric tube and smaller aliquots of water or normal saline with airway protection in obtunded patients. Both single dose and multiple dose activated charcoal have been administered after lavage. However, its benefit is not clear and complications include aspiration pneumonia, vomiting, diarrhoea, constipation, ileus, etc. A recent study suggests that if administered within one hour of ingestion, it may improve outcome. However, if patient needs resuscitation, removal should not be given priority and patient should be resuscitated first. Atropine acts as physiological antidote as it antagonises the muscarinic receptor mediated actions of excessive acetyl choline. However, it has little effect at nicotinic sites. It blocks excessive tracheobronchial secretions, bronchoconstriction, salivation and bradycardia. Unlike glycopyrrolate which cannot cross blood brain barrier, it counteracts the effects of ACh in CNS. It has also been shown to enhance neuromuscular transmission and transmitter release possibly by acting on muscarinic presynaptic inhibitory receptors which are involved 1940 in the feed back mechanism of transmitter release. Though

optimum dose is not known, the first doses are generally given as boluses followed by infusion if dose requirement is large. The initial dose is 2 mg intravenously repeated every 5 to 10 minutes until signs of atropinisation appear, i.e. pulse rate >80 beats/ min, pupillary dilatation, drying of axillae and clear chest. After this it can be given as boluses or as infusion to maintain the atropinisation (0.02 to 0.08 mg/kg/min), the later being considered better with dose being titrated by clinical response. Glycopyrronium bromide has been used in place of atropine. Its effects are similar to atropine but there is less CNS toxicity as compared to atropine as it does not cross blood brain barrier. The use of oximes is controversial. Oximes reactivate the AChE by removing the phosphoryl group from inactivated enzymes. As ageing takes longer with diethyl compounds than with dimethyl compounds, it is likely that oximes may lead to better reactivation in the former. Pralidoxime is the oxime used worldwide. It occurs in two forms, i.e. pralidoxime chloride and mesylate, the latter being less effective. Its major effect is on the peripheral nervous system as it does not cross the blood brain barrier easily. Its main action is to effect recovery of neuromuscular transmission at nicotinic synapses. Complications of oximes include hypertension, cardiac dysrhythmias, headache, blurred vision, dizziness, etc. Obidoxime can lead to hepatic failure. A recent double-blind, randomised study from Sri Lanka has shown a higher mortality in the group treated with high-dose pralidoxime though in some previous studies a better outcome in patients given high-dose pralidoxime was observed.Thus, role of oximes is still controversial. Diazepam is the standard treatment for organophosphorous induced seizures. Mortality in OP Poisoning The mortality in most large series is between 7% to 12%. Death is usually a result of respiratory paralysis.The other complications which can lead to fatality are asphyxia as a result of increased bronchial secretions and bronchoconstriction and rarely pulmonary oedema. Occasionally serious cardiac arrhythmias can lead to fatality. The mortality can be greatly reduced if patients are provided atropine and respiratory assistance in time. NERVE GAS POISONING Nerve gases used in warfare are organophosphates (soman, sarin, etc.). They are powerful irreversible inhibitors of ChE. In addition they phosphorylate other proteins and part of their toxicity may be due to this. The usual oximes are not effective in nerve agent poisoning. CARBAMATES Carbamate poisoning, e.g. Baygon poisoning (Propoxyfur) is increasingly being seen in urban areas in India. They are commonly used in households to kill cockroaches.They produce toxicity similar to that of OP poisoning. The management is similar except that oximes are contraindicated. RECOMMENDED READINGS 1.

Eddlestone M, Singh S, Buckley N. Acute organophosphorous poisoning. Clin Evid 2003; 10: 1652-63.

2.

Pesticides.Ellenhorn’s Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Ed: Mathew J Ellenhorn, 1997. Williams and Wilkins. 1614-30.

26.4 The term corrosive poison encompasses alkaline and acidic agents which cause tissue destruction when they come in contact with mucous membranes. While Lye is the commonest ingested corrosive in the West, acidic agents are more often ingested in the developing world. Corrosive poisoning is often accidental in children, but in adults suicidal ingestion is common. Suicidal acid ingestion in the form of toilet cleaning agents has been one of the commonest form of corrosive poisoning for the last 3 decades. CORROSIVE AGENTS (Table 1) Caustic injury is usually produced by strong alkaline or acidic agents. Acid ingestion is common in India where hydrochloric acid and sulphuric acid are easily available as toilet cleaners. Commercially available liquid alkali, sodium hydroxide (e.g. Harpic) is the commonly ingested alkali in India. Laboratory workers (hydrochloric acid, nitric acid, sulphuric acid) and goldsmiths (aqua regia) ingest acids accidently. In recent years, button-cell battery ingestion in children is also being increasingly recognised. Table 1: Common Corrosive Agents Acidic Corrosives Total cleaners Antirust compounds Soldering fluxes Automobile battery fluid Slate cleaner

: : : : :

Hydrochloric acid, Sulphuric acid Hydrochloric acid, Oxalic acid Hydrochloric acid Sulphuric acid Hydrochloric acid

Alkaline Corrosives Drain cleaners Surface cleaners Laundry and dishwasher Clinitest tablets Industrial strength bleach

: : : : :

Sodium hydroxide Ammonia, Phosphates Phosphates, Carbonates Sodium hydroxide Sodium hydroxide, Calcium hypochlorite

The extent of injury following corrosive ingestion depends upon the nature of the corrosive agent ingested, its physical state, amount and concentration and the duration of contact with the mucosa. Acid solutions cause immediate pain which causes the person to spit the corrosive out. However, if the ingestion is intentional the corrosive is swallowed before the protective reflexes can be evoked. Severity of injury is also influenced by the physical state of the corrosive (solid or liquid). Soild crystalline agents (e.g. sodium hydroxide crystals, potassium permanganate crystals) tend to adhere to glossopharyngeal, palatal and upper oesophageal mucosa producing deep burns limited to the corresponding area. Liquid alkalis and acids, because of their easy deglutition and high specific gravity, pass rapidly through the oesophagus. Injury pattern also depends upon the postprandial state of the patients. If the stomach is full the agent is rapidly diluted and gastric mucosa is spared. When the stomach is full, the corrosive bolus flows rapidly from the gastro-oesophageal

Corrosive Poisoning Rakesh Kochhar sphincter along the lesser curvature to the pyloric antrum where maximum damage occurs. It was earlier believed that alkalis bite the oesophagus due to liquefaction necrosis of the squamous epithelium, and lick the stomach due to dilution by its acidic contents. Acids were believed to spare the oesophagus and damage the stomach. However, we have shown that concentrated alkalis and acids, both cause similar damage to oesophagus as well as the stomach. Solid corrosives in powder form, like caustic soda, more often cause oropharyngeal burns while liquid corrosives damage the oesophagus and the stomach. PATHOPHYSIOLOGY Concentrated acids produce coagulative necrosis with a protective eschar. This coagulum tends to limit the penetration into deeper muscular coats. But sloughing and expulsion of large areas of the surface lining of the stomach and oesophagus with secondary infection and perforation may pose problems. In severe cases associated with perforation, the resulting peritonitis or mediastinitis can lead septicaemia and its sequelae. Apart from oesophageal injury causing strictures because of antral pooling of the caustic agent, some patients may develop pyloric obstruction or antral stenosis or hourglass deformity. These can develop within weeks to months after ingestion of the agent. Alkaline caustic agents rapidly penetrate into tissues and produce injury by liquefaction necrosis with intense inflammation and saponification of mucous membrane, submucosa and muscularis mucosa within 2 to 3 days of contact. Mucosal sloughing occurs 4 to 7 days after injury. Stricture formation starts by 3rd week, although it can occur for the first time several years later. CLINICAL PRESENTATION Acute Phase (1 to 10 days) This is characterised by acute symptoms like pain, dysphagia, haematemesis, etc. Laryngeal oedema can cause hoarseness of voice and stridor. Aspiration of the caustic agents into airways can cause chemical bronchitis. Full thickness necrosis can produce perforation leading to mediastinitis, pleural effusion, empyema or peritonitis. Septicaemic shock is a common cause of death in acute phase. Subacute Phase (11 to 16 days) There is transient decrease in above mentioned symptoms. Chronic Phase (28 days to months) Characterised by oesophageal strictures causing dysphagia, and gastric stenosis causing gastric outlet obstruction. ENDOSCOPIC FINDINGS AND CORRELATION WITH OUTCOME Symptoms and signs are poor indicators of degree and extent of damage to the gastrointestinal tract. Radiological studies are also not sensitive. The best method to stratify patients with

1941

acute corrosive ingestion is upper gastroduodenal endoscopy whose safety has been well established. Flexible endoscopy can be performed safely at any time from 6 to 96 hours of ingestion, provided the patient is stable and there is no evidence of perforation. However, it should be avoided in the sub-acute phase (5 to 15 days) after corrosive intake when the tissues slough and there is increased danger of perforation. On the basis of endoscopic findings, corrosive burns have been classified into grades 0, 1, 2 and 3 (Table 2). Most perforations and fatalities in the acute phase occur in patients with grade 3b injury, while strictures develop in patients with grade 2b or worse injury. Therefore, such patients need to be kept under close supervision. Table 2: Endoscopic Classification of Corrosive Burns Grade 0 Grade 1 Grade 2a Grade 2b Grade 3a

Grade 3b

Normal examination Oedema, hyperaemia of the mucosa Friability, haemorrhage, erosions, blisters, whitish membrane exudate and superficial ulceration Grade 2a + deep discrete or circumferential ulceration Multiple ulcerations and small, scattered, nonconfluent areas of necrosis (area of brown-black or greyish discolouration) Extensive necrosis, confluent necrosis

6 to 8 weeks, patients require nutritional support with total parenteral nutrition or feeding jejunostomy. The latter is preferred in India. Recently, endoscopically placed naso-jejunal tubes are being used for maintaining enteral nutrition in these patients. Chronic Phase Late sequelae include oesophageal and/or gastric cicatrisation. It is essential to do a barium study to assess the site, extent and nature of oesophageal and gastric stenosis (Figures 1 to 4). Generally, endoscopic treatment is offered 6 to 8 weeks later, once re-epithelialisation has taken place. 1. Oesophageal strictures are often long, tortuous, multiple and very tight (Figures 1 and 2). They require repeated dilatation endoscopically with bougies or balloons and recurrences are frequent. Corrosive oesophageal strictures

MANAGEMENT Acute Injury The management of acute corrosive injury consists of recognition and treatment of acute complications and treatment of sequelae. Early treatment includes maintaining the patient nil per orally, intravenous fluids, airway maintenance and supportive treatment. After resuscitation, acute complications like perforation and peritonitis should be ruled out by radiograph chest, radiograph abdomen and a radiological soluble contrast study, if indicated. Upper gastrointestinal endoscopy should be done to evaluate the severity of burn. Airway management may require tracheostomy. Treatment of infections is an essential part of early management. There is sufficient evidence that gastric lavage, use of emetics, or purging agents are contraindicated, since these cause more harm than any good. Neutralisation of the corrosive agents with weak acid or alkali used to be done in the past. But its efficacy could never be proved probably due to the rapid action of acids or alkalies. Dilution with water is also not useful as it may cause more harm by liberation of heat. Hence, neutralisation is contraindicated. Antibiotics are given only when patients have symptoms and signs of secondary infection. Steroids have no role in prevention of late sequelae. The only indication of using steroids could be laryngeal oedema. Parenteral steroids may lead to systemic infection in a bed-ridden patient. Indications for surgery include perforation of oesophagus or stomach, massive upper gastrointestinal bleed and full thickness burns of oesophagus or stomach with charring. Patients are unable to have normal diet in the first few weeks after acute corrosive ingestion due to mucosal oedema and ulceration. Later development of cicatrisation in the 1942 oesophagus and stomach precludes normal feeding. Hence for

Figure 1: Barium swallow showing a long stricture involving middle and lower thirds of oesophagus in a patient with sulphuric acid ingestion (Anteroposterior view, left; left oblique view, right).

Corrosive Poisoning Figure 3: Barium meal study showing a dilated stomach with total obstruction at pylorus in a patient with hydrochloric acid ingestion.

Figure 2: Barium swallow showing a single short mid-oesophageal stricture in a patient with toilet cleaner ingestion.

are difficult to dilate but over three-fourths of them respond to endoscopic dilatation. It has been shown that combining intralesional steroid injections with dilatation is very rewarding in difficult strictures. Recently, self expanding plastic stents have also been used in such patients with good results. Patients who cannot be dilated or have frequent recurrences are subjected to esophageal bypass using a jejunal or colonic loop or gastric pull up. 2. Gastric cicatrisation leads to pyloric and/or antral stenosis (Figures 3 and 4), clinically presenting as recurrent vomiting. Such patients often require surgery with antrectomy or partial gastrectomy. Some patients have linitus-plastica like deformity involving a large part of the stomach requiring subtotal or total gastrectomy. Recently, endoscopic balloon dilatation has been used successfully to treat pyloric stenosis due to corrosive injury. 3. Oesophageal carcinoma: Risk is estimated to be 1,0003,000-folds and it usually occurs 20 to 30 years after an acute injury.

Figure 4: Barium meal study showing two strictures, one at body-antrum junction and another at pylorus in a patient with sodium hydroxide ingestion.

SUMMARY In India, acid ingestion is more common than alkali ingestion. Strong acids and alkalis cause equal injury to oesophagus and stomach. Management of acute injury involves resuscitation, maintenance of airways and supportive care. At 6 to 8 weeks barium studies are done to assess for chronic sequelae. Endoscopic dilatation of oesophageal strictures and localised pyloric stenosis form the first line of treatment. Surgical treatment is indicated for long oesophageal strictures, in patients who fail to respond to dilatation and those with long segment of gastric stenosis. RECOMMENDED READING 1.

Zargar SA, Kochhar R, Nagi B, Mehta SK. Corrosive acid ingestion: spectrum of injury to upper gastrointestinal tract and natural history. Gastroenterology 1989; 97: 702-7.

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26.5

Pritam Gupta, Ankur Gupta

The most commonly used alcohol is ethyl alcohol (ethanol). Unlike ethanol, methyl alcohol (methanol) is extremely toxic. Two other alcohols commonly used (though not as much as methanol and ethanol) are propyl alcohol and butyl alcohol. Prompt recognition and treatment of patients intoxicated with these substances can reduce the morbidity and mortality associated with these alcohols.

Table 1: Systemic Effects of Alcohol

ACUTE ALCOHOL POISONING The term alcohol in common use refers to ethyl alcohol. At low doses, alcohol can have some beneficial effects such as decreased rate of myocardial infarction, stroke, gallstones and possibly vascular and Alzheimer’s disease. However, if taken in large amounts, it can be toxic as well as fatal. The characteristic flavour of alcoholic beverages is due to organic compounds called congeners, such as propyl alcohol, octyl alcohol, glycerine, aldehyde, esters and certain acids.The total content of congeners rarely exceeds half per cent.

100% to 150 mg%

Metabolism Twenty per cent of alcohol is absorbed from oral cavity, oesophagus, stomach and the rest from small intestine. About 60% of diluted alcohol is absorbed within half an hour if taken on an empty stomach.The rate of absorption is increased by rapid gastric emptying, absence of fats and proteins, optimal dilution of 20% by volume and carbonation. Five per cent of alcohol is excreted in breath and another 5% through urine. The peculiar odour of alcohol is due to excretion of alcohol from skin glands. Ninety per cent of alcohol is metabolised in the liver. Alcohol is oxidised into acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde in turn gets converted to acetate and fatty acids by aldehyde dehydrogenase and acetyl-CoA. Finally, acetate enters the general pool and oxidises into carbon dioxide (CO2) and water (H2O) through the Kreb’s cycle pathway. Clinical Manifestations Ethanol depresses primarily the reticular activating system. In lower concentrations, it causes depression of more specialised and sensitive cells of the cerebral cortex (centers regulating conduct, judgement and self-criticism), with release of their inhibitory tone and leads to unrestrained behaviour. Increasing concentration progressively depresses brain function. Finally, the vital centres in the midbrain and medulla are depressed, which may cause cardiorespiratory failure and death. It also causes generalised vasodilatation, especially in the skin. It is hypnotic and diaphoretic. The toxic effects of alcohol depend upon its concentration in the blood (Table 1). The clinical manifestations can be classified in 3 stages: 1. Stage of excitement 2. Stage of incoordination 1944

Alcohol Poisoning

3. Stage of narcosis

Blood Alcohol Concentration

Effects

0% to 50 mg% 50% to 100 mg%

No significant effect or mild euphoria Decreased inhibitions and attention span, increased self confidence, slurring, alteration of judgement, nystagmus Mental confusion, emotional instability, ataxia, impaired memory, sleepiness, slowed reaction time Loss of coordination, drowsiness, exaggeration of emotions, dizziness, disorientation, thickened speech Stupor, marked decrease in response to stimuli, marked incoordination, possibly coma Anaesthesia, depression of responses, respiratory failure, deep coma, death

150% to 300 mg%

300% to 400 mg%

400 mg% and above

Cause of Death In alcohol intoxication, death may be due to the depressive effects on brainstem respiratory centre or due to aspiration of vomitus. Deaths due to acute overdose of alcohol are not as common as due to the chronic effects of alcohol. Differential Diagnosis The differential diagnosis of acute alcohol intoxication includes all causes of depressed levels of consciousness such as infections of brain, head injury, intracerebral haemorrhage, brain tumours and other metabolic conditions affecting the brain like hypoglycaemia, hyponatraemia, hepatic encephalopathy, uraemia or drug overdoses. Management of Acute Alcohol Intoxication Unabsorbed ethanol may be removed by gastric lavage. Adequate ventilation with maintenance of airway is important in a comatose patient. Sodium bicarbonate may be administered to alkalinise the urine. Hypoglycaemia is common and should be corrected with dextrose infusion along with simultaneous administration of 100 mg of thiamine parenterally. In a lifethreatening emergency haemodialysis may be done to lower ethanol levels rapidly. METHYL ALCOHOL POISONING Methanol is a common ingredient in antifreeze, paints and solvents. It is also used in photocopying fluid, shellacs, and windshield-washing fluids. Poisoning usually follows ingestion of contaminated alcohol beverages or ‘methylated spirits’. Intoxication in industrial settings follows absorption across the skin or lung. Methanol is primarily metabolised in the liver via alcohol dehydrogenase into formaldehyde which is subsequently

Clinical Picture It causes early temporary central nervous system (CNS) depression followed by a latent period lasting 6 to 24 hours before the development of metabolic acidosis and visual symptoms. Significant ingestion causes nausea, vomiting and abdominal pain. Its effects on the CNS resemble those of ethyl alcohol, although in low doses it does not have a euphoric effect. Visual symptoms present as falling visual acuity and photophobia. Specifically, vision is often described as a ‘snow field‘, though a variety of visual complaints including blindness may be verbalised. Early signs include optic disc hyperaemia and decreased pupillary light reflex. Ingestion of only 10 mL can cause blindness and 30 mL can be fatal. Arterial pH seems to correlate best with formate levels and pH (< 7.2 is a severe intoxication). Up to two-thirds of patients have raised serum amylase levels. Autopsy reveals haemorrhagic pancreatitis. Seizures are seen in severe intoxication. Computed tomography usually shows cerebral oedema or even necrosis in the basal ganglia (a Parkinsonian-like state is sometimes seen with recovery). Serum methanol levels should be obtained when this diagnosis is suspected. Both the osmolal and anion gap should be obtained in addition to liver function tests, renal function tests and plasma glucose levels. Management Ipecac/gastric lavage is useful only if patient presents within 2 hours of ingestion. Activated charcoal is not indicated. Seizures should be best treated with phenytoin since this will have less of a CNS depressant effect than diazepam. Folinic acid should be administered at a dose of 1 mg/kg, with a maximal dose of 50 mg. It should be repeated every 4 hours. If folinic acid is not immediately available, folic acid can be substituted at the same dose. Metabolic acidosis should be treated with sodium bicarbonate. Specific antidotes—ethanol or fomepizole should be used to prevent formation of formic acid (Table 2). Haemodialysis should be considered in certain situations (Table 3). The guidelines for the use of ethanol and fomepizole have been summarised in Tables 4 and 5, respectively. ETHYLENE GLYCOL Ethylene glycol is an odourless, colourless, sweet-tasting liquid, which is used in many manufacturing processes. It is probably most commonly used as an antifreeze. It is absorbed rapidly from the gastrointestinal tract. Ethylene glycol itself is nontoxic, but it does get metabolised into toxic compounds. Ethylene glycol is oxidised via alcohol dehydrogenase into glycoaldehyde which subsequently undergoes metabolism via aldehyde dehydrogenase into glycolic acid.The conversion of glycolic acid

Table 2: Indications for Treatment of Ethylene Glycol or Methanol Poisoning with Ethanol or Fomepizole Documented plasma levels >20 mg/dL or Recent history of ingestion and osmolal gap >10 mmol/kg Strong clinical suspicion and at least 2 of the following: pH 72 hour) because of decreased metabolism (a depressed cardiac output, reduced blood flow to the liver and kidneys), formation of active metabolites, saturation kinetics prolong elimination at the high plasma concentrations that typically occur with overdose, and more common use of long-acting preparations. Management Restoration of heart rate can be achieved by atropine, isoprenaline, amrinone, dopamine, dobutamine, epinephrine or norepinephrine. For managing hyperkalaemia and hypoglycaemia, glucose with insulin may be instituted. Because glucagon is both diagnostic and therapeutic, it can be administered empirically in a dose of 2 to 10 mg and response checked. It is considered drug of choice by many toxicologists and it acts by stimulating cAMP production through nonadrenergic pathways resulting in enhanced myocardial contractility, heart rate, and AV conduction. Benzodiazepines are the drugs of choice if seizures occur. Calcium Channel Blockers (CCBs) The three types of CCBs may all produce a physiologically depressed toxidrome. In 2008, the US National Poison Data System reported 10,398 exposures to CCBs, resulting in 12 deaths (0.11%) and 63 major outcomes (0.6%). Presentation Hypotension and bradycardia are typical presentations but reflex tachycardia after exposure to dihydropyridines can also occur. Pulmonary oedema, nausea, vomiting, hyperglycaemia are commonly present. Severe hypotension may lead to mesenteric ischaemia and colonic infarction. Paralytic ileus may be present. Since sustained release preparations are commonly used, presentations may be delayed. Even a single tablet of a CCB can be fatal in children. Management Restoration of cardiovascular parameters as for beta-blockers should be instituted. In severe cases a bolus dose of calcium chloride (10 to 20 mg/kg up to 1 to 3 g) is the preferred therapy. Bolus infusion of glucagon (0.05 to 0.20 mg/kg, over 1 to 2 minutes) is useful. For refractory cases, intravenous bolus of regular insulin with 50% dextrose may have some benefit. PHENYTOIN Symptoms of toxicity appear above plasma concentration of 1952 20 μg/mL. However, there is a large inter-individual variation.

Presentation of toxicity depends on the route of administration of phenytoin. Data from the United States of America suggest moderate morbidity rates of 22%, major morbidity in 1.88%, and fatality in 0.17% of phenytoin overdose cases. Presentation In an emergency setting when fosphenytoin intravenously is administered, toxicity symptoms (cardiac arrhythmias with hypotension and/or CNS depression) may appear if given at a fast rate (more than 150 mg of phenytoin sodium equivalents per minute). Toxicity due to acute oral overdosage leads to cerebellar or vestibular symptoms. Chronic oral toxicity presentations include behavioural changes, increased frequency of seizures, gastrointestinal symptoms, gingival hyperplasia, and osteomalacia. Management GI decontamination to limit the systemic burden with multiple dose activated charcoal and control of seizures, if any, with benzodiazepines are the mainstay of treatment. Digoxin Various studies suggest that approximately 1.1% of outpatients on digoxin, and 2% to 18% of inpatients on digoxin have manifestations of toxicity. The incidence has declined due to increased awareness about drug interactions, decreased use of digoxin to treat heart failure and arrhythmias, and the availability of accurate rapid radioimmunoassays to monitor drug levels. Toxicity usually appears at a concentration > 2 ng/mL and is more likely to occur in those with impaired renal function, hypokalaemia, hypercalcaemia and hypomagnesaemia. Presentation Cardiac arrhythmias range from ventricular arrhythmias to atrioventricular blocks to sinus bradycardia. Non-cardiac symptoms include anorexia, nausea, vomiting, abdominal pain, halos, photophobia, fatigue, dizziness, delirium, and psychosis. Management Further doses of digoxin should be stopped. Conduction delays and blocks should be treated with atropine. Intravenous potassium may help in junctional or ventricular automaticity, lidocaine or phenytoin for ventricular tachyarrhythmias. Antidigoxin antibody is indicated for dysrhythmias associated with haemodynamic instability, altered mental status, K+ >5 mEq/L, serum digoxin level >10 ng/mL in adults at steady state and ingestion of >10 mg in adults or >0.3 mg/kg in children. The dose is calculated as either (mg ingested) x 0.8/0.6 or [serum level (ng/mL) x 5.6 x body weight (kg)/1000]/0.6. Methylxanthines As is the case of digoxin, the number of reported cases of theophylline toxicity is decreasing for similar reasons. The toxicity may occur in two settings – in an emergency setting when aminophylline may be used, or chronic toxicity due to repeated oral administration. Presentation Rapid administration of aminophylline may even lead to sudden death. At concentrations more than 20 μg/mL, headache,

With chronic toxicity, the concern is that of seizures which may be refractory to treatment. Management Decontamination with charcoal, especially if sustained release preparations are used, propranolol for the management of tachyarrhythmias with hypertension, any beta-blocker if hypertension is not present, diazepam, phenytoin or barbiturates for seizure control are the mainstay of treatment. Haemoperfusion or haemodialysis are indicated for unstable vital signs, seizures and plasma concentration of theophylline more than 80 to 100 μg/mL for acute overdose and 40 to 60 μg/mL for chronic exposure. Metoclopramide or ondansetron may be used for vomiting, and IV fluids/pressor agents for hypotension. Iron Iron overdose is one of the leading causes of fatality from toxicological agents due to non-intentional ingestion in children although the incidence has decreased considerably. Ingestion of 40 mg/kg or more of elemental iron is associated with serious toxicity. Generation of oxidative free radicals is the main mechanism of injury. Iron tablets can be visualised on abdominal radiograph if taken within 2 hours of ingestion. Presentation Iron poisoning may be classified into 5 distinct stages (Table 3). It is important to know them because the second recovery stage may lure the treating doctor into a false sense of security and lead to pre-mature discharge from the hospital. Table 3: Stages of Iron Poisoning Stage 1: Gastrointestinal Usually occurs within 6 hours after exposure Nausea and diarrhoea, often with excessive fluid and blood loss Stage 2: Latent This deceptive stage is characterised by resolution of GI symptoms Usually occurs 6 to 12 hours after ingestion and may last for 24 hours Stage 3: Metabolic/Cardiovascular Metabolic acidosis and cardiovascular symptoms Stupor and coma Most patients die during this phase It can start very early (6 to 8 hours), depending on severity of exposure, and it can last up to 2 days Stage 4: Hepatic Elevated liver enzymes and bilirubin levels with coagulopathy Hypoglycaemia Stage 5: Delayed Scarring of the healing GI tract. The stomach and/or intestines may be affected, resulting in gastric outlet or intestinal obstruction Experienced weeks after a severe poisoning

Management Polyethylene glycol is the preferred agent for gut decontamination. Intravenous fluids and sodium bicarbonate may be needed for fluid and electrolyte balance. Patients with systemic

symptoms should be given intravenous desferrioxamine. An initial dose of 1 g is given, either intravenously at a maximum rate of 15 mg/kg per hour, or by intramuscular injection; subsequent doses of 500 mg may be given, by infusion over 4 to 12 hours or intramuscularly at intervals of 4 to 12 hours, to a maximum of 6 g in 24 hours. Deferiprone is an orally active iron chelator used in the treatment of iron overload in patients with thalassaemia for whom desferrioxamine is unsuitable or ineffective. It may be given by mouthing doses of 25 mg/kg three times daily. Doses above 100 mg/kg daily are not recommended.

Drug Overdose

palpitation, nausea, hypotension, precordial pain, restlessness and agitation occur. Tachycardia, arrhythmias and seizures are important causes of concern.

Warfarin Warfarin overdose presents as excessive anti-coagulation reflected in elevated levels of Internationalised Normalised Ratio (INR) (Table 4). Table 4: Excessive Anticoagulation Shown by Increased INR INR Value

Management

0.5-6 6-8 (No bleeding/ Minor bleeding) >8 Major bleeding

Reduction in dose or withdrawn Stop warfarin Vitamin K1 (0.5 mg IV or 2.5 mg of IV dose given IV) Stop warfarin, Vitamin K (5 to 10 mg by slow intravenous infusion, concentrate of II, VII, IX, X) and fresh frozen plasma

Antipsychotics Typical antipsychotics have by and large a wide therapeutic index. Presentation Overdosage may result in neuroleptic malignant syndrome characterised by extreme hyperthermia, ‘lead pipe’ skeletal muscle rigidity causing dyspnoea, dysphagia, and rhabdomyolysis, autonomic instability, fluctuating consciousness, leucocytosis, and elevated creatine phosphokinase. The newer antipsychotic agents were evaluated for their effects in overdosage in a study in UK. Symptoms were most marked with clozapine, with a majority of patients experiencing agitation, dystonia, central nervous system (CNS) depression and tachycardia. Olanzapine and sulpiride produced a range of different symptoms, including cardiac arrhythmias with sulpiride and most patients who had taken risperidone were asymptomatic. Management The treatment of malignant syndrome includes immediate withdrawal of neuroleptic drugs, intravenous infusion of dantrolene, and oral administration of bromocriptine; or the combination of levodopa-carbidopa. Other measures include the use of benztropine, lorazepam if catatonic symptoms persist, or electroconvulsive therapy (ECT ) if psychotic symptoms persist. PROMETHAZINE Promethazine, a first generation antihistaminic is commonly used for management of vomiting and cough. Presentation The important feature of promethazine overdose is delirium. Central nervous system (CNS) depression and anti-cholinergic 1953

effects, including delirium, agitation and hallucinations are important features. Delirium may be masked by CNS depression. Dystonic reactions, psychosis in the absence of other anticholinergic symptoms or signs and neuroleptic malignant syndrome (NMS) may also occur. Management Dystonic reactions respond well to benztropine or diphenhydramine. Early administration of charcoal may reduce the occurrence of delirium.

Management There is no specific antidote for Li+ intoxication, and treatment is supportive. Electrolyte and fluid balance is important. Dialysis is indicated for patients exhibiting symptoms of toxicity or patients with serum Li+ concentrations greater than 4 mEq/L in acute overdoses or greater than 1.5 mEq/L in chronic overdoses.

Isoniazid Acute ingestion of 1.5 g of INH can cause mild toxicity, 6 to 10 g causes severe toxicity and 15 g is usually fatal.

Phenobarbitone The plasma concentration of 10 to 35 microgram/mL is usually associated with attainment of therapeutic response.

Presentation Signs and symptoms of overdosage include slurred speech, hallucinations, metabolic acidosis, hyperglycaemia, respiratory distress or tachypnoea, convulsions and coma; fatalities may also occur.

Presentation At high doses nystagmus and ataxia may occur and the typical barbiturate-induced respiratory depression may become severe. Overdosage can prove fatal; toxic effects include coma, severe respiratory and cardiovascular depression, with hypotension and shock leading to renal failure. Hypothermia may occur, with associated pyrexia during recovery. Skin blisters (bullae) occur in about 6% of patients with barbiturate overdose.

Management In adults an initial intravenous dose of pyridoxine hydrochloride equivalent to the estimated amount of isoniazid ingested (or, if the amount ingested is unknown, pyridoxine hydrochloride 5 g) has been recommended by the UK National Poisons Information Service for the management of convulsions; diazepam should also be given. For children the recommended dose of pyridoxine hydrochloride is 70 mg/kg (to a maximum of 5 g). If convulsions continue or recur, this dose may be repeated. Oral activated charcoal (50 g for adults and 10 to 15 g in children) may be considered if this is given within 1 hour of ingestion of isoniazid. Lithium Lithium is a narrow therapeutic index drug. Moreover it is subject to clinically significant drug interactions. Toxicity manifests more in those with renal failure, dehydration, hyponatraemia or those on diuretics. Presentation Acute intoxication is characterised by vomiting, diarrhoea, tremors, ataxia, coma, and convulsions. The more serious effects involve the nervous system and include mental confusion, hyper-reflexia, gross tremors, dysarthria, seizures, and cranial

1954

nerve and focal neurological signs, progressing to coma cardiac arrhythmias, hypotension, albuminuria, and death.

Management Gastric lavage, multiple doses of activated charcoal (MDAC), airway protection, oxygenation, mechanical ventilation, IV fluids and vasopressors are the mainstay of treatment. The urinary elimination of phenobarbital (pKa of 7.2) may be enhanced with alkalinisation of the urine by sodium bicarbonate with the aim of maintaining urinary pH between 7.5 and 8. Haemodialysis or haemoperfusion are indicated for phenobarbital poisoning in the presence of renal failure and shock with ileus. CONCLUSION Drug overdosage is an important problem with significant morbidity and mortality. Though the ideal management would occur at poisoning and toxicology centres, more often than not these cases need to be managed at primary or secondary care centres. Supportive management is the mainstay of treatment and antidotes are helpful in very few poisonings. Limited dispensation policies, purchase on prescription could help bring down the incidence of suicidal overdosage.

26.8

Snake Bite Poisoning HS Bawaskar

INTRODUCTION Snake bite envenomation is a common acute life-threatening medical emergency. More than 200,000 snake bites are reported in the country and an estimated 35,000 to 50,000 people die each year. Majority of snake bite deaths go unreported as many victims go to traditional healers and many deaths occur before reaching hospital. AETIOLOGY There are about 216 species of snakes identifiable in India, of which 52 are poisonous. The major families of poisonous snakes in India are Elapidae which includes common cobra (Naja naja, Figure 1A), king cobra and common krait (Bungarus caeruleus, Figure 1B), Viperidae includes Russell’s viper (Figure 1C), Echis carinatus (saw scaled or carpet viper, Figure 1D) and pit viper and hydrophiidae (sea snakes). Snake venom is not a substance evolved to attack man or big vertebrates, but is intended to paralyse the prey before swallowing. Venom secretion in all venomous snakes appears to vary in seasons. In warmer months its output is more than in the cold season. Similarly, darker the snake, more is the venom it secretes. Most snakes inject 10% of available venom in a single strike except Russell’s viper which injects 75% of stored venom in one bite and is responsible for high morbidity and mortality in India.

Figure 1A: Common cobra (Naja naja).

Figure 1B: Common krait (Bungarus caeruleus).

Figure 1C: Russell’s viper (Vipera russellii).

Figure 1D: Saw-scaled viper (Echis carinatus).

PATHOPHYSIOLOGY Snake venoms are not single toxins but a cocktail of many components: enzymes, polynucleotide toxins, nontoxin proteins, carbohydrates, metals, lipids, free amino acids, nucleotides and biogenic amines. The content and potency of venom in any snake varies with size, age, diet, climate, and time of year. Moreover, a small snake’s immature venom may not respond to routine anti-snake venom. Procoagulant enzymes are the major factor in viper venom, which stimulates blood clotting and consumption of fibrinogen, causing disseminated intravascular coagulation (DIC). Russell’s viper venom contains several different procoagulants which activate various steps of the clotting cascade. Fibrinolytic activity of the viper venom is so fast that sometimes within 30 minutes of the bite, the coagulation factors are so depleted that blood does not clot. Haemorrhagins are zinc metalloproteinases, which damage the endothelial lining of the blood vessels causing spurting of red blood cells and spontaneous systemic bleeding. Cytolytic or necrotic toxins damage the cell membranes and stimulate apoptosis. These digestive hydrolases, polypeptide toxins and other factors increase permeability resulting in local swelling and nonhealing ulcers and gangrene of the bitten part. Haemolytic and myolytic phospholipases A2 (PLA2) damage cell membranes, endothelium, skeletal muscle, nerve and red blood cells. Presynaptic neurotoxins are phospholipids A2 that damage nerve endings, initially releasing acetylcholine transmitter, then interfere with its release. Postsynaptic neurotoxins are 1955

polypeptides which compete with acetylcholine for receptors in the neuromuscular junction and lead to curare-like paralysis (cobra venom). The amount of venom injected at the time of bite depends on the species and size of the snake and the mechanical efficiency of the bites. At times snake may be able to control whether or not venom is to be injected at the time of bite. This is the reason why irrespective of bite by poisonous snake, sometimes there is no systemic sign of envenomation, i.e. dry bite.

of body or from vene-puncture sites is seen within 90 to 120 minutes of a bite. Occasionally, in untreated patients, bleeding can persist for 1 to 2 weeks in the form of blood-stained sputum, haematuria and then disappears of its own. Such patients are markedly anaemic and report to hospital for weakness or nonhealing bleeding cellulitis. Natural immunity against the Echis carinatus venom develops in cases of repeated bites by the same species in endemic areas as reported in Jammu region. Renal failure due to Echis carinatus has been reported from Puducherry and Jammu areas, but not from Maharashtra.

ECHIS CARINATUS OR SAW-SCALED VIPER OR CARPET VIPER It is 1 to 3 feet long, head is sub-ovate with short rounded snout, body is cylindrical, short and covered with rough, serrated flank scales, neck is distinctly constricted. It is pale brown or tawny with dark brown. A cruciform or trident or arrow type or just like the bird foot print shaped mark is seen on head. It flourishes in hot and humid climate in the coastal regions of India. It is alert, diurnal in habit and capable of quick movement when necessary. It hibernates in the winter. Readiness with which it bites on smallest provocation with extremely rapid strike makes it one of the more dangerous snakes. It forms a double coil in the form of figure of 8 with its head in the centre a striking position. It is viviparous producing 3 to 15 young at a time. It injects 0.0046 gram venom at the time of bite. Farmers, hunters, labourers, and persons walking barefoot in jungles and rocky areas are often bitten by this snake. Clinical Manifestations Local manifestations Within an hour of the bite, swelling develops over the bitten part. Fang marks or abrasions with clotted blood are seen (Figure 2). Venom is of big molecular size and is circulated through the lymphatics, hence within 60 to 120 minutes the victim experiences a painful lymphadenopathy of the drainage area of the bitten part. Ecchymoses are seen over the bitten part or may spread over lymphatic drainage areas. Acute bleeding in the form of gum bleeds (Figure 3) or bleeding from abrasions on any other part

Figure 3: Acute bleeding from gums and oral cavity due to Echis bite.

RUSSELL’S VIPER OR DABOIA OR VIPERA RUSSELLII SIAMENSIS It inhabits ten south Asian countries and ranks amongst one of the topmost important causes of snake bite mortality. While protecting the paddy and wheat from the rodent (rats) population, it kills many farmers unlucky enough to tread on it. It is a 3 to 5 feet long snake; the head is covered with small scales and without shields. The body is massive and cylindrical, narrowing at both ends; the head is flat, triangular with short snout, large gold flecked eyes with vertical pupils and large open nostrils. Its belly is round with constricted neck. Typical rows of oval arranged in two rows is characteristic of Russell’s viper. Its natural prey includes mice, rats, frogs, lizards, snakes, and birds. The young snakes are cannibalistic. The females produce 20 to 60 young usually around the month of June or July. Length of fangs in an adult snake is 16 mm and curved. The amount of venom injected at the time of bite is 63 ± 7 mg.

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Figure 2: Two fang marks with bleeding spot at fang marks over the second toe due to Echis bite.

Clinical Manifestations Local manifestations The victim experiences severe local pain at the site of the bite, active bleeding from fangs marks within a few minutes, rapid swelling progressing to the whole limb within six to eight hours (Figure 4). Ecchymoses and blebs occur over the bitten part. Because of oedema of muscle and bleeding there is development of compartment syndrome characterised by swelling, painful passive movement, and loss of sensation over the nerve areas passing through the compartment. Subsequently, wet gangrene or nonhealing ulcers develop. Lymph nodes proximal to the bite become enlarged and tender.

Krait is the most poisonous snake, its venom being 10 times more poisonous than cobra venom. It is 1 to 4 feet long, with enlarged hexagonal vertebral scales, uniform white or red belly and narrow white crossbars on the back, more or less distinctly in pairs, the crossbars are typically absent near the head and neck region. The common krait resides in the vicinity of human habitation, near the wattle and daub, mud and small hut dwellings. Krait is a nocturnal, terrestrial snake that enters human dwellings in search of prey such as rats, mice, and lizards. It eats even the small snakes (cannibalism). The common krait is regarded as the most dangerous species of venomous snake in the Indian subcontinent. Most bites occur during the cooler months of June to December when snakes may, during the course of their hunting activity, linger in a person’s bedding to take advantage of the warmth therein. Figure 4: Extensive swelling with ecchymosis due to Russell’s viper bite and recovery after 8 days.

Systemic manifestations Hypotension and shock are due to sudden liberation of bradykinin into the circulation, bleeding and loss of fluid in swollen part, bleeding in the adrenal glands, or peritoneal or massive blood loss by haematemesis or haemoptysis. Haemostatic failure: Pro-coagulant content of venom initiates rapid thrombosis, hypofibrinogenaemia and consumptive coagulopathy. In human victims of Russell’s viper bite, the injected dose of venom is insufficient to cause massive fatal intra-vascular coagulation within a minute of the bite, unlike in animals. Once the patient’s blood has become defibrinated and incoagulable, spontaneous systemic bleeding ensues. Haematuria, bleeding in the skin, and pituitary haemorrhage can occur. Russell’s snake bite victims can subsequently develop amenorrhoea, Sheehan’s syndrome, loss of libido due to hypopituitarism, as reported from southern India. Enhanced capillary permeability is seen in the form of pleural and pericardial effusion, ascites, and conjunctival congestion/ haemorrhage. High fatality is due to hypotension and resistant shock syndrome due to capillary leaks.

Snake Bite Poisoning

ELAPIDAE POISONING Common Indian Krait (Bungarus caeruleus); local names: kala gandait, kala taro, kandar, manyar, chitti, kattu viriyan, valla pamboo.

Clinical Manifestations Majority of the cases of snake bite are reported between 11 pm to 5 am, usually when the person is asleep and the reflexes are greatly diminished; and the krait, having sharp small fangs, injects maximum venom in such a person. The victim might experience mild pain at the site of bite, paraesthesiae or numbness, without any local marks or swelling or bleed, hence the bite is neglected and falsely initially attributed to an ant or rat. Venom is small molecular size hence directly absorbed in the circulation. The venom stimulates the autonomic nervous system thus within 20 to 30 minutes of the bite, victims experience a transient abdominal colicky pain, bradycardia, sweating, vomiting, raised blood pressure. Subsequently, within 30 minutes to 18 hours the venom attacks presynaptic acetylcholine receptors resulting in ptosis (Figures 5A to C), pooling of saliva, dysphagia, dyspnoea, inter-nuclear opthalmoplegia, weakness of neck muscles, respiratory muscles and lastly the diaphragm. Patient complains of blurred vision,

Renal failure: 20% to 40% cases subsequently develop anuria, oliguria and acute renal failure. Renal angle tenderness is the most important clinical sign for early diagnosis of renal failure. There is serial rise in blood urea and serum creatinine with acidosis and hyperkalaemia. Tubular damage by venom itself, interstitial nephritis, haemoglobinuria, hypotension, and microthrombi in the kidney contribute to acute tubular necrosis. Renal failure is the commonest cause of death. Neurological effects: Ptosis, bulbar palsy, inter-nuclear ophthalmoplegia and respiratory paralysis due to presynaptic neuromuscular block in a Russell’s viper bite has been reported from Kerala and Sri Lanka. Green pit viper and bamboo pit snake bite cases, reported from Kerala, are characterised by local oedema and rarely a systemic bleeding disorder. Coagulopathy and renal failure has been reported due to Hump-nosed pit viper snake bite.

Figures 5A to C: Manifestations of krait bite: (A) ptosis with bulbar palsy; (B) after recovery; and (C) fang marks over the ear lobules.

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diplopia and lands in respiratory paralysis, coma and anoxic cardiac arrest. Venom induced paralysis of pupillary muscle causes non-reacting pupils. After recovery, a few patients had signs and symptoms of peripheral neuropathy. Many a times, patients succumb to iatrogenic respiratory infection or adult respiratory distress syndrome. Cobra bite Cobra bite tends to occur during the day time, when the transportation is more readily available. Moreover, because of its known severity, victims report to hospital early. Cobra venom is a cardiotoxic, neurotoxic, haematotoxic and cytotoxic. The fangs of a cobra are small and sharp. Its venom is small molecular size hence rapidly absorbed into the circulation. Soon after a bite, the victim experiences severe pain at the site of bite with fang marks covered with blood clots. Rapid development of swelling over the bitten part, ecchymoses, blebs, and massive damage of skin and subcutaneous tissue due to myocytolysis can occur. If the victim saw the biting hooded cobra, massive liberation of endogenous catecholamine into the circulation due to fear of death can actually result in lethal cardiac arrhythmias or cardiogenic shock due to massive myocardial infarction. Sinus bradycardia, A-V block and hypotension are due to cardiodepressant action of the venom. Sudden respiratory arrest without any other neurological manifestations can occur resulting in anoxic cardiac arrest. Rapid ptosis and bulbar palsy accompanied with respiratory depression can occur. Rarely, haematotoxic effects are seen. Blurring of vision and loss of accommodation are the earliest neurological signs of envenomation. Locked-in syndrome This may be seen in few cases, but such victims recover totally within 3 to 4 days if treated properly by maintaining oxygen saturation with proper ventilator support, maintaining electrolytes and nutrition and prevent iatrogenic infection. This

phenomenon is due to blocked post-synaptic acetylcholine receptors including pupillary muscle which are rich in acetylcholine receptors. Sea snakes Sea snakes are seen all over the coastal region. Sea snake is accidentally handled by fishermen during fishing. Its venom is neurotoxic, myotoxic and haematotoxic. Soon after a bite, the victim experiences severe muscle pain, marked tenderness all over the muscles, trismus, muscular paralysis, respiratory arrest, without local manifestations at the site of bite. Myotoxic effects of venom causes hyperkalemia and myoglobinuria causing acute tubular necrosis. Management Figure 6 outlines the management of snake bite envenomation. Reassurance is important to allay anxiety and fear of death. Local incision, tight tourniquet or suction, and electric shock are to be discouraged. Patient should be shifted to the nearest equipped medical facility. Immobilisation of the bitten part by a splint, keeping the bitten part below heart level is preferred. It is worthy to apply crepe bandage (with a pressure enough that one can easily introduce the finger between skin and bandage) to krait bite case if victim took more than 30 minutes but less than 2 to 3 hours to reach the hospital. This helps to delay the absorption of venom and moreover, may prevent rapid development of respiratory paralysis. Treatment with anti-snake venom (ASV) History of snake bite or evidence of fang marks are not an indication for administration of ASV. There should be signs and symptoms suggestive of envenomation. Initially, 100 mL ASV is to be added to 200 mL of crystalloid solution and administered over 60 minutes by intravenous route in a victim of krait, cobra and Russell’s viper envenomation. It

Figure 6: Flow chart for management of venomous snake bite. ASV = Anti-snake venom; N = Neostigmine; A = Atropine; RF = Renal failure; DIC = Disseminated intravascular coagulation

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Hyperkalaemia is managed on standard lines – intravenous calcium gluconate, diuretics, insulin-glucose drip, salbutamol nebulisation and if required, dialysis.

In case of elapidae envenomation, 50 mL of ASV can be administered if there is no improvement within 30 to 60 minutes after the initial dose; while the total initial dose required for Echis carinatus envenomation is 20 to 40 mL over one hour and 20 mL over the next 24 hours.

Anaphylaxis can result from ASV, but test dose of ASV is not essential. Recently, it is reported that adrenaline can be used as prophylaxis before starting ASV. Earliest symptom of anaphylaxis is vomiting sensation, warm sensation in ears or head, itching behind ears, urticaria, itching all over body, hypotension, tachycardia, bronchospasm, dysphagia, swelling of tongue and lip, feeling of obstruction in throat. ASV should not be given by rapid intravenous bolus as it may activate complement and result in a severe reaction. One should keep watch for appearance of anaphylaxis for 10 to 180 minutes after administration of ASV. While diluting ASV if there is a precipitate, it should be discarded as such precipitated proteins are more likely to cause severe anaphylaxis.

ASV may be administered even after 12 to 14 days after viper bite if systemic toxicity is present. After the initial dose of ASV, if active bleeding such as haematemesis, haematuria, bleeds from the wound do not disappear within 20 to 30 minutes, particularly in viper bite, one can repeat 20 to 50 mL ASV as an extra bolus. Twenty minute whole blood clotting test (20WBCT) is the gold standard bedside test and can be performed by unskilled staff. Before injecting ASV, from same venepuncture 2 to 3 mL of blood is withdrawn and added to a dry glass tube (not washed with detergent), and then kept standing for 20 minutes. If the tip of the blood did not clot, hypofibrinogenaemia is confirmed. This test should not be repeated earlier than 6 hours after administration of ASV, as the liver takes six hours for synthesis of coagulant factors. 20WBCT test decides further requirement of ASV. This test is important for diagnosis and also indicates the improvement. Once the venom gets attached to the target organs (receptors) such as neuromuscular receptors, red blood cells, platelets, renal tubules, and myocardium, then any amount of ASV will not be able to reverse the effects. Elapidae venom blocks the acetylcholine receptors, this action of venom can be reversed by neostigmine in the dose of 25 microgram per kg per hour preceded by atropine. Post-synaptic receptors blocked by cobra venom can be totally reversed by choline-esterase inhibitor, while in krait bite venom which blocks both pre- and post-synaptic receptors, neostigmine may help to delay the respiratory depression in early stage. Need for artificial ventilation is indicated by grade 3 power, pulling of saliva, or tidal volume below 200 mL. Hypotension, bradycardia are to be treated with dopamine drip and atropine. Complete heart block in cobra bite needs isoprenaline drip, ASV and temporary pacemaker. Renal failure: Early administration of ASV, mannitol, diuretic and acetylcysteine may help to prevent the renal failure in Russell’s viper bite. Close monitoring of urine output is important to detect early renal failure in Russell’s viper bite. Early renal failure is treated by intravenous frusemide 200 to 500 mg or torsemide by continuous intravenous drip and dopamine drip with fluid restriction. Haemodialysis or peritoneal dialysis may also need to be offered in established renal failure cases. Profuse bleeding can be treated by blood transfusion. Shock due to accumulation of fluid in compartment syndrome or muscle damage can be prevented by surgical decompression, but the following criteria should be fulfilled before any surgical procedure: (1) marked tenderness over muscles, (2) pain during passive movement of muscles, and (3) loss of sensation or hypoaesthesia in the supply of a nerve passing through the compartment.

Snake Bite Poisoning

neutralises the circulating venom. While the venom is absorbed slowly from the site of the bite, which acts as a depot, can be neutralised by 20 to 30 mL of ASV at 6-hourly intervals.

Intra-muscular injection should be avoided if the patient’s blood fails to clot. Total requirement of ASV dose can be reduced by preparing mono-specific ASV or purified F(ab)2 ASV. ELISA kit for detection of venom antigen helps a treating doctor know the exact species of snake and even help to monitor the circulating venom antigen, thus the dose of ASV. Prevention Firewood, dry cow dung, cattle shed and rubble should be kept away from residential areas. Old storage rubble, particularly in old house, should be handled in full sunlight. Rubble in the attic should not be handled blindly. Barefoot walking in darkness for open toilet in grown grass should be avoided, or one should go out with a torch and a heavy stick so as to vibrate the place before stepping. Proper care of rats, mice and lizards must be taken. No attempt should be made to catch the snake or to kill it. Killed snake should not be handled. Thick electric rubber gloves with rubber shoes should be worn at the time of handling the crops husk. A bamboo cot with scrupulous use of a mosquito net prevents scorpion sting, krait and mosquito bite alike. The victim should report as early as possible to the nearby primary health centre where enough storage of ASV is kept ready. Training in appropriate use of antivenom and protocol of indications for its use should be arranged at general hospital level to ease the crisis of supply of ASV. It is important to note that already applied tourniquet to the part at site of venomous snake bite should not be released until full dose of snake antivenom is administered. RECOMMENDED READINGS 1.

Bawaskar HS, Bawaskar PH. Envenoming by the common Krait (Bungarus caeruleus) and Asian Cobra (Naja naja): clinical manifestations and their management in a rural setting. Wilderness and Environmental Medicine 2004; 15: 257-66.

2.

Bawaskar HS, Bawaskar PH. Profile of snakebite envenoming in Western Maharashtra, India. Trans R Soc Trop Med Hygiene 2002; 96: 79-84.

3.

Bawaskar HS, Bawaskar PH, Punde DP, Inamdar MK, Dongare RB, Bhoite RR. Profile of snake bite envenoming in rural Maharashtra, India. JAPI 2008; 56: 88-95.

4.

Warrell DA. Snake Bite. Lancet 2010; 375: 77-88.

5.

Warrell DA. The clinical management of snake bites in the Southeast Asian region. Southeast Asian J Trop Med Pub Health 1999; 30: 1-85.

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26.9

Scorpion Sting HS Bawaskar

Scorpion envenomation is a major public health problem in tropical and sub-tropical countries, especially in Africa, MiddleEast, Latin America and India. At times it poses a significant lifethreatening acute time limiting cardiovascular emergency. Irrespective of different species of scorpion, similar cardiovascular effects are reported. Irrespective of the understanding of the pathophysiology and management, the morbidity and fatality remains high in rural areas due to nonexistent medical facilities and the delay in hospitalisation due to superstitions and faith in village healers. Scorpion envenoming has been underestimated as this problem is faced by majority of underdeveloped and developing countries. Since the advent of prazosin therapy the fatality has dropped from 29% to less than 1%.

The scorpion envenomation has been frequently reported from Puducherry, Karnataka, Tamil Nadu, Andhra Pradesh, Saurashtra, Uttar Pradesh, Bihar and Marathwada and Western Maharashtra. Thousands of scorpion stings are reported annually from India and 15% to 20% of these stings manifest with systemic symptoms. Farmers are more prone to get stung by scorpion during handling debris and paddy husk in the months of April to early June and September to October as due to sudden rise in environmental temperature, scorpions come out of their hides. The sting during these months is more potent and prone to serious envenomation. Scorpion is nocturnal in habit and people walking bare foot become their victim more commonly.

The Indian red scorpion Mesobuthus tamulus (Figure 1) is the most lethal amongst all the poisonous species of scorpions.

SCORPION Nearly 1,000 species of scorpion are known worldwide, which belongs to six families. However, only the scorpion belonging to the family Buthidae, secretes neurotoxic venom that is toxic to human; around 86 species of this family are found in India. M. tamulus, an Indian red scorpion, is venomous and its envenomation is fatal if not treated in time. Its claws are red coloured, but tail, legs and body is covered with khaki coloured cuticles. It is 2.5 to 4 inches in length. The tail consists of stout segments with terminal bulb containing pair of telson venom secreting salivary glands. It actively secretes venom at the time of sting by a sharp semi-curved stinger. The stinger is 2 to 4 mm in size and human skin thickness is 1.5 to 4 mm. Scorpion venom is rich in neurotoxin. The black scorpion Palmaneus gravimanus is less poisonous (Figure 2). It is seen in Kerala, Vidharbha and Marathwada region of India. It is bigger in size as compared to red scorpion. It inflicts severe and excruciating painful sting. Its claws are broad and thick and strong while tail consists of thin segments.

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Figure 1: Photograph showing an Indian red scorpion (Mesobuthus tamulus).

Figure 2: Photograph showing a black scorpion (Palmaneus gravimanus).

Scorpion Sting

Scorpion Venom All scorpion species secrete venom. Venom is a mixture of various active substances; of these neurotoxins are the most important. Neurotoxins consist of different small sized proteins with sodium and potassium cations, which interfere with the neurotransmission. Venom action on neurotransmitter is rapid and fast. It contains peptide neurotoxin that opens the sodium channels (beta-toxin). The scorpion venom depolarises the cell membrane; in addition it also inhibits the deactivation of sodium channels (alpha-toxin). There is massive release of endogenous catecholamines in to the circulation due to delayed activation of sodium neuronal channel by the venom. The venom of the M. tamulus (Indian red scorpion), Buthus martensii (Chinese scorpion) and Leiurus quinquestriatus (yellow scorpion) causes autonomic storm by stimulating autonomic nervous system (ANS). Charybdotoxin another component of the venom inhibits the calcium dependent potassium channels; similarly iberiotoxin isolated from M. tamulus has similar action on potassium channels. Scorpion venom also contains serotonin, which may cause local pain at the site of the sting. The venom of Tityus species has a kallikrein inhibitor causing raised bradykinin levels. Venom of Tityus serrulatus from Trinidad is pancreotoxic, responsible for the development of acute pancreatitis. CLINICAL MANIFESTATIONS Clinical effects of the envenoming depend upon the species of scorpion and dose of venom injected at the time of sting. The severity of envenoming is related to age, size of scorpion and the season of the sting. High fatality rate is seen in children. The early or pre-monitory clinical manifestations characterised by vomiting, profuse sweating all over the body (Figure 3), priapism (Figure 4), cold extremities and mild tolerable pain. This pain becomes severe and excruciating when extremities become warm, a sign of recovery.

Figure 4: Priapism.

Local Manifestations Local pain or severe excruciating pain is the only clinical manifestation seen in 35% of cases in a recent series. In 57%, 33% and 11% cases; lower extremities, upper extremities and the other part of the body are the sites of sting, respectively. Severe pain radiates along the corresponding dermatomes. Local oedema, urticaria, fasciculation and spasm of underlying muscles are seen at the site of sting due to persistent stimulation of pain conducting receptors and the liberated serotonin. Due to pain there is transient bradycardia, transient rise in blood pressure and mild sweating with warm extremities. Sudden tap at the site of sting induces severe pain and sudden withdrawal of the part called ‘tap sign’. Patient continuously moves the stung part of body or holds it firmly to find a comfortable position.

2. Systemic manifestations.

Systemic Manifestations Soon after scorpion sting the victim suffers from the autonomic storm and shows all pre-monitory signs and symptoms. The red scorpion venom is potent sodium channel activator and stimulates the ANS resulting in sudden pouring of catecholamines in the circulation. Both sympathetic and parasympathetic twigs are stimulated leading to ‘autonomic storm’, characterised by initial parasympathetic stimulation clinically detected in form of vomiting once or twice, profuse sweating all over the body (4 to 12 hours), ropy salivation (Figure 5), priapism (6 to 8 hours), mydriasis, bradycardia, hypotension, transient premature

Figure 3: Profuse sweating.

Figure 5: Ropy salivation.

Clinical presentations can be divided into following two grades: 1. Local manifestations—severe local pain without systemic involvement

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ventricular beats. Sympathetic stimulation is characterised by propped eyes, puffy and anxious facies, oculogyric crisis, chest discomfort, perioral paraesthesias, at times tingling and numbness all over body and cool extremities. Skin over hands, feet, palm and sole look like a washer-man hands as they appears finely wrinkled and cold. Clinical manifestations at times are apparently diverse irrespective of similar pathology. In some patients there is minimal local pain on arrival but as the peripheral circulation improves with time and warming, they start experiencing excruciating pain. Severe transient muscle spasm may occur due to the loss of electrolytes. Clinical manifestations depends upon the time elapsed between sting and hospitalisation and the treatment received at periphery. The major manifestation includes hypertensive crisis and pulmonary oedema (PE) which may be fatal if not treated timely. Hypertension Upto 45% of victims with systemic involvement were found to have hypertension when reported within 15 minutes to 11 hours after the sting. Children may present with agitated look, confusion, generalised convulsion, transient hemiplegia, oculogyric crisis, bilateral extensor plantar response, propped up eyes and a puffy face suggestive of hypertensive crisis. It may be difficult to measure accurate blood pressure in such children. Majority of these cases complained of headache, chest discomfort, suffocation, giddiness and paraesthesia. Transient initial hypotension is due to hypovolaemia secondary to acetylcholine excess, it is further aggravated by hot climatic conditions in summer months of the tropics. Pulmonary oedema PE occurs in upto 30% severe scorpion sting cases with respiratory failure. PE develops within 30 minutes to maximum 36 hours. In up to 8% cases massive PE may be life-threatening. Clinically PE can be suspected when respiratory rate is >24 per minute, orthopnoea, intractable cough, low volume fast thready pulse, narrow pulse pressure, summation gallops, systolic murmur and moist basal rales, central cyanosis. Intractable cough with massive expectoration of blood mixed froth from the mouth and nostril with central cyanosis, hypo- or hyper-tension and loud death rattle sound heard are suggestive of massive PE. Alpha receptors stimulation plays an important role in the pathogenesis of PE. Disseminated intravascular coagulation, coma, convulsion, miosis, mydriasis and hemiplegia, aphasia, cerebral infarction, transient bilateral cerebellar syndrome and subdural hematoma have been reported during pre-prazosin era. Acute renal failure due to scorpion sting is rare. However, ill-treated, delayed reporting of a case may result in death due to multi-system organ failure and acute respiratory distress syndrome.

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After 20 to 30 hours of recovery from autonomic storm, the victim develops asymptomatic warm extremities, accompanied with bradycardia, hypotension with prolonged QTc interval (0.50 to 0.65 sec) on electrocardiogram (ECG). He may look exhausted. The depletion of tissue catecholamines following autonomic storm is the cause and patient usually recovers within 72 to 96 hours without any intervention. This phenomenon does not occur if victim receives scorpion antivenom and prazosin simultaneously.

Fatality Victim can die suddenly due to ventricular arrhythmias which usually occur within 15 to 30 minutes of sting. Many victims die from severe PE, brain haemorrhage and multi-system organ failure, if not treated properly and in time. INVESTIGATIONS Total leucocyte counts are raised to 11,000 to 26,000 due to venom induced interleukin-6 and tumour necrosis factor-α release. Cardiac CPK MB is raised. Reduction in serum amylase and serum calcium levels may be observed. There is raised serum glucose, potassium and reduction in insulin level. Chest radiograph may reveal unilateral or bilateral batwing or patchy PE (Figures 6A and B). At times secondary respiratory infection in the form of consolidation is seen in a hospitalised patient recovering from PE. Mild cardiomegaly may be present. In author’s series of cases of PE due to scorpion sting, the followup of more than 15 years did not show any cardiovascular abnormality.

A

B

Figures 6A and B: Chest radiographs showings (A) pulmonary oedema in a patient and (B) after recovery.

Electrocardiogram ECG is one of the most important diagnostic and easily available investigation. Not a single victim with systemic involvement has normal ECG. Sinus bradycardia seen in early hypertensive cases with a heart rate of 42 to 60 per minute, ussually persisted for 3 to 4 hours. The other common findings are ventricular premature contraction, couplets, transient nonsustained ventricular tachycardia and rarely fatal ventricular arrhythmias (Figure 7). The sinus tachycardia, injury to conducting system in the form of left anterior hemiblock, bundle branch block, complete heart block and marked tented T waves may be the other common findings. The tall T waves may mimic acute myocardial infarction (AMI). Elevated ST segment with small Q wave is also often seen in lead 1 and AVL. Severe PE cases showed low voltage pattern with PQRST alterans with ST segment depression. Recovering victim’s ECG showed large T wave with wide base and round top suggestive of delayed depolarisation with prolonged QTc, accompanied with asymptomatic bradycardia and hypotension. The severity of ECG changes did not correlate with clinical condition. Echocardiography Echocardiography shows poor global contractility 12 to 15 hours after sting with low ejection fraction, decreased systolic ventricular performance and mitral incompetence. Abnormal diastolic filling persisted for five days to four weeks. There is

Scorpion Sting

Figure 7: Electrocardiogram of a patient showing ventricular ectopics.

good echocardiographic correlation between clinical improvement and return of left ventricular function.

syndrome in scorpion sting. Electrolyte imbalance should also be corrected.

Mild envenomation causes severe vasoconstriction and hypertension; while predominant left ventricular dysfunction with normal systemic vascular resistance with PE is seen in severe scorpion sting. However, severe hypotension depends upon the fluid balance, while hypotension and shock with warm extremities occurs in terminal stage due to biventricular dysfunction and terminal vasodilation (warm shock).

Prazosin An α-1 adrenergic receptor blocker reduces preload, left ventricular impedance without causing tachycardia. It reverses the metabolic syndrome evoked due to excessive catecholamines release. Prazosin is a pharmacological and physiological antidote to scorpion venom actions. It also inhibits sympathetic outflow in CNS. It inhibits phosphodiesterase, thereby enhancing a cGMP level which is one of the mediators of nitric oxide synthesis. It enhances insulin secretion which is inhibited by venom. Thus, its pharmacological properties can antagonise the haemodynamic, hormonal and metabolic effects of scorpion venom (Figure 8). It can be administered orally in a dose of 250 to 500 µg/Kg in children and 500 to 1000 µg/kg

MANAGEMENT No scorpion sting should be taken as benign unless observed for 24 hours, irrespective of species involved. On the basis of pathophysiology, therapeutic effort should be directed against venom, the clinical manifestations of the over stimulated ANS and after effects of excessive catecholamine and correction of hypovolaemia. The incision at the sting site or tourniquet is not advisable and patients who come for medical care after 4 hours of sting and do not show signs of systemic envenomation can be treated symptomatically without prazosin or scorpion antivenom. Local Envenomation Mild pain can be abolished by application of ice packs over the site of sting. Severe excruciating pain can be transiently relieved by local anaesthesia (lignocaine without adrenaline). However, oral diazepam and nonsteroidal anti-inflammatory drugs (NSAIDs) with first initial dose of lignocaine can give prolonged relief from pain. At times, severe intolerable pain patient tossing in bed without signs of autonomic storm injectable opoid (pentazocin). Systemic Envenomation Dehydration leading to hypovolaemia is due to vomiting, excessive salivation and profuse sweating. It should be corrected by oral rehydration. Intravenous crystalloids or hydration by nasogastric tube may be necessary in a confused and agitated victim. Fluid deficit must be corrected since hypovolaemia is one of the proposed mechanisms of shock

Figure 8: Flow chart showing effects of prazosin (venom antidote).

1963

in adults and should be repeated every 3 hourly until the signs of clinical improvement appear or till dry and cool extremities persist. If the initial dose has been vomited, it should be repeated. Due care should be taken to avoid postural fall in blood pressure which is a known side-effect of prazosin (first dose phenomenon). Postural hypotension should be treated by lowered head position and intravenous fluids. Since the advent of prazosin the fatality due to severe scorpion sting has reduced to less than 1%. Prazosin is poor man’s scorpion antivenom. Scorpion antivenom It is available for clinical use. Venom causes transient parasympathetic and prolonged sympathetic stimulation. Ongoing cholinergic phenomenon is suggestive of free circulating

hours in warm hypotensive shock patients. Unconscious patients with cardio-respiratory failure may also require invasive or non-invasive mechanical ventilatory support. A step-wise management of scorpion sting is shown in Figure 9. Cardiac arrhythmias are many times self-limiting. Intravenous amiodarone should be used with caution as it may precipitate massive PE, marked bradycardia and cardiac arrest. Captopril, glucose insulin potassium drip and L-carnitine have also been tried to alleviate the venom effects on the heart but does not approved indication. Atropine, steroids, antihistamines, beta-blockers, calcium channel blockers, excessive diuretics, adrenalines and narcotics are to be avoided as these do more harm than good in scorpion envenoming.

Figure 9: Management of scorpion sting. ASV = Anti-scorpion venom; SNP = Sodium nitroprusside; NTG = Nitroglycerin; NIV = Non-invasive ventilation; MV = Mechanical ventilation

scorpion venom, which can be neutralised by antivenom, while sympathetic stimulation suggests after effects and fatality is due to sympathetic over activity. Scorpion antivenom is more effective if a victim is brought in a stage of acetylcholine excess that is early stages of scorpion sting. Early use of scorpion antivenom in addition to prazosin hastens the recovery. Total dose of antivenom required is 30 to 100 ml. However, scorpion antivenom is expensive and always in short supply. No test dose is required as there are high circulating catecholamines and anaphylaxis is very rare. Supportive Management PE is the most important cause of mortality and should be treated with propped up position, nasal oxygen, intravenous loop diuretics, oral prazosin. Massive PE may also require immediate oral nitroglycerin (NTG) spray to reduce the pulmonary congestion and intravenous NTG drip or if available sodium nitroprusside 4 to 5 µg/kg/minute. Blood pressure should be closely monitored and maintained at the level of systolic 80 to 90 mm Hg. Inotropic support with dopamine and 1964 dobutamine 5 to 15 mg/kg/minute is advocated for 36 to 48

PREVENTION Scorpions are killed by organophosphorous pesticides. A false ceiling of plastic sheet should be put under the roof of hut to prevent scorpions falling in bed from loose tiles of roof. Shoes and clothes should be checked before wearing. Shoes should be packed with paper or cloth so as to prevent the entry of scorpion in night. Hand gloves made of thick rubber should be worn while harvesting fire wood, dry cow dung, lifting paddy, jowar (sorghum) and sugar cane husk. Children should not be allowed to go outside in early darkness without shoes. Simple sandal or slipper did not prevent the sting. One should not put hand blindly in crevices, doors or old storage material during night hours and bedding or cot should kept at distance from mud house wall and one should not backrest on mud wall. RECOMMENDED READINGS 1.

Bawaskar HS, Bawaskar PH. Efficacy and safety of scorpion antivenom plus prazosin compared with prazosin alone for venomous scorpion (Mesobuthus Tamulus) sting: randomised open labet clinical trial. British Medical Journal 2010; 341: c7136.

2.

Bawaskar HS. Scorpion sting. Quart Medi Rev 2009;60:26-45.

26.10 INTRODUCTION Fluorine being electronegative and reactive of all elements does not occur in free form in the nature. This element combines directly with most elements and indirectly with few to form fluorides, which are the 13th commonest element in earth’s crust. Fluorides being ubiquitous in nature are present in nearly all foods and natural waters.The relationship between optimum fluoride intake and decreased incidence of dental caries and osteoporosis has been recognised. Endemic skeletal fluorosis is a disease caused by excessive ingestion of fluorides through water, food or both. The upper limit of optimum fluoride level in drinking water for a tropical country like India is 0.5 ppm. The upper limit of safe total intake of fluoride from food and water per day for an adult is 6 mg. Biological effects of fluoride intoxication are related to the total amount of fluoride ingested whatever the source be it food, water, beverages or all. INCIDENCE First ever cases of endemic skeletal fluorosis in the world and its neurological manifestations were recorded from Podili, Darsi and Kanigiri areas of Prakasam district in Andhra Pradesh in 1937. Subsequently, the cases of fluorosis were reported from other regions of Andhra Pradesh and also from other parts of India and the world. It is now estimated that 66 million people are living in endemic areas of fluorosis, which are spread over 275 districts out of 619 in the country and these are located in 20 states and union territories, such as Andhra Pradesh, Assam, Bihar, Chhattisgarh, Delhi, Gujarat, Haryana, Jharkhand, Karnataka, Kerala, Jammu and Kashmir, Madhya Pradesh, Maharashtra, Orissa, Punjab, Rajasthan, Uttar Pradesh, Uttarakhand, Tamil Nadu and West Bengal. The populations in endemic areas are at risk of developing skeletal fluorosis and 6 million people are crippled because of it. Hence, skeletal fluorosis is a major public health problem not only in India but also in 25 odd countries. EPIDEMIOLOGICAL STUDIES Ten million of people living around the world are affected by fluorosis, and hence, factors governing the development of chronic fluoride intoxication need to be understood so that effective measures can be instituted to contain it. The factors which govern the causation of fluorosis are the following: 1. High levels of fluoride in drinking water supplies and foodstuffs in the endemic areas. Fluoride levels in natural waters in India vary from 0.2 ppm to 42.5 ppm. Fluorosis is predominantly a rural problem because 90% of rural water sources are ground water whereas all major cities get their water from perennial rivers, which have optimum levels of fluoride. Fifty per cent of ground water sources in our country have excess fluoride and the crops cultivated by water having high amounts of fluoride leads to high content of fluoride in cereals and vegetables in these areas. Hence, significant amounts of fluorides also come from food in

Fluorosis D Raja Reddy endemic regions. The total daily intake of fluorides from water and food in three villages of high endemic areas of Nalgonda varied from 54.66 mg to 75.76 mg. 2. Tropical weather and hard manual labour activity increases the intake of water and fluoride. 3. Diets deficient in calcium, magnesium and vitamin C aggravate fluoride toxicity. Optimum intake of calcium in the diet reduces the amount of fluoride absorbed from the gut. Magnesium has a peculiar relationship with fluoride and its optimum intake helps in elimination of fluoride from the body. Vitamin C is beneficial in some way in reducing fluoride toxicity. Diets deficient in calories and calcium intake increases the incidence of skeletal fluorosis in endemic areas. The National Nutrition Monitoring Bureau and National Family Health survey reports from India reveal gross malnutrition of rural population and also their lower intake of calcium especially among growing children, which may explain the high incidence of fluorosis in rural areas of our country. 4. Renal disease aggravates the incidence of fluorosis by the increased deposition of fluoride in the bones since diseased kidneys cannot handle fluoride excretion from the body. This may explain the severe forms of fluorosis in Prakasam district even though drinking water contains mostly 1 ppm to 3 ppm of fluoride and it rarely exceeds 6 ppm and the majority of cases investigated had kidney disease. 5. Presence of abnormal amounts of certain trace elements, such as strontium, arsenic, silica, uranium, chromium, etc. in drinking water supplies and foodstuffs also affect fluoride metabolism. Ninety-four drinking water samples from endemic areas in Andhra Pradesh were investigated for their content of fluoride and strontium. Fluoride levels ranged between 0.1 ppm and 9.5 ppm with a mean fluoride content of 2.1 ppm whereas strontium levels varied between 4.9 ppb and 9931.7 ppb with a mean of 1591.2 ppb. Strontium is a bone seeking element akin to calcium and fluoride which causes osteogenesis and bone changes similar to fluoride and now is the preferred drug for the treatment of post-menopausal osteoporosis. Arsenic is known to aggravate fluoride toxicity in experimental studies and this element may play a role in fluorosis in eastern parts of our country where arsenic is a known hazard. Silica, uranium and chromium are nephrotoxic if taken in abnormal amounts through water and these elements may be responsible for the high incidence of kidney disease in some endemic areas of India such as Prakasam. AETIOPATHOGENESIS In fluorosis, there is an overall increase in bone mass and calcification and ossification of ligaments and inter-osseous 1965

fasciae along with periosteal new bone formation and development of exostoses on long bones and osteophytes on the spine. These changes in skeleton underlie the clinical manifestations of fluorosis. CLINICAL FEATURES Chronic fluoride intoxication presents an extraordinary degree of uniformity in its clinical manifestations. It occurs in humans as dental and skeletal fluorosis, since 96% to 99% of fluoride retained in the body combines with mineralised bones because of its affinity to calcium phosphate moiety, and hence, skeleton suffers. Dental and skeletal stages are separated by a prolonged, relatively symptom-free interval during which the skeleton does not stop accumulating fluoride. In its advanced stages, skeletal fluorosis causes crippling deformities and neurological complications. Dental Fluorosis Dental fluorosis mainly involves enamel but severe intoxication may affect dentine as well as pulp. Enamel fluorosis occurs when fluoride concentrations in or in the vicinity of the forming enamel are excessive during its preeruptive development. Mottling of teeth is one of the earliest and most easily recognisable features noticed in the first decade of life (Figure 1). Both sexes are equally affected. It is the permanent teeth that are affected and they lose their normal creamy white translucent colour and become rough, opaque and chalky white. Pitting and chipping are other marks of fluorosis. Brown, yellow or black pigment gets deposited on the defective enamel and once established tends to remain there permanently. Incidence of dental fluorosis in endemic areas exhibits a linear relationship to the fluoride content of water but it may also vary with other factors. Dental fluorosis does not obviously occur, when there has been no exposure to excess fluoride in the first decade of life.

Skeletal Fluorosis Early in the development of fluorotic changes in the skeleton, the patients often complain of a vague discomfort and paraesthesia in the limbs and the trunk. Pain and stiffness in the back appear next, especially in the lumbar region, followed by dorsal and cervical spines. Restriction of the spine movements is the earliest clinical sign of skeletal fluorosis. The stiffness increases steadily until the entire spine becomes one continuous column of bone manifesting a condition referred to as ‘poker back’ (Figure 2). When the condition becomes severe and chronic, pathology spreads from axial skeleton to various joints in the limbs owing to the involvement of the joint capsules, the related ligaments, tendinous attachments to the bones and interosseous membranes. The involvement of the ribs gradually reduces the movement of the chest during breathing, which finally leads to restrictive lung disease. With the increasing immobilisation of the joints due to contractions, flexion deformities may develop at hips, knees and other joints, which make the patient bed-ridden (Figure 3).

Figure 1: Characteristic mottling of the teeth in dental fluorosis. Mottling is most conspicuous on the upper incisor teeth.

Pre-Skeletal Stage The duration of this stage may vary with the amount of daily fluoride ingested. Reportedly, it ranges from 10 years to 30 years or even longer in endemic areas. It is usually free of any signs or symptoms in its early stages in endemic regions. However, various reports from Europe and America suggest that there would be symptoms corresponding to gastrointestinal, musculoskeletal, respiratory and visceral systems during this stage. The majority of these visceral symptoms may be due to allergy to fluoride in susceptible individuals or the effect of fluoride on the various target organs and these are 1966 nonspecific.

Figure 2: Skeletal fluorosis manifesting with restriction of spine movements, which ultimately leads to ‘poker back’.

Fluorosis Figure 4: Gross deformities of lower limbs in the residents of Yellareddyguda of Nalgonda, India, which is high endemic village for fluorosis.

But there have been few reports of fluorosis with neurological complications from countries other than India. The patients suffering from neurological manifestations varied in age from 20 to 70 years and, in the case of younger age groups, these complications may be traced to higher levels of daily fluoride ingestion. The men were reported to have been affected more frequently than the women. Similar findings were reported by other investigators from India, except for one lone report from Rajasthan where females slightly predominated over males and also developed fluorosis earlier than men. Figure 3: Crippling stage of skeletal fluorosis manifesting with neurological deficits and joint changes.

The stage at which skeletal fluorosis becomes crippling usually occurs between 30 and 50 years of age in the endemic regions. Newcomers to a hyperendemic region may sometimes develop symptoms of skeletal involvement within 4 years of their arrival. Men suffer more than women from severe affects of the disease presumably because their work usually more strenuous than that of women. In regions with very high fluoride content, the disease may affect younger age groups including children. The longer the exposure to fluoride higher will be its incidence. Endemic Genu Valgum Deformities occur most notably in weight-bearing lower limbs in children poorly nourished with low calcium intake in endemic areas. There is increased calcium turnover in the cases of endemic skeletal fluorosis. Diets poor in calcium provoke secondary hyperparathyroidism. This, in turn, leads to osteoporosis and deformities of weight-bearing lower limb bones (Figure 4). Neurological Manifestations of Skeletal Fluorosis The neurological sequelae in skeletal fluorosis manifesting usually as radiculomyelopathy arise principally because of the mechanical compression of the spinal cord and nerve roots brought about by osteophytosis and sclerosis of the vertebral column. But the neural toxicity attributable to fluorides is yet to be established. Neurological complications arise at a late stage of the disease in about a tenth of the total number of skeletal fluorosis cases.

It is the cervical cord rather than the dorsal cord that is commonly affected by fluorosis although, lumbar spine is usually the first to exhibit skeletal changes caused by fluorosis, compression of cauda equina rarely occurs because its roots are so easily accommodated that by the time these are pressed upon, other parts of the spinal cord would have been affected. Although the disease develops slowly but relentlessly, the neurological deficits may sometimes be precipitated by a minor trauma. Such cases present a wide spectrum of neurological deficits, which may be found manifesting either the lower motor neuron or the upper motor neuron defects or both, which is much more common. These may be found along with those caused by skeletal fluorosis resulting in restriction of spine movements. It is to be noted that in fluorosis abnormalities of higher functions of cerebrum or cranial nerve palsies except eighth nerve are rarely encountered. Peripheral Neuropathies Exostoses, which mainly develop around the knee, elbow and ankle, may press upon the median, ulnar or lateral popliteal nerves. Even meralgia paresthetica has been reported to occur in fluorosis. Fluorotic patients may also manifest entrapment syndromes involving other peripheral nerves. DIAGNOSIS Urinary, Serum and Bone Fluoride Estimations Urinary fluoride levels are the best indicators of fluoride intake. Since fluoride excretion is not constant throughout the day, 24-hour samples of urine are more reliable than random or morning samples. There is a linear relationship between urinary fluoride levels and fluoride intake. The urinary and serum levels of fluoride in normal and fluorotic cases are listed in Table 1 1967 below.

Table 1: Serum and Urine Fluoride Levels in Healthy Adults and Patients of Fluorosis Group

Number

Range mg/L/ppm

mg/L/ppm

Healthy adults

500

0.03 to 0.13

0.08

Patients of fluorosis

17

0.04 to 0.28

0.16

24-hr/mg/ppm

mg/L/ppm

Healthy adults

60

0.38 to 1.82

0.88

Patients of fluorosis

17

0.68 to 7.80

3.28

Serum fluoride levels

Urine fluoride levels

Mean

Stage II Thick primary trabeculae merge with sclerotic secondary trabeculae to make bone homogenously dense, bone contours become uneven, calcification of paraspinous, sacrospinous and sacrotuberous ligaments. Stage III Axial skeletal bones demonstrate the typical radiological features. Calcification is marked at the insertion of muscles and tendons. Ossification of interosseous membranes of forearm bones is diagnostic sign of fluorosis (Figure 6).

Bone fluoride content measures the extent of bone fluoride retention and is a useful complement of bone histological studies for the diagnosis of skeletal fluorosis. In skeletal fluorosis, fluoride content varies between 6000 and 8400 ppm in bone ash, normal fluoride content ranges between 500 and 1000 ppm or mg/kg. Radionuclide Bone Scan Technetium labelled methylene diphosphonate (99mTc-MDP) bone scanning measures skeletal metabolism and in skeletal fluorosis shows mostly a super scan appearance and in some cases joints abnormalities (Figure 5).

Figure 6: Radiograph of forearm bones of a patient with fluorosis. The forearm bones are dense with calcification of a portion of interosseous membrane. Prominent bony tuberosities and musculotendinous attachments are noteworthy.

Osteosclerosis is well known effect of chronic fluoride intoxication, which can also manifest with osteoporosis and osteomalacia in endemic areas with poor nutrition. Hence, the radiological changes are varied and these seem to be dependent upon calcium intake by the individuals. Posterior

Anterior

Figure 5: Technetium-99m scans of skeleton in an individual with skeletal fluorosis suggesting an appearance of ‘super scan’. There is high bone turnover in endemic skeletal fluorosis with increased tracer uptake in axial and appendicular skeleton. There is reduced soft tissue uptake, absent renal images and ‘tie sign’ in the sternum. Increased metabolic turnover of bone, impaired collagen synthesis and increased avidity for calcium are the features of fluoride toxicity.

Radiology In fluorosis, radiological findings closely parallel the pathological changes. In adults, the radiological findings can be categorised into three stages: Stage I Findings mainly confined to the axial skeleton, trabeculae appear 1968 rough and bone appears ground glass.

Imaging Computed tomography (CT) is the best imaging modality for visualisation of bone pathology and provides more details than plain radiographs. The CT is better to visualise the direction of the osteophytes, a finding which may help in surgical planning. Spinal canal and root canal stenosis are also better appreciated with CT. The calcified ligaments are visualised with much more clarity and earlier than by plain radiograph, so are the indentations of the epidural space and the alterations in the spinal canal. By reconstruction, CT provides exact dimensions of the ossified intra-spinal ligaments, such as posterior longitudinal ligament and yellow ligaments. Magnetic resonance imaging (MRI) being non-invasive obviates the difficulties in performing myelography and also delineates soft tissue structures and changes in the spinal cord. It is worthwhile to image the entire spine that may demonstrate

a balanced diet having adequate calcium, magnesium and vitamin C should be promoted to reduce the toxicity of fluoride. MEDICAL TREATMENT Patients with skeletal fluorosis, when kept off fluoride intake, register a negative fluoride balance while continuing to excrete large amounts of fluorides for years. It is obvious that excretion of fluorides mobilised from the skeleton through urine and faeces is a very slow and prolonged process lasting for many months to even years. Hence, this method is not practicable.

Fluorosis

incidental pathological lesions peculiar to fluorosis. Fluorotic vertebrae are hypointense in both T1- and T2-weighted images and these are diagnostic (Figure 7).

Studies, both in vitro and in vivo, have been done to study the effect of various drugs on the binding of fluoride and also on the excretion of fluoride. Serpentine was used to increase fluoride excretion in human fluorosis with some success. Serpentine, a naturally occurring mineral, is chemically a magnesium meta silicate and has enormous capacity to absorb fluoride at a wide range of pH. There is a need to do long-term studies to see the effectiveness of these various agents in human fluorosis.

Figure 7: Magnetic resonance imaging of dorsal spine. T1 (left) and T2 (right) weighted images demonstrating hypointense signal of the vertebral bodies suggestive of sclerosis in skeletal fluorosis, which is diagnostic. Note the cord compression at multiple levels from calcified ligamentum flavum.

DIFFERENTIAL DIAGNOSIS In endemic areas, the diagnosis of dental and skeletal fluorosis does not present much of a problem. In industries, where fluoride toxicity is a known hazard, skeletal fluorosis marked by restriction of spine movements can easily be diagnosed. In early stages of skeletal fluorosis patients complain of arthritic symptoms, which have to be differentiated from other types of arthritis. Diseases that are associated with osteosclerosis also need to be considered in the differential diagnosis. In children and young adults, genu valgum and other deformities have to be distinguished from those associated with rickets and sometimes with osteodystrophies. When sclerosis of the vertebral column is not marked, calcification of the interosseous membrane of forearm, a radiographic sign of fluorosis, should suggest the diagnosis of fluorosis. Endemic Fluorosis In India over 50% of ground water sources have excess of fluoride and affect more than 150,000 villages. Potable water supply with permissible levels of fluoride though desirable cannot obviously be made available to the vast number of people neither can they be shifted from their area of domicile. Thus, there is a rationale to press into service water-purifying or defluoridation plants in those areas. Defluoridation plants are based on Nalgonda method of lime and alum and domestic units were based on filtration of fluoride-rich water with PAC granules, which are activated alumina. Aluminum has been incriminated in the causation of two neuro-degenerative diseases, namely Parkinsonism and amyotrophic lateral sclerosis. Defluoridation methods are expensive and difficult to maintain and they also increase aluminum levels of filtered water. Hence, these methods are not preferred. Nutrition appears to play a crucial role in the incidence and severity of fluorosis and hence

SURGERY IN SKELETAL FLUOROSIS Neurological manifestations of fluorosis are mainly mechanical in nature. However, surgery is obviously of little help in the alleviation of neurological deficits in view of the extensive prevalence of the disease. Surgical decompression is only possible in such of those early cases in which the compression is confined to a limited segment of the vertebral column, but managing even these patients bristles with problems because of rigidity of spine and restrictive lung disease. However, in recent years with accurate localisation of the compression, its extent in both vertical and axial planes by imaging, fiberoptic intubation, better illumination and instrumentation during surgery for drilling and removal hard fluorotic bone and postoperative ventilatory support made surgery safe and effective in alleviation of mechanical compression in fluorosis. The results of surgery are better in the case of cervical and lumbar areas and poor in the case of dorsal cord compressions. It is also not known what happens to all those patients after surgery, when they go back to their endemic areas and again start to consume high-fluoride-containing water and food. PREVENTION OF FLUOROSIS The best approach to tackle this public health menace will be prevention since no cure is possible once the disease sets in. RECOMMENDED READINGS 1.

Jolly SS, Singh BM, Mathur OC, et al. Epidemiological, clinical and biochemical study of endemic dental and skeletal fluorosis in Punjab. Br Med J 1968; 4: 427-9.

2.

Pandit CG, Raghavachari TNS, Rao DS, et al. Endemic fluorosis in south India: A study of the factors involved in the production of mottled enamel in children and severe bone manifestations in adults. Indian J Med Res 1940; 28: 533-58.

3.

Raja Reddy D. Skeletal fluorosis. In: Vinken PJ, Bruyn GW, editor. Handbook of Neurology. Amsterdam: North Holland Publishing Co; 1979; pp 465-504.

4.

Reddy DR, Deme SR. Endemic Skeletal Fluorosis. Hyderabad: Nallakunta. Ramayya Vidyapeetam; 2010.

5.

World Health Organization. Fluorides: environmental health criteria Monograph No. 227. WHO monograph No. 227. Geneva: WHO; 2002.

1969

26.11 Lathyrism is a neurodegenerative disease characterised by spastic paraplegia following excessive consumption of the legume Lathyrus sativus. Lathyrus sativus forms the staple food of poor villagers, especially during the period of food scarcity following a flood or famine. Lathyrism has been reported from Asia, Africa and Europe. However, in recent years, it has only been reported from developing countries such as Bangladesh, Ethiopia, India and Nepal. In India, epidemics have been reported from Maharashtra, Madhya Pradesh (Satna and Rewa), Bihar, West Bengal and Uttar Pradesh (Unnao) with an incidence between 0.3% and 2.5%. CURRENT STATUS OF LATHYRISM IN INDIA Currently, lathyrism is not a major health problem in India, and hardly any patient have been reported after the last epidemic of lathyrism in Unnao (UP) in 1984. This is because of the ban on the trade of L. sativus seeds in India. PATHOPHYSIOLOGY L. sativus is known to contain a number of toxic amino acids. Intraperitoneal injection of an alcoholic extract of L. sativus produces opisthotonus and leg weakness in chicks. Two free amino acids, β-N-oxalylamino-L alanine (BOAA) and β diaminopropionic acid have been found to be toxic in animal models, such as rats, mice and monkeys. L. sativus treated monkeys also had prolongation of central motor conduction time. These results suggest pyramidal tract dysfunction following L. sativus or BOAA intoxication. The only autopsy report including the brain is of a patient who developed lathyrism 31 years prior to death. On brain histology, loss of giant Betz cells and shrinkage of pyramidal neurons in the pre-central gyrus were observed. The other studies reported spinal cord autopsy findings which include distal and symmetrical degeneration of lateral and central corticospinal tracts associated with degeneration of spinocerebellar tracts and tractus gracilis. In another patient, who developed lathyrism 31 years ago, some changes in anterior horn cells with swelling, Hirano bodies and dispersion of Nissl bodies were seen. In the absence of precise neuropathological studies including motor areas, it is not clear whether lathyrism primarily originates in the neurons or is a central distal axonopathy involving the pyramidal tracts. BOAA excitotoxic hypothesis suggests that molecular pathology of lathyrism could start at the neuronal level in motor cortex with secondary degeneration of pyramidal fibres in spinal cord. BOAA also produces seizures in experimental animals because it is a potent glutamate agonist. Glutamate also results in neuronal death when post-synaptic glutamate receptors are over stimulated for a long period. The concentration of BOAA in lathyrus plants varies from 0.1% to 1%. It has been suggested that BOAA could selectively inhibit the brain mitochondrial enzyme NADH dehydrogenase. In 1970

Lathyrism UK Misra, J Kalita monkeys, pyramidal tract dysfunction has been produced by feeding L. sativus for 3 to 10 months or BOAA for 3 months. The affected monkeys develop tremors, myoclonic jerks and increased tone in the legs. Another non-protein amino acid of L. sativus, β-isoxazoline alanine (BIA) is also neurotoxic to neurons in culture, but to a lesser extent than BOAA. BOAA toxicity is more pronounced in younger animals compared to the older ones. Brain lesions are mainly observed in areas where blood brain barrier is normally absent. CLINICAL FEATURES Lathyrism affects adolescents and young adults who are otherwise healthy. Females, however, are less commonly affected. Lathyrism can present in 3 ways. Sudden onset of leg weakness on getting up from sleep is the most common presentation; subacute onset of walking difficulty occurs in some patients or insidious progression of spastic paraplegia occurs rarely. Majority of patients complain of leg stiffness, weakness and heaviness prior to the onset of paraparesis. Some patients may also complain of cramps and calf pain, unsteadiness, leg paraesthesia and urgency of micturition. On neurological examination, the patients have spastic paraplegia, scissoring gait, exaggerated knee and ankle reflexes and extensor plantar response. Crossed adductor reflex and patellar and ankle clonus may also be present. Cranial nerves, cerebellar functions and sensations are normal. Upper limbs are also normal. Associated peripheral neuropathy has been reported from Bangladesh and lower motor neuron signs from Israel, but these are not found in our experience. The disability in lathyrism is graded according to the need for help for walking. Most patients walk slowly without the need of a stick (no stick stage), while others need one or two sticks (one or two stick stage) and those crawling on hands and knees (Crawler stage) (Figure 1). Non-invasive transcranial motor stimulation studies have been employed to evaluate the conduction in motor pathways. Central motor conduction time to lower limbs in lathyrism reveals mild to moderate slowing in majority of patients. Occasionally, central motor conduction time may be normal or even markedly prolonged. These results are consistent with the wide spectrum of involvement of motor pathways. Somatosensory evoked potentials are normal which is consistent with normal sensations in lathyrism. DIAGNOSIS The diagnosis of lathyrism is based on the typical clinical findings and history of consumption of L. sativus. There are no specific laboratory tests. The patients of lathyrism should

Lathyrism

be differentiated from primary lateral sclerosis, hereditary spastic paraplegia, nutritional myelopathy, early spinal cord compression, HTLV myelopathy and multiple sclerosis, especially in an endemic area. TREATMENT Treatment includes elimination of L. sativus from the diet in all cases. This may result in improvement in some patients, but in majority, the spasticity persists. Symptomatic relief may be obtained by antispasticity drugs such as baclofen, tizanidine and diazepam. Physiotherapy may also help. Botulinum toxin has been tried, but cost limits its use. For preventing lathyrism, cultivation and trade of L. sativus should be discouraged and alternative cultivation such as rice and wheat should be encouraged. Giving food aid of grains and pulses will stop the people from consuming L. sativus. The toxicity of L. sativus can be reduced by soaking it for 24 hours and repeated changing of the soaking water. RECOMMENDED READINGS

Figure 1: Different stages of clinical severity of lathyrism.

1.

Misra UK, Sharma VP. Peripheral and central conduction studies in neurolathyrism. J Neurol Neurosurg Psychiatry 1994; 57: 572-7.

2.

Misra UK, Sharma VP, Singh VP. Clinical aspects of neuro-lathyrism in Unnao, India. Paraplegia 1993; 31: 249-54.

1971

26.12 DEFINITION AND EPIDEMIOLOGY Dropsy (from Hydropsy) is the description referring to a collection of serous fluid in all or any of the body’s cavities or in the meshes of its tissue. Epidemic dropsy is the condition characterised by extensive progressive oedema of the legs caused by the ingestion of mustard oil (cooking media) derived from mustard seeds (Sinapis albae) contaminated with seeds of the plant Argemone mexicana. Argemone mexicana normally grows as a weed in many parts of India, the seeds of which resemble brown mustard seeds that contaminate the mustard oil with toxic alkaloids of the benzophenanthridine group.

Epidemic Dropsy Navneet Sharma contamination, but quantitative demonstration of alkaloids requires HPLC (detects 0.001% contamination by Argemone oil). TREATMENT Patients can present to the emergency department with pulmonary oedema. General measures recommended are: bed

The first record of epidemic dropsy was from the state of Calcutta in the year 1877 and since then numerous outbreaks of this condition have occurred in different parts of India. In the latest Delhi epidemic in 1999, there were 60 casualties and 3,000 victims had to be hospitalised. In 2002, another outbreak of epidemic dropsy occurred in Uttar Pradesh affecting 21 individuals. AETIOPATHOGENESIS AND CLINICAL FEATURES For clinical features of epidemic dropsy to develop, the estimated level of contamination of edible mustard oil with Argemone oil is ~0.5% to 1%. The route of exposure, aetiopathogenesis and clinical features are shown in Figure 1. The toxic alkaloids in Argemone oil cause an increase in permeability of blood vessels in different organs, i.e. heart, skin, liver, lungs, kidneys and eyes. Ocular manifestations occur in 12% cases and gastrointestinal symptoms in 52% to 84% of cases. Death has been reported due to cardiac and respiratory failure in 5% of cases. In 25% cases, oedema persists beyond 2 months and in 10% beyond 5 months. LABORATORY ABNORMALITIES Anaemia, leucopaenia and thrombocytopaenia have been reported. Anaemia is often normocytic normochromic. Mild impairment of renal and hepatic functions is present. Hypoalbuminaemia is a universal finding and combined respiratory alkalosis and metabolic acidosis is also present along with restrictive pulmonary ventilation defects. The chest radiograph may reveal pleural effusion, pulmonary oedema or pneumonia. Echocardiography is characteristically normal suggesting noncardiogenic pulmonary oedema as the cause for breathlessness. DIAGNOSIS It is usually straightforward when a history of contaminated oil use is forthcoming. In sporadic cases, a high index of suspicion is necessary for the diagnosis. The nitric acid test can be done easily at bedside on oil samples to detect 1972

Figure 1: The aetiopathogenesis and clinical features of epidemic dropsy.

PREVENTIVE MEASURES Mustard oil that is marketed should be subjected to rigid quality control measures to detect contamination and if found so, withdrawl from the markets. RECOMMENDED READINGS 1.

Khilnani GC, Trikha I, Malhotra OP, Prabhakaran D, Pande JN. Pulmonary Functions in patients with epidemic dropsy. Indian J Chest Dis Allied Sci 2003; 45: 25-9.

2.

Rangan C, Barceloux DG. Food contamination. Dis Month 2009; 55: 263-91.

Epidemic Dropsy

rest, oxygen inhalation, salt and fluid restriction, inotropic agents for hypotension and diuretics. For type 1 respiratory failure, noninvasive ventilation (NIV) is a promising treatment modality. Antioxidants like vitamin E and C and vitamin B complex although used have little evidence to support their use. Although, ACE-inhibitors, ARB’s and aldosterone antagonists can be used for managing congestive heart failure (CHF), yet, their use has not been validated. Glaucoma is managed medically, but may need surgical intervention and follow-up with opthalmological services.

1973

26.13 INTRODUCTION Patients with heavy metal poisoning generally present with multi-system involvement producing gastrointestinal, cardiovascular, neurologic and renal effects. The most common heavy metals and their compounds producing poisoning are mercury, lead, arsenic, antimony, cadmium, bismuth and thallium. Of these, poisoning with mercury, lead, arsenic, copper and thallium are of great concern to the general public and the medical community. The present Chapter will deal with the toxicology of these heavy metals. ARSENIC Arsenic is widespread geologically and exists in elemental, organic and inorganic (trivalent and pentavalent) forms with each of them having different toxicities. Arsine gas is the most toxic, followed by trivalent arsenic compounds (e.g. sodium arsenite, arsenic trioxide, potassium arsenite). Pentavalent inorganic arsenicals (e.g. lead arsenate, arsenic acid, calcium arsenate) are less soluble and less toxic. Elemental arsenic is considered to be nontoxic. Most of the organic arsenic compounds (melarsoprol, arsanilic acid) are less toxic than inorganic arsenic salts. Seafood contains arsenic in the form of organoarsenicals (e.g. arsenocholine and arsenobetaine), which are nontoxic. Sources of Exposure Arsenic is used in the manufacture of pesticides and rodenticides in the agricultural industry. It is widely used in timber preservatives, termicides, herbicides, glass production, specialised alloys and pigments. In many parts of the world, arsenic is a natural contaminant of ground waters. Sodium arsenate is used as an ant-killer. Fowler’s solution, which was used in the treatment of psoriasis, contains 1% potassium arsenate. Melarsoprol is used to treat trypanosomiasis. Arsenic trioxide is occasionally used in the treatment of relapsed acute promyelocytic leukaemia. Arsenic toxicity can occur when arsenic-containing solutions are exposed to acids. Arsenic Poisoning in India A number of cases of chronic arsenic poisoning due to drinking of contaminated underground water have been reported from West Bengal. The maximum permissible limit recommended in the absence of an alternative source of potable water in the affected areas by the World Health Organization (WHO) in groundwater is 10 µg/L. However, in India, the accepted level is below 50 µg/L. The levels are higher than 50 µg/L in several districts of West Bengal. More than 40 million people live in the arsenic-affected region of the state. It is suspected that about 5 million people drink arsenic-contaminated water in West Bengal. Recent reports indicate the propensity of arsenicosis affecting other states in the Ganga/Brahmaputra plains too. Northeastern states; Bihar, Jharkhand, Uttar Pradesh, Andhra 1974 Pradesh and Chhattisgarh are also reported to be in the grip of

Heavy Metal Poisoning Praveen Aggarwal this deadly disease. This makes it one of the world’s worst calamities in recent times. Mechanism of Toxicity Both inorganic and organic arsenic salts may be absorbed after oral ingestion. However, because of low solubility, many pentavalent arsenic compounds are excreted in the stool before dissolution. Arsine gas is very rapidly absorbed from lungs. Trivalent arsenic compounds inhibit pyruvate dehydrogenase complex via inhibition of sulfhydryl groupcontaining cellular enzymes, which results in reduced citric acid cycle activity and reduced gluconeogenesis. Pentavalent arsenic produces toxicity by converting into trivalent arsenic. In addition, pentavalent arsenic produces toxicity by uncoupling oxidative phosphorylation resulting in ineffective generation of adenosine triphosphate. Arsine becomes localised in the red blood cell, which results in rapid and often severe haemolysis. Another postulated mechanism for toxicity produced by various heavy metals, including arsenic, lead and mercury, is generation of reactive free radicals, which produce cellular damage, depletion of enzyme activities, damage to lipid bilayer and DNA. Clinical Features Although as little as 1 mg of arsenious oxide can produce acute toxicity, doses in the range of 20 mg of arsenic in adults are often associated with severe symptoms. The lethal dose has been estimated at 200 mg to 300 mg. Exposure to large doses produces acute toxicity while exposure to substantially lower amounts over a period of time will result in chronic toxicity. Arsine gas poisoning Initial symptoms of acute arsine poisoning are generally vague and include headache, weakness, nausea, vomiting and abdominal pain. Within a few hours, the patient develops intravascular haemolysis leading to jaundice, haemoglobinuria and acute renal failure. Acute arsenic poisoning The symptoms of acute intoxication may be evident within minutes of arsenic ingestion or may be delayed for several hours if food is present in the stomach. Acute exposure leads to vomiting, watery (may have ‘rice water’ appearance), and later bloody stools and severe abdominal pain. This can result in electrolyte imbalance, hypotension and shock. Cardiotoxicity manifests as altered myocardial function, electrocardiogram (ECG) changes (prolongation of QT interval and abnormal Twaves) and arrhythmias. Acute encephalopathy can develop and progress over several days and results in delirium, coma and convulsions. Occasionally, peripheral neuropathy with a glove and stocking distribution may occur acutely. Other features include acute respiratory distress syndrome, hepatitis,

Patients who have been poisoned acutely with lower amounts of arsenic develop less severe manifestations, which include gastroenteritis that may continue for several days. Following acute intoxication, patients often develop additional features. Peripheral sensorimotor neuropathy typically develops in 1 to 3 weeks. This may mimic Guillain-Barré syndrome. Encephalopathic features include headache, drowsiness, reduced memory, hallucinations and seizures. A few patients develop haemoptysis and patchy infiltrates in the lungs. Skin manifestations are alopaecia, oral lesions and macular rash. Mees’ lines [transverse white bands (1 to 2 mm wide) on the nails] may develop but are uncommon. Similar lines have also been described in thallium, lead poisoning, Hodgkin’s disease and renal failure. Chronic arsenic poisoning Arsenicosis has been defined by the WHO working group as a chronic health condition arising from prolonged ingestion (not less than 6 months) of arsenic above a safe dose, usually manifested by characteristic skin lesions, with or without involvement of internal organs. Chronic exposure to arsenic produces muscle weakness, myalgias, abdominal pain, and excessive salivation and lacrimation. Typical manifestations of chronic arsenic poisoning include pruritus, hyperpigmentation or less commonly, hypopigmentation of skin with a ‘raindrop’ pattern and thickening (hyperkeratosis) of palms and soles, which sometimes may show nodularity (Figure 1). Sometimes, macular areas of depigmentation may appear on normal skin or hyperpigmented background producing the distinctive appearance of ‘leucomelanosis’. Symmetrical peripheral neuropathy, involving both sensory and motor neurons, is common and the patient presents with paraesthesias, numbness, pain and muscular weakness of the extremities. The neuropathy is generally axonal and preferentially affects the large fibres.

Haematological abnormalities include varying degrees of anaemia, leucopenia and thrombocytopaenia. Anaemia is most commonly normocytic and normochromic. Basophilic stippling may be seen. Cardiovascular features include conduction abnormalities and prolongation of QT interval. Acrocyanosis and Raynaud’s phenomenon occur occasionally and may progress to endarteritis and frank gangrene of the extremities (black-foot disease).

Heavy Metal Poisoning

haemolytic anaemia and rhabdomyolysis. Acute renal failure may develop due to fluid loss, myoglobinuria, haemoglobinuria or direct renal toxicity. Fever may develop in a few patients. A garlic-like odour of breath may help in diagnosing arsenic poisoning. Fatalities occur within one to four days due to cardiovascular collapse.

Chronic exposure to arsenic may lead to hepatomegaly and non-cirrhotic portal hypertension. Other uncommon features include development of diabetes mellitus and restrictive lung disease. Arsenic has been classified as a carcinogen and the patients may develop Bowen’s disease, squamous and basal cell carcinomas of skin and lung and bladder carcinomas. Arsenic poisoning has also been shown to cause immunosuppression. Table 1 lists some of the common clinical features of chronic arsenic poisoning. Table 1: Clinical Features of Chronic Arsenic Poisoning Cutaneous

Melanosis: Fine freckled or spotted pigmentation (raindrop pigmentation); diffuse hyperpigmentation; guttate hypopigmentation on normal or hyperpigmented background (leucomelanosis) Hyperkeratosis: Keratotic papules with thickening of palms and soles Malignant/Pre-malignant lesions: Bowen’s disease, squamous cell carcinoma, basal cell carcinoma

Neurological

Peripheral neuropathy: Predominantly sensory

Peripheral Raynaud’s phenomenon, claudication, gangrene vascular disease (black-foot disease) Respiratory

Chronic bronchitis, pulmonary fibrosis, bronchiectasis

Hepatic

Non-cirrhotic portal fibrosis, cirrhosis of liver, portal hypertension

Gastrointestinal Anorexia, nausea, chronic diarrhoea Haematological Anaemia, leucopaenia, thrombocytopaenia

Diagnosis Arsenic is radio-opaque and an abdominal radiograph may reveal a radio-opaque substance in the gut. However, it is rapidly absorbed from the gastrointestinal tract and radiographs taken in cases of known arsenic ingestions are usually negative. Blood levels of arsenic are not of much use in diagnosing poisoning. Urinary arsenic levels are required to make a definitive diagnosis of arsenic exposure. Excretion of arsenic of more than 100 μg in 24 hours or 50 μg/L is abnormal. The urine specimen should be collected in a metal-free container. Since most laboratories measure total urinary arsenic, patients should be told to avoid seafood for at least 3 days prior to urine collection. Arsenic levels in hair and nails are also useful in diagnosis of chronic poisoning (normal arsenic levels in hair and nails are below 0.5 mg/kg and 1 mg/kg, respectively). A single dose of arsenic can be detected at the distal tip of the nails about 100 days after the exposure.

Figure 1: Photograph showing nodular hyperkeratosis of soles in a patient with chronic arsenic poisoning. Courtesy: Dr M Ramam, All India Institute of Medical Sciences, New Delhi.

Treatment Treatment of acute arsenic poisoning should include decontamination, chelation and supportive care. Since profuse vomiting is a common early symptom, gastric lavage may not 1975

be necessary, but should be considered in every case. Whole bowel irrigation is another option for decontamination. Since activated charcoal does not adsorb arsenic, its role is limited to unknown ingestions. Intravenous fluids are frequently necessary to assure adequate intravascular volume. Electrolytes must be monitored and imbalances corrected when necessary. Glucose levels and glycogen stores should be maintained by parenteral administration of dextrose.Treatment of cardiotoxicity may require vasopressors. Haemodialysis may be indicated for renal failure; however, it does not remove significant amount of arsenic and is not indicated if renal function is normal. The chelation therapy in acute arsenic toxicity consists of dimercaprol (British anti-Lewisite) and should be started immediately in suspected acute poisoning before laboratory confirmation. However, there is some evidence that BAL may increase arsenic transport into brain. It is available in vials containing 3 ml solution with 100 mg BAL/ml. It should be administered by deep intramuscular injection. Dimercaptosuccinic acid (DMSA) and dimercapto-1-propane sulphonate (DMPS) appear to be better alternatives than BAL in most patients who are not critically ill. The DMPS is administered in a dose of 5 mg/kg intravenously every 4 hours till the patient can be able to tolerate the medication orally. The oral dose in adults is 400 mg every 4 hours for a week. The recommended dose of DMSA is 10 mg/kg every 8 hours for 5 days and then 10 mg/kg every 12 hourly. D-penicillamine has not been shown to be efficacious in patients with arsenic poisoning. Chelating agents have frequently been considered for treatment of chronic arsenic toxicity and arsine toxicity; however, their usefulness is yet to be established. The only treatment presently available for arsine poisoning is exchange transfusion or haemodialysis if renal failure develops. LEAD Lead is ubiquitous in the environment but has no physiologic role in our biological systems. It exits in elemental form (e.g. bullets), as well as in inorganic and organic forms. Inorganic lead compounds include lead oxide, lead chromate, calcium plumbate and lead sulphide. Tetraethyl lead, the anti-knock compound added to gasoline, is an organic lead compound. Sources of Exposure Lead is a persistent metal that is present in the environment (in water, soil and dust). Table 2 gives common sources of lead exposure. Table 2: Common Sources of Lead Paint (lead-based) Household dust Lead water pipes Soil around the home Herbal and traditional remedies Food-storage articles: Lead-glazed ceramic ware, lead crystals and lead-soldered cans Paint on children’s toys Industrial: Smelting, soldering, battery making, ship building, glass manufacture

The most common sources of inorganic lead exposure include 1976 paints and lead-contaminated soil. Lead-based paints are still

widely used in developing countries. Lead pigments (usually lead carbonate) account for as much as 50% of many white household paints and a thumbnail-sized chip of this paint may contain as high as 200 mg of lead. Lead-based paints have also been used in toys. Studies from India have reported lead levels within permissible limits as well below 600 ppm in latex paints but the levels have been found to be high (upto 1,40,000 ppm) in most samples of enamel paints. Among the enamel paints, white paints have been found to have the lowest concentration of lead while yellow and orange with the highest concentration. More than 30% samples of floor dust in Delhi homes have been shown to contain excessive lead. Drinking water is also a major source of lead exposure as leaded plumbing components continue to be used in water pipes. Food storage articles like lead-glazed ceramic ware, lead crystals and lead-soldered cans may contain significant amount of lead. Industries classically associated with lead exposure include smelting, battery making, ship building and glass manufacture. Automotive and industrial emissions are the major contributors to lead in air. Use of lead-free petrol has reduced lead toxicity produced by automotive emission to a large extent and has resulted in marked reduction in lead levels among children in developed nations as well as in India. Chronic sniffing of petrol may produce lead poisoning. Recycling of automobile batteries is another source of lead exposure. Surma (kohl, kajal) has also been reported to produce lead encephalopathy in children. Many samples of surma contain as much as 88% of lead sulphide. Sindoor contains a high amount of lead (roughly 57% by weight) and may produce lead toxicity if used as food-colouring agent. Many herbal preparations may contain significant amounts of heavy metals with lead content ranging from 5 µg/g to 37,000 µg/g. Another source of lead is the consumption of illicit liquor which is contaminated by lead (moon shine). Swallowing foreign bodies containing lead and retained lead bullets in joints have been linked to chronic poisoning. Mechanism of Toxicity The amount of inorganic lead absorbed through gut is about 10% to 15% of the ingested quantity; for pregnant women and young children, the amount can increase upto 50%. The absorption of lead is enhanced if the diet is deficient in iron, calcium and zinc. Approximately 30% to 40% of inhaled lead is absorbed into the blood-stream. Inorganic lead is minimally absorbed through the skin, but tetraethyl lead (leaded gasoline) is well absorbed through skin. Once absorbed, 99% of circulating lead is bound to erythrocytes for approximately 30 to 35 days and is dispersed into the soft tissues over the following 4 to 6 weeks. Lead is stored in bones for up to 30 years. When bone metabolism increases (e.g. during pregnancy and lactation, fracture healing and chelation therapy), stored lead leaves the bone and re-enters the circulation and can increase the risk of lead toxicity. It can also expose the foetus to lead if mother had lead exposure previously. Lead poisoning is also known as saturnism or plumbism. Lead forms complexes with sulphur, nitrogen and oxygen, and exerts its toxic effects by combining with sulfhydryl groups in proteins,

Lead also interferes with excitatory neurotransmission by glutamate, which is the transmitter at more than half the synapses in the brain and is critical for learning. N-methyl-Daspartate receptor is blocked selectively by lead. This compromises permanent retention of newly learned information. It is thought that lead affects the renin-angiotensin system, causing hypertension. Clinical Features Acute lead poisoning The symptoms of lead toxicity are often vague and may arise acutely, even though the poisoning is usually chronic. Acute lead poisoning is uncommon. It can result from inhalation of large quantities of lead. In children, ingestion of large oral dose from various sources can produce acute poisoning. It can also occur in children with pica. Characteristics of acute poisoning are abdominal colic, constipation, fatigue, anaemia, renal failure, peripheral neuropathy, renal insufficiency, and in severe cases, encephalopathy (coma, convulsions, papilloedema). Vomiting is common in children. Neuropathy is generally of pure motor type resulting in foot and wrist drop. Chronic lead poisoning The important clinical symptoms and signs of chronic lead poisoning are given in Table 3. Chronic lead poisoning in children Chronic lead toxicity is more common, and in children, presents with pallor, underweight, short stature, loss of appetite, intermittent vomiting, constipation, headache and neuropsychological disturbances (irritability, nervousness, tremors, intermittent lethargy). Features compatible with lead encephalopathy include drowsiness, irritability, seizures, gait disturbances, evidence of increased intracranial tension and coma and can occur if exposure to lead continues. The probability of developing encephalopathy increases with rising lead levels and becomes significant when the levels exceed 70 μg/dL. Clinically important colic, peripheral neuropathy and chronic renal disease are uncommon in children as compared to adults. Chronic lead poisoning in adults Adults often present with abdominal colics, anaemia, hypertension and peripheral motor neuropathy. Renal toxicity has been well documented in occupationally exposed workers and it manifests as proximal tubular damage, glomerular sclerosis and interstitial fibrosis. Presentation may include proteinuria, impaired transport of glucose and organic anions and tubulointerstitial nephritis with or without renal failure. It can also precipitate gout (lead-induced gout or saturnine gout). Encephalopathy is rare in adults but neuropsychiatric features

may develop. Occasionally, patients may develop lead line or Burton’s line, which is a grayish-black line, at the junction of teeth and gums. It develops due to deposition of lead sulphide pigment formed by the lead molecules reacting with hydrogen sulphide in the oral cavity. There is an association between elevated blood lead levels and higher risk of amyotrophic lateral sclerosis. Table 3: Clinical Features of Lead Poisoning

Heavy Metal Poisoning

thus inhibiting sulfhydryl-dependent enzymes. It may act as an inhibitor or agonist of calcium-dependent processes. Lead inhibits several steps in haeme synthesis. It inhibits D-aminolevulinic acid dehydratase, producing increased levels of delta-aminolevulinic acid (ALA) in blood and urine. Several studies have shown that accumulation of ALA induces reactive oxygen species generation, which produces oxidative damage. Lead also inhibits coproporphyrinogen oxidase and ferrochelatase causing increased urinary coproporphyrin III and erythrocyte protoporphyrin concentrations, respectively.

Apparently asymptomatic (lowest exposure; blood lead levels may be below 10 μ g/dL) Reduced learning and memory Lowered IQ Impaired speech Hyperactivity Low exposure Myalgia Paraesthesia Fatigue/lethargy Irritability Mild abdominal discomfort Change in taste Moderate exposure (additional features) Arthralgias Inability to concentrate Short-term memory loss Tremor Headache Diffuse abdominal pain Vomiting Constipation Hypertension High exposure Abdominal colic Paresis or paralysis (wrist and foot drop) Papilloedema Somnolence, coma Seizures Lead line on gingival tissue (Burton’s line)

Chronic petrol sniffing Tetraethyl lead and its metabolites are highly neurotoxic. The clinical features vary from nonspecific symptoms, such as loss of appetite, lethargy and irritability, to altered mental status, psychosis, tremors, ataxia, myoclonus, chorea and seizures. Some of these features may be related to the associated toxic aromatic hydrocarbons contained in petrol. In the case of severe exposure, death may occur within a few hours or may be delayed for several weeks. Anaemia is uncommon with organic lead exposure. Elevated lead levels in pregnancy Elevated blood lead levels during pregnancy are associated with an increased risk of preterm births and can increase the risk of spontaneous abortion. The first pregnancy carries the greatest risk of lead toxicity. Blood lead levels may actually increase in women during pregnancy as a result of increased mobilisation of lead from bones into the blood. Lead freely crosses the placenta, and there is a strong correlation between maternal and umbilical cord blood lead levels. Because of incomplete blood-brain barrier, the effect of lead on the foetus’s central nervous system is greater during gestation and in the first 3 years of life than in later life. The effects of lead exposure on the 1977

foetus during gestation may be manifested after birth by low performance on cognitive tests. However, it is still unclear if lead is a teratogen. Subclinical effects Recent studies evaluating the relationship between blood lead levels and neurobehavioural performance have shown the evidence of effect at levels below 10 μg/dL – the current level considered excessive for children. At low-level exposure to lead, subclinical effects on central nervous system are the most common effects seen in children. As blood lead concentration increases by 10 μg/dL, the intelligence quotient decreases by 2 to 3 points. The child may become inattentive, hyperactive and disorganised. Delinquency is seen as the child grows. There is no evidence that chelation will reverse cognitive impairment. Diagnosis Measurement of blood lead levels is the standard screening test for lead toxicity. There is no toxic threshold for lead, i.e. there is no measurable level of lead in the body below which no harm occurs. For diagnostic purpose, blood lead levels above 10 μg/dL are considered abnormal although some neurological damage may occur even at lower levels. Blood lead level is only a reflection of recent or continued lead exposure and does not adequately reflect past exposure or accumulated bone lead levels. In case of acute ingestion, abdominal radiograph may show radio-opaque lead chips. A normocytic anaemia with basophilic stippling of the red blood cells and abnormal liver function results are characteristics of lead poisoning. However, basophilic stippling and anaemia only occur after significant levels of exposure; at blood lead levels over 50 μg/dL in adults and 25 to 40 μg/dL in children. The urine may show protein and glucose. Lead lines are dense transverse bands at the metaphyses of long bones. These lines generally develop after months of exposure. Since laboratory analysis of lead levels cannot be readily performed, children with unexplained encephalopathy should undergo radiography of the knees to look for dense metaphyseal band. Measurement of erythrocyte protoporphyrin (EP) was used as an inexpensive screening test during 1970s. However, it is no longer recommended as it usually does not rise unless blood lead levels are above 25 to 35 μg/dL. Further, it may be elevated in iron deficiency states, porphyria, cirrhosis of liver and alcoholism.The EP assays may still be used if facilities to estimate blood lead levels are unavailable. The threshold for EP is 30 μg/dL. Similarly, calcium disodium edetate mobilisation test, which was used to assess lead excretion after a single dose of edetate, is not recommended at present. Cortical bone lead measured by radiographic fluoroscopy, is considered a sensitive biomarker for cumulative lead exposure and correlates well with historical rather than current blood lead level measurements. Treatment Treatment of lead toxicity involves prevention of further exposure, decontamination, supportive care and chelation. Lavage should be used for recent ingestions. Whole bowel irrigation is recommended for ingestion of lead-containing 1978 foreign bodies. It is generally not indicated for lead paint chips.

Activated charcoal does not bind lead. Seizures from lead encephalopathy may be resistant to benzodiazepines and phenobarbital; in such cases, measures to reduce intracranial pressure (mannitol, steroids, hyperventilation) are recommended. The options for symptomatic treatment of abdominal cramps are limited because these symptoms do not respond well to relaxants or analgesics. In patients with pronounced anaemia, transfusion may become necessary. Dietary advice includes adequate intake of iron, calcium and vitamin C. Adequate iron and calcium stores may decrease lead absorption and vitamin C may increase renal excretion. The current recommendations for the management of children and adults with high lead levels are given in Tables 4 and 5. Table 4: Treatment of Lead Poisoning in Children Blood Level

Treatment

80 μg/dL

Start treatment with CaNa2EDTA or DMSA If encephalopathy present, give BAL and CaNa2EDTA

Dimercaptosuccinic acid (DMSA) or succimer is effective in both children and adults. It is recommended if blood lead levels are 45 to 69 μg/dL in children or 70 to 100 μg/dL in adults, provided serious features including encephalopathy are not present. In contrast to BAL, DMSA is a more specific chelator of lead, arsenic and mercury while sparing essential metals such as zinc, calcium, copper, magnesium and iron. It is administered in a dose of 10 mg/kg every 8 hours for five days followed by 10 mg/kg every 12 hours for another 14 to 21 days. An alternative is to give repeated courses of 10 mg/kg every 8 hours for 5 days with a gap of 1 to 2 weeks between the courses. The length of course may be tailored to individual patient’s response as indicated by the assessment of blood lead concentration. Oral DMSA and parenteral CaNa2EDTA are both effective chelators of lead. There is currently insufficient data, however, to conclude that either antidote is superior in enhancing lead excretion. Both antidotes resolve the symptoms of moderate and severe lead toxicity rapidly. In tetraethyl lead, chelator therapy is almost completely ineffective. D-penicillamine has also been used for lead poisoning.The usual dose is 25 to 40 mg/kg in four divided doses a day for 1 to 6 months. The adult dose is 1 to 1.5 g/day. The drug should be taken on an empty stomach. It may be useful in mild lead poisoning or when unacceptable adverse effects to both edetate and DMSA have occurred.

Various chelating agents useful in heavy metal poisoning are given in Table 6. Antioxidants Antioxidant molecules are thought to play a crucial role in counteracting free radical induced damage to macromolecules and have been found to heel the free radical mediated cell damage. Antioxidants like vitamin E, vitamin C, β-carotene and α-lipoic acid have been shown to be beneficial in studies conducted on animals with heavy metal poisoning.

Heavy Metal Poisoning

Chelation therapy The current recommendation is to use a combination of intramuscular BAL and intravenous calcium disodium edetate (CaNa2EDTA) if blood lead levels are above 70 μg/dL in children or 100 μg/dL in adults. Unlike EDTA, BAL chelates lead from the brain also. An initial dose 50 mg/m2 of BAL is given by deep intramuscular injection and 4 hours later, CaNa2EDTA 1000 mg/ m2/day is begun via continuous intravenous infusion. The BAL is then continued simultaneously at a dose of 300 mg/m2/day in divided doses for every 4 hours. If encephalopathy is present, the daily doses of BAL and CaNa2EDTA are 450 mg/m2 and 1500 mg/m2, respectively. The treatment is given for 5 days. Courses of CaNa2EDTA can be repeated every 2 to 5 days.

MERCURY Mercury occurs geologically in its elemental state and as inorganic salts (e.g. mercuric chloride, mercuric iodide, mercuric oxide, mercuric sulphide, mercurous chloride) and organic salts (e.g. ethylmercury, methylmercury, merbromin, phenylmercurial salts). Elemental mercury readily volatises at standard temperature (0°C) and its presence in an open container can result in significant air concentrations in unventilated or poorly ventilated spaces. Sources of Exposure Mercury is used in the manufacture of batteries, latex paint, urethane, polyvinyl chloride, scientific instruments and fungicides. It is also used in gold mining and refining and electrical industry. Organic salts such as merbromin and nitromersol are still used widely as topical antiseptics. Organomercurials have been used in human and veterinary medicines as an antiseptic, but the widest use has been in agricultural fungicides. Calomel (mercurous chloride) was used extensively in medicines. It is still being used in some creams and laxatives.Thiomersal, a long-chain alkyl mercury compound is widely used as a preservative in pharmaceutical industry. Some of the herbal medicines also contain inorganic mercury. Mercury-containing disc batteries may lead to mercury toxicity when ingested. Industrial discharge into rivers and streams has been a major source of mercury pollution. The major dietary contribution comes from seafood. There is accumulation of potentially toxic

Table 6: Chelating Agents in Heavy Metal Poisoning Chelating Agent

Dose

Precautions/Side Effects 2

Dimercaprol (BAL, British anti-lewisite)

300 to 450 mg/m /d in 6 divided doses for 3 to 5 days deep intramuscularly

CaNa2EDTA (edetate)

1000 to 1500 mg/m2/d for 5 days intravenously as infusion

DMSA (succimer)

10 mg/kg every 8 hourly for 5 days, then 10 mg/kg every 12 hourly orally 5 mg/kg every 4 to 6 hourly orally or intravenously 25 to 40 mg/d orally in 2 to 4 divided doses (maximum 1 g/day) orally

DMPS (dimercapto-1propane sulphonate) D-penicillamine

First dose precedes CaNa2EDTA by 4 hours Do not administer iron concurrently May produce hypertension, tachycardia, a constricting feeling in the chest, burning sensation in throat, lacrimation, urticaria, haemolysis (in G-6PD deficient patients) Monitor renal functions Ensure adequate urine flow May produce fever, myalgia, tremors, headache, hypotension, vomiting, mild increase in liver enzymes, hypercalcaemia Monitor liver functions, blood counts May produce vomiting, diarrhoea, metallic taste, elevated liver enzymes, drowsiness, neuropathy, skin rash, nasal congestion, cardiac arrhythmia Can be administered orally as well as parenterally To be given empty stomach Monitor total leucocyte counts, platelets, haemoglobin, liver and renal functions Contraindicated in patients with penicillin allergy May produce rashes, arthralgia, lymphadenopathy, urticaria, vomiting, diarrhoea, bone marrow depression, nephrotic syndrome, neuropathy 1979

quantities of mercury in freshwater fish in some lakes with acid water. Acidification increases bacterial formation of methylmercury, which then enters the food chain. Minamata disease was the first outbreak of methylmercury poisoning caused by consumption of methylmercury-containing seafood from the Minamata Bay in Japan in 1953. Later, another mass methylmercury poisoning was reported from Iraq where it was caused by contaminated bread. Mechanism of Toxicity After the inhalation of elemental mercury, approximately 80% is absorbed from the lungs and can cross the blood-brain barrier. The absorbed mercury is also rapidly oxidised to inorganic mercury in the red cells and tissues, which does not cross the blood-brain barrier effectively. After oral ingestion, elemental mercury is essentially unabsorbed. Inorganic mercury and phenylmercury are absorbed 7% to 15% after oral ingestion. These mercury compounds cross the blood-brain barrier poorly. Methylmercury is readily absorbed in the gastrointestinal tract. Mercurials bind to sulfhydryl groups present on the cell membranes and enzymes and cause their toxicities. Mercuric ions also accumulate in the kidneys, causing acute renal failure due to the necrosis of the proximal tubular epithelium, usually within 24 hours. Clinical Features Toxicity of mercurials depends on the form of mercury and on whether the exposure is acute or chronic. Acute elemental mercury poisoning Acute inhalation of elemental mercury results initially in pulmonary toxicity causing cough, haemoptysis, tachycardia, pulmonary oedema, cyanosis and death. Gastrointestinal features include vomiting, diarrhoea, metallic taste, dysphagia and salivation. If the patient survives, headache, blurred vision and encephalopathy can occur. Some patients develop cardiac arrhythmias, tremors, renal dysfunction and gingivostomatitis. Survivors of acute inhalation may develop interstitial lung fibrosis. Oral ingestion of elemental mercury is associated with low risk of toxicity due to its limited absorption. Features of mercury toxicity may develop if there is inordinate delay of mercury passage through the gastrointestinal tract. In addition, mercury lodging in the appendix can cause appendicitis or a ruptured appendix. Systemic features of mercury poisoning are usually absent after parenteral administration. Local features after parenteral administration include abscess formation with discharge of mercury granules, thrombophlebitis and granuloma formation. Embolisation of mercury may result in the presence of multiple, tiny spherules of mercury in various organs, including lungs, which are visible on a plain chest radiograph. Occasionally, intravenous injection of elemental mercury can cause severe pneumonitis and embolisation of the pulmonary vasculature, which can subsequently lead to hypoxia.

1980

Acute inorganic mercury poisoning Acute exposure to inorganic mercury salts results initially in gastrointestinal toxicity manifesting as abdominal pain, nausea, vomiting and in severe cases, bloody diarrhoea. This may result in vascular collapse. In high doses, renal necrosis and acute renal

failure may occur and this is related to both hypovolaemia and direct renal toxicity. Acute organic mercury poisoning Acute exposure to phenylmercury and related organic mercury compounds other than methylmercury causes toxicity similar to that of inorganic mercury poisoning. Acute exposure to methylmercury causes similar effects that occur after its chronic exposure, but the onset of symptoms may be as early as 15 days after its ingestion. Chronic mercury poisoning Chronic exposure to elemental mercury vapour, inorganic mercury and phenylmercury produce similar toxic features. These include dermatitis, loosening of teeth, gingivitis, salivation, stomatitis, intention tremor and a neuropsychiatric syndrome called ‘erethism’. The features of erethism include loss of appetite, insomnia, emotional lability, loss of self-control and memory loss. Another syndrome, ‘acrodynia’ or ‘pink disease’ is characterised by painful, erythematous extremities, sweating, photophobia, tachycardia, hypertension, insomnia and irritability. It is probably a hypersensitivity reaction which occurs only in children and does not occur in newborns or adults. Renal dysfunction, ranging from proteinuria to immune-complex-mediated nephritis especially membranous nephropathy may occur. Chronic methylmercury poisoning Chronic exposure to methylmercury causes neurotoxicity with onset one to two months after initial exposure. Clinical features include cerebellar ataxia, dysarthria, constriction of visual field, hearing impairment, sensory disturbances in the distal parts of the extremities, and emotional and cognitive defects. Foetal exposure to methylmercury may cause cerebral palsy, microcephaly, mental retardation and developmental delay. Dental amalgams Dental amalgam, used to restore carious lesions in teeth, is approximately 50% metallic mercury. Small amounts of mercury vapour liberated by chewing may be inhaled and may result in measurable levels of mercury in the body. However, at present, there is no evidence that exposure to mercury from dental amalgams is associated with adverse psychosocial outcomes or other clinical features of chronic mercury poisoning. Mercury in vaccines Thiomersal, which contains approximately 50% ethylmercury, has been widely used as a preservative in multiuse vials of vaccines. In the United States, it has been removed from most childhood vaccines by 2001 as a precautionary measure. At present, there is no data to support that thiomersal may account for adverse neurodevelopmental outcomes in children. Diagnosis Diagnosis of mercury poisoning is aided by the determination of mercury levels in whole blood, 24-hour urine samples and hairs. For elemental mercury and mercury salts, whole blood mercury levels reflect only very recent exposure while urinary mercury is a better marker for chronic exposure. In contrast, since methylmercury (an organomercurial compound) is mainly excreted in bile, urinary level is a poor measure of exposure.

Abdominal radiographs can be used to document the presence of ingested mercury and to evaluate the potential benefit of gastric lavage. If the respiratory tract is involved, a chest radiograph may be helpful. Treatment Acute mercury poisoning is best managed by discontinuing the exposure, providing supportive care and removal of metal from the body. Patients with pneumonitis from acute elemental mercury inhalation require oxygen, close monitoring of respiratory status and if required, assisted ventilation. Although ingestion of elemental mercury is often nontoxic, some patients may require surgical removal of metal that is entrapped in the intestines or appendix. In case of subcutaneous injection of mercury, surgical removal of mercury and surrounding granulated tissue is important. Radiographs and blood, urine and hair assays for mercury are aids for instituting treatment with chelators. Ingestion of inorganic mercury requires supportive treatment with aggressive fluid replacement and if required, haemodialysis. Patients should also be started on chelation therapy. Gastric lavage has been recommended for acute organic salt ingestions, especially if mercury is visualised on abdominal radiographs. Lavage may be done with protein-containing solutions, such as milk or egg white, as mercury may be bound to the administered sulfhydryl-containing proteins. Whenever mercury poisoning is suspected in critically ill patients, chelation therapy should be started regardless of the suspected form of mercury; however, chelation may be ineffective at reversing toxicity from chronic organic and chronic elemental mercury exposure. Dimercaprol has been extensively used for inorganic mercury poisoning. However, it is contraindicated in methylmercury poisoning. The DMSA and 2,3-dimercaptopropane-1-sulphonate (DMPS) are useful for both inorganic and elemental mercury poisoning. The DMSA is administered in a dose of 30 mg/kg per day. The duration of treatment is adapted to the evolution of clinical manifestations and urinary mercury levels. D-penicillamine is also useful in mercury poisoning although its efficacy is only about 30% of that with DMSA. It is administered in a dose of 250 mg 6 hourly along with pyridoxine (40 mg/day). This is continued till the urinary mercury levels fall below 500 μg/L after which the dose is reduced to 250 mg thrice daily. The DMPS has also been used with N-acetylcysteine (NAC) and haemodialysis as a part of a successful regimen for acute methylmercury poisoning. The NAC has also been used as a single agent in the treatment of acute elemental mercury poisoning. Oral DMPS may also be useful in mercury inhalational poisoning. COPPER Copper is an ingredient of several vital enzymes. It exits as elemental copper or as salts. Elemental copper is not toxic, but many of its salts are poisonous. Common salts include cupric acetoarsenite (Paris or Vienna green), cupric arsenite (Scheele green), cupric oxide, and copper or cupric sulphate (‘neela

thotha’). Most of the salts of copper are greenish in colour except for copper sulphate, which is blue in colour. Copper compounds are used as insecticides and fungicides and also as pigments. Acute or chronic copper poisoning can occur when copper ions are leached from copper pipes. Storage of acidic substances, such as orange juice in copper containers, may cause poisoning. Copper sulphate poisoning, one of the most common poisonings in 1960s and 70s in India, has reduced significantly over the past four decades.

Heavy Metal Poisoning

Blood mercury levels are the best indicator of acute exposure to methylmercury, while hairs may be the best specimen for the evaluation of chronic exposure. Normal levels of mercury in whole blood and urine are below 10 μg/L and 50 μg/L, respectively.

Mechanism of Toxicity In an acute intoxication, a high fraction of copper is bound to serum albumin and is biologically active. It is actively involved in oxidation-reduction reactions in the body, which is responsible for its toxicity. It inhibits several enzymes including mitochondrial electron transport chain and also disrupts lipid membranes. It also inhibits sulfhydryl groups on enzymes, including glucose-6-phosphate dehydrogenase and glutathione reductase, which may be responsible for haemolysis. Clinical Features Acute poisoning The average fatal dose of copper sulphate is 10 to 20 g. Initial features of acute poisoning include myalgia, retrosternal pain, abdominal pain, vomiting (greenish or bluish) and diarrhoea. Gastric perforation or haemorrhage can occur due to ulceration. Acute intravascular haemolysis occurs within 24 hours and can lead to anaemia, jaundice and renal failure. Jaundice may also occur due to liver injury. Some patients may develop methaemoglobinaemia due to oxidation of haeme and this may precede haemolysis. The central nervous system effects include agitation, convulsions and coma and are usually related to hepatic failure. Hypotension and cardiovascular collapse occur due to fluid loss from gastrointestinal tract; direct effects of copper on heart and vascular tree may also contribute to shock. Chronic poisoning Chronic exogenous copper poisoning is uncommon. Chronic inhalation of copper sulphate spray used as an insecticide can produce interstitial lung disease, the latter having histiocytic granulomas containing copper on biopsy. In children, consumption of copper-containing supplements over long periods may produce liver damage and cirrhosis. Other features include malaise, weakness, headache, dizziness, tightness in the chest, and leg and back pain. Diagnosis Following acute copper poisoning, liver function tests and haemogram may reveal evidence of haemolysis and liver damage. Blood copper level more than 1.5 mg/dL indicates serious copper toxicity. Elevated copper levels are also seen in patients with inflammatory conditions. Urinary copper levels are also elevated (normal urinary copper value < 25 μg/day). Treatment Aggressive supportive care is the mainstay of management of patients with acute copper poisoning. The fluid and electrolyte balance must be ensured. Gastrointestinal decontamination is usually not required as the patient vomits within minutes of ingesting a copper salt. When the patient presents early after ingestion, administration of milk may help, as albumin present 1981

in milk combines with copper. Haemodialysis is of little use in enhancing excretion of copper. Since methaemoglobin produced by copper is released into plasma due to intravascular haemolysis, methylene blue is not useful for its treatment.

examination of hair root shows deep black pigmentation in more than 95% cases. The definitive diagnosis can be made by blood and urine thallium levels. Normal urine thallium levels are less than 5 μg/L.

Chelation therapy is indicated when haematological or hepatic manifestations are present even though the efficacy of chelators is not well studied. Most commonly recommended chelator initially is BAL as the patient has vomiting, and therefore, oral Dpenicillamine cannot be given. When tolerated, D-penicillamine should be started. The DMSA may be used in patients with mild symptoms. Use of DMPS may worsen haemolysis and therefore, is not recommended in copper poisoning.

Treatment The initial treatment is supportive and includes gastric decontamination if the patient presents shortly after ingestion. Activated charcoal is useful in adsorbing substantial amount of thallium salts.

THALLIUM Thallium metal is nontoxic, but its salts are highly toxic. Thallium salts are tasteless, colourless and odourless. Thallium sulphate and nitrate were used as rodenticides. Some thallium salts are occasionally used as cockroach poison. It is still used in some homeopathic medicines. Thallium is widely used in industry. It is used in imitation jewellery, which sparkles rather like diamonds. It is also used as an alloy, a catalyst, and for making low-temperature thermometers and semiconductors. Thallium isotopes are used in nuclear medicine. Mechanism of Toxicity Thallium salts can be absorbed from the skin as well as by inhalation and ingestion. After absorption, thallium distributes throughout the vascular space in the first few hours. After several hours to days, it enters the nervous system and other tissues of the body. Thallium associates with the Na+/K+ ATPase channel with 10 times the affinity of potassium. Once intracellular stores of thallium accumulate, thallium interferes with the function of a number of enzymes by binding sulfhydryl groups and ultimately inhibiting cellular respiration, disrupting calcium homeostasis, and interacting with riboflavin and riboflavin-derived cofactors. Secondary riboflavin deficiency can then result in dermatitis, alopaecia, Mees’ lines and neuropathy. The fatal dose of thallium is estimated to be 10 to 15 mg/kg. Clinical Features The initial clinical features of thallium intoxication are nonspecific and usually develop after several hours of exposure. The gastrointestinal symptoms are usually not severe and include nausea, vomiting, abdominal pain and diarrhoea or constipation. Within 2 to 5 days, the patient may develop paraesthesia, burning pain in feet and hands, motor weakness, respiratory depression, nystagmus, optic atrophy, cranial nerve palsies, delirium, convulsions and coma. The picture may resemble Guillain-Barré syndrome superficially, but sensory neuropathy and preservation of reflexes exclude this syndrome. Tachycardia and hypertension frequently develop during the first or second week of intoxication. Within 2 to 3 weeks, skin lesions (acne, palmar erythema, dry skin and occasionally a ‘butterfly’ rash on the face) and alopaecia develop. The hair is lost in large tufts and within three weeks, the whole of head is bare. Mees’ lines on the nails may be seen in 2 to 4 weeks. Cardiac arrhythmias may occur up to 2 months after exposure. Diagnosis Abdominal radiographs may demonstrate radio-opaque 1982 material in the gut when patient presents early. Microscopic

Administration of potassium increases the excretion of thallium in the urine by 2 to 3 times. However, it can potentially increase neurologic toxicity due to mobilisation of thallium from its stores, and is therefore, not recommended. Administration of B-complex vitamin may be useful. Haemodialysis and haemoperfusion have been used with some success. Traditional chelators are of little use in thallium poisoning. Prussian blue (potassium ferric hexacyanoferrate) can be used as a chelator. Oral Prussian blue binds with thallium in the gut and also interferes with enterohepatic circulation. It reduces half-life of thallium by 50% in animal models. The dose is 250 mg/kg/day in 2 to 4 divided doses. CONCLUSION Heavy metal poisonings with lead, mercury, arsenic, copper and thallium are infrequently encountered; however, early recognition of these poisonings is required for efficacious treatment and a favourable outcome. A thorough history (including occupational) and physical examination are essential for the accurate diagnosis. RECOMMENDED READINGS 1.

American Academy of Paediatrics. Policy Statement. Lead exposure in children: prevention, detection, and management. Pediatrics 2005;116:1036-46.

2.

Bradberry S, Vale A. A comparison of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning. Clin Toxicol 2009; 47: 841-58.

3.

Caravati EM, Erdman AR, Christianson G, et al. Elemental mercury exposure: an evidence-based consensus guideline for out-ofhospital management. Clin Toxicol 2008; 46: 1-21.

4.

Das NK, Sengupta SR. Arsenicosis: diagnosis and treatment. Indian J Dermatol Venereol Leprol 2008; 74: 571-81.

5.

Flora SJ, Mittal M, Mehta A. Heavy metal induced oxidative stress and its possible reversal by chelation therapy. Indian J Med Res 2008; 128: 501-23.

6.

Ibrahim D, Froberg B, Wolf A, et al. Heavy metal poisoning: clinical presentations and pathophysiology. Clin Lab Med 2006; 26: 67-97.

7.

Igata A. Epidemiological and clinical features of Minamata disease. Environ Res 1993; 63: 157-69.

8.

Kumar A, Gottesfeld P. Lead content in household paints in India. Sci Total Environ 2008; 407: 333-7.

9.

Mukherjee SC, Saha KC, Pati S, et al. Murshidabad—one of the nine groundwater arsenic-affected districts of West Bengal, India. Part II: dermatological, neurological, and obstetric findings. Clin Toxicol 2005; 43: 835-48.

10. Saper RB, Kales SN, Paquin J, et al. Heavy metal content of ayurvedic herbal medicine products. JAMA 2004; 292: 2868-73. 11. Zhao G, Ding M, Zhang B, et al. Clinical manifestations and management of acute thallium poisoning. Eur Neurol 2008; 60: 292-7.

26.14

Miscellaneous Poisoning Subhash Varma, Vikas Suri

CARBON MONOXIDE POISONING Carbon monoxide (CO) is a colourless, tasteless and odourless (lavender odour at extremely high concentrations) gas with a density of 0.97 that of air.

Cardiovascular symptoms and signs include chest pain from myocardial ischaemia, palpitations from arrhythmia, mildly to severely mottled skin from diminished circulation, poor capillary refill, hypotension, and cardiac arrest.

Sources of Carbon Monoxide Sources of CO from combustion include fuel, engine exhaust and gas/coal-heater emissions, smoke from accidental fires and fumes from cupolas of steel foundries, pulp paper mills and formaldehyde-producing plants. Indoor burning of charcoal or animal dung produces a disproportionate level of accidental CO intoxication. CO poisoning can also result from inhaling methylene chloride or volatile liquids found in degreasers, solvents and paint removers.

The symptoms and signs of CO toxicity are exacerbated by circumstances that increase neurologic and myocardial oxygen demand.

Mechanism of CO Toxicity Since CO has 200 to 250 times greater affinity for haemoglobin than oxygen, it displaces oxygen from oxyhaemoglobin (HbO2) and converts it into carboxyhaemoglobin (COHb) causing decreased oxygen delivery to tissues. It also shifts the oxygen dissociation curve to left and reduces oxygen availability to the tissues further. It also acts as cellular poison as it competes with oxygen for other haemoproteins such as myoglobin, peroxidase, catalase and cytochromes.High-oxygen-extracting organs such as the brain and the heart easily become dysfunctional from CO intoxication. Activation of inflammatory processes and resultant lipid peroxidation play a role in the development of neurological damage. They contribute to the development of systemic inflammatory response syndrome (SIRS) and delayed neurological sequelae (DNS). Clinical Features Signs and the symptoms of CO poisoning are related to effects of hypoxaemia predominantly on the heart and brain. Concentrations of CO, duration of exposure as well as level of activity of the victim at the time of exposure have a bearing on clinical picture. Acute Poisoning Headache is the earliest symptom of mild to moderate toxicity. Subsequently dizziness, nausea, dyspnoea and loss of muscle control develop. Severe CO intoxicated patients have cherry pink colour of the skin, nails and mucosa. Ophthalmoscopy may show retinal discolouration with bright red retinal veins, flameshaped retinal haemorrhages or papilloedema. In severe cases hypotension, bradycardia, bradypnoea and noncardiogenic pulmonary oedema may develop. Neurologic symptoms and signs include fatigue, malaise or flulike symptoms, nausea, vomiting, dizziness, weakness, lethargy, difficulty in thinking, concentration and memory, emotional lability, paraesthesia, somnolence, stroke, coma, seizure, and respiratory arrest.

Subacute Poisoning Secondary injury from ischaemia due to CO poisoning can manifest within a few days of exposure as peripheral neuropathy, skin lesions (bullae and purpuric spots), rhabdomyolysis, renal failure, circulatory shock, noncardiogenic pulmonary oedema, disseminated intravascular coagulation and multi-organ failure. Glycosuria and albuminuria are often present. Delayed Neurologic Sequalae (DNS) DNS can arise 3 to 240 days after apparent recovery in approximately 40% of patients with significant CO exposure. These include headache, weakness, dizziness, nausea, aphasia, apraxia, apathy, disorientation, hallucinations, rigidity, gait disturbances and faecal and urinary incontinence. DNS generally occurs within 20 days of CO poisoning but deficits may persist for a year or longer. DNS correlates poorly with COHb levels. However, loss of consciousness, advancing age and neurological signs during acute intoxication may increase the risk. Chronic Exposure Long-term, low level exposure may result in light-headedness, persistent headaches, confusion, memory loss, nausea, vomiting and depression that tend to get better on cessation of exposure. Long-term exposure to CO can promote the development of atherosclerosis and polycythaemia. Diagnosis Acute CO poisoning is suspected on a suggestive history but the diagnosis of chronic CO intoxication is extremely difficult. Standard pulse oximetry does not differentiate COHb from HbO2 and is a poor indicator of CO exposure. Eightwavelength pulse oximeters capable of measuring COHb and methaemoglobin are being developed but need further validation. COHb is estimated by spectrophotometry. It may be tested on bedside by adding 10 mL of distilled water and 1 mL of 5% sodium hydroxide (NaOH) to 1 mL of patient’s blood. The solution turns straw yellow when COHb concentration is < 20% and stays pink when it is > 20%. Non-invasive pulse co-oximeters capable of photo-spectroscopic measurements of COHb are in development stage. On-site CO-oximetry determination of COHb levels correlate reasonably well with the signs and symptoms of CO injury.

1983

However, the predictive values of COHb levels falls considerably by the time, the patient gets to the emergency department after breathing air as well as prehospital oxygen administration but a rough correlation can be made with various clinical manifestations (Table 1). Table 1: Symptoms of Acute CO Poisoning Based on Blood Carboxyhaemoglobin Levels Carboxyhaemoglobin Level

Clinical Features

5% in normal circumstances. Estimation of methaemoglobin in the blood is needed to confirm the diagnosis. Normal methaemoglobin levels are 10%) of hydrogen peroxide is ingested, the patient may develop coma, cyanosis, hypotension, heart block, metabolic acidosis and seizures. Treatment If there is gastric dilatation due to oxygen, a Ryle’s tube should be inserted to decompress it. Otherwise, the management is symptomatic. RECOMMENDED READINGS 1.

Agarwal P, Wali JP. Diagnosis and Management of Common Poisoning; 1st Edition. Oxford University Press; New Delhi, 1997; pp 389-401.

2.

Judith E Titinalli, et al. Textbook of Emergency Medicine, 6th Edition, The McGraw-Hill Companies, Inc, 2004.

3.

Mathiharan K, Patnaik AK. Medical Jurisprudence and Toxicology; 23rd Edition. Butterworth 2006; 62: 426.

4.

Wright RO, Lewander WJ, Woolf AD. Methaemoglobinaemia: Aetiology, pharmacology and clinical management. Ann Emerg Med 1999; 34: 646-56.

Section

27

Environmental Medicine Section Editor: Randeep Guleria 27.1

Basic Considerations of Environmental and Occupational Diseases Randeep Guleria 27.2 Climate Change—Health and Disease Anil Gurtoo 27.3 Environmental Pollution Ashok A. Mahashur 27.4 Air-Borne Pollutants and Smoke-Related Hazards Rajeev Gupta 27.5 Drowning, Near-Drowning and Submersion Injury Yudh Dev Singh 27.6 Electric Shock and Lightning Injury Naveet Wig, Sourabh Malviya 27.7 Effects of Extremes of Temperature Rajvir Bhalwar 27.8 High Altitude Medicine Anuj Chawla 27.9 Aviation Medicine J.S. Kulkarni 27.10 Radiation Hazards A.M. Samuel 27.11 Environmental Disasters M.E. Yeolekar, Milind Y. Nadkar

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27.1

Basic Considerations of Environmental and Occupational Diseases

INTRODUCTION Environmental and occupational health is emerging as an important discipline in medicine due to the change that is occurring in climate due to industrialisation and urbanisation. It is being increasingly recognised that environmental factors have an important link with many chronic and infectious diseases. Deaths from heart disease and respiratory illness increase during heat waves and many diseases such as malaria, dengue, chikungunya and cholera are sensitive to changes in the climate. According to the World Health Organization (WHO), ‘In its broadest sense, environmental health comprises those aspects of human health, disease and injuries that are determined or influenced by factors in the environment. This includes the study of both the direct pathological effects of various chemical, physical and biological agents, as well as the effects on health of the broad physical and social environment, which include housing, urban development, land use and transportation, industry and agriculture’. The WHO estimates that 24% of the global diseases burden and 23% of all deaths can be attributed to environmental factors. Also, environmental factors have a much bigger impact in developing countries than developed ones and this effect is seen much more in the vulnerable population like children and elderly. Environmental medicine encompasses human illness or dysfunction that may occur due to environmental factors. Many diseases are affected by environmental factors. These include diarrhoea, lower respiratory tract infections, injuries, malaria, perinatal conditions, chronic obstructive pulmonary disease, coronary artery disease, lead toxicity and drowning. Illnesses that occur due to workplace environmental factors are termed as occupational diseases. In a developing country like India, the burden of various diseases increases due to environmental factors. It is estimated that 94% diarrhoeal disease burden can be attributed to environmental factors like unsafe food, unsafe drinking water and poor sanitation and hygiene. Similarly, there is strong evidence in our country linking lower respiratory tract infection to indoor air pollution caused by the use of solid fields in household. Almost 42% of acute lower respiratory tract infections in developing countries are attributable to environmental factors. Besides this the close link between vector borne diseases and environmental conditions is well established. Also, factors like deforestation, increasing vehicular traffic, migration from rural to urban areas, decreasing water resources and inadequate drainage system are important environmental factors that contribute to infectious diseases. Occupational diseases also form an important but often neglected part of human health. It is estimated that in India about 45,000 fatal injuries and 17 million non-fatal injuries occur 1990

Randeep Guleria due to occupational factors. It has been estimated that in India prevalence of silicosis is 6.2% to 34% in mica minors, 4.1% in manganese miners, 30.4% in lead and zinc miners, 9.3% in coal miners, 27.2% in iron foundry workers and 55% in state pencil workers. Also asbestosis occurs in about 3% of asbestosis miners and 21% of mill workers in India. Also, it is estimated that about 28% to 47% of textile workers are exposed to dust and suffer from byssinosis. Broadly, environmental diseases could be caused by exposure to harmful and toxic agents through air, water, soil and food. Environmental exposure can cause or aggravate a number of diseases like asthma, dermatitis, etc. In many cases these disease do not have a unique presentation and can present to different specialties. Environmental diseases occurring through air pollution are a major cause of concern and their prevalence is increasing. The important environmental pollution consists of air pollution, water pollution and the recent emergence of Ewaste which may be the crux of environmental diseases. AIR POLLUTION Air pollutants affect the human body through the inhalational route. There are more than hundred substances which pollute the air we breathe and that can harm human health. Pollutants are generally classified as primary or secondary pollutants. Chemicals which are directly emitted from a source are known as primary pollutants. These include sulphur dioxide, nitrogen oxides, carbon monoxide, volatile organic compounds, etc. Also particulate matter emitted due to combustion from a source such as automobile exhaust, heating, cooking and from industrial sources are primary pollutants. Secondary pollutants are those pollutants that are formed from a chemical or photochemical reaction in the atmosphere. On exposure to sunlight volatile organic compounds and nitrogen oxides reacts photochemically and after a complex series of chemical reactions produces pollutants which are harmful. Ozone is an important secondary pollutant and can produce significant adverse effects on human health. Other secondary pollutants include formaldehyde, nitric acid, and different aldehydes. Sulphur Dioxide Sulphur dioxide is produced mainly by burning of coal and by the combustion of fossil fuels in power plants. Sulphur dioxide is mainly absorbed in the upper airways as it is water soluble. Some of it reaches the lower airways and causes bronchoconstriction. It can therefore worsen asthma. Nitrogen Dioxide Nitrogen dioxide is emitted from automobiles. Nitrogen oxides play an important role in the reaction which occurs in the atmosphere and leads to the formation of ozone. They also form nitrate particles and acid aerosols. Exposure to nitrogen dioxide for a short term leads to changes in airway responsiveness

Carbon Monoxide Carbon monoxide is produced mainly due to motor vehicle emission. In urban areas more than 80% of carbon monoxide emission may be due to motor vehicles. Besides this, the combustion of coal, oil and gas also leads to carbon monoxide production. Carbon monoxide quickly enters the blood stream and forms carboxyhaemoglobin which causes more systemic effects. It reduces oxygen delivery to the tissues and may have a serious health threat to those with underlying heart disease. Lead The atmospheric levels of lead have decreased due to the use of unleaded fuel. However, lead toxicity continues to be a problem due to the exposure occurring in drinking water. Lead exposure leads to adverse effect on the central nervous system, kidney and liver. Lead toxicity can lead to lower intelligence, learning deficits and behavioural disturbances. Ozone Ozone is produced as a secondary pollutant and is a component of photochemical smog. Ozone is a pulmonary irritant and an oxidant. Exposure to ozone causes cough, chest tightness and wheezing. It also leads to a decline in lung function. Ozone also affects mucous membrane and causes pulmonary inflammation and has both a local and systemic effect on immune system. Patients with underlying respiratory illness like asthma and chronic obstructive airway disease are more prone to the harmful effect of ozone. High ozone concentrations have been linked with increased hospital admissions for pneumonia, COPD and asthma. Particulate Matter Particulate matter consists of liquid or solid mass contained in an aerosol. It is a mixture of numerous different chemicals with varying properties. Particulate matter was initially expressed as total suspended particulates (TSP). Subsequently the term PM10, i.e. suspended particulates with a mean aerodynamic diameter of 10 microns or less was used. It was later realised that still finer particulate matter can be harmful and the term PM2.5, i.e. particulate matter with a mean aerodynamic diameter of 2.5 or less was used. Broadly particulate matters from 2.5 microns to 10 microns in diameter are coarse particulate matter. Coarse particulate matter consists of mainly of airborne soil dust and elements such as silicon and aluminium. Fine particles are those with a diameter of less than 2.5 microns. They are formed mainly from combustion or from photochemical reactions and are composed mainly of sulphate and organic material. Particles of more than 10 microns are mainly filtered in the upper airways and do not reach the lower airways. Smaller particles between 2.5 microns to 10 microns reach the lower airway and are deposited there. Particles less than 2.5 microns go deeper and reach the alveolar region and cause damage in this area. Indoor Air Pollution Indoor air pollution has a significant effect on human health globally. This effect is more pronounced in developing countries. It is estimated that more than 60% of households in India use biomass fuels as energy source. Wood, roots, crop residue, cattle

dung are amongst the biomass substances used for energy source. Biomass cooking converts 6% to 20% of the fuel carbon to toxic substances due to poor combustion. The harmful air pollutants that are emitted by using biomass fuel include carbon monoxide, particulate matter, hydrocarbons, oxygenated organics and chlorinated organic compounds. There is now a strong evidence linking indoor air pollution exposure to a number of illnesses especially lung diseases. Indoor air pollution is linked to acute lower respiratory tract infection. In adults there is a strong association of indoor air pollution and chronic obstructive lung disease especially in women who start cooking in rural areas at an early age. Also, there is evidence to suggest that biomass exposure in pregnant women may lead to an increase in low birth weight neonates and increased chance of still births.There is also some epidemiological evidence linking exposure to indoor air pollution to lung cancer and tuberculosis although the association is not that strong. Biomass exposure also significantly contributes to fine particulate matter exposure, i.e. PM2.5. Exposure to PM2.5 may lead to a higher chance of lower respiratory tract illness and still births in pregnant women. WATER POLLUTION Water is essential for human survival. Water pollution constitutes another serious risk to health. Water pollution occurs when energy and substances are released and that degrades the quality of water for other users. Anything that is added to water that is more than its capacity to break it down constitutes water pollution. Chemical pollution of surface water causes major health problems as it can be used directly for drinking or it may contaminate shallow wells which are used for drinking. Usually, it is human action which is responsible for water pollution, although it may occur naturally as happens when water flows through soil with high acidity. Ground water, which is much deeper, has very few pathogens as it gets filtered when it passes through many underground layers. It can be polluted by toxic chemicals like fluoride and arsenic which may be present in the soil or the rock layers. Similarly, pollution of coastal water can cause contamination of sea food. The global effect of water pollution has not been studied in detail, and is limited to mainly outbreaks of waterborne infections or certain chemical toxins in limited areas, i.e. arsenic in drinking water in Bangladesh, mercury poisoning in the United States, etc. Acute exposure to contaminated drinking water can cause inflammation to the eyes, skin and the gastrointestinal tract. Chronic exposure to contaminated water can cause significant health effects and can lead to liver and kidney damage. This occurs due to chronic exposure to copper, cadmium, arsenic, mercury, chromium and chlorobenzene. Endocrine effects have been reported and problems relating to reproduction, development and behaviour have also been observed.

Basic Considerations of Environmental and Occupational Diseases

and deterioration in pulmonary function in individuals with underlying lung disease. Long term exposure may lead to increased chance of recurrent respiratory tract infections and alter lung mechanics.

ELECTRONIC WASTE (E-WASTE) Pollution due to electronic and electrical waste has rapidly grown over the last decade. Waste which is generated from used electronic devices and household appliances constitutes E-waste. This waste comprises of a wide range of equipments and devices such as computers, mobile phones, refrigerators, washing machines, air conditioners, etc. E-waste may contain many toxic substances which may be harmful to the environment and human health. This can have a significant 1991

economic and social impact on society. The E-waste obsolescence rate in India for 2005 was estimated to be 1,46,180 tonnes, and it is estimated that this will exceed 8,00,000 tonnes by the year 2012. A large number of hazardous substances can be found in E-waste. These include lead, cadmium, chromium, mercury and plastics. Uncontrolled burning, disposal and dismantling of E-waste can cause a number of problems including air pollution and water pollution. There is a lack of an environmentally effective recycling infrastructure for E-waste and this leads to pollution of the environment. There is, therefore, a need to increase public awareness about the harmful effects of E-waste and develop an effective recycling and disposal plan to prevent or minimise air and water pollution. CONCLUSION It is important to understand that environmental and occupational health problems will have a number of acute and chronic effects on human health. This can be both for infectious and non-infectious illnesses. A holistic view is needed to address the problem of environmental health where agriculture, animal husbandry, public health, water safety and air pollution need to be looked at in a combined manner for education, planning

1992

and resource allocation. A close team work between scientists, public health professionals and administrators is needed for integrated vertical and horizontal planning. For clinicians an awareness about the health effects of pollution is important as this will help in the prevention and proper management of many diseases associated with both air and water pollution. RECOMMENDED READINGS 1.

Brrok RD et al. Air pollution and cardiovascular disease: a statement for healthcare professionals from Expert Panel on Population and Prevention Sciences of the American Heart Association. Circulation 2004; 109:2655-71.

2.

Brunekreef B, Holgate ST. Air pollution and health. Lancet 2002; 360: 1233-42.

3.

Cropper ML, Simon NB, Alberini A, Arora S, Sharma PK. Health benefits of air pollution control in Delhi. American Journal of Agricultural Economics 1997; 79:1625-9.

4.

IRGSSA (2004) Management, handling and practices of E-waste recycling in Delhi. IRGSSA India.

5.

Pope CA, Dockery DW. Health effects of fine particle air pollution: Lines that connect. Journal of the Air & Waste Management Association 2006; 56(6): 709-42.

27.2

Climate Change—Health and Disease

INTRODUCTION Our planet, Earth, which is some 4.5 billion years old, has been through at least 5-mass extinctions.The first extinction is known as Ordovician (439 million years back) and this was followed by Devonian (354 million years), Permian-Triassic (252 million years), Cretaceous-Tertiary (65 million years) and PaleoceneEocene Thermal Maximum (PETM) 55 million years ago. All these species extinctions are thought to be triggered by global climate change. The worst happened during the PermianTriassic extinction event, which is also known as ‘the great dying’, when some 90% of marine and 70% of land species were wiped out, consequent to a large scale build up of green house gases (GHGs) and a temperature rise of more than 8°C caused probably by a large scale volcanic eruption over Siberia. The most recent is the PETM, occurred some 55 million years ago as a result of sudden release of vast quantum of GHGs that triggered a surge in global temperatures of about 5°C to 8°C over a span of a few thousand years and lasted 100,000 years. The source of GHGs is speculated to have arisen from the destabilisation of beds of frozen methane hydrate sequestered at the ocean’s bottom. The release of frozen sea bed methane was probably triggered by an anomaly in the thermo haline circulation (THC) that pushed down warm waters leading to the release of sea bed methane (a green house gas with a warming potential 25 times of carbon dioxide). ANTHROPOGENIC CLIMATE CHANGE In the landmark study of temperature change, Charles Keeling in 1958 began recording monthly carbondioxide (CO2) levels at Mauna Loa observatory, atop a 3,970 m high extinct volcano in Hawaii. Measurements taken over the past 50 years reveal two superimposed trends. (i) A progressive rise in CO2 levels from 275 ppm in 1958 to 385 ppm at present, and (ii) Superimposed upon the rising CO2 curve, a sharp annual rise and fall in CO2 by about 50 ppm.This see-saw corresponds to the thickening and thinning of the photosynthesising green cover on account of seasonal shedding (winters) and gaining (summers) of green leaves in the Northern Hemisphere. This gave rise to the famous Keeling’s Curve: The annual seesaw atop a steadily rising CO2 concentrations. In parallel to the rising CO2 the average surface global temperature has already increased by 0.76°C above the pre-industrial levels and the sealevel by 4 cm (is rising at 3 mm/year). The Intergovernmental Panel on Climate Change (IPCC) was formed in 1988, it states that the evidence for global warming is unequivocal and is due to human activity (anthropogenic). The Green House Effect If our Earth lacked its gaseous atmosphere, all the incoming solar energy would be radiated back in to the space and the

Anil Gurtoo average surface temperature would plunge to –18°C. However, on account of the heat trapping effects of atmosphere, the Earth’s surface temperature averages at 14.4°C. This is called the ‘green house effect’. Out of the total sunlight that reaches earth: 1. About 30% gets reflected back to the outer space by reflectivity of bright surfaces such as low level clouds, dust, snow and ice. This reflective property of bright/white surface is called ‘Albedo’ and is a factor in cooling. Conversely, darker surfaces like ice-cleared sea absorb the incoming solar energy and are a factor in warming (low albedo). 2. More than 20% of sunrays are absorbed by the atmosphere mainly by water vapour. 3. The remaining 50% is absorbed by the Earth’s surface – land, forests and oceans. Of this 50% is absorbed by the Earth, a third or so is re-radiated back as infrared waves (heat waves). Most of this radiated infrared is absorbed by the green house gases (GHGs) present in the atmosphere, which then radiate some of it to the outer space and some back to the Earth, thus keeping the mean surface temperature warm at 14.4°C. The Green House Gases The main GHGs are CO2, methane, water vapour, ozone, nitrous oxide (N2O) and chlorofluorocarbons. Carbondioxide CO2 forms some 0.04% of the atmosphere and is the main green house gas. Its present concentrations are the highest ever recorded at 384 ppm, and rising by 1 ppm to 2 ppm per year as a consequence of human activities. Historical data from the 650,000 year old ice-core samples from Vostok, Antarctica reveal that atmospheric CO2 levels have always held constant between 180 ppm (during ice-ages) and 280 ppm for most of our Earth’s geological past. While the natural CO 2 is produced by the decomposition of dead organic matter and exhalations of humans and animals, the anthropogenic CO 2 is generated mainly by the combustion of fossil fuels (coal, oils and gas) and land clearing for agriculture. Of the total CO2 thus released to atmosphere, nearly 50% is absorbed back by the natural sinks: the oceans and the land (chiefly by plant photosynthesis) in an equal measure of 25% each. The remainder stays up in the air as a green house gas for nearly 100 years. Methane (CH4) It is a far more potent GHG with a warming potential 25 times that of CO 2. But its residence time is only 10 years and its atmospheric concentration has stayed low at 2 ppm. In nature it is produced from the livestock (aerodigestive processes), decaying organic matter, and the anthropogenic component is generated by: untreated sewage, industrial actions, rice 1993 cultivation, livestock rearing and land fills.

Water vapour Though a weak GHG, it acts mainly as a force multiplier through a positive feedback effect wherein, as the temperatures rise, more and more of vapour gets released due to enhanced evapotranspiration, this extra-vapour in turn further enhances the warming, which in turn further increases the amount of vapour. Such a spiralling signal enhancement (temperature rise) is termed as positive feedback effect. Ozone (O3) Ground level (harmful) ozone is produced when sunlight acts upon the aerosols present in the stagnant air masses and smog. It is this ground-level ozone that causes the excess cardiorespiratory mortality. Its concentration has stayed fixed at 0.03 ppm and has a residence time of only a few days. Quite the contrary, the high level (stratospheric) of ozone acts as a shield to the harmful UV light. It is here that its decrease (ozone hole) due to anthropogenic CFCs, leading to an increased influx of UV radiation. Nitrous oxide (N2O) It is present in concentrations of 3 ppm, but with a warming potential 300 times of CO2 and a residence-time of 300 years. In nature, it is produced mainly by lightening thunders and soil

Figure 1: The epidemiological triangle of climate change and its health effects.

1994

ENSO = EL-Nino Southern Oscillation; GHGs = Green House Gases.

bacteria, whereas, its anthropogenic sources lie in diesel based combustion and fertiliser use. Chlorofluorocarbons Produced as a result of human actions (refrigeration, aerosol products), these are extremely potent with warming potentials 124 to 14,800 times of CO2 (hydrofluorocarbons); 7,400 to 12,200 times of CO2 (perfluorocarbons); and 22,800 times of CO 2 (sulphur hexafluoride). They form around 1 ppm of the air but are extremely long lived. They have been responsible for the causation of ozone hole. HEALTH EFFECTS OF CLIMATE CHANGE The health impacts resulting from climate change can be framed in terms of an integrated model centred on the ‘epidemiological triangle’ is conceptualised in Figures 1 and 2. The key variables are displayed in Figure 1, while Figure 2 displays the ‘upstream domains’ which stress the epidemiological triad and destabilise it. The ‘downstream domains’ depict the health outcomes and their socioethical implications. Tipping Points A term that refers to a critical threshold, beyond which even a minor perturbation can lead to the emergence of a new state.

Climate Change—Health and Disease

Figure 2: Upstream and downstream domains responsible for destabilisation of epidemiologic triangle.

Once a tipping event is triggered after the crossing of the tipping point or threshold, there is no turning back, even if all the GHG emissions were to end. Lenton et al have identified several sectors of Earth’s ecological systems that might cross the tipping points leading to nonlinear outcomes including several orders of magnitude larger than predicted by current models (Table 1). PATTERNS OF CLIMATE SENSITIVE DISEASES The added burden of climate change sensitive diseases will further worsen the already existing health inequities creating enormous challenges to public health. Though complex and interdependent, for clarity’s sake, one could divide the resultant health outcomes as: (1) direct; and/or (2) indirect impacts of climate change. Direct Health Impacts Results from extreme weather events such as heat waves, sudden flooding, storms and cyclones, droughts and inundation due to

Table 1: Important Tipping Points in the Climate Change and their Consequences S. No.Tipping Event 1. 2. 3. 4. 5.

6.

7. 8.

Consequences

Loss of Arctic Summer Sea ice

Higher average global temperatures Greenland ice sheet meltdown Global sea level rise up to 7 m Collapse of West-Antarctic ice shelf Global sea level rise up to 5 m Increased frequency and intensity Increased droughts in of EI-Nino events South Asia and Africa Amazon rain forest die-back Massive species extinctions, decreased rainfall, massive loss of carbon-sinks Changes in Indian Monsoon Widespread drought System (Strengthening EI-Nino will weaken monsoons) Collapse of thermo Extremes of winters and haline circulation summers over Europe Thawing of Tundra’s Meltdown and release of permafrost frozen methane hydrates

1995

sea level rise. All of these events are set to increase in both amplitude and frequency as a consequence of climate change. A partial glimpse of some recent extreme events is given in Table 2. Table 2: Recent Extreme Events of the World Place

Event/Consequence

Andhra Pradesh heat wave, 2003

Killed 1,421 people

Orissa heat waves, 1998 & June 2005

June 2005, Bhuvaneshwar recorded a high of 46.3°C. In year 1998, the heat wave claimed >1,000 lives

Mumbai, India, July 2005

Heaviest rainfall ever recorded in a single day in the last 100 years: 944 mm.

Pan-India monsoon deficit Recurring Monsoon deficit-induced induced droughts serious droughts: 2000-2002, 2009. Cherrapunji, Meghalaya, 2005

The world‘s wettest place went through a rain deficit-induced drought

European heat wave, 2003 Caused 70,000 deaths

Scanning through the European heat mortality data, a question begins to form; how could a simple heat spell of 35°C to 40°C end up killing 70,000 people? Clearly, the heat wave need not have to be extreme in order to kill. This phenomenon of multiplier effect (disproportionately wider and stronger health impact) may well hold true for most other climate sensitive diseases. In the Europe of 2003, it was a combination of a sequence of hot days coupled with unusually hot and humid nights, cityscapes built for a cooler weather and a population culturally and physiologically un-acclimatised to heat that contributed to the multiplier effect. Indeed, most of the heat mortality seems to be a function of higher night time minimum temperature, duration of heat wave, pre-existing background vulnerabilities (extremes of age, cardiorespiratory disease and poverty), amount of ozone and PM10 in the near ground stagnant air pollution, and heat island effect. More than the day time maximum, it is the night time minimum which determines the degree of heat stress. According to IPCC, the 12 warmest years in the past 150 years have been during the last 13 years with 1998 being the warmest, followed by 2005, 2002, 2003 and 2004. Defining heat wave as a stretch of at least 5 days with highs of 5°C above average, IPCC estimates that the heat waves are likely to become more frequent and longer across most of the planet, especially towards the middle and upper-middle latitudes involving the central and southern Europe, the Western USA and Eastern Asia.

1996

windows and the geographic range of diseases such as malaria, dengue, chikungunya, yellow fever, filaria caused by mosquitoes and leishmaniasis by sand fly. 3. Their distribution is determined by ecological synergies between a set of variables such as temperatures, rainfall, humidity, flooding or drought, sea level rise, phytoplankton and algal blooms on sea surface, EL-Nino Southern Oscillation (ENSO) and changes in water salinity. Rodent migratory behaviour is often dictated by changes in food sources, cropping patterns, grain storage, flood or drought induced displacements. 4. The extrinsic incubation period of an infective agent within its vector is sensitive to changes in temperature and humidity. 5. If both the agent (Plasmodium) and the vector (Anopheles) are competent and robust in the newly warmed and humid climate, then both will multiply and spread very rapidly giving rise to sudden emergence of explosive epidemics. 6. Like the climate itself, malaria incidence too displays a nonlinear threshold—tipping point response in reaction to minor temperature changes. 7. The growth of mosquito and parasite population densities in response to warming can be several orders-of-magnitude larger than what the unit change in temperature would suggest. 8. Some scientist has demonstrated that, just half-a-degree centigrade increase in temperature can amplify into a 30% to 100% increase in mosquito population. 9. Likewise, the Lancet-UCL Climate Change Commission believes that a small increment in the risk for climatesensitive diseases such as diarrhoea, malnutrition, dengue, etc. could snowball into disproportionately large increases in total disease burden. 10. As regards to the possible epidemiologic behaviour of malaria in India, WHO estimates that: (a) 10% more states may offer breeding-favourable climatic conditions throughout the year with respect to base year 2000; (b) transmission windows for malaria are likely to increase in the North and North-Western areas from the present 4 – 6 months to 7 – 9 months; and that (c) by the year 2080, malaria may move up in altitude up to elevations of 1,800 m. 11. Dying or drying rivers often fragment into a series of stagnant pools that serve to increase mosquito breeding rates.

Indirect Effects on Health Climate-sensitive diseases share some epidemiologic commons. 1. They display indirect transmissions employing either a vector (mosquitoes, ticks, fleas, flies), or a vehicle (water or food borne).

12. Counter intuitively, a drought or drying may actually trigger mosquito-based epidemics. Drought and water shortages often trigger social behaviours that lead to increased water storage in household containers that increases the density of peri-domestic dengue transmitting Aedes mosquito. In fact, the chikungunya outbreak of 2004 that began in drought-affected Lamu in coastal Kenya and spread to India via the islands of Indian Ocean, also displayed climatesensitivity.

2. Insects being cold-blooded, a minor change in temperature can amplify into a large biologic effect on disease transmission. Therefore, climate change can act as a force multiplier and alter the incidence, seasonal transmission

13. Climate phenomena such as: EL-Nino events and the resultant sea surface warming are also linked with the emergence of cholera epidemics. Vibrio cholerae thrives in warm, saline sea waters in association with the floating

CLIMATE-SENSITIVE HEALTH BURDENS WHO believes that climate change has been responsible for 5.5 million disability adjusted life years (DALYS) lost in 2000 on account of diarrhoea, malaria, malnutrition and accidents due to extreme weather events. Heat Stress The IPCC in 2007 made projections that superimposed upon the global rise in mean surface temperature and there will be trend of extreme variability leading to frequent and intense heat waves. While the phenomenon of excess mortality resulting from heat waves is well recognised, warmer than average temperatures per se are also associated with higher mortality rates. Most of this vulnerability will be located in cohorts with poor adaptive capacities such as: the older age and the very young, the urban poor, those with chronic medical conditions (particularly, cardiovascular and respiratory diseases), and in the socially isolated. Infact Curiero and Mc Michael et al have characterised the relationship between temperature and mortality as a: ‘J-shaped curve’, such that the mortality increases with both colder and warmer temperatures beyond a certain optimal temperature at which it is the lowest. During the 2003 European heat wave, IPCC (2007) estimates that while France experienced 15,000 excess deaths, the total for Europe was estimated to be 35,000 excess deaths. Also IPCC expects a rise in frequency and intensity of global warming triggered extreme

weather events (cyclones, flash floods and droughts) which will adversely impact public health through a combination of direct and indirect effects. Changes in Climate-Sensitive Infectious Disease Burden Climate change is not likely to result in the emergence of new or unforeseen diseases but an exacerbation of the existing disease burdens engendered through a redistribution of the classic determinants of health such as air, water, food, shelter, temperature and humidity. Of particular concern are the vector borne diseases which are bound to expand across geographical range due to climate change-induced alterations. Malaria and Climate Change Climate change increases malaria transmission by amplifying growth enabling factors such as the optimum temperature windows between 15°C and 39°C for the favourable development of both the vector (mosquito) and the parasite (plasmodium). Global warming will ensure that the transmission windows for malaria will remain open for 10 to 12 months in much of the central, coastal and north-eastern India from the present duration of 6 to 7 months.

Climate Change—Health and Disease

blooms of zooplankton and phytoplankton (which themselves proliferate with the warming seas). In Bangladesh, seasonal plankton blooms in the Bay of Bengal are correlated with sea-surface warming and the emergence of cholera outbreaks. Few scientists reported a strong correlation of inter-annual variability of cholera with (1) sea surface temperatures in Bay of Bengal; (2) EL-Nino Southern Oscillation (ESNO); (3) the extent of flooding in Bangladesh over short periods of 7 years. Similar finding was also reported from Lima, Peru where EL-Nino induced winter time warming of 5°C during 1997-98, was correlated to >200% daily admissions for diarrhoea as compared with the baseline. In fact, they observed that with every 1°C rise in air temperature above normal, there was an 8% increase in hospital admission rates for childhood diarrhoea.

Ambient Air Pollution Tropospheric (ground level) ozone production is forecast to increase as a function of rising average temperatures (IPCC, 2007). Ozone is formed via sunlight driven photo-chemical reactions involving nitrogen oxides and hydrocarbon precursor aerosols. Warmer temperatures are known to amplify these ground level ozone generating reactions. Fossil fuel burning also worsens the particulate air pollution. Both ozone and particulate matter air pollution have been associated with increased risks of mortality and morbidity resulting from the respiratory and cardiovascular events (WHO, 2006). RECOMMENDED READINGS 1.

Commission on Social Determinants of Health, Final Report. Geneva:WHO; 2008.

2.

Duncan Clark. In: Robert Henson, editor. A Rough Guide to Climate Change; 2nd Ed. London: Rough Guides Ltd; 2008.

3.

IPCC. Climate change 2007: impacts, adaptation and vulnerability: contribution of working group II to fourth assessment report of the IPCC, New York: Cambridge University Press; 2007.

4.

Lancet and University College London Institute for Global Health Commission. Managing the health effects of climate change. Lancet 2009; 373:1693-733.

1997

27.3 Industrialisation and urbanisation have resulted in the deterioration of urban air quality. Amongst the environmental pollution, air pollution is most deleterious to the respiratory system as the pollutants are inhaled directly into the respiratory tract. The sources of air pollution are vehicular emissions and indoor industrial smoke. ‘Air pollution’ comprises of a diverse nature of chemical emissions including gaseous combustion products, volatile chemicals and aerosols (particulates). The most common pollutants are ozone, carbon monoxide, sulphur dioxide and nitrogen dioxide. OZONE Ozone gas is a very strong oxidant, reacting with biomolecules to form ozonides and free radicals. The ozone-induced inflammation is mediated from prostaglandins (PGE2, PGF2, TXB2), neutrophils, fibronectin, interleukin-6, cytokines, etc. These lead to increased airway permeability, macrophage function impairment leading to increased susceptibility to bacterial infection. Ozone has different health implications in stratosphere and troposphere. In the stratosphere (ozone layer) 10 to 15 km above the earth, ozone presents a critical barrier to solar ultraviolet radiation and prevention from skin cancers, cataracts, etc. Symptoms Ozone-induced illnesses include conjunctival irritation; lower respiratory tract irritation, cough and shortness of breath, wheezing, reduced tidal volume, nausea, malaise and headache. It also causes a peculiar type of pain which is substernal, mainly tearing or burning in character which is more severe during inspiration. Asthmatic children playing outdoors are roughly 20% to 40% more likely to suffer from asthmatic exacerbation. Ozone leads to impairment of pulmonary function and increased hyper-reactivity of airways. Persons at risk include asthmatics, chronic obstructive lung disease (COLD) and those who are active outdoors for prolonged periods like athletes, policemen, labourers, construction workers, etc. PARTICULATES More than 70% of the population in the world lives in areas with high particulate levels. The particulate air pollution is a heterogeneous classification of liquid and solid aerosols which include emissions from fuel combustion (coal, oil, and biomass), transportation and high temperature industrial processes. The large particles above 10 microns get deposited in the nasal and tracheobronchial regions and smaller particles less than 10 microns penetrate directly into the lungs. Symptoms Acute signs and symptoms include restricted activity, 1998 respiratory illnesses and exacerbation of asthma and chronic

Environmental Pollution Ashok A Mahashur obstructive pulmonary disease (COPD). The group at large-risk includes the elderly and persons with chronic heart and lung diseases. There is reduced pulmonary function leading to increased morbidity due to respiratory illnesses and cardiac illnesses. CARBON MONOXIDE Carbon monoxide (CO) exposure is usually high due to local accumulation of CO in heavy traffic. Indoor levels are generally low in the absence of strong indoor sources. Sources of CO exposure include inside passenger car, proximity to busy roads, constructions site parking areas and traffic tunnels. Their important contributors include traffic volume, traffic speed, and winter season. Health Effects Health effects are due to decrease in oxygen carrying capacity of blood and disruption of cytochrome function. The symptoms usually consist of headache, fatigue and flu-like symptoms. Risk groups include smokers and those with coronary artery disease (CAD), peripheral vascular disease and COPD. Adverse cardiac effects include decreased exercise capacity, arrhythmias, etc. SULPHUR DIOXIDE Sulphur dioxide (SO2) gas is formed during combustion of sulphur containing fuel (coal and oil). The major health effects are breathing difficulty, respiratory illnesses, alteration in pulmonary defences and aggravation of existing cardiovascular disease. Children, elderly persons and persons with asthma, cardiovascular disease and chronic lung disease are more susceptible to adverse health effects associated with SO 2. The SO2 reacts in the atmosphere to create sulphuric acid (H2SO4) and form acid aerosol (acid rain). NITROGEN DIOXIDE Nitrogen dioxide (NO2) is released from fossil-fuel combustion. It reacts in the presence of sunlight and VOCs to form ozone gas and contributes atmospheric reaction to the formation of nitrous and nitric acid aerosols. Health Effects It is absorbed in both large and small airways. Their high concentration (more than 200 ppm) is very dangerous causing lung injury, fatal pulmonary oedema and bronchopneumonia. Lower concentration causes impaired mucociliary clearance, particle transport, macrophage function and local immunity. AIR TOXICS Toxic air pollutants is a term applied to certain volatile chemicals, pesticides, herbicides, metals and radio nucleotides, released in atmosphere by various industrial processes. They reach the general population by direct pulmonary assimilation.

Diagnosis of respiratory illness related to ozone, NO2 particulates, SO2, diesel, and air toxics is clinical and presumptive, based on a history of elevated community pol-lutant levels, especially in combination with prolonged exposure outdoors with elevated workloads. The soft clues include an association with typical symptoms (ocular and upper respiratory irritation, chest pain, shortness of breath, cough, wheezing, nausea, malaise, headache), and signs (conjunctival and upper respiratory inflammation, pulmonary inflammation or infection, wheezing, prolonged expiratory phase).The chest pain associated with ozone exposure is characteristically exacerbated during inspiration and relieved during expiration, resulting in a decreased tidal volume. Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and diffusion lung capacity for carbon monoxide (DLCO) may be reduced and methacholine responsiveness may be increased. Differentiation from other common causes of respiratory illnesses is not well defined, and several aetiologies may contribute to an individual’s illness. Similarly, atmospheric concentrations of multiple pollutants often fluctuate simultaneously, making precise aetiologic differentiation rarely practical. INCINERATORS POLLUTION Particulate and gaseous emissions from municipal solid waste incineration depend on the waste stream composition and incinerator engineering and operation, but typically include heavy metals (Hg, Pb, As, Cd, Cr, Mn, Ni, Sb, Se, Zn, V ), polychlorinated dibenzodioxins, dibenzofurans, and polycyclic aromatic hydrocarbons, in addition to acid gases and oxides of nitrogen, sulphur and carbon. Batteries, fluorescent light bulbs, magazine dyes, papers, plastics are sources of metals; lead and cadmium are emitted mostly in the particulate fraction, while mercury is more in gaseous form. Incinerator ashes contain high concentrations of metals. Chlorine and fluorine are emitted as acid gases, and contribute to halogenated aromatic organic compound formation. Proximity to incinerators has been associated with local lead soil distribution; the association of dioxin exposure with incinerators is less consistent. The major route of dioxin ingestion is in animal fat foods (milk, eggs, animal flesh), although plant deposition and inhalation contribute small amounts. Dioxins have also contaminated herbicides which are widely sprayed along highways and rail-road rightof-ways. Nonetheless, cow’s milk may be more contaminated with dioxins near municipal solid waste incinerators. A recent ecological study found stomach and lung cancers to be elevated in communities near municipal solid waste incinerators in Great Britain. This preliminary and unconfirmed finding is an outcome of concern in light of parallel cancer elevations in a study of MSW workers. Increasing attention is being paid to dioxin and mercury emissions from medical waste incinerators. DIESEL AND AUTOMOBILE EXHAUST/HEALTH EFFECTS Diesel exhaust contributes to ambient sulphur oxides, ozone precursors, and aerosols, seems to contribute to chronic respiratory morbidity and mortality and probably contributes to the cancer risk of urban air pollution. Mutagenic and carcinogenic compounds (such as PAHs) are adsorbed to diesel soot.

In humans, occupational case control and cohort studies have found a small but generally consistent association of prolonged exposure to high diesel concentrations, when adjusted for cigarette smoking, with a relative risk (RR) of lung cancer incidence of 1.4 to 1.7 in the best studies. While most studies have problems with exposure assessment, wide confidence intervals and low effect magnitude. A recent meta-analysis of over 20 studies examining occupational exposure to diesel exhaust, confirmed a statistically significant RR of 1.33 for lung cancer, with adjustment for cigarette smoking.

Environmental Pollution

Diagnosis

Heavy exposure to diesel is clearly associated with pulmonary inflammation, with some evidence of increased incidence of respiratory symptoms (cough, phlegm, and wheezing) and small work shift pulmonary function decrements; heavily exposed cohorts may have elevated risks of mortality from chronic lung disease (COPD and respiratory infection). Acute Respiratory Effects Four acute respiratory effects of air pollution are well established; asthmatic attacks, hyper-reactive airways, respiratory infections, and reversible changes in lung functions. Asthma is a condition in which the airways suddenly narrow, obstructing the flow of air through the lungs. The narrowing is caused by spasms of the small muscles that encircle the airways and by the release of thick, excessive mucus that plugs them. Air pollution can bring on asthmatic attacks. Attacks have also been associated with ozone and particulate pollution. In areas surrounding power plants and smelters, SO 2 and sulphate particulates cause bronchospasm. It is not known whether air pollution can actually cause asthma or whether it only triggers asthmatic attacks. Hyper-reactive airways are those that constrict much more readily than average in response to foreign matter. Unlike asthma, some constriction of the airways is a normal defence mechanism to prevent inhaling noxious substances in persons with hyperreactive airways.The airways respond to levels that do not bother most people. The symptoms are similar to asthma—shortness of breath, coughing, and wheezing. SO2 particulates, ozone, and NO are known to stimulate airway reactivity. The incidence of respiratory infections, particularly in children, is increased by air pollution. Upper respiratory infections, such as cold, influenza and sore throat are associated with sulphate, sulphur dioxide, and particulates in outdoor air. NO2 released indoors by cooking gas stoves, is associated with more frequent cold in children under the age of 10 compared with children who live in homes equipped with electric appliances. Animal studies show that concentrations of ozone and NO2 typical of peak pollution episodes lower the resistance to bacterial infections such as pneumonia and acute bronchitis. Air pollutants disable the clearance mechanisms that remove viruses and bacteria from the respiratory tract and incapacitate the cells that fight the infections. Short-term, reversible changes in lung function are also caused by air pollutants. For example, the maximum amount of air that can be inhaled or exhaled in one second is reduced in both children and healthy adults when exposed to elevated pollutant concentrations, but this returns to normal when exposure ceases. Whether such changes indicate that long-term damage is being done is not known at present. 1999

Chronic Respiratory Effects The two chain effects of long-term exposure to air pollutants, aside from lung cancer, are COPD and changes in the development and ageing of the lungs. COPD is actually a group of diseases that share the common symptoms of breathlessness. Because a clear-cut diagnosis is often impossible until after death, the conditions are grouped together. The group includes chronic bronchitis, emphysema, and small airways disease. Chronic bronchitis involves the persistent secretion of excessive amounts of mucus into the airways; its leading symptom is a lasting phlegmatic cough. Emphysema is a destruction of the wall of the air sacs (alveoli) and is indicated by breathlessness without cough. Small airway disease involves inflammation and narrowing of the smallest airways (bronchioles) and is the earliest sign of smoking-induced COPD. These diseases can appear separately or together. The long-term survival is influenced strongly by how susceptible the individual is to respiratory infections such as influenza and pneumonia. About 10 million people in the United States of America are afflicted with COPD. The main causes of COPD are smoking, occupational exposures to such substances as coal and cotton dusts, high concentration of SO2, and particulates and genetic factors. Air pollution plays a role in several ways. Some evidence suggests that a history of respiratory infections during childhood may contribute to pulmonary disease in old age, and as previously mentioned, air pollution increases childhood infections. Air pollution has been linked to COPD in recent studies of Mormons, a group with a very low rate of smoking. The longer and greater the exposure to outdoor levels of SO2 and sulphate particulates, the more prevalent and severe the disease symptoms. Studies in laboratory animals have shown that long-term exposure to NO2 and ozone causes destruction of alveolar walls, similar to emphysema. Lung growth is also affected by air pollution. The lungs typically grow until the age of 20, and then slowly decline in their ability to hold air with age. Slowed rates of lung growth have been observed in children aged 6 through 12 exposed to certain indoor air pollutants. The changes are greatest in homes with smokers. A smaller adult lung size means less reserve against the inevitable shrinkage of the lungs with old age and against the onset of obstructive pulmonary disease, which occurs more commonly at older ages. Lung Cancer Cancer of the lung is the leading fatal cancer among both men and women, responsible for over one-fourth of all cancer deaths. Smoking is the major cause of lung cancer. Air pollution causes some fraction of lung cancers, but exactly how much is in

2000

dispute. Some experts contend that air pollution causes only a small percent of all cases, while others argue that it is 20% or more. It is clear that carcinogenic compounds are present in indoor air and polluted outdoor urban air. Chemical analysis of air show the presence of cancer-causing by-products of burning such as benzo-[a]-pyrene and dioxins, fibres such as asbestos, and metals such as arsenic and cadmium. Toxicological studies show that extracts of polluted air can produce lung tumours in mice, rats, and hamsters and cause injury to the genetic material deoxyribonucleic acid. Studies in human populations have found increased cancer rates around smelters and factories, in cities compared to rural areas, and with duration of exposure to pollution. The major question has been to what extent these materials alone have caused cancer compared with tobacco smoke. Tobacco smoke interacts synergistically with other carcinogens, including radon, asbestos, arsenic, and alcohol, to increase the underlying cancer risk. Many people who have never smoked are exposed passively to tobacco smoke either at work or at home. These and other problems blur the role of air pollutants in producing lung cancers. Nevertheless, there are estimates that between 5,000 and 20,000 cases of lung cancer per year are caused by radon, with most cases occurring among smokers. Non-Respiratory Effects Air pollution affects organs in the body other than the lungs. Once inhaled, pollutants can be absorbed into the blood stream and can reach all areas of the body. Air-borne lead has caused nervous disorders in children, including learning disabilities and hyper-activity, kidney damage leading to high blood pressure in both children and adults and outright poisoning. Lead levels have dropped dramatically in the last 15 years as leaded gasoline has been phased out, but deposits on the ground from earlier years are a lingering source of exposure. Benzene is a cause of leukaemia in rubber and chemical workers and is present in the air from refinery operations and gasoline combustion. Benzene in outdoor air has been attributed to cause cancer. Various other organic solvents are associated with nervous system disorders in workers, but again, concentrations are so low that it is difficult to ascribe any particular cases to such exposures. CO may play a part in the development of ischaemic heart disease, in which the heart muscle does not get enough oxygen over long periods and its tissues slowly die. Similarly, the added strain on the heart and lungs caused by a lack of oxygen during peak CO episodes when smoking cigarettes or when stuck in rush hour traffic may trigger heart attacks. While evidence of CO playing a widespread role in heart diseases is not conclusive at the moment, most experts think it is possible.

27.4

Air-Borne Pollutants and Smoke-Related Hazards Rajeev Gupta

INTRODUCTION Environmental toxins are major risk factors for disease. The Global Burden of Diseases Study has reported that unsafe water, sanitation and hygiene, indoor smoke from solid fuels and smoking tobacco use are the leading risk factors for mortality and disease burden, especially in low income developing countries such as India (Table 1). Urban outdoor air pollution, lead, global climate change, risk factors for injury, industrial carcinogens, air-borne particulates, ergonomic stressors and noise are other important environmental and occupational risk factors. In this chapter, we shall focus on some of these factors— outdoor air pollution, indoor air pollution from solid fuels, environmental tobacco smoke, occupational particulate matter and common industrial toxins.

studies, and the second American Cancer Society Prevention Study reported an increase of 3% to 6% in mortality for every 10% change in air-pollution levels in USA. Pollutants are generated from power plants, industrial complexes, automobiles and other vehicles and none of the pollutants occur in isolation. Pollutants change by chemical reactions after being emitted. Sulphur oxide can convert to acid sulphates and oxides of nitrogen and oxidants from automobiles react with sunlight to produce ozone. The symptoms and disease associated with air pollution are the same as conditions associated with smoking. Respiratory infections in children are associated with chronic exposure to traffic-related gases and respirable particles. Studies in urban locations in developed countries have reported higher

Table 1: Risk Factors for Mortality and Burden of Disease Globally and in Developing Countries (Global Burden of Diseases Study) Rank

Global

Developing Countries, e.g. India

Mortality

Burden of disease

Mortality

Burden of disease

1.

High blood pressure

2. 3.

Smoking and tobacco use High cholesterol

Childhood and maternal underweight Unsafe sex High blood pressure

Childhood and maternal underweight Unsafe sex High blood pressure

4.

Smoking and tobacco use

Unsafe water, poor sanitation and hygiene High cholesterol Smoking and tobacco use

7.

Childhood and maternal underweight Unsafe sex Low fruit and vegetable intake High BMI

Childhood and maternal underweight Unsafe sex Unsafe water, poor sanitation and hygiene Indoor smoke from solid fuels

8.

Physical inactivity

9. 10.

Alcohol Unsafe water, poor sanitation and hygiene

Indoor smoke from solid fuels Iron deficiency High BMI

5. 6.

Alcohol Unsafe water, poor sanitation and hygiene High cholesterol

Indoor smoke from solid fuels Low fruits and vegetable consumption Iron deficiency anaemia Vitamin A deficiency

Zinc deficiency Iron deficiency anaemia Vitamin A deficiency High blood pressure Smoking and tobacco use High cholesterol

BMI = Body mass index.

OUTDOOR AIR POLLUTION Air pollution is an important determinant of population health. The World Health Organization (WHO) estimates that, at the global level, 1.4% of all deaths and 0.8% of disability-adjusted life years are the result of particulate air pollution. The shortterm health effects of particulate and gaseous air pollutants have been well documented. A combined analysis of data from 124 large cities in Europe and North America reported an estimated increase in rate of deaths from any cause ranging from 0.2% to 0.6% for an increase in ambient small particle (PM2.5) concentrations of 10 microgram per cubic metre. The long-term effects of exposure to major air pollutants (particulate matter, ozone, sulphates, sulphur dioxide, nitrous oxides, and carbon monoxide) have been well-documented in large cohort

cardiopulmonry hospitalisations and mortality. Pubic health measures such as stricter ambient air quality standards, publicising pollution alerts and avoidance of polluted areas have been useful to prevent and control the ill-effects of outdoor pollution. INDOOR AIR POLLUTION Indoor air pollution is due to widespread use of unprocessed solid fuels (biomass and coal) for cooking and space heating in India and other developing countries, often in unventilated situations. The 1991 Indian Census, for the first time, asked a question about the primary household fuel used and reported that at a national level 81% of households primarily used biomass fuel (dung, crop-residues and wood). 2001

High pollutant concentrations result from emission factors from such fuels in simple small scale combustion devices and frequently result in high indoor air particulate concentrations that could lead to PM10 concentrations of more than 2,000 μg/ m3 in some households. It has been estimated that 400,000 to 550,000 premature deaths can be attributed annually to the use of such biomass fuels and indoor air pollution in India, mainly due to acute respiratory infections, chronic obstructive pulmonary disease (COPD), lung cancers, pulmonary tuberculosis, asthma and coronary artery disease (CAD) (Figure 1). This pollution also leads to frequent upper airways infections in subjects with and without underlying COPD and is a leading cause of disability-adjusted life years (DALYs) and high person sick-days in India. The pollution levels are more in urban than rural locations but can be very high in individual households. Exposure is not only the number of people involved, but also a function of frequency and duration of contact-person hours of exposure.

At the global level, India seems to have some 30% of all household solid-fuel stoves, although the estimates are generally much less reliable than in India where fuel use is determined in the national census. On that basis, the total world health impact on women and children would be roughly three times larger than the Indian estimates. The alarming scale of toxicity of indoor air pollution argues for additional efforts to understand and ameliorate the conditions that lead to such severe pollution levels in the village and urban slum homes of India and elsewhere in the Third World. At the very least, they call for a serious effort to conduct the medical and abatement research that would pin down more accurately the impact of pollution and effective ways to reduce it. ENVIRONMENTAL TOBACCO SMOKE Smoking is rampant among Indian men and environmental tobacco smoke (ETS) should be an important health issue (Figure 2). The health hazards due to exposure to ETS are increasingly being established. ETS contains thousands of chemicals including 43 known carcinogens. Known health effects of ETS exposure are lung cancer in non-smokers, childhood disorders such as bronchitis, and perhaps, heart disease. Workplace exposure to ETS is widespread and is influenced strongly by the type of smoking policy in the workplace. To decrease ETS exposure, efforts to restrict public smoking have proliferated over the past decades. These restrictions have emanated from government as well as voluntary measures by various private industries. Ban on public smoking are effective in reducing non-smokers’ exposure to ETS. Workplace smoking bans also influence the intensity of smoking among employees and may increase quit smoking rates. In addition to the health benefits from smoke-free workplaces, there are likely cost savings to employers who implement such policies.

Figure 1: Estimated distribution of causes of annual death burden of 400-550 thousand due to indoor air pollution in India. ARI = Acute respiratory infections; COPD = Chronic obstructive pulmonary disease; TB = Tuberculosis; CAD = Coronary artery disease.

Salient features of indoor pollution in India and many developing countries as compared to developed countries are: (i) the biomass fuels produce relatively more organic compounds (e.g. benzene, formaldehyde, 1, 3-butadiene, polyaromatic hydrocarbons) and fossil fuels produce more sulphur oxides; (ii) chemical characteristics of the particles produced by biomass combustion are different; (iii) indoor pollutant concentrations are more during the day (because of household cooking) and place women and young children at greater risk; (iv) exposure levels in poorly ventilated biomass fuel areas are 10 to 50 times greater than urban outdoors in developed countries; (v) people exposed to indoor pollution in India are the poorest, most stressed and youngest as compared to other countries; (vi) implications on long-term health are unclear; (vii) misclassification of outcomes due to confounding by smoking exists; (viii) the attributable risk of indoor pollution on health outcome is difficult to quantify; (ix) there are no large scale data on the level of indoor air pollution in India using systematic sampling strategies; and (x) the estimates of mortality and DALYs are not well-defined. Therefore, it is essential that larger studies be conducted in India and other developing countries to better assess the role 2002 of indoor pollution.

Figure 2: Age-specific prevalence of smoking among men and women in India (National Family Health Survey-2).

ETS is also an indoor pollutant. Increases in prevalence of respiratory illnesses and reduced level of pulmonary function, measured by simple spirometry, are found in children of smoking parents. Recent meta-analyses for lung cancer and cardiopulmonary diseases, combining data from the best of ETS exposure studies suggest a 25% increase in relative risk. OCCUPATIONAL INORGANIC AND ORGANIC DUSTS Table 2 shows the broad categories of chemical and biological substances that are related to occupations and can lead to

Occupational Exposures

Respiratory Diseases

Inorganic dusts Asbestos: Mining and processing

Asbestos related fibrosis, pleural disease, cancer, mesothelioma

Silica: Mining, stone cutting, sandblasting, quarrying

Fibrosis (silicosis), progressive massive fibrosis, cancer, silicotuberculosis, COPD

Coal: Mining

Fibrosis (coal workers pneumoconiosis), progressive massive fibrosis, COPD

Beryllium: Processing alloys

Acute pneumonitis, chronic granulomatous disease, cancer

Other metals: Aluminium, chromium, cobalt, nickel, titanium, tungsten

Acute pneumonitis, lung cancer, asthma, etc.

Organic dusts Cotton dust: Milling, processing

Byssinosis, chronic bronchitis, COPD

Grain dust: Farmers, milling, bakers

Asthma, chronic bronchitis, COPD

Other agricultural dusts: Fungal spores, vegetable products, insect fragments, animal dander, bird and rodent faeces, endotoxins, microorganisms, pollens

Hypersensitivity pneumonitis, asthma, chronic bronchitis

Wide variety of industrial chemicals and toxins

Bronchitis, emphysema, etc.

pulmonary disease. Multiple agents are responsible for such occupational lung diseases but in India only a few toxins such as asbestos, silica, coal-dust, cotton-dust, grain dust and other toxic chemicals are important. Asbestosis One important pulmonary disease is due to asbestos and several different mineral silicates including chrysolite, amosite, and anthophyllite. In addition to workers involved in mining, milling and manufacturing of asbestos, those involved in construction trades are also exposed. Community exposure can result from use of asbestos containing mine or mill-tillings such as landfills, road surface or playground material. In India, asbestos has been used extensively since mid-1900s and it is only recently that it is being replaced by synthetic mineral fibres such as fibreglass or slag wool. The major health effects from exposure to asbestos are pleural and pulmonary fibrosis and cancers of the respiratory tract, pleura and, rarely, peritoneum. Asbestosis is diffuse interstitial fibrosis that is directly related to intensity and duration of exposure. Usually moderate to severe exposure of more than 10 years is required for disease to become manifest and can occur following exposure to any asbestiform fibres. The disease resembles other forms of diffuse interstitial fibrosis with decrease in lung volumes and diffusing capacity. Chest radiographs can be used to detect a number of manifestations of exposure such as parietal pleural plaques. Interstitial disease causes linear opacities in lower lung fields, which then spread to middle and upper zones. High resolution CT scan of lungs shows distinct changes of subpleural curvilinear opacities 5 mm to 10 mm parallel to pleural surface. There is no specific therapy and supportive care is similar to other interstitial lung diseases. Lung cancer (of all histological types) is the most frequent cancer associated with asbestos exposure. A minimum latency of 15 to 19 years is reported between first exposure and the disease. Use of CT scan for screening high risk individuals is being evaluated. Mesotheliomas are also associated with asbestos exposure. Relatively short asbestos exposures for 10 years of exposure persons with recurrent symptoms develop obstructive lung disease. Grain dust exposure is common in India, but the exact data of illnesses due to this exposure are not available. The presence of obstructive airways disease in grain dust workers is similar to smokers with persistent cough, dyspnoea and wheeze. Farmer’s lung is due to exposure to moldy hay containing spores of thermophilic actinomycetes. In UK, the disease occurs in 10 to 50 per 1000 farmers; reliable data are not available in India. Acute Farmer’s lung presents as fever, chills, malaise, cough and dyspnoea without wheezing, 4 to 8 hours after exposure and is diagnosed by history of exposure. In chronic disease, there is history of repeated attacks after exposure and patchy fibrosis can occur in lungs. For those patients who present with hypersensitivity pneumonitis, a careful inquiry about occupation, hobbies or other home environmental exposures is necessary to uncover the source of aetiological agent.

2004

OCCUPATION-RELATED HYPERSENSITIVITY PNEUMONITIS These conditions are also known as extrinsic allergic alveolitis and are due to inflammation of alveoli and terminal airways in susceptible hosts by repeated inhalation of a variety of organic agents (Table 3). Causes of hypersensitivity pneumonitides are typically designated by colourful names denoting occupational risk associated with the disease. The frequency of these conditions varies with the environmental exposure and the specific antigen involved. The diseases are immune-complex mediated reaction and cell-mediated hypersensitivity is important. The early reaction is characterised by infiltration of polymorphs in alveoli and small airways and T-cell mediated mononuclear cell infiltration leading to granuloma formation occurring later. The clinical picture is that of an interstitial pneumonitis which varies from patient to patient. The presentation can be acute, subacute or chronic and at times the diagnosis may be difficult. These conditions need to be differentiated from collagen vascular diseases, drug-induced lung diseases and sarcoidosis.

Table 3: Examples of Occupational Exposure-Related Hypersensitivity Pneumonitis Disease and Occupational Exposures

Antigen and Source

Bagassosis Bird fancier’s lung

Thermophilic actinomycetes; sugarcane Parakeet, pigeon, chicken, turkey proteins; avian droppings or feathers Contaminated sewage; Cephalosporium

Cephalosporium pneumonitis Cheese washers’ lung Chemical workers’ lung Compost lung Detergent workers’ lung Farmers’ lung Furriers’ lung Humidifier or air-conditioner’s lung (ventilation pneumonitis)

Malt workers’ lung Miller’s lung Miscellaneous medications

Mushroom workers’ lung Potato riddlers’ lung Streptomyces albus lung Suberosis Thatched roof disease Tobacco workers’ disease Winegrower’s lung Woodworker’s lung

Penicillium casei; moldy cheese Isocyanates; polyurethane foam, varnishes, lacquer Aspergillus; compost Bacillus subtilis enzymes; detergent Thermophilic actinomycetes; moldy hay, grain, silage Animal fur dust; animal pelts Aureobasidium pullulans, Candida albicans, Thermophilic actinomycetes, mycobacterium spp, etc. Contaminated water in humidification or air-conditioning systems Aspergillus fumigatus or A. clavatus; moldy barley Sitophilus granarius; infested wheat flour Amiodarone, bleomycin, efavirenz, gemcitabine, hydralazine, hydroxyurea, isoniazid, methotrexate, paclitaxel, penicillin, procarbazine, propranolol, riluzole, sirolimus, sulphasalazine Thermophilic actinomycetes; mushroom compost Thermophilic actinomycetes; moldy hay around potatoes Streptomyces albus; contaminated fertiliser Penicilium gabratum; cork dust Saccharomonospora viridis; dried grasses and leaves Aspergillus spp; mold on tobacco Botrytis cinerea; mold on grapes Wood dust, Alternaria; oak, cedar, pine and mahogany dusts

CLINICAL FEATURES The exact magnitude of the problem is unknown but there is no question that large numbers of individuals are at risk for developing serious respiratory disease as a result of environmental and occupational exposures. For example, for populations over age 15, 15% to 20% of the burden of asthma and COPD is estimated to be due to occupational factors in USA. In India, the burden may be greater given the high level of exposure. The patient’s history is of paramount importance in assessment. Detailed inquiry into specific work practices is required and temporal association of exposure at work and symptoms provides clues to occupation-related diseases.

Many mineral dusts produce characteristic alterations in the mechanics of breathing and lung volumes that indicate a restrictive pattern. Exposure to organic dusts or chemical agents may result in occupational asthma or COPD. Measurement of FEV1 before and after a working shift can be used to detect a bronchoconstrictive or acute inflammatory response. Chest radiograph is useful for detecting and monitoring the response to mineral dusts, certain metals and organic dusts which are capable of inducing hypersensitivity response. The International Labour Organization International Classification of Radiographs of pneumoconiosis classifies chest radiographs according to the nature and size of opacities and extent of pulmonary involvement on a 12-point scale. Small rounded opacities are seen in silicosis and coal-worker’s pneumoconiosis and linear opacities in asbestosis. Chest radiograph is insufficient to diagnose extent of the disease in a given patient and CT scan of the chest (regular and high resolution) has improved the sensitivity of identification of diffuse parenchymal abnormalities. Other procedures that may be of use are identification of heavy metals in urine; skin prick testing or specific IgE antibody titres for evidence of immediate hypersensitivity; specific IgG precipitating antibodies for agents causing hypersensitivity pneumonitis; or assays of specific cell-mediated immune responses. Sometimes, a bronchoscopy to obtain

bronchoalveolar lavage fluid and transbronchial biopsy of lung tissue may be required for histological diagnosis and differentiation from specific forms of lung diseases and infections. Rarely, video-assisted thoracoscopic surgery to obtain a larger sample of lung tissue may be required for specific diagnosis. CONCLUSION Environmental health issues, especially lung diseases, are a major cause of disability and death in India. Despite a large number of legal provisions, the numbers are enormous and it has been estimated by the International Labour Organization that more than 400,000 people die every year due to work related problems including accidents, injuries and chronic diseases. Management of these diseases is currently limited to the prevention and treatment of symptoms and pulmonary manifestations. Increased awareness of the disease conditions, adequate preventive measures and timely interventions are critical to control these diseases.

Air-Borne Pollutants and Smoke-Related Hazards

History provides of exposure to potentially toxic agents at home, hobbies, exposure to second hand smoke, and proximity to traffic and industrial facilities should be obtained. The physical examination of patients with suspected environmental lung diseases may help to differentiate the nature and severity of the pulmonary condition. Unfortunately, these findings do not point to the specific causative agent and other information must be used to arrive at the aetiological diagnosis.The investigations include pulmonary function testing and chest imaging. Measurement of exposure is included if reliable environmental data are available.

RECOMMENDED READINGS 1.

Ezzati M, Lopez AD, Rodgers A, Hoorn SV, Murray CJL, and the Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet 2002; 360:1347-60.

2.

International Labour Organization. Guideline for the Use of ILO International Classification of Radiographs for Pneumoconiosis. Geneva. International Labour Office; 2002.

3.

Jha P, Jacob B, Gajalakshmi V, Gupta PC, Dhingra N, Kumar R, et al, for the RGI-CGHR Investigators. A nationally representative case-control study of smoking and death in India. N Engl J Med 2008; 358:1137-47.

4.

Mandal AK. Strategies and policies deteriorate occupational health situation in India: a review based on social determinant framework. Ind J Occup Environ Med 2009; 13:113-20.

5.

Pandita S. Status of occupational safety and health in India. Available at: http://infochangeindia.org/index2.php?option=com_content&do_pdf =1&id=7722.

6.

Smith KR. National burden in disease in India from indoor air pollution. Proc Natl Acad Sci USA 2000; 97:13286-93.

7.

Speizer FE, Balmes JR. Environmental lung disease. Harrison’s Principles of Internal Medicine; 17th Ed. New York: McGraw Hill; 2008: pp. 1611-9.

2005

27.5 INTRODUCTION Drowning is defined as a process resulting from suffocation by submersion/immersion in a liquid, usually water. Near drowning is defined as survival of the victim, at least temporarily, after suffocation by submersion in water. Drowning accounts for nearly 150,000 deaths annually worldwide, including approximately 6,000 fatalities in the United States of America. Near drowning events are estimated to occur many times more than reported drowning deaths. There are approximately 2 million survivors after a drowning event, annually, worldwide. Drowning remains one of the common causes of accidental death worldwide and continues to be associated with high morbidity and mortality. The American Heart Association in its resuscitation guidelines suggests, that the term ‘drowning’ should refer to a mortal submersion event in which the victim dies within 24 hours, while the term ‘submersion injury’ should be used till the time of drowning-related death. In this classification scheme, the term ‘near-drowning’ has been abandoned. A swimmer may fall victim to drowning because of overexertion, exhaustion, panic, inability to cope with swift water current or effects of cold water. DROWNING PROCESS The process of drowning is a continuous process which starts with the victim’s airway being below the surface of the liquid with breath held voluntarily. This is then usually followed by laryngospasm which is involuntary and secondary to the presence of liquid in the oropharynx. The victim is unable to breathe air during this period, leading to hypercarbia, hypoxia and acidosis due to carbon dioxide retention and oxygen depletion. During this period, the victim frequently swallows large quantities of water. Respiratory movements may become very active but no gas exchange takes place due to obstruction at the level of the larynx. As arterial oxygen tension drops further, laryngospasm abates, and the victim actively inhales varying amount of liquid. Depending on the composition and volume of the liquid aspirated and duration of submersion, changes occur in the lungs, body fluids, blood-gas tensions, acidbase balance and electrolyte concentrations. Surfactant washout, pulmonary hypertension, and shunting, all contribute to the occurrence of hypoxaemia. Water at 10°C or less has marked cardiovascular effects, including increased blood pressure and ectopic tachydysrhythmias. A victim can be rescued at any time during this drowning process and the chain of events may be interrupted. In absence of effective resuscitative measures multiple organ dysfunction and death usually occurs, mainly due to tissue hypoxia. Posthypoxic encephalopathy is the most common cause of death in hospitalised victims who have suffered from the drowning 2006 process.

Drowning, Near-Drowning and Submersion Injury Yudh Dev Singh PATHOPHYSIOLOGY Principal physiologic consequence of immersion injury is prolonged hypoxaemia. After initial gasping, and possible aspiration, immersion stimulates hyperventilation, followed by voluntary cessation of breathing and a variable degree and duration of laryngospasm. This further leads to hypoxaemia. Depending upon the degree of hypoxaemia and resultant acidosis, the patient may develop cardiac arrest and cerebral ischaemia. Prolonged asphyxia leads to relaxation of the airway, which permits the lungs to fill with water in many victims (‘wet drowning’). Most swimmers initially hyperventilate so as to prolong the duration of underwater swimming. By this procedure, they reduce the arterial partial pressure of carbon dioxide (PaCO2). As the individual swims, oxygen is consumed, partial pressure of oxygen (PaO2) falls to the levels of 30 to 40 mm Hg, but PaCO2 does not rise sufficiently in time to trigger the urge to breathe. This situation may lead to cerebral hypoxia and loss of consciousness, resulting in drowning. Lungs are the target organ of submersion injury. Other systems get affected secondary to hypoxia and ischaemic acidosis. Fluid aspirated into the lungs produces pulmonary vasoconstriction and hypertension which is mediated through the vagal stimulation. Based on available evidence from animal studies, significant pathophysiological differences between fresh-water and salt-water aspiration have been emphasised. In fresh-water drowning hypoxaemia occurs due to inactivation of pulmonary surfactant, resulting in worsening of lung compliance and atelectasis. Perfusion of poorly ventilated areas of the lung results in intrapulmonary shunting of as much as 75% of blood flow and may lead to ventilationperfusion mismatch. Aspirated hypotonic fluid rapidly passes from the lungs into the intravascular compartment, leading to volume overload and dilutional effects on serum electrolytes. Hypoxaemia in hypertonic salt-water drowning is secondary to fluid movement into the alveoli caused by the establishment of an osmotic gradient between the capillary-alveolar membrane leading to massive pulmonary oedema and hypertonic serum. The difference between salt and fresh-water drowning is more obvious among persons who are dead on arrival than among victims who are brought to the hospital alive. Both, fresh and salt-water, produce an inflammatory reaction in alveolarcapillary membrane leading to an outpouring of plasma-rich fluid into alveoli. Individuals who survive the initial course of near drowning are at risk for development of acute respiratory distress syndrome (ARDS). Drowning Without Aspiration of Fluid (Dry Drowning) Dry drowning is a controversial subject as few authorities do not accept this entity, but it has been reported in 10% to 20%

MANAGEMENT It is important to initiate aggressive basic and advanced cardiac life support measures promptly as success of initial resuscitation and duration of submersion are strong determinants of longterm prognosis. On-Site Resuscitation The victim should be removed from the water as soon as possible. Restoration of airway patency, breathing, and circulation must be ensured. Mouth-to-mouth breathing should be attempted at the earliest, if possible, even while the victim is in water. Time should not be wasted in attempting chest compressions while in the water since this has not been shown to be effective instead in unconscious patient the cardiopulmonary resuscitation should be started immediately by keeping the victim’s back over a dry hard surface. Heimlich manoeuvre is not recommended because attempting subdiaphragmatic pressure may increase the risk of aspiration. Obstruction caused by foreign bodies or debris should be looked for. Victim may have other associated conditions, like seizures, head and neck injuries, and these should be kept in mind while attempting initial resuscitation on site or during transportation to a hospital. Management in a Hospital On arrival adequate airway must be ensured. Elective intubation may have to be considered even in the absence of respiratory depression with an intention to protect the airway. Attention should be focused to ensure adequate breathing to achieve satisfactory oxygenation and ventilation. Individuals who have hypoxaemia and unable to maintain adequate saturation with 100% oxygen may benefit from mechanical ventilator support with positive end-expiratory pressure (PEEP) while alert patient may be given a trial of non-invasive ventilation Bi-level/ continuous positive airway pressure (BIPAP/CPAP) before invasive ventilation. Hypoxaemia and hypercarbia are detrimental to the goal of achieving successful central nervous system (CNS) resuscitation, therefore, pulse oximetry, capnography and blood gases may be monitored. Clinical evaluation of cardiac status and peripheral perfusion must be done to assess haemodynamic status. Severe metabolic acidosis may worsen myocardial function and sodium bicarbonate along with fluids may be required to reverse the abnormality of acidosis. Hypovolaemia

correction with isotonic fluids may be necessary but fluids should be used judiciously as these victims have an increased risk for developing cerebral oedema. Victims may have associated hypothermia and may need to be treated for hypothermia. As thermal conductivity of water is 20 times greater than that of air, hypothermia may occur even in tropical waters with temperature as high as 91°F, if protective clothing is not worn and victim is in water for a long time. It is advisable to remove all wet clothing, wrap the victim in a warm blanket and place in a warm area protected from wind. Rewarming with forced hot air or warm water bath may be tried. Active core re-warming by warm water, intra-gastric irrigation, peritoneal dialysis, haemodialysis and extracorporeal circulation, all utilising a system of warming by perfused fluid, have been advocated. There have been few documented survivals after prolonged cold drowning. Patients who have nearly drowned are likely to have long intensive care unit stay, predisposing them to nosocomial infections. Despite efforts at minimising barotrauma many patients, who have nearly drowned and who required ventilatory support, may develop ARDS. The management of these victims is similar to other non-submersion injury patients who have ARDS.

Drowning, Near-Drowning and Submersion Injury

of drowned patients in the medical literature. It is more common in adults and is characterised by little or no fluid in lungs. Death occurs due to profound laryngospasm. Entry of water is prevented by laryngospasm. When spasm relaxes due to terminal asphyxia, outpouring of thick mucus may also prevent entry of water. Associated hypothermia may further aggravate impairment of consciousness and motor activity. Recently, the concept of dry drowning has been challenged and it is felt that presence of fluid in the lungs is must to classify victim as having died due to drowning. Victims found deceased in the water and do not demonstrate any evidence of water aspiration at autopsy should be considered as having probably died of some other cause.

Laboratory Diagnostic Studies Diagnostic studies in an individual who had nearly drowned include serum electrolytes, serum creatinine, blood urea, arterial blood gases (ABG) to evaluate the extent of hypoxaemia, status of ventilation, and acidosis, and haemoglobin levels. Toxicology studies, including alcohol levels, may be considered based on the clinical situation. The clinician should obtain a baseline electrocardiogram to look for any cardiac arrhythmia and to evaluate the QTC interval. Routine computed tomographic imaging of the head is not necessary at the initial stage unless an associated head injury is suspected based on the victim’s neurological status. Prevention Epidemiologically, nearly half the number of persons who drown is in their teens and about 35% possess good swimming skills. Various factors contributing to drowning accidents include limited swimming ability, unattended children at water bodies, drugs and alcohol abuse, existing medical problems like epilepsy and risky behaviour in water, especially in rainy season in India where flash floods are not uncommon. Mandatory lifeguards at swimming pools and beaches, improvement in recreational water bodies safety standard, relevant health education and cardiopulmonary resuscitation training of lay public has potential to reduce the death rate from accidental drowning. RECOMMENDED READINGS 1.

Idris AH, Berg R, Bierens J, Bossaert, et al. Recommended guidelines for uniform reporting of data from drowning. Circulation 2003; 108:2565-74.

2.

Lunetta P, Modell JH, Sajantila A.What is the incidence and significance of ‘drylungs’ in bodies found in water? Am J Foren Med Pathol. 2004; 25:291-301.

3.

Layon AJ, Modell JH. Drowning: Update 2009. Anesthesiology 2009; 110: 1390-401.

2007

27.6

Electric Shock and Lightning Injury

Electrical and lightening injuries are not very uncommon, nearly always accidental, and generally preventable. These environmental injuries cause aggressive pathological lesions which may result in heavy functional and aesthetic consequences. The treatment of these injuries presents many complex multi-level problems which require a proactive approach and treatment. ELECTRIC SHOCK Definition The passage of electric energy through the human body triggers complex reactions which affect the anatomical, histological, biochemical and structural composition. The tissue damage caused by electric current varies from a transient increase in cell membrane permeability to immediate coagulation necrosis of large volumes of tissue. Epidemiology Electric shocks are more frequent in developing and underdeveloped countries having inefficient electric energy system. Overall electrical burns account for 4% to 6.5% of admissions to burn units. Except Turkey (16%), India is having higher incidence rate (3% to 9%) than USA (3%), China (3% to 5%) and Slovakia (2.7%). In a recent Indian study, the amputation rate due to electrical injuries was found to be 4.5% and mortality rate of 3.7%. The electrical injuries have bimodal distribution of age with work-related injuries in adults, and accidents in children particularly below 6 years, more due to oral contact. Male to female ratio is approximately 2:1 in childhood, while in adults more than 90% of victims are men. Pathophysiology The type and extent of an electrical injury is determined by voltage, current strength, the resistance to flow, the duration of contact with the source, the pathway of flow, and the type of current. In the following section, each is explained briefly. Voltage (V) Electrical injuries are typically divided into high-voltage and low-voltage injuries, using 500 V or 1,000 V as the cut-off, but above 40 V is also dangerous . Voltage is expressed by Ohm’s law: V=I×R where, I is current in amperes, R is resistance in ohms, and V is potential in volts. Current (I) It is the amount of energy that flows through an object. A very narrow range exists between the threshold of perception of current (0.2 to 0.4 mA) and let-go current. The level above 2008 which a person becomes unable to release the current source

Naveet Wig, Sourabh Malviya because of muscular tetany is a ‘let-go current’. The effect of current to the body depends on the intensity and varies from tingling sensation, to let-go-current, skeletal muscle tetany, respiratory muscle paralysis, ventricular fibrillation and asystole. Resistance (R) It is the impedance to electrical flow across the gradient and depends on electrolyte and water content of the body tissue. Tissues with higher resistance have a tendency to heat up and coagulate which further increases the resistance. Dry skin has a resistance of approximately 100,000 ohms which further decreases with moisture. Sweating decreases the skin’s resistance to 2,500 ohms to 3,000 ohms and by immersion in water to 1,200 ohms to 1,500 ohms. The level of tissue resistance varies with the tissues as shown in Table 1. Table 1: Resistance of Body Tissues Least

Intermediate

High

Nerves Blood Mucous membranes Muscle

Dry skin

Tendon Fat Bone

Duration of contact In general, longer the duration of contact with high-voltage current, greater will be the heating and degree of tissue destruction caused by the current. Type of circuit Electrical circuits are direct current (DC) or alternating current (AC). Direct current causes single muscle contraction and throws the victim away, while by alternating current victim can grasp current source due to muscle tetany (at 40 Hz to 110 Hz). Pathway Amount of heat generated, type of injury and tissue/organ affected is determined by pathway of current. Greatest degree of damage occurs at the current source and contact points over the body. Mechanisms of Injury The primary electrical injury is burns. Secondary, blunt trauma results from falls or being thrown from the electrical source. Types of electrical burns Electrical burns can be classified into direct or indirect and can be classified into four subgroups. The electrothermal burns are due to direct contact while electric arc, flare and flash injury, are due to indirect injury. 1. Electrothermal burns: These are the result of low voltage electric burns with a limited affected area, caused by direct contact with the current source.

Clinical Manifestations Clinical features are according to action of current, its pathway and organ affected in between as described in Table 2. Table 2: Clinical Features according to Organ Involved Organ/System

Clinical Features

Head/ENT

Facial burn, cataract (delayed), perforated tympanic membrane, cervical spine injuries Cardiac arrest and sudden death (>1000 volts), arrhythmias, ventricular fibrillation or atrial fibrillation, first or second degree heart block or bundle branch block, myocardial infarction or rupture (rarely), venous/arterial thrombosis

Cardiovascular system

Skin

Variety of burns (superficial, partial or fullthickness), peculiar is ‘kissing burn’

Musculoskeletal system

Muscle necrosis, mummification of tissues leading to gangrene, compartment syndrome, fracture and dislocation of long bones, spinal fractures and injuries

Nervous system

Confusion, difficulty with short-term memory and concentration,seizure,loss of consciousness, peripheral nerve damage, weakness and paresthesias of limbs, ascending paralysis, amyotrophic lateral sclerosis, or transverse myelitis (delayed)

Psychiatric

Depression, anxiety, job failure, aggressive behaviour and suicide

Respiratory

Chest wall muscle paralysis, respiratory arrest

Renal

Myoglobinuria, rhabdomyolysis, acute tubular necrosis, acute renal failure

Other systems

Rarely direct liver injury, focal pancreatic and gallbladder necrosis, intestinal perforation and fistula formation, stress ulcers, burn ileus

ENT = Ear, nose and throat.

Complications  Cardiac arrest leading to hypoxic brain damage  Renal failure due to myoglobinuria, acute tubular necrosis (ATN)  Stress ulcers  Burn infections like clostridial myositis  Pneumonia  Sepsis  Multi-organ dysfunction syndrome (MODS)  Tissue loss, fractures and amputations  Delayed neuropsychiatric manifestations

Management Pre-hospital care Secure the scene, like power source should be turned off. Spine immobilisation may be required in case of spinal injury. Initial resuscitation Initiate prolonged cardiopulmonary resuscitation (CPR), in case of cardiorespiratory arrest and do proper cardiac monitoring. See Chapter 11, Section 7. Specific therapy Rhabdomyolysis: Alkalisation of urine, intravenous fluids, mannitol and furosemide may prevent development of renal failure.

Electric Shock and Lightning Injury

2. Electrical arcs: It is a current spark formed between two objects of differing potential that are not in contact with each other, usually a highly charged source and a ground. Because the temperature of an electrical arc is approximately 2,500°C to 5,000°C, it causes very deep thermal burns at the point where it contacts the skin. 3. Flame: Ignition of clothing causes direct burns from flames. 4. Flash: When the current does not actually enters the body, but the heat from a nearby electrical arc or current source splashes over the body causes thermal burns and is called the flash burns.

Electrolytes correction, i.e. hyperkalaemia. Burn and wound care: Proper debridement, escharotomy, antibiotic dressing and prophylactic systemic antibiotics. Extremity injuries: Early fasciotomy, carpal tunnel release, amputation (extensive damage). LIGHTENING INJURY Definition Lightening injury is caused by a unidirectional, massive, current impulse with several return strokes back to the cloud, which is neither the direct or alternating current, lasting for a very short period, leading to mild superficial burns to various systemic injuries. The duration of lightening bolt is 1/100 to 1/1,000 of a second, voltage of approximately 1 billion V, currents ranging from 12,000 to 200,000 A and the temperature dissipation of about 30,000 K. Epidemiology The incidence is likely to be more common in males of less than 35 years of age, as they indulge in more outdoor activities. Lightening is more common near the equator. Extreme temperatures are generally the most common environmental killers. Mechanism of Injury Lightening injury may occur by direct contact or indirect contact with the light stricken object. Direct contact Orifice entry: It strucks head and may enter eyes, ears and mouth to flow internally. Indirect contact Side flash or splash: Lightening jumps from primary striking object to a nearby person on its ground. Ground current or step voltage: A difference in electrical potential between person’s feet may occur when lightening flows through the ground, current then flows through person rather than the ground. Blunt trauma: Injury occurs if the person is thrown away by lightening current. Clinical Manifestations Lightening injuries causes minor injuries, cardiac arrest and other manifestations as presented in Table 3.

2009

Table 3: Features of Lightening Injury Organ/System

Clinical Features

Head/ENT

Skull fractures and cervical spine injury (blunt trauma), tympanic membrane rupture, disruption of the ossicles and mastoid, CSF otorrhoea, haemotympanum, and permanent deafnesss Corneal lesions, uveitis, iridocyclitis, hyphema, vitreous haemorrhage, optic atrophy, retinal detachment, and choroidoretinitis Cardiac arrest due to asystole, ventricular fibrillation (rare), other dysrhythmias Mottling, burns: Linear, punctate, feathering (‘Litchenberg Figures’), or thermal burns Fracture and dislocation of long bones, spinal fractures and injuries Keraunoparalysis (transient paralysis), permanent paresis or paraesthesias, anterograde amnesia, peripheral nerve damage, intracranial haemorrhages, seizures, loss of consciousness, delayed muscle atrophy Depression, anxiety Pulmonary contusion and haemorrhages Blunt abdominal injuries

Eye

Cardiovascular system Skin Musculoskeletal system Nervous system

Psychiatric Respiratory Other systems

Complications of Lightening  Cardiac arrest and death  Iatrogenic complications secondary to over aggressive management  Hearing loss from tympanic membrane rupture  Spinal injuries  Neurologic damage—paraplegia or haemiplegia  Neuropsychiatric manifestations  Chronic pain syndromes Treatment Pre-hospital care  Victim and caregiver should guard themselves from another lightening injury.  Spinal immobilisation.

2010

Hospital care  Observation only, if minor injuries and superficial burns.  Immediate aggressive and persistent cardiopulmonary resuscitation in case of cardiac arrest.  Keraunoparalysis and transient unconsciousness may require observation.  Consultation for the injuries to ear, eyes and blunt trauma injuries from respective specialists. Prognosis Morbidity and mortality are largely affected by the particular type of electrical contact involved. Proper resuscitation with monitoring of limb tissue pressure and wound care can maximise tissue salvage; reduce renal failure, and increased survival of patients with lightening and high-voltage electric injuries. CONCLUSIONS Electrical and lightening injuries are environmental injuries causing various anatomical, structural and functional disturbances in the body. Electrical injuries may cause superficial or deep burns and various complex injuries to the organs, burn infections and renal failure. While lightening injury may not cause severe burns but can result in more cardiac and neurological damage. Electrical injuries require more intense management, like burn wound care, aggressive fluids and treatment pertaining to systemic complications than lightening injuries. RECOMMENDED READINGS 1.

Buja Z, Arifi H, Hoxha E. Electrical burn injuries: an eight year review. Ann Burns Fire Disasters 2010; 23: 4-7.

2.

Fish RM. Electric injury, Part I:Treatment priorities, subtle diagnostic factors, and burns. J Emerg Med 1999; 17: 977-83.

3.

Lee RC. Injury by electrical forces: pathophysiology, manifestations, and therapy. Curr Probl Surg 1997; 34: 677-764.

4.

Price T, Cooper MA. Electrical and lightening injuries. In: Marx J, Hockberger R, Walls R (editors). Rosen’s Emergency Medicine; 5th Ed: vol 3. Mosby Co; 2002: pp. 2010-20.

27.7

Effects of Extremes of Temperature

INTRODUCTION The term ‘heat stress’ or ‘cold stress’ is applied to any degree of environmental heat or cold that causes physiological thermoregulatory mechanisms to get activated. Human beings are homoeothermic creatures whose physiology attempts to maintain a constant core body temperature of 37°C (range 36°C to 38°C). Obviously, this requires balancing of the body heat production with heat loss which is achieved by a combination of physiological mechanisms (as peripheral vasodilatation or vasoconstriction, changes in heart rate, sweating or shivering) and behavioural mechanisms (increase or decrease in voluntary physical activity, seeking appropriate shelter, etc). In addition, environmental conditions, viz. temperature, humidity and speed of air also greatly determine whether a person will be subjected to thermal stress. Therefore, prevention and management of thermal stress disorders requires an understanding of these physiological, behavioural and environmental mechanisms and manipulating them appropriately. For the purpose of thermo-regulation, the human body can be conceived of having two ‘layers’—an outer periphery or ‘shell’ consisting of skin, subcutaneous tissue and muscles, and an inner ‘core’ consisting of brain, heart and viscera. EPIDEMIOLOGY OF HEAT STROKE Adverse effects of heat stress are an important cause of morbidity and mortality not only in the developing countries but in the developed countries as well. In India, 3,194 deaths due to heat stroke (HS) have been recorded over the 5-year period 1999 to 2003; the actual magnitude may be much more. The central and northern plains, western deserts and tropical forest areas of north-east have environmental conditions causing heat stress during the months of April to September. The risk is much higher among certain categories (Table 1). Table 1: Persons at High Risk of Heat Stress Extremes of age (65 years) Pregnancy Occupation—workers in military, agricultural, construction and industrial settings, labourers, sports-persons and miners Low level of physical fitness Lack of acclimatisation to environmental heat Obesity High ambient temperature, high atmospheric humidity, low air velocity Alcohol use—acute and chronic Skin diseases—extensive prickly heat, psoriasis, pyoderma Sleep deprivation Co-existing febrile illness, renal, thyroid, cardiovascular and metabolic diseases Previous history of heat-illness Use of drugs or habit forming substances—phenothiazines, anticholinergics, ACE-inhibitors, MAO-inhibitors, cocaine, amphetamines, anti-histamines ACE = Angiotensin converting enzymes; MAO = Monoamineoxidase.

Rajvir Bhalwar PATHOPHYSIOLOGY As a part of thermo-regulatory process, even an increase of 1°C in the temperature of blood generates signals to the hypothalamic thermo-regulatory centre leading to increase in heart rate and cardiac output, which coupled with the sympathetic cutaneous vasodilatation increases the skin blood flow. Sweating is activated and its evaporation cools the body surface, unless the air surrounding the body is fully saturated with water, i.e. having relative humidity (RH) of 100%. Increasing the movement of air in contact with the body also increases cooling by promoting evaporation of sweat. Sweating, however, leads to loss of water and salt, which may be as high as 2 litres per hour under conditions of high humidity and physical exertion. If the water and salt are not replaced adequately and concurrently, the fluid reserves would be depleted, even though the body core temperature may not be very high. This condition is called ‘heat exhaustion’ (HE). However, at times, the thermoregulatory response may be overwhelmed by the hot environment, even though the fluid and salt reserves of the body may be adequate. Such thermo-regulatory failure, coupled with exaggerated acute phase response (increased production of inflammatory cytokines and endothelium derived vasoactive factors and activation of coagulation process) and alterations in the expression of heat shock proteins (HSPs), leads to ‘heat stroke’. For these reasons, a number of cases of HE, if not properly managed, would also pass on to HS. Following HS, a multiple organ dysfunction syndrome (MODS) results from a complex interplay between the cytotoxic effects of heat and the inflammatory and coagulation responses of the host. CLINICAL FEATURES OF HEAT STROKE The classical clinical description of HS is the triad of hyperpyrexia (rectal temperature >40°C), central nervous system (CNS) dysfunction and anhidrosis. Anhidrosis, however, is not a diagnostic requirement since it may appear later when volume depletion is severe. Moreover, in cases which initially start as HE or cases of HS which occur among young people who have been exerting physically, the skin may be moist. Brain dysfunction is usually severe (coma, stupor or delirium), but may sometimes be subtle, manifesting as inappropriate behaviour or impaired judgement. In fact, any person who develops irrational or confused behaviour following exposure to heat stress either with or without a history of physical exertion, should be treated as a potential HS patient. Other clinical features include evidence of dehydration, shock, convulsions and, sometimes, mild icterus. Two forms of HS are recognised, viz. the classical HS (CHS) and the exertional HS (EHS) form. It is important to recognise the clinical differences between the two forms (Table 2). 2011

Table 2: Differences Between Classical Heat Stroke and Exertional Heat Stroke (EHS) Characteristic

CHS

EHS

Age group Previous health status Concurrent activity Habit of drug use Sweating Skin Rhabdomyolysis

Elderly Usually compromised Sedentary Often present Often absent Dry Unusual

15 to 45 years Healthy Strenuous activity Usually present Frequently severe May be moist Excessive

DIFFERENTIAL DIAGNOSIS Heat stroke should be considered as a possibility in any patient who presents with elevated body temperature and altered mental functions. Important and common diseases which need to be excluded are tropical infectious diseases like cerebral malaria, encephalitis and meningitis. Other diseases which need to be considered are thyroid storm, phaeochromocytoma, status epilepticus, cocaine and amphetamine abuse, delirium tremens and cerebro-vascular accident especially pontine haemorrhage. The diagnosis of HS is usually one of exclusion and the typical history of exposure to hot environment during the immediate past is an indication towards heat stress hyperthermia.

TREATMENT HS must be treated as a serious medical emergency. Delay in institution of appropriate therapy by even few minutes may make all the difference between life and death. The treatment objectives are: firstly, rapid cooling to bring down the core temperature to below 39°C and reducing it by approximately 0.2°C per minute; secondly, rehydration and care of comatose patient; and, thirdly, to support the organ system function. Cooling measures should be stopped once core temperature falls below 39°C. The steps in the management of HS at two different levels (first aid level, primary care/solo physician level and hospital level) are shown in Tables 3 and 4, respectively. Table 3: Management at First Aid Level Record rectal temperature. If it is not possible to record rectal temperature, record oral temperature and add 0.5°C Try and move patient to a cooler and shaded place Remove the clothes Spray skin with water at 25°C to 30°C or wrap the patient with a sheet soaked in water at 25°C to 30°C Continue fanning manually or with an electrical fan Keep vigorously massaging the skin to prevent cutaneous vasoconstriction during cooling If available, place ice packs or towel soaked in cold water around the neck, axillae and groin

LABORATORY INVESTIGATIONS

Nurse in the comatose position; clear oral secretions

Blood should always be drawn for a peripheral blood smear for malarial parasite as well as for other infectious causes of hyperpyrexia with CNS dysfunction. Laboratory findings of HS include haemoconcentration, mild leucocytosis, elevation of blood urea, and in some patients of EHS, hypoglycaemia. Impaired blood coagulation with lowered prothrombin, low platelet counts, hypofibrinogenaemia and features of disseminated intravascular coaglation (DIC) may be seen. Serum electrolyte studies generally show normal or high chlorides, hypokalaemia, hypocalcaemia, and hypophosphataemia. Enzyme studies show increase in creatine phosphokinase (CPK), serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels. If rhabdomyolysis or acute renal failure (secondary to acute tubular necrosis) has set in, urine will show myoglobinuria, proteinuria, and hyaline and granular casts, and there will be an increase in blood uria nitrogen (BUN) levels.

Transport to the medical facility as an emergency

Complications The most serious complication of HS is MODS, manifesting as hepatic failure, renal failure, cerebellar damage, cerebral oedema and arrhythmias. Rhabdomyolysis and DIC are other serious complications. PROGNOSIS HS must be treated as an emergency. Mortality may be as high as 30% to 50% among cases where treatment is delayed. Mortality is directly proportional to the level of core temperature and its duration. Prolonged coma of more than 2 hours is a poor prognostic indicator. Among survivors, neurological recovery generally occurs but some deficit may persist in up to 20% of the cases. Survivors of HS, who have suffered for hyperpyrexia for a 2012 few hours may get permanent brain damage.

Table 4: Management at the Hospital (Secondary/Tertiary Care Level) Continue cooling measures Start monitoring core temperature with a thermometer calibrated to measure high temperature (40°C to 47°C) In case temperature is not reducing, immerse the patient in tub containing cold or iced water, keep the head and neck outside the water surface In case patient is shivering, give intravenous (IV) chlorpromazine 25 mg to 50 mg Intubate the patient, establish ventilatory support, give oxygen inhalations Continue IV fluids; maintain mean arterial pressure at 60 mm Hg; if required, consider administering a vasopressor Frequently monitor blood electrolytes to guide the IV fluid therapy In case there is evidence of shock, cerebral oedema or adrenal insufficiency, administer IV hydrocortisone hemisuccinate 100 mg or betamethasone 4 mg to 8 mg If facilities exist, give a cold gastric lavage after intubating the patient Antipyretics do not seem to have any role. There are reports about efficacy of dantrolene sodium but the same have not been proven by clinical trials If there is evidence of rhabdomyolysis or acute renal failure, give IV normal saline, furosemide 40 mg, mannitol 0.25 g/Kg body weight and 250 ml of 4% IV sodium bicarbonate. Heparinisation may be required if there is evidence of DIC Advice bed rest for about 7 days after recovery from heat stroke since temperature control mechanisms may remain labile after recovery

PREVENTION OF ADVERSE EFFECTS OF HOT ENVIRONMENT 1. Avoid exposure to outside environment during summer, from 10 am to 5 pm, unless necessary. 2. Keep drinking water regularly, especially if exerting. Drink 250 to 300 ml water every half an hour even if not thirsty.

Table 5: Salient Differentiating Features Between Heat Stroke (HS) and Heat Exhaustion (HE) Aspect

HS

HE

Cause Warning signs

Inadequacy or failure of heat loss mechanisms Headache, weakness, loss of consciousness

Excessive fluid loss leading to hypovolaemia Gradual weakness, excessive sweating, anxiety, nausea, syncope

Manifestations

Hot, dry skin with little sweating; full, bounding and rapid pulse, very high temperature (usually >40°C)

Pale, greyish, clammy skin; weak, slow pulse; low blood pressure; temperature moderately raised (usually 4 or total score greater than 5

Treatment The guidelines for management of AMS are shown in Table 5. Table 5: Guidelines for Management of AMS Do not worsen the hypoxia Avoid physical exertion Prevent further gain in altitude Correct the hypoxia Inhaled oxygen @ 2 to 4 L/min Treat symptoms NSAIDs for headache Anti-emetics for nausea/vomiting Tablet Acetazolamide 250 mg, 8 to 12 hourly if symptoms severe If symptoms persist or worsen Dexamethasone 4 mg 6 hourly, orally, IM or IV Descend to lower altitude Actual descent where possible Simulated descent using recompression chambers

Complications AMS may progress to HACE or HAPE, if not promptly managed or if the hypoxia is worsened due to physical exertion and/or a further gain in altitude. Prognosis and prevention AMS is usually a benign self-limiting condition if promptly recognised and treated. It can be prevented by slowing the rate of ascent to HA (Table 6) and by proper acclimatisation. Tablet acetazolamide (125 to 250 mg 12 hourly) started 24 hours prior to ascent to HA and continued for three days at HA is the drug of choice for prevention of AMS. Tablet dexamathasone (4 mg 6 hourly) can be considered in case of sulphonamide sensitivity but is not routinely recommended due to the potential complications of steroid therapy and interference with the normal acclimatisation process. Table 6: Recommended Rates of Ascent at High Altitude Above 2,500 m to 3,000 m altitude: Gain in sleeping altitude should not exceed 300 to 600 m per day Allow one rest day for every 1,000 m gain in altitude Delay further ascent if symptomatic, wait till symptoms subside

Contd...

Descend to lower altitude if symptoms persist or deteriorate

High Altitude Cerebral Oedema (HACE) Definition and epidemiology HACE is a potentially fatal condition that can develop in an individual suffering from AMS or HAPE or can occur in isolation. It is defined as the onset of ataxia, altered consciousness or both in an individual who has AMS or HAPE.The incidence varies with altitude and ranges from 0.5% to 4%.

Treatment HACE is a medical emergency requiring immediate descent to lower altitude (Table 7). Simulated descent using recompression chambers can be life saving where actual descent is not possible. Portable recompression chambers, where available, can generate pressures up to 130 mm Hg and simulate a descent of about 6,000 ft (Figure 3).

High Altitude Medicine

Aetiopathogenesis The probable pathogenesis of HACE is as shown in (Figure 1).

Figure 3: An indigenously manufactured portable recompression chamber showing full pressurised state (130 mm Hg).

Table 7: Guidelines for Management of High Altitude Cerebral Oedema (HACE) Figure 1: Aetiopathogenesis of high altitude cerebral oedema (HACE). Source: Hackett PH, Roach RC. High altitude illness. N Engl J Med 2001; 345: 107-14.

Clinical features A change in mental status and ataxia are the classical features of HACE. The former may range from lassitude, apathy and confusion to frank coma. Associated findings may include papilloedema, retinal haemorrhages and cranial nerve palsy. Diagnosis HACE is largely diagnosed clinically (Figure 2), since imaging facilities are rarely available at most HA locations. Where available, the magnetic resonance imaging (MRI) usually shows increased signal intensity in the region of the corpus callosum and splenium.

Do not worsen the hypoxia No physical exertion Prevent further gain in altitude Correct the hypoxia Immediate descent to lower altitude Actual descent where possible Simulated descent using recompression chambers Supplemental oxygen via facemask at 2 to 4 L/min Pharmacotherapy Dexamethasone 8 mg initially orally/IM/IV followed by 4 mg every 6 hours. Tablet acetazolamide 250 mg, 8 to 12 hourly if descent to lower altitude is delayed Injection mannitol to reduce intracranial pressure

Complications HACE can be fatal if not managed as a medical emergency. Prognosis and prevention HACE is a life-threatening condition. The mortality may be as high as 25%, even with prompt institution of therapy. Prevention of HACE is by slowing the rate of ascent to HA (Table 6) and following a proper acclimatisation schedule. High Altitude Pulmonary Oedema (HAPE) Definition and epidemiology HAPE is a non-cardiogenic pulmonary oedema characterised by pulmonary hypertension, leading to extravasation of fluid from the intravascular compartment in the lungs of healthy individuals with no underlying cardiac or pulmonary disease. HAPE usually occurs on the second or third day of arrival at HA. The reported incidence varies from 0.5% to 15%, depending on the rate of ascent and altitude reached.

Figure 2: Algorithm for clinical diagnosis of high altitude cerebral oedema (HACE). Source: Hackett PH, Roach RC. High altitude illness. N Engl J Med 2001; 345: 107-14.

Aetiopathogenesis Elevated PAP due to hypoxic pulmonary vasoconstriction is central in the pathogenesis of HAPE (Figure 4). Exposure 2019

of the basement membrane to the protein-rich oedema fluid results in secondary inflammation, activation of coagulation and generation of microthrombi in the lungs. Pre-existing inflammation may make the endothelium more prone to disruption. Vigorous physical exertion in unacclimatised individuals and exposure to low environmental temperatures may precipitate or aggravate HAPE by raising the PAP.

Figure 5: Chest radiograph of a patient with high altitude pulmonary oedema showing non-homogenous opacities in the right middle and lower zones.

Table 8: Clinical Criteria for Diagnosing High Altitude Pulmonary Oedema (HAPE) History of recent gain in altitude WITH Any two of the following symptoms: Cough Dyspnoea at rest Chest discomfort Weakness/fatigue AND Any two of the following signs: Crackles/wheeze in at least one lung field Central cyanosis Tachycardia Tachypnoea Figure 4: Aetiopathogenesis of high altitude pulmonary oedema (HAPE). Source: Hackett PH, Roach RC. High altitude illness. N Engl J Med 2001; 345: 107-14.

Clinical Features Dry cough and reduced physical performance for the given altitude in an individual recently arrived at HA suggest HAPE. Dyspnoea and chest discomfort are common. Pink frothy sputum and respiratory distress occur later in the illness. Orthopnoea and haemoptysis are uncommon. Resting tachycardia and tachypnoea become pronounced as the illness progresses. Crackles and wheeze are usually present in more than one lung field. Diagnosis The clinical diagnostic criteria for HAPE are shown in Table 8. Investigations may reveal the following:  ECG: Sinus tachycardia, right ventricular strain, right axis deviation, right bundle branch block (RBBB) and P wave abnormalities.  Chest radiograph (Figure 5): Normal cardiac shadow, prominent pulmonary arteries and patchy infiltrates, generally confined to the right middle and lower lobes, may involve both lungs in severe cases. 2020

Treatment HAPE is managed as shown in Table 9. Elevated PAP usually reduces with correction of hypoxaemia. Drug therapy must be considered where administering oxygen and/or reduction of altitude is not possible. Nifedipine successfully lowers elevated PAP in most HAPE patients. Inhaled nitric oxide (NO) and phosphodiesterase inhibitors, such as sildenafil and tadalafil have shown promising results. Inhaled salmetrol has been reported useful in reducing PAP and improving oedema clearance. Table 9: Guidelines for Management of High Altitude Pulmonary Oedema (HAPE) Do not worsen the hypoxia No physical exertion Prevent further gain in altitude Correct the hypoxia Descend to lower altitude Actual descent where possible Simulated descent using recompression chambers Supplemental oxygen via face mask @ 2 to 4 L/min Pharmacotherapy to lower pulmonary artery pressure Nifedipine 10 mg orally followed by 30 mg sustained release 12 hourly

Prognosis and prevention HAPE can be managed with a mortality of less than 1% if recognised in time and promptly treated. Slowing the rate of ascent to HA and following a proper acclimatisation schedule can successfully prevent HAPE. Nifedipine (20 to 30 mg of extended release formulation 12 hourly) is advisable in susceptible individuals. Inhaled salmetrol has also been reported useful for prevention of HAPE. Differential Diagnosis of Acute HA Illnesses Many clinical conditions may mimic acute HA illnesses (Table 10). The diagnosis of AMS and HACE must be reconsidered if the onset of symptoms is after 3 days of arrival at HA, headache is absent, there is a rapid improvement of symptoms with fluid replacement or no improvement with oxygen therapy, acetazolamide, dexamethasone and descent to lower altitude. Table 10: Differential Diagnosis of Acute High Altitude Illnesses Acute mountain sickness/high altitude cerebral oedema Dehydration Exhaustion Hypoglycaemia Carbon-monoxide poisoning Migraine CNS infections Acute psychosis Stroke Transient ischaemic attack CNS tumour High altitude pulmonary oedema Bronchial asthma Acute bronchitis Pneumonia Congestive cardiac failure Pulmonary embolism Myocardial infarction Hyperventilation syndrome

SUBACUTE AND CHRONIC HIGH ALTITUDE ILLNESSES Subacute Mountain Sickness (SMS) Two distinct forms of SMS syndromes, which bear similarity with Brisket disease in cattle, have been described in humans. Subacute Infantile Mountain Sickness (SIMS) SIMS is reported predominantly in the Han Chinese living in Tibet. It occurs in infants born at lower altitudes and subsequently taken to HA. The prevalence increases with altitude and decreases with age. Symptoms start with poor feeding and lethargy, followed by dyspnoea, cough and signs of cardiac failure. SIMS is usually fatal. The pathophysiology involves muscularisation of pulmonary arterioles and medial hypertrophy of small pulmonary arteries, which is in contrast to concentric laminar intimal proliferation seen in primary pulmonary hypertension. The elevated PAP results in right ventricular hypertrophy and cardiac failure. Prompt reduction of altitude can lead to complete resolution of the condition.

Subacute Adult Mountain Sickness (SAMS) SAMS was first described in 1990 in Indian soldiers stationed at extreme altitude for 3 to 6 months. Symptoms begin with shortness of breath and edema and progress to gross anasarca. Patients show features of severe congestive cardiac failure with right ventricular hypertrophy, right axis deviation and T wave inversion in leads V1 to V6. The pathophysiology includes severe pulmonary arterial hypertension coupled with polycythaemia, possible myocardial dysfunction and alteration in body fluid homeostasis. Abnormalities return to normal within 12 to 16 weeks of descent to lower altitude.

High Altitude Medicine

Complications HAPE can be fatal if not recognised and treated promptly. Severe HAPE can worsen the hypoxaemia of HA and precipitate HACE.

Chronic Mountain Sickness (CMS) or Monge’s Disease Definition and epidemiology First described by Carlos Monge in 1925, the consensus statement of the VI World Congress on Mountain Medicine 2004 defines CMS as a clinical syndrome that occurs in HA natives or long term residents at altitudes above 2,500 m, characterised by excessive erythrocytosis, severe hypoxemia and in some cases moderate/severe pulmonary arterial hypertension, which may result in cor pulmonale, leading to congestive cardiac failure. The reported incidence of CMS in Tibetans is 0.91%. Aetiopathogenesis CMS was attributed to a loss of acclimatisation in already acclimatised individuals; however, a low hypoxic ventilatory response is no longer considered an important aetiological factor. A likely possibility is markedly raised erythropoietin (EPO) levels. The raised haematocrit due to elevated EPO raises blood viscosity, worsens tissue hypoxia, and results in further elevation of EPO levels and genesis of a vicious cycle. Patients of CMS also have increased PAP, possibly due to elevated blood viscosity. Clinical features The clinical features of CMS are shown in Table 11. Table 11: Clinical Signs and Symptoms of Chronic Mountain Sickness (CMS) Symptoms Headache Breathlessness Dizziness Palpitations Sleep disturbance Fatigue Localised cyanosis Burning of palms and soles of feet Dilatation of veins Muscle and joint pains Anorexia Lack of mental concentration Alterations in memory Clinical/Investigative findings Excessive erythrocytosis Haemoglobin >19 g/dL in females and >21 g/dL in males Raised pulmonary arterial pressure (not mandatory) Features of heart failure (not mandatory) Chest radiograph Prominent pulmonary arteries ECG Right ventricular hypertrophy Right atrial enlargement Proteinuria

2021

Diagnosis CMS is diagnosed clinically (Table 11) in patients living at altitudes greater than 2,500 m, with normal lung function and without chronic pulmonary or other medical conditions that worsen the hypoxaemia. Treatment Descent to lower altitudes is the treatment of choice. Other modalities of treatment have variable results (Table 12). Table 12: Guidelines for Management of Chronic Mountain Sickness (CMS) Migration to lower altitudes is the treatment of choice Other modalities of treatment with variable results Phlebotomy to reduce haematocrit Oxygen supplementation and respiratory training Calcium channel blockers to reduce pulmonary artery pressure Inhaled nitric oxide 40 ppm or nitric oxide 15 ppm with 50% oxygen to lower pulmonary artery pressure Medroxyprogesterone 20 to 60 mg/day for 10 weeks to stimulate ventilation Tablet acetazolamide 250 mg/day for 3 weeks

Complications and prognosis CMS may result in cor pulmonale and congestive cardiac failure. Migration to lower altitude corrects the hypoxaemia and haematocrit returns to normal in 2 to 3 weeks. Right ventricular hypertrophy and elevated PAP normalise in about two years. High Altitude Pulmonary Hypertension (HAPH) Definition HAPH is a clinical syndrome characterised by raised mean or systolic PAP, right ventricular hypertrophy, cardiac failure, moderate hypoxaemia and absence of excessive erythrocytosis. It occurs in HA residents with no underlying cardio-pulmonary disease. Aetiopathogenesis Remodelling of the pulmonary vasculature with muscularisation of pulmonary arterioles is the likely cause of the raised PAP. The elevated blood viscosity due to erythrocytosis is probably a contributory factor. Clinical features HAPH presents with dyspnoea, cough, cyanosis, sleep disturbance, irritability and features of right heart failure. Diagnosis HAPH is diagnosed as shown in Table 13, after ruling out other cardio-pulmonary causes of pulmonary hypertension. Treatment Descent to lower altitude is desirable. The raised PAP can be reduced using calcium channel blockers (Nifedipine 20 to 30 mg 12 hourly), inhaled NO (15 ppm with 50% O2 or 40 ppm for 15 min), phosphodiesterase inhibitors and prostaglandins.

2022

Complications and prognosis Prompt descent to lower altitudes improves symptoms and the PAP returns to normal in 2 to 6 months. Untreated, the condition results in right heart failure.

Table 13: Diagnostic Criteria and Investigation Findings in High Altitude Pulmonary Hypertension (HAPH) Raised pulmonary artery pressure Mean pulmonary artery pressure >30 mm Hg Systolic pulmonary artery pressure >50 mm Hg Haemoglobin Males 30%. At 0.1 Gy, increase of 0.1% to 1%. 3. The foetal absorbed dose >0.5 Gy at 7 to 13 weeks: substantial risk of IUGR and central nervous system damage. 4. 0.25 to 0.5 Gy at 7 to 13 weeks: parental decision with physician’s guidance.

Although exposure to ionising radiation carries a risk, it is impossible to completely avoid exposure. Radiation has always been present in the environment and in our bodies. However, we can avoid exposure. Although one cannot sense ionising radiation, there is a range of simple, sensitive instruments capable of detecting small amounts of radiation from natural and man-made sources. 1. Dosimeters: These can measure an absolute dose received over a period of time. The TLDs are normally used to obtain your official dose of record. TLDs are processed routinely at the end of each calendar quarter. TLDs are sensitive to beta, gamma, and neutron radiation. 2. Self reading pocket dosimeters (SRPDs): The term SRPDs applies to a variety of devices which can be read by the wearer to determine the dose received. SRPDs are used as supplemental devices to aid in dose tracking during activities where elevated doses are possible. 3. Pocket ion chambers (PIC): These are small instruments which operate on the principle electroscope. Typically, the range of the PIC is 0 to 200 mR. This is one of the most common supplemental dosimeters used in radiation areas. 4. Electronic dosimeters (ED): These are sometimes used instead of and in addition to PICs when it is helpful to have additional capability of dose or dose rate alarm functions. 5. Geiger counters and scintillometers: These measure the dose rate of ionising radiation directly. 6. Film badge dosimeters: These enclose a photographic film which will get exposed to radiation.

Radiation Hazards

This means that if the whole body is exposed to 1 Sv of ionising radiation, an extra 4% chance of contracting a cancer that will be fatal many years after the exposure. The word ‘extra’ is used because one normally has a 20% to 25% chance of dying from cancer.

In addition, there are 3 ways for personal protection: 1. Time: Limiting or minimising the exposure time to reduce the dose. 2. Distance: The intensity of exposure reduces as a square of the distance from the source. 3. Shielding: Barriers of lead, concrete or water are protective against radiation, such as gamma and neutrons. That is why certain radioactive materials are stored or handled under water or by remote control in rooms constructed of thick concrete or lined with lead. There are special plastic sheets for stopping beta rays and air will stop alpha particles. It should be noted that the setting of a dose limit is equivalent to specifying a maximum acceptable level of risk. It is not acceptable to be exposed to the full extent of the limit if a lower dose can be reasonably achieved. The average dose received by an occupationally exposed worker is less than 0.2 mSv per year. RECOMMENDED READINGS 1. 2. 3. 4.

MINIMISING HEALTH EFFECTS OF IONISING RADIATION Life style abnormalities, natural disasters and accidents are greater risk factors than exposure to small amounts of radiation as encountered in medical exposures and in radiation workers.

5.

Some scientists assert that low levels of radiation are beneficial to health (this idea is known as hormesis).

7.

6.

Fliedner TM, Cronkite EP, Bond VP, editors. Assessment of Radiation Effects by Molecular and Cellular Approaches. Ohio: AlphaMed Press; 1995. Nuclear science in society.ANSTO. Biological effects of radiation Topic 4. 2005. Open Source Radiation Safety Training Module 3: Biological Effects Princeton University. Environment and Health 2005. National Council on Radiation Protection and Measurement. Ionising radiation exposure of the population of the United States, NCRP Report No. 93, Bethesda, MD 1987. National Research Council, Committee on the Biological Effects of Ionising Radiation (BEIRV). Washington, DC: National Academy Press; 1990. Biological Effects of Ionising Radiation. BEIR 111. US National Academy of Science: National Academy Press; 1980: pp. 74-5. Basic Radiation Protection Criteria. US National Council on Radiation Protection Report no. 39, pp. 58-60. 2033

27.11 Emergency management is the discipline that involves preparing for disaster before it occurs, disaster response (e.g. emergency evacuation, quarantine, mass decontamination, etc.), and rebuilding society after natural or humanmade disasters have occurred. In general, any emergency management is the continuous process to manage hazards in an effort to avoid or ameliorate the impact of disasters. Effective emergency management relies on integration of emergency plans at all levels of government and nongovernment involvement. PHASES IN EMERGENCY MANAGEMENT Mitigation Mitigation efforts attempt to prevent hazards from developing into disasters altogether, or to reduce the effects of disasters when they occur. The mitigation phase differs from the other phases because it focuses on long-term measures for reducing or eliminating risk. Mitigation is the most cost-efficient method for reducing the impact of hazards; however it is not always feasible. Preparedness Preparedness is a continuous cycle of planning, organising, training, equipping, exercising, evaluation and improvement activities. It ensures effective coordination and the enhancement of capabilities to deal with natural disasters, acts of terrorism, and other man-made disasters. Response This phase includes the mobilisation of the necessary emergency services and first responders in the disaster area. Recovery The recovery phase aims at restoring the affected area to its normal state. The focus of this phase is different from response phase; recovery efforts are started after immediate needs are addressed. EMERGENCY MANAGEMENT IN INDIA National Disaster Management Authority of India, a government agency under the Ministry of Home Affairs is India‘s Institutional Mechanism for effective disaster management. In recent years, there has been a shift in emphasis from response and recovery to strategic risk management and reduction. There is more emphasis on community participation rather than a governmentcentred approach with network of Emergency Response Centres and Crisis Management Group and strengthening the Institutional Frameworks for regulatory.

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Efforts involve the provision of emergency management training for first responders, the creation of a single emergency telephone number, and the establishment of standards for EMS staff, equipment and training.

Environmental Disasters ME Yeolekar, Milind Y Nadkar TRIAGE Triage means to sort. When there is sudden flux of patients in emergency room or at the site of disaster one needs to prioritise which patients need treatment earlier than others. Triage is essential in medical emergencies, including the pre-hospital setting, disasters, and during emergency room treatment. Types of Triage Simple triage Simple triage is usually used in a scene of a mass-casualty incident. It helps to sort patients into those who need critical attention and immediate transport to the hospital and those with less serious injuries. This triage can be started before transportation becomes available. Simple triage and rapid treatment (START) START is a simple triage system that can be performed by lightlytrained lay and emergency personnel in emergencies. It does not intend to supersede or instruct medical personnel or techniques. Colour codes (flags) are attached to patients for identification and management. Triage separates the injured into four groups:  The deceased who are beyond help (Black).  The injured who can be helped by immediate transportation (Red).  The injured whose transport can be delayed (Yellow).  Those with minor injuries, who need helpless urgently (Green). Advanced triage In advanced triage, doctors decide that some serious patients should not receive advanced care because they are unlikely to survive. Advanced care will be used on patients with less severe injuries. However, advanced triage has ethical implications. It is used to divert scarce resources away from patients with little chance of survival in order to increase the chances of survival of others who are more likely to survive. ENVIRONMENTAL DISASTER An environmental disaster is a disaster that is due to human activity and should not be confused with natural disasters; but forced human movement, as in Haiti, can cause cholera, after flooding from hurricane. Industrialisation all over the world has introduced several chemicals in the environment causing exposure to wide variety of toxic agents for the people living in such environment. The respiratory tract tends to bear the maximum brunt of such exposure leading to upper and lower respiratory tract inflammation. The upper respiratory tract through the anatomical structures like nasal turbinates and the cough reflex usually removes maximum amount of toxic gases inhaled. The dose reaching into the lower respiratory tract however is cumulative and produces long-term inflammation due to impairment of mucociliary clearance and alveolar macrophage defence.

Following are two examples of large scale disasters due to environmental accidents. The gas leak in Bhopal (MP), 1984, the union carbide gas leak December 3, 1984 has become a memorable day for the city of Bhopal in Madhya Pradesh, India. Shortly after midnight, a poisonous gas cloud escaped from the Union Carbide India Limited (UCIL) pesticide factory. The cloud of poisonous gas containing 15 metric tons of methyl isocyanate (MIC) escaped from the factory covering an area of more than 30 square miles. The casualty was four thousand and many more suffer from chronic disease consequential to gas exposure, today. This incident happens to be one of the worst known industrial environmental disasters. Chernobyl: Russian nuclear power plant explosion (1986) Reactor stress at nuclear power plant in Ukraine resulted in ten times increase in energy production than the normal level and finally culminated into explosion by the escaped steam and formation of an atmospheric cloud containing approximately 185 to 250 million curies of radioactive material caused fire instantly killing 31 people. Immediate aftermath of the earthquake and Tsunami in Japan, March 2011 was the melting of fuel rods in the nuclear reactors causing nuclear blast radiation disaster. Graded response to nuclear/radiologic emergencies has become necessary. Growing concern over ocean contamination. Radiation It is naturally present in our environment and has been since the birth of this planet. Life has evolved in an environment, which has significant levels of ionising radiation. It comes from outer space (cosmic) and the ground (terrestrial). The average annual radiation exposure from natural sources is about 300 millirem (3 millisieverts). In addition, man-made sources of radiation from medical, commercial and industrial activities contribute another 60 mrem (0.6 mSv) to our annual radiation exposure. One of the largest of these sources of exposure is medical X-rays. Diagnostic medical procedures account for about 40 mrem (0.4 mSv) each year. Biological effects of radiation Biological effects of radiation on living cells may result in three outcomes; firstly, injured or damaged cells repair themselves, resulting in no residual damage; secondly, cells die, much like millions of body cells do everyday, being replaced through normal biological processes; and thirdly, cells incorrectly repair themselves resulting in a biophysical change.

Ammonia It is mostly used in fertilisers, as a solvent in textile, leather, paper, and pulp industries and also in petroleum refining processes and cold storage. Exposure occurs mostly in the setting of an industrial accident. Toxicity depends on duration of exposure. It usually gets dissolved in moisture present in eyes, oral cavities, pharynx, and lungs and gets converted into ammonium hydroxide which is responsible for its corrosive action. Patients usually present with headache, salivation, swelling around eyes and lips, lacrimation, blurred vision, corneal opacification with scarring if head and face are involved. Cough, dyspnoea, bronchospasm,and consolidation occur when lungs are involved. Abdominal pain and severe vomiting leads to shock in patients with gastrointestinal tract involvement. Skin manifestations include erythema, oedema, blisters and vesicle formation.Treatment is to remove the patient from environment, if skin exposure occurs wash the whole body thoroughly with water. Administration of intravenous fluid becomes necessary in those with severe vomiting and hypovolaemia. Corticosteroids can be used during acute exposure along with antibiotics. Ventilatory support may be required in some cases.

Environmental Disasters

General Mechanism of Injury Due to Toxic Chemicals Massive acute exposure leads to inhalation of irritant gases resulting in acute inflammatory reaction in the respiratory mucosa mainly in the form of capillary damage and oedema, and severity of damage essentially depends on concentration of gas in the environment, solubility in water and duration of the exposure.The inflammatory reaction produced by noxious gases is similar for almost all agents but the severity differs depending on the above mentioned factors. It can range from mild respiratory inflammation to alveolar oedema, shock and disseminated intravascular coagulation (DIC) syndrome—the last one accounting for most of the fatalities in inhalational disasters.

Sulphur Dioxide See Chapter 3 on Section 27 Environmental Medicine. Carbon Monoxide Carbon monoxide is a colourless, odourless gas formed when substances containing carbon are burnt with an insufficient supply of air. The combustion of fuels such as petrol, gas, coal and wood generate emissions of carbon monoxide. Motor vehicles are the main source of in urban areas. Exhaust emissions contain carbon monoxide from incomplete burning of fuel in the engine. Carbon monoxide can have serious health impact on humans. When inhaled, the carbon monoxide binds to the haemoglobin in the blood (and becomes carboxyhaemoglobin) in place of oxygen and is carried through the blood stream. This reduces the oxygen-carrying capacity of the red blood cells and decreases the supply of oxygen to tissues and organs, especially the heart and brain. This can be a serious problem for people with cardiovascular disease. Most people in the community need to be exposed to a level of 200 ppm for several hours before they start to feel effects. Carboxyhaemoglobin formation is reversible when the person is no longer exposed to carbon monoxide. Treatment The treatment for carbon monoxide poisoning is to immediately remove the victim from the exposure without endangering oneself. The main medical treatment for carbon monoxide poisoning is 100% oxygen by a tight-fitting oxygen mask. Oxygen hastens the dissociation of carbon monoxide from haemoglobin, improving tissue oxygenation by reducing its biological half-life. Hyperbaric oxygen is also used in the treatment of CO poisoning; hyperbaric oxygen also increases carboxyhaemoglobin dissociation and does so to a greater extent than normal oxygen. Hyperbaric oxygen may also facilitate the dissociation of CO from cytochrome oxidase. Further specific treatment for other complications such as seizure, cardiac abnormalities, pulmonary oedema, and acidosis may be required. Late development of neuropsychiatric impairment is one of the most serious complications of 2035

poisoning. Prevention remains a vital public health issue, requiring public education on the safe operation of appliances, heaters, fireplaces, and internal-combustion engines, as well as increased emphasis on the installation of carbon monoxide detectors.

Acute phase: Exposed person exhibits dyspnoea, nausea, headache, tachycardia, and weakness, and may complain of pleuritic chest pain.These symptoms develop after a lag-period of few hours. Bronchospasm appears in most cases and pulmonary oedema in few.

Chlorine Chlorine is a halogen element used as a reagent in plastic manufacturing and paper industries and also used in drinking water and swimming pool water to kill harmful bacteria. It is also used as part of the sanitation process for industrial waste and sewage. Chlorine gas can be pressurised and cooled to change it into a liquid so that it can be shipped and stored. When liquid chlorine is released, it quickly turns into a gas that stays close to the ground and spreads rapidly. Chlorine gas can be recognised by its pungent, irritating odour, which is like the odour of bleach. The strong smell may provide an adequate warning to people that they have been exposed. The gas appears to be yellow-green in colour. Chlorine itself is not flammable, but it can react explosively or form explosive compounds with other chemicals such as turpentine and ammonia. Mechanism of toxicity is the generation of hypochlorous acid, hydrochloric acid and chloramine gas which is formed when ammonia and bleach are mixed. These byproducts cause coagulative necrosis and oxidative damage. Symptoms of respiratory tract usually predominate after chlorine exposure. During or immediately after exposure to dangerous concentrations of chlorine, the following signs and symptoms may develop like cough, chest tightness, burning sensation in the nose, throat, and eyes, watery eyes, blurred vision, nausea and vomiting. Burning pain, redness, and blisters appear on the skin if exposed to chlorine gas. Difficulty in breathing may appear immediately if high concentrations of chlorine gas are inhaled, or may be delayed if low concentrations of chlorine gas are inhaled. Pulmonary oedema occurs on severe exposure. Management usually involves leaving the area where the chlorine was released and getting to fresh air. Remove clothing and rapidly wash entire body with soap and water, and get medical care as quickly as possible. Treatment is largely supportive as no antidote for chlorine is available.

Subacute and chronic phase: Pulmonary oedema clears in few days and patient passes into an asymptomatic phase lasting for 2 to 5 weeks. The X-ray of chest appears normal and the patient may have mild dyspnoea. After 3 to 6 weeks there is a relapse of symptoms and the patient develops progressive dyspnoea, cough, and cyanosis. Chest X-ray shows multiple, discrete, nodular opacities. In severe cases, hypoxia and CO2 retention may be fatal.

Nitrogen Dioxide Exposure to oxides of nitrogen occurs in welders using acetylene torches, coal miners, chemical industries manufacturing dyes, farmers who work with silage when it is called as silo fillers disease, smoke from cigarettes, cigar pipes and diesel fumes. Nitrate concentration is increased in grain plants by the use of fertilisers. Nitrates combine with organic acid to form nitrous acid which in turn decomposes to nitrous oxide (N2O), nitrogen tetraoxide (N2O4) and nitrogen penta oxide (N2O5). N2O and N2O4 are responsible for injury to lungs. The threshold limit of nitrous oxide is 5 ppm, and humans exposed to even to 50 ppm for short duration are also at risk of developing acute lung injury. Nitrogen dioxide is a powerful oxidant and is capable of causing extensive damage to respiratory epithelial cells. Clinical course can be divided into following stages: Super acute stage: This phase follows immediately after exposure. Patients suffer severe hypoxia and formation of methaemoglobin. Most are critically ill and may succumb before 2036 medical aid can be made available.

The treatment is mainly supportive. Methaemoglobinaemia, if present, should be treated with IV methylene blue. Corticosteroids may be helpful in some cases. Ozone See Chapter 3 of Section 27 Environmental Medicine. Isocyanates These compounds are used in paint, furniture, rubber and pesticide industry. Commonly used isocyanates are toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), naphthalene diisocyanate (NDI), hexamethylene diisocyanate (HDI). These compounds cause pulmonary and skin manifestations. Pulmonary manifestations are mainly due to bronchoconstriction and may lead to toxic bronchitis and asthma, accelerated decline in FEV1 and extrinsic alveolitis. Skin manifestations range from localised itching to widespread eczema. Treatment is symptomatic. Phosgene It is a colourless gas heavier than air with a musty odour resembling mown hay, commonly used in pesticide industry. On exposure it produces irritation with coughing and sense of suffocation. Large exposure can cause increased capillary permeability resulting in large shifts in body fluids and shock with pulmonary oedema. Marked bronchiolar and bronchial congestion occurs early and emphysematous lesions may occur as delayed sequelae. General Treatment Treatment of all noxious gas exposure is similar as basic mechanism is identical for many of them. Prime importance should be given to maintenance of airway and circulation. As per requirement continuous positive airway pressure (CPAP) and intermittent positive airway pressure (IPPV) should be provided. Antibiotics should be used only if infection is suspected, otherwise prophylactic antibiotics have no role. Corticosteroids are recommended in acute phase to prevent bronchiolitis. Methylprednisolone 1 gm every 12 hourly can be used for three days. RECOMMENDED READINGS 1.

National Disaster Management Guidelines. Management of Nuclear and Radiological Emergencies. A publication of National Disaster Management Authority, Government of India. ISBN 978-81-906483-7-0 February 2009. New Delhi.

2.

Smith E, Wasiak J, Sen A, Archer F, Burkle FM Jr. Three decades of disasters: a review of disaster-specific literature from 1977-2009. Prehosp Disaster Med 2009; 24:306-11.

3.

Tamura Y, Fukuda K. Earthquake in Japan. Lancet 2011; 377(9778):1652.

Section

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Miscellaneous Section Editor: R.K. Singal 28.1

Geriatric Medicine Vinod Kumar 28.2 Sexual Medicine Prakash Kothari 28.3 Sports Medicine Anant Joshi 28.4 Diet in Medical Diseases Siddharth N. Shah 28.5 Care of Terminally Ill Anil Chaturvedi 28.6 Exercise and Yoga in Health and Disease S. Dwivedi, Shiva Narang 28.7 Adult Immunisation R.K. Singal, A.K. Agarwal 28.8 Perioperative Management Prabha Adhikari 28.9 Law and Medicine N.K. Grover 28.10 Travel Medicine Yash Pal Munjal 28.11 Nanotechnology and Nanomedicine Ramchandra D. Lele

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28.1 DEFINITION AND EPIDEMIOLOGY Geriatric medicine is the specialised branch of medicine that deals with medical problems of older persons. United Nations term older persons as those aged 60 years or above and in India also, cut off point is 60 years. This cut off point is purely arbitrary and does not necessarily indicate the onset of ageing process or age-related disorders in an individual. In fact, older persons are highly heterogenous, lot showing great variations in agerelated physiological decline and age-related disorders. Generally, age-related decline in strength, vision, memory, locomotion, nutrition, immunity and homeostasis develop slowly while onset of disease may be abrupt. There is a steady increase in the ageing of our population and therefore geriatric medicine has to be established in our country while it is well-established in other countries. Demographic trends reveal that population of older persons is growing faster than that of general population. Since 1950, life expectancy in India at birth has almost doubled from 32 years to 65 years. Total Indian population was 350 million in 1950, 1112 million in 2006 and this is projected to be 1572 million in 2050, i.e. a percentage increase of 40% in a matter of 44 years. In contrast, population of older persons (60+) which was 19 million in 1950 and 90 million in 2006 will be 330 million in 2050, thus showing a much greater increase (270%). Moreover, amongst them, the older ones (above 80 years) are growing at a fast pace. Their population which is 0.8 million in 1950, 9 million in 2006 which is projected to be 53 million in 2050, i.e. a rise of almost 500%. These very elderly people are usually weaker, more frail, insecure and dependent, and suffer more often from age-related diseases, neglect and abuse as compared to young olds (60 to 79). GERIATRIC MEDICINE VERSUS GENERAL MEDICINE Older persons frequently suffer from multiple disorders, require long-term treatment with multiple drugs and may often need physical and rehabilitative therapy for various residual disabilities. Some diseases occur more often and some occur almost exclusively in older persons. Degenerative disorders like cardiovascular disease, chronic obstructive pulmonary disease, diabetes, osteoarthritis and infection-related disorders like pneumonias, urinary tract and other infections occur more frequently in older persons while diseases such as Alzheimer’s disease, prostatic hypertrophy, postmenopausal osteoporosis, and macular degeneration occur almost exclusively in old age. Clinical presentation of many disorders in old age may be atypical and different. In old age, myocardial infarction may occur without chest pain, infection may be without fever and hypertension may be without a rise in diastolic pressure. Obstructive jaundice in older person is more likely to be of malignant origin. Bacteriuria, impaired glucose tolerance and premature ventricular contractions do not have the same degree of prognostic gravity as in younger subjects. An older 2038 person is more vulnerable to confusion or drowsiness in

Geriatric Medicine Vinod Kumar response to an acute event compared to young person. Thus, approach to a geriatric patient should be different. Developing a rapport with an older patient, art of history taking and of being a patient listener, assessing him comprehensively and ordering only limited but necessary investigations, are some of the requisites of a geriatric physician. CLINICAL ISSUES IN GERIATRIC PRACTICE Older persons seek medical advice more than any other segment of adult population. In a developing country like India, where demographic transition has occurred faster, but public hygiene has remained inadequate, older persons often suffer from double burden of diseases, i.e. both degenerative and infection-related diseases. Consequently, increasing number of people surviving longer into old age suffer from type 2 diabetes, coronary heart disease, hypertension, stroke, chronic obstructive pulmonary disease, Alzheimer’s disease, osteoarthritis, osteoporosis, prostatic hypertrophy, cataracts, macular degeneration, and cancer, etc. and at the same time they are vulnerable to infections involving respiratory (including TB), urinary and digestive tract. Acute infections may present atypically with absence of fever and leucocytosis; instead, they may present with impaired intellect/ memory, incontinence, instability or immobility—the so called ‘geriatric giants’. Malnutrition, occult hypothyroidism, renal injury, depression, urinary incontinence and sexual problems are also common in old age.For a detailed description of geriatric disorders, reader is referred to consult a ‘Textbook of Geriatrics’. Following description highlights some of the important diseases in old age. The Frail Older Person and the Frailty Syndrome Older persons who become physically weak, tired, underweight, and unable to easily walk are termed as frail. They have reduced physiological reserve and are unable to carry out activities of daily living in stressful situations. They are often 80+ and may get disabled by falls, infections, drug reactions or bereavements.When frail individuals have several impairments like undernutrition, osteoporosis, muscle loss, neuronal loss, it is then termed as frailty syndrome. Frail subjects are prone to falls and fractures. Undernutrition is brought about by reduced appetite and taste, bowel dysfunction, and physical inactivity in old age while hormonal factors and calcium/vitamin D deficiency additionally contribute to osteoporosis. Muscle loss or sarcopaenia in old age is due to reduced protein intake, sedentarism, diabetes, and atherosclerosis. Hormonal deficiency also leads to frailty. Gradual neuronal loss and cognitive impairment occurs in many frail older persons. Prevention and treatment of frailty syndrome includes physical activity, adequate protein, calcium and vitamin intake, use of ACE inhibitors and hormone replacement therapy together with control of underlying disorders. Osteoporosis Ageing is associated with progressive bone loss and osteoporosis with increased risk of hip and other fractures. It is more prominent

Falls in Older Persons Falls are common in old age due to various diseases and are contributed by changes that occur with ageing. Balanced and upright posture in humans is maintained by central structures of cortex, sub-cortex and cerebellum which co-ordinate the sensory inputs from visual, vestibular and proprioceptive organs and by muscular activity, especially of the lower limbs. With ageing, physiological changes occur in the nervous system like impairment of vision and hearing, reduction of proprioceptive and vibratory sensations, increased sway, altered gait and poor positional control predispose to falls. Falls best defined as sudden unintentional change in position causing a subject to land on ground or on lower level constitute a common problem in older persons. Recurrent falls mean two or more falls in six months. Risk factors are advancing age, female sex, cognitive and sensory impairment, polypharmacy and poor psychosocial and environmental factors. Falls may cause mild, moderate or severe bodily injury and even fractures and subdural haematoma. More than 80% of hip fractures in older persons are due to falls. Causes of falls are multiple. Drugs and even an unrelated acute event like pneumonia or dyselectrolytaemia can manifest as fall. An easy way for students to remember common causes of falls is to recall the words FALL SINDROME in which I replaces Y in the word syndrome (Table 1). Table 1: Causes of Falls F : Falls from extrinsic causes – uneven floors, defective staircases, footwear and poor lighting A : Arrhythmias L : Lower limb Neuropathy L : Lower limb diseases like Osteoarthritis, Foot calluses, Bunions, and Hammer toes S : Syncope – Aortic stenosis, Heart block, Mitral prolapse, Obstructive Cardiomyopathy I : Instability N : Neurological diseases – Vertebro-Basilar Insufficiency, Hemiplegia, Pakinsonism D : Defects of Cognition, Vision and Hearing R : Recurrent falls O : Orthostatic hypotension and Orthopaedic problems of old age M : Muscle weakness, especially of the lower limbs E : Epilepsy and Seizures

A thorough history of the patient and family members, systemic clinical examination to identify various diseases and their relationship to falls and relevant investigations are essential. Assessment of cognition, muscle strength, postural stability, proprioceptive sensation and balance should be carefully carried out. Treatment of older persons presenting with falls include management of injury and associated illnesses, if any. Specific treatment depends on the underlying condition. Regular exercise and use of limbs are imperative. Interventions to improve strength, balance and endurance are also important.

Geriatric Medicine

in menopausal women due to cessation of oestrogen secretion. Risk factors for osteoporosis fractures include female sex,advancing age, small built, calcium and vitamin deficiency, sedentarism, smoking, alcoholism and caffeine excess. Diagnosis is made by measuring bone mineral density (BMD) by dual energy X-ray absorptiometry (DEXA) which is also useful in predicting fractures and monitoring of therapy. Detection in asymptomatic stage and prevention of fractures is important. Preventive methods include adequate intake of calcium (1,200 mg/dL) and vitamin D (400 to 800 IU/dL), walking and antigravity weight bearing/muscle strengthening exercises, fall prevention, smoking cessation and avoidance of alcohol intake. Sunlight exposure for at least 15 minutes a day for 3 times a week is good source of vitamin D. Hormone therapy for osteoporosis has now been largely replaced by use of safer drugs like bisphosphonates (alendronate, risedronate, ibandronate, pamidronate, zandronate), selective oestrogen receptor modulators, the SERMs (raloxifen, tamoxifen), calcitonin and teriparatide.

Dementia This is a clinical syndrome characterised by a decline in cognitive, intellectual and memory function due to disease process affecting the central nervous system. There is difficulty in many functions like problem solving, judgement, abstract thinking, geographic orientation, etc.There is no loss of consciousness and hence it is different from delirium. Minor memory lapses, such as forgetting one’s keys or forgetting names do not ordinarily mean dementia. However, if one gets lost in familiar surroundings or fails to recognise spouse, diagnosis of dementia can be considered. Dementia is detected by the use of criteria of the diagnostic and statistical manual of mental disorders (DSM IV). Many diseases can result in dementia. Commonest are Alzheimer’s disease (AD), a progressive and irreversible cause of dementia and the muIti-infarct dementia (MID) also known as vascular dementia. Other causes of dementia are subdural haematoma, normal pressure hydrocephalus, hypothyroidism, head trauma, alcoholism, brain tumour and vitamin B12 deficiency, many of which are reversible with treatment. Generalised neuronal loss in the cortex is the main histological change seen in cases of dementia. There is diffuse cerebral atrophy accompanied by enlargement of third and lateral ventricles. Atrophy of hippocampus is prominent. Senile plaques and neurofibrillary tangles (NFT) characterise AD. Plaques are extracellular lesions and are scattered throughout the cerebral cortex and hippocampus. They consist of beta amyloid. NFTs are in the nerve cell cytoplasm and contain tau proteins. Clinical features include slow onset of forgetfulness, loss of interest in surroundings, impairment in social skills and personality. Depression may occur in early stages. Disorientation in time and space later followed by language impairment, aphasia, apraxia fits and paralysis are common. Finally, patient may start vegetating and death may ensue by intercurrent infection. Diagnosis of AD is supported by any of the neuro-imaging modalities like CT scan, magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT) and by ruling out other causes of dementia. Unless a dementia is due to treatable cause, management depends more on care of the patient rather than by curative methods. This is most applicable to AD. Advice to family and social support are key actions of treatment, drugs are practically of no value. Neuroprotectives, N-methyl-D-aspartic acid (NMDA) antagonists, anti-inflammatory agents and cholinesterase inhibitors like tacrine, donepzil, rivastigmine and galantamine are claimed to have beneficial effects on cognitive functions. Ancillary treatment includes alprazolam for disturbed sleep, anti-psychotics for restlessness and haloperidol for emotional stability. 2039

Urinary Incontinence It is involuntary passage of urine through urethral orifice, a common problem in older persons and a common cause of hospitalisation. It is commoner in females. It contributes to pressure sore, urinary tract infection and depression. Risk factors include smoking, chronic cough, depression, obesity, multiparity, oestrogen depletion and constipation. Apart from sanitation problems and interference in daily life, severe cases of urinary incontinence can have important social repercussions. Causes of urinary incontinence are either established or transient (Table 2). Causes of established urinary incontinence include cerebral or spinal cord lesion, stroke, dementia, bladder disease, Parkinsonism and myelopathy. Latter are best recalled by student by using the mnemonic DIAPERS. Table 2: Transient Causes of Urinary Incontinence D : Delirium I : Infection of urinary tract A : Atrophic senile vaginitis P : Pharmaceuticals or drug induced P : Psychological causes like depression E : Excessive urine output R : Restricted mobility S : Stool impaction

Evaluation of urinary incontinence is done by history and physical examination including neurological, rectal and gynaecological examination. Specific tests include cystoscopy, urodynamic studies, cystometry and sphincter electro-myography. Treatment depends on the cause. Many cases are relieved spontaneously. General measures include psychological support, behaviour modification, frequent toileting schedule, provision of bedpans and urinals, urethral sphincter and pelvic floor exercises, bladder training, treating of infections and in extreme cases supra-absorbable pads, pessaries and indwelling catheters. Biofeed training is sometimes resorted too. Pharmacological treatment includes anti-cholinergics and spasmoIytics for hyper-reflexive or unstable bladders. Examples are oral imipramine 25 mg twice a day or oxybutyrin 2.5 to 5 mg three times a day or propanthaline. Oestrogens can be useful for atrophic vaginitis. Menopause, Andropause and Hormone Replacement Therapy As a short-term consequence of oestrogen deficiency, menopause is accompanied by vasomotor symptoms (hot flushes, sweating), urogenital atrophy (dryness of vagina, dyspareunia, urinary incontinence) and depressive moods while postmenopausal morbidity of coronary heart disease, osteoporosis, dementia and cancers is believed to be due to chronic oestrogen deficiency. Oestrogen or hormone replacement therapy (HRT ) should therefore have some benefits. For premenopausal women, 20 µg of ethinyl estradiol plus 1 mg of norethindrone (progestin) daily for 21 days can eliminate vasomotor symptoms and restore regular cyclicity. They also protect against ovarian and endometrial carcinomas and increase the bone density. But, a history of thromboembolism, breast cancer, unexplained vaginal 2040 bleeding, smoking and liver disease is contradiction to the use

of HRT. In that case, progestin only drugs, e.g. 0.35 mg of norethindrone daily or medroxyprogestrone (Depo-provera injection 150 mg IM every 3 months) can be given even though it does not regularise the cycles. Although postmenopausal hormone therapy (PHT) is also known to provide benefits for vasomotor, urogenital and psychological symptoms, its long-term use in osteoporosis is no longer preferred due to serious side effects. With regard to colorectal cancer, some risk reduction has been reported with HRT, but its role is doubtful in cognitive decline and dementia. With regard to cardiovascular disease prevention also, role of HRT is of questionable value. In the heart and oestrogen/ progesterone replacement study (HERS), not only the fact that 4 years of HRT resulted in no difference in coronary heart disease compared to placebo, but there was, in fact, a 50% increase in the risk of coronary events. Removing or adding of progestin made no difference to the results. Furthermore, results of Women’s Health Initiative (WHI) study suggested an early increase in cardiovascular risk on HRT use both in terms of coronary heart disease and stroke. Definite risks of HRT include endometrial cancer, venous thromboembolism, breast cancer and gall bladder disease. Risk of endometrial cancer goes up with the duration of therapy with unopposed oestrogen treatment. Use of progestogen eliminates this risk of endometrial cancer. Risk of breast cancer also increases with duration of oestrogen treatment and addition of progestin further raises this risk. Risk of thromboembolism is increased both by oestrogen alone and by oestrogen/progestin combination. Like menopause in females, andropause occurs in males due to decline of androgenic hormone with ageing. Andropause, however, not universal to all men, is a gradual process and is not associated with any sudden event like menopause in females. There is a decrease in testosterone and serum inhibin with an increase in sex hormone binding globulin (SHBG). Apart from fatigue, depression, loss of energy and sex drive, andropausal males have increased risk of cardiovascular problems and osteoporosis. Treatment of andropause is testosterone replacement therapy. Testosterone enanthate can be given intramuscularly every two weeks. Testosterone should not be used for preventive purposes. Prostate and breast cancers, enlarged prostate, liver, kidney and heart disease and diabetes are contraindications for testosterone treatment. Age-Related Macular Degeneration (AMD) AMD is the leading cause of painless, slowly progressive visual loss in older persons. The term AMD is used to describe a variety of pigmentary and atrophic changes in the macula associated with the best corrected vision of 6/9 or worse. AMD is bilateral and progressive but its early recognition by routine eye checkups and photocoagulation form the most important strategy. Precise prevalence rates of AMD in our country are not available. In USA, AMD affects 11% of population of 65 to 74 years old and 28% of population over 74 years old. Because the ageing population is rapidly increasing, burden of AMD will increase in India also. AMD is divided into two types: the dry or non-exudative form and the wet or exudative form, latter being less common, but encountered more frequently and is more responsible for

Pressure Sores These are also known as bed sores or decubitus ulcers. These lesions of skin breakdown occur with significant frequency in those older persons whose body parts are subject to pressure, friction, shearing (two layers of skin slide on each other) and maceration (softening of skin by moisture). Skin, subcutaneous tissue, muscle and even bone and joints can be involved. Risk factors include immobility, inactivity, faecal and urinary incontinence, malnutrition and decreased consciousness. Anaemia, infection, peripheral vascular disease, oedema, diabetes mellitus, stroke, dementia, alcoholism, fractures and malignancies compound the problem. In advanced cases, osteomyelitis may be present. Strategies to prevent bed sores include frequent changing in the patient’s position, avoiding head end elevation beyond 30°, using special beds, surfaces like convoluted foam bed, alternating pressure mattresses, water mattresses, air fluidised beds and keeping the skin clean and dry. Treatment of pressure sores involves intensive nursing care. In the later stages, treatment of wound infection and mechanical, surgical or chemical debridement may be done. Irrigating solutions other than normal saline should be avoided. A wet-to-dry dressing is gently packed according to wound size and shape. HEALTHY AGEING Curative or tertiary care for numerous acute and chronic geriatric diseases is quite expensive and does not address the issue of maintaining long-term good health related quality of life by cost-effective strategies for disease prevention. Positive health practices of regular physical exercise, healthy diet, no-smoking, vaccinations, periodic checkups and stress management practised over the life course form the basis of healthy ageing and are capable of compressing the duration of period of morbidity in old age. Joint family system, informal support network, social and spiritual enrichment also contribute to healthy happy old age. Timely detection and correction of clinical and socioeconomic impairments and taking corrective measures compliments healthy ageing. Based on standard techniques, a comprehensive geriatric assessment of vision, hearing, locomotion, cognition, nutrition, depression, activities of daily living (ADL), instrumental activities of daily living (IADL), home environment, living arrangements, social and family support, financial dependence, smoking and alcoholism can be carried out by health provider in about 45 minutes.

REHABILITATION AND PHYSICAL THERAPY Rehabilitation refers to a combination of physiatrist, i.e. physical, occupational and speech therapy, psychiatric counselling; social, and economic rehabilitation. Obviously, a number of experts are needed. In India, vital role of cost-effective community based rehabilitation (CBR) by trained community health worker and cost-effective indigenous assistive devices will be more relevant. Rehabilitation is often needed after prolonged bed rest, e.g. stroke, hip fracture, myocardial infarction, etc. to help regain functional independence and carry out ADL as a useful member of the society once again. Rehabilitation includes various exercises, training in ADLs (bathing, feeding, toileting and transferring) and lADLs (cooking, cleaning, shopping, etc.), treatment of pain and inflammation, etc.

Travel Medicine

severe visual loss. Fluorescein angiography, amsler grid and contrast sensitivity are useful investigative methods to evaluate AMD. Treatment for dry AMD is non specific. Antioxidants and sunglasses have been used. Many patients benefit by organ LASER photocoagulation. Recurrences are, however, high after photocoagulation. Recently introduced non-LASERS as the form of photodynamic therapy (PDT) or transpapillary thermo therapy (TTT) are other therapeutic options. Monthly intravitreal injection of leucentis (ranibizumab) or avartin (bevacizumab) significantly retards visual deterioration and improves the vision in AMD cases.

TERMINAL AND RESPITE CARE More than others, older persons need palliative or terminal care which is a total care of terminally ill patients with untreatable diseases like cancer and Alzheimer’s and covers physical aspects like pain and distress as well as psychological, social and spiritual aspects. Terminal care can be offered at home, the hospice and at a general hospital. A hospice is neither a hospital, nor a home but in fact a combination of both where a dedicated team of physician, nurse, social worker and a counsellor provide effective relief through nursing, medical and social care, including bereavement counselling. General hospital settings are largely unsuitable for terminal care as the system is geared towards cure based on short-term stay while the home may be ideal. An important component of terminal care is care of the dying patient. Patient’s preferences should dictate the type of care to be provided in bringing about a satisfying end from patient’s point of view. A knowledge of law, will, power of attorney, and resuscitation is also important for patient’s wishes. Respite care is temporary supportive care of an older person by a substitute care giver. Respite care is often sought by the original care giver to, relieve the strain of care giving which may prove to be physically, emotionally and financially draining on him and other family members. RECOMMENDED READINGS 1.

Bhatla PS. Lecture Series in Geriatrics. New Delhi. Health Care Promotion Trust; 2000.

2.

Caruso LB, Silliman RA. Geriatric medicine. In: SA Fauci, E Braunwald, DL Kasper et al, editors Harrison’s Internal Medicine; 17th Ed. Vol. 1; New York: McGraw Hill; 2008:pp.53-62.

3.

Dey AB. Handbook on Health Care of the Elderly. New Delhi. World Health Organisation, Ministry of Health and All India Institute of Medical Sciences.

4.

Kumar V. Ageing: Indian Perspective and Global Scenario. New Delhi. All India Institute of Medical Sciences; 1996.

5.

Liebig PS, Rajan SI. An Ageing India: Perspectives, Prospects and Policies. J Ageing and Social Policy. 2003;15(2-3):1-234.

6.

Rosenblatt DE, Natrajan VS. Primer on Geriatric Care. Cochin: Pixel Studio; 2002.

7.

Sharma OP. Geriatric care. A Text Book of Geriatrics and Gerontology; 3rd Ed. New Delhi: Viva Books; 2008.

2041

28.2 Sexual disorders are one of the most common disorders of human functioning and deserve attention of almost all physicians regardless of their particular speciality. An overview of sexual disorders is given in this chapter. DIAGNOSIS OF A SEXUAL DISORDER For a precise diagnosis of male and female sexual dysfunctions, four cardinal parameters need to be probed in particular along with the routine history of the patient. Male Desire Erection Penetration Orgasm

Female Desire Lubrication Penetration Orgasm

These four parameters cover every possible facet of the reported sexual dysfunction and helps quickly in pinpointing the diagnosis.The evaluating method of history taking is precise and effective in a clinical/office set-up. This procedure has already been successfully tried in more than 50,000 patients. Desire Sexual desire is an instinctual inclination towards sensual gratification. In other words, it is the readiness to feel erotic. Increase or decrease in sexual desire can be evaluated by considering the information about frequency of sexual thoughts and masturbation or frequency of sexual intercourse. Increase or decrease in desire could be because of psychogenic or organic causes. The common psychological causes leading to decline in sexual desire could be because of depression, schizophrenia, following intake of certain drugs like antihypertensives, psychotropics, anti-androgens, cimetidine and certain ayurvedic preparations which contain rauwolfia alkaloids and addictive agents like ganja. Sometimes, dislike of partner or partner’s behaviour, disturbed interpersonal relationship and fatigue may interfere with an individual’s sexual desire. Testes manufacture testosterone and gets metabolised in the liver. Any testicular or hepatic pathology can lead to reduction in desire. Often chronic debilitating illnesses and androgen insensitivity syndrome could contribute to decline in desire. Desire could increase in mania and in schizophrenia (because of loosening of inhibitions). Often sudden increase in desire could be following frontal lobe brain tumours, head injuries and temporal lobe epilepsy. It may also suddenly increase following intake of alcohol or marijuana. Erection It is essential to differentiate psychological erectile dysfunctions from organic erectile dysfunctions. If a man is able to achieve and/or sustain an erection of adequate quality in one situation 2042 (i.e. sleep, early morning on full bladder, during masturbation),

Sexual Medicine Prakash Kothari but unable to achieve the same at the time of coitus; then the problem is situational (psychogenic) and not constitutional (organic). This is the hallmark to differentiate the two varieties of erectile dysfunctions. Psychological erectile dysfunction is characterised by sudden onset and selective nature while in organic erectile dysfunction, the onset is usually gradual and it is non-selective in nature. That means an individual will have erectile dysfunction in all situations and with all partners. Erectile dysfunction could be primary or secondary. If an individual experiences the erectile dysfunction from the very beginning, it is known as primary and if it is developed later (after normal functioning for a specific period), it is called secondary. Lubrication Lubrication is the barometer for female sexual arousal. It is akin to erection in males. Decrease or increase in lubrication may lead to coital discomfort and/or pain. The common causes of inadequate lubrication are lack of adequate foreplay or arousal, local vaginal infections and endocrine imbalance. There could be increase in lubrication because of allergy or increased sexual arousal, often because of unknown aetiology. Penetration A man may have adequate sexual desire, stiff erection but would lose his stiffness prior to penetration. This is largely because of anxiety over sexual situation coupled with fear of failure. Sometimes despite the adequate erection and continued sustenance, penetration may not be possible because of inadequate knowledge of female sexual anatomy and sexual positions. Any evidence of pain in the penis at the time of penetration could lead to decline in erection. Often phimosis (pain and/or difficulty in retracting the foreskin over the glans penis) could be the cause. Vaginismus and rarely obstructive vaginal pathology in females could be responsible for a man’s inability for successful penetration. Vaginismus is a condition where there is an involuntary spasm (severe contractions) of the outer one-third of the vagina during an attempt, or in anticipation of an attempt of vaginal penetration, thereby making penile penetration impossible. Hence, examination of the female partner is necessary prior to implementing the therapy even in a case of male sexual dysfunction. There are occasions where an individual may lose an erection immediately after penetration. This could be because of anxiety, distraction or a lax vagina leading to inadequate peno-vaginal contact. Orgasm Orgasmic disorders have so far been described as ejaculatory disorders in male despite the fact that there is a clear-cut neurophysiological distinction between the two. Orgasm occurs between the two ears whereas ejaculation in men and vaginal contractions in women occur between the two legs. Orgasm in

CLASSIFICATION OF ORGASMIC DISORDERS Orgasmic disorders can be best classified as early, delayed, impaired (reduced) and absent (inability to experience) orgasmic responses. Early Orgasmic Response (EOR) If an individual experiences orgasm earlier than his expectation, which is within the rational limits, is termed as early orgasmic response. EOR is a better terminology than premature ejaculation in males as it does not propagate the myth that ejaculation and orgasm are synonymous and the diagnostic label focuses on exact pathology per se (Though EOR in women is not described hitherto in the literature, it does exist in the females).

for example in prepubertal boys, elderly individuals with very low serum testosterone and sometimes following long-term use of drugs like carbamazepine. In this situation, the orgasmic ability of an individual remains intact but there is no antegrade or retrograde ejaculation whatsoever. Sometimes, vaginal contractions in females are akin to ejaculatory contractions in males. Majority (but not all) of women may experience vaginal contractions at the time of orgasm. EXAMINATION AND INVESTIGATIONS Along with routine physical examination, one needs to check perianal sensations, anal sphincter tone and autonomic nervous system imbalance as and when required. Screening tests like routine blood (to rule out any anaemia), blood sugar fasting and 2 hours after lunch, lipid profile need to be carried out as a routine. Serum testosterone and sex hormone binding globuline (SHBG) may be advised if there is clinical suspicion of testosterone deficiency. Other hormone investigations like prolactin, thyroid may be advised to rule out any underlying pathology. Other Investigations Nocturnal penile tumescence rigidity (NPTR) monitoring NPTR monitoring by Rigiscan can help in determining the rigidity and sustenance of erection. This is a precise and noninvasive test to rule out psychogenic erectile dysfunction or confirm organic erectile dysfunction.

Delayed Orgasmic Response (DOR) Here, an individual does experience orgasm, but with a delay. The common causes include reduced arousal, fear, fatigue, anaemia, diabetes and reduced testosterone levels. Sometimes, inadequate penovaginal contact, e.g. lax vagina leading to not so firm grip on penis could be a contributing factor.

Intrapenile injection This procedure involves an injection of vasoactive drugs (papaverine combined with chlorpromazine or phentolamine and/or prostaglandin E1) directly into the corpora cavernosa of the penis. The erectile response and the amount of drug that is required to produce erection, gives a clue to the clinician whether the erectile dysfunction is psychogenic or organic.

Impaired Orgasmic Response (IOR) This categorises a condition in which there is reduction in the intensity of orgasmic pleasure. This could be psychogenic, due to low testosterone levels and sometimes following drugs like brown sugar and cocaine. Myopathies and neuropathies are known to cause this particular disorder.

Doppler examination This is a non-invasive technique which helps in determining the patency of the superficial and deep blood vessels of the penis and their ability to dilate after an injection of vasoactive drugs.

Absent Orgasmic Response (AOR) In this condition, an individual fails to experience orgasmic pleasure in the conscious stage. If there is no evidence of ejaculation including absence of sleep emissions, then this condition may be described as a ‘total’ AOR. Myopathies and neuropathies are the frequent causes of this particular disorder. This classification is precise, focuses exactly on the pathology and does not propagate any myths. In addition, the classification has a distinct advantage of male and female parallelism. The classification EOR, DOR, IOR and AOR encompasses all the male and female orgasmic disorders. Following the orgasm, the ejaculate usually comes out through the urethral meatus in spurts, i.e. antegrade ejaculation. But at times following orgasm, the ejaculate does not come out in antegrade fashion and instead goes backward into the bladder due to bladder neck disturbances, e.g. surgery involving bladder neck, etc. This is known as retrograde ejaculation. Sometimes, there may not be any formation of semen (absent ejaculate)

Sexual Medicine

males is usually followed by ejaculation. However, orgasm can occur without ejaculation and vice-versa. In females, the peak of sexual pleasure, i.e. orgasm is usually accompanied by rhythmatic contractions in the vagina. The feeling of ‘enough and nothing more!’ is the litmus test to gauge whether a woman has experienced orgasm or not. Orgasm in a male and a female can be best defined as ‘an explosive, cerebrally encoded, neuromuscular response, at the peak of sexual arousal by psychobiological stimuli, the pleasurable sensations of which are experienced in association with dispensable pelvic physiological concomitants’. Ejaculation in men and vaginal contractions in women is not a must for orgasm.

Penile blood pressure This is a screening test used for erectile dysfunctions. Penile systolic blood pressure (obtained by using a Doppler probe and tying a special cuff around the penis) divided by the systolic blood pressure of the arm, gives the peno-brachial index (PBI). Abnormal reading may give indication of vascular insufficiency leading to erectile dysfunction. Infusion cavernosometry and cavernosography Cavernosometry involves infusion studies with normal saline, helpful in diagnosing venous leaks responsible for inadequate erection. Cavernosography is a graphic study by X-rays of the penis (by injecting contrast medium), which determines the abnormal draining channels responsible for erectile dysfunctions. Electromyography (EMG) EMG studies could help to diagnose neurological lesions causing erectile dysfunction, impaired or absent orgasmic response and in conditions like squirtless seminal dribble (emission). Note: EMG, infusion studies and PBI are not much utilised now. 2043

TREATMENT In psychosexual dysfunctions, the physician must emphasise the fact that he is treating a relationship and not the individual. The treatment aims at symptom removal which may require adequate blending of supportive psychotherapy coupled with behaviour modification and use of medication, etc. as and when necessary. Clearing of the myths and misconceptions and imparting adequate knowledge of sex and sexuality usually helps undo ignorance and reduce anxiety. However, if there is any evidence of major depression, schizophrenia, disturbed marital relationship and those with rigid defenses need to get their problem sorted out prior to implementing sex therapy. The starting point for the most sexual dysfunctions would be sensate focus exercises. This includes sensuous interplay by avoiding sexual interaction. Intercourse is forbidden in initial stages, hence the performance anxiety is allayed completely. The couple is immersed in situation of physical intimacy short of intercourse. The initial sessions consist of tactile stimulation without any genital touch. Here, one partner tries to explore the areas with maximum arousal and verbalises his/her feelings, likes and dislikes. Partners are requested to touch each other in a way that helps trigger relaxation and not anxiety. If one is passive during an exercise, and the partner’s touch is triggering the anxiety, then one needs to convey the same to the partner. The main thought patterns which contribute to anxiety are spectatoring, racing thoughts and performance thoughts.These exercises help to relieve sexual boredom and gradually increase sexual arousal. Although sexual desire and arousal are not the same, often they do reinforce each other. Enhanced arousal leads to increased sexual desire which in turn leads to more arousal. The main focus is on non-demand interactions. When you are the active partner, caress for your own pleasure. When you are passive, allow yourself to follow the sensations and enjoy them without any anxiety to respond. Initially, the genital touch is prohibited but later genital touching is permitted without demand to produce erection. Treatment of Male Sexual Disorders Strategy for psychological erection disorders 

Pleasure without erection



Pleasure with erection



Extra vaginal orgasm



Penetration without orgasm



Coitus

Some cases of psychological and organic erectile dysfunctions can be helped effectively by medicines like sildenafil citrate (50 to 100 mg). The medicines need to be taken an hour before the anticipated sex act, preferred on empty stomach and one can take maximum of one tablet in 24 hours. The effect usually lasts for 6 to 8 hours. This particular tablet has no role on desire or orgasm, but it helps to enhance the rigidity and sustenance of already achieved partial (semi stiff ) erection. This medication is contraindicated in those who are taking nitrates (for heart conditions or hypertension), alpha blocker for prostate problems and those who have retinopathy. The other drug is tadalafil (10 to 20 mg) that has a more lasting effect up to 24 to 36 hours. However, patients reported a shade better quality of 2044 erection with sildenafil as compared to tadalafil (Table 1).

Table 1: Medicines and Its Side Effects Generic Name

Sildenafil

Tadalafil*

Availability in milligrams Onset of action (minutes) Duration of action in hours Interference in absorption with food

25/50/100 30 to 45 6 to 8 Yes

10/20 30 to 45 24 to 36 No

Side Effects** Headache Visual disturbances Flushing Back pain and myalgia Dyspepsia Rhinitis Flu-like syndrome

+++ ++ ++ + +++ ++ +

++ ++ ++ ++ ++ ++

* May cause dizziness; ** As encountered by the author in his clinical practice

In those patients, where there is evidence of testosterone deficiency (revealed by clinical and metabolic evaluation), testosterone may be implemented orally or by injection. Intramuscular depot injections of testosterone undecanoate need to be taken once in 3 months. Often these medicines are more effective, once the testosterone deficiency is overcome. In elderly individuals, however, care needs to be taken to do prostate specific antigen investigation and transrectal ultrasonography of prostate prior to implementing testosterone therapy. The second option could be intra-penile self injection with vasoactive drugs, such as papaverine in combination with chlorpromazine, phentolamine and prostaglandin E1. Prostaglandin E1 can be used alone also. However, 1 out of 3 patients report of pain in the penis following injection of prostaglandin E1. Sometimes the erection achieved by the papaverine injection fails to subside leading to priapism. In such situations, physicians should be aware of the method to relieve the same, failing which a surgeon can help drain the blood from the penis resulting in detumescence of the penis. However, prostaglandin E1 is relatively free from the side effect of priapism, though more expensive and has difficult availability. If the above procedure fails, one may consider penile implant prosthesis surgery for the erectile dysfunction. Following this surgery, the pleasure at the time of orgasm and the ability to father a child remains unchanged. The types of penile implant surgeries available are listed in the Table 2. Table 2: Types of Penile Implant Surgeries

Cost Appearance Comfort Hardness Device failure Surgery Failure rate Types

Non-Inflatable

Inflatable

Less Always erect Less Fixed Less Less time Less Flexible Malleable

More Under your control More Adjustable More More time and skill More Three-piece Two-piece One-piece

The author in his clinical practice found these methods good as adjuncts, but not as a mainstream treatment regime. Paroxetine (20 mg), or clomipramine (25 mg), to be taken 4 hours and 6 hours, respectively prior to the anticipated sex act help delay climax in most individuals. Sometimes, a combination of paroxetine (10 mg) and clomipramine (10 mg), 6 hours prior to the anticipated sex act has also proved beneficial. Depoxetine (30 to 60 mg), 2 hours prior to coitus can help delay in climaxing in most individuals. This medicine has relatively fewer side effects and found to be more effective. Delayed orgasm (Retarded ejaculation) Along with supportive psychotherapy and behaviour modification, enhancing sexual arousal is the main key of the treatment programme. Researchers have observed that diabetes may be the cause of orgasmic/ejaculatory disturbance. However, it seems to impair erectile mechanism much more frequently as compared to orgasmic mechanism. Testosterone deficiency, if present, needs to be treated and may help increase sexual arousal in cases of delayed orgasmic responses. Pubococcygeal (PC) muscle exercises may prove to be beneficial. Positions like woman’s legs crossed and doggie usually prove beneficial in providing better grip and friction, leading to enhanced sexual arousal culminating in early climax. Impaired and absent orgasm Addictive drugs like brown sugar and cocaine are known to cause these dysfunctions. Hence, it is best to remain away from them. PC muscle exercises may prove to be beneficial. Enhanced sexual arousal by any means may prove useful. Vibrating the undersurface of the glans penis by a simple body vibrator can help achieve orgasm/ejaculation. Treatment of Female Sexual Disorders Vaginismus Treatment essentially comprises of supportive psychotherapy, behavioural desensitisation, relaxation exercises and gradual insertion of user friendly vaginal dilators/trainers. Anxiety born out of any myths and misconceptions needs to be cleared. It needs to be emphasised that vagina is highly elastic

and is capable of accommodating any size of object, be it a finger for genital examination or head of a baby during delivery. Prognosis in the treatment of vaginismus is excellent. No psychotropic drugs or surgery is required in the course of treatment. Painful sexual intercourse (Dyspareunia) Most often, when the woman is not adequately aroused and the man makes an attempt to enter, because of lack of lubrication, it leads to painful penetration at the time of intercourse. Hence, devoting more time to foreplay helps resolve the majority of problems. Local vaginal infection and hormone imbalance could also hamper lubrication. Other less common reasons for persistent pain at the time of intercourse could be because of hymenal and other obstructive vaginal pathology, urethral disorders or congenital malformations of the vulva or vagina. It could also occur following postoperative scars and atrophic vulvo-vaginitis, common in menopausal years.

Sexual Medicine

Treatment of Orgasmic Disorders (Male) Early orgasm (Premature ejaculation) Many techniques have been used to delay orgasm. The methods commonly used may include doing mental arithmetic during the sex act, applying a local anaesthetic ointment to the glans penis prior to penetration and wearing a condom to decrease sensitivity. Other methods include the following:  Pelvic muscles exercises  Interrupting and restarting the flow of urine repeatedly  Practising Vajroli mudra and Ashwini mudra  The ‘squeeze or stop-start’ technique

Orgasmic disorders Early orgasm in females has not been described hitherto. But this particular disorder needs to be treated in the same manner as one is treating the early orgasmic disorder (premature ejaculation) in males. Delayed/impaired/absent orgasm in females can be best helped by increasing sexual arousal, pelvic floor muscle exercises, modifying the coital position, using a lubricant or substituting necessary diet and/or hormones (if there is a clinical and metabolic evidence of deficiency). Supportive psychotherapy and behaviour modification are of crucial importance. Lax vagina This may occur following childbirth. It can be best prevented by proper management of labour with perineal support, an adequate and timely episiotomy and perinatal exercises. A lax vagina can be benefitted by Kegel’s exercises. It involves contraction of the perineal muscles—a phenomenon akin to holding the urine and releasing it. Twenty such contractions and relaxations, three times a day, may help increase the muscle tone. If this does not work, one may consider vaginal reconstructive surgery for severe cases. While treating the sexual disorders, the physician needs to be comfortable with his own sexuality as well as the subject of sexuality. Human understanding, empathy and offering of the adequate sex knowledge are the most powerful remedies, the value of which tends to be neglected in this modern age. Their increased application can obviate the majority of the use of tranquilisers and the so called sex tonics. RECOMMENDED READINGS 1.

Masters & Johnson. Human Sexual Inadequacy, USA: Little Brown & Co.

2.

Kothari P. Sex & You. India, Mumbai: VRP Publishers.

2045

28.3 Since the beginning of the modern Olympic age, the world of sports and athletic performance has undergone several important transformations. Sports have become professional; it pays to play which makes it mandatory to give your best and for that, fitness is the key. An offshoot of the corporate culture, recreational athletics (weekend warriors) are on the increase. The overburdened executive, who exercises over weekends to get rid of stress, is often more concerned about his weight, aerobic capacity, strength and this is injury prone than the professional athlete. Exercise science or the science of exercise is the application of medical sciences to sports to better human performance and the application of sports or exercise as a therapy in the management of disease. Sports medicine, in the present day sense, has a relatively short history. In 1912, the first official Congress for Sports Medicine was held in Germany. The modern definition of sports medicine was coined in 1958 in Cologne- ‘Sports Medicine includes those theoretical and practical branches of medicine which investigate the influence of exercise, training and sport on health and disease and study the bad effects of lack of exercise to produce useful results for prevention, therapy, and rehabilitation of the athletes. SPORTS MEDICINE AS A SPECIALITY With sports becoming increasingly professional, the athlete needs all possible inputs to improve performance. A top tennis star today moves with his contingent of a personal trainer, a coach, a psychologist and a nutritionist. Till recently, sports medicine was a hobby of doctors who participated in sports. Today it is a profession and sub-speciality in itself. Departments of exercise science exist in universities offering degree and diploma courses. Olympic federations and national sports team have their own sports testing facilities. Exercise physiologists, physicians, surgeons, psycho- and physiotherapists, trainers are all part of an ever expanding team of sports medical specialists. ATTRIBUTES (COMPONENTS) OF FITNESS For the athlete, ‘your weight is right for your height’ is just not enough. Sports activities can be divided according to their energy requirements, motor skills requirement and power requirements. Some activities are predominantly aerobic, e.g. long distance running; others are anaerobic, e.g. sprint events; and still others require a combination of both, e.g. middle distance running. Football, rugby, badminton are examples of activities that require alternate aerobic and anaerobic commitment. Power events often demand great acceleration 2046 like linear as in shotput and javelin throw, and circular or

Sports Medicine Anant Joshi centrifugal as in discus and hammer throw. Gymnastics and diving are events that require extreme skill, although not by the exclusion of strength or power. Every sport requires a blend of different fitness attributes. These include aerobic, anaerobic capacities, muscular strength, local muscular aerobic and anaerobic endurance, muscular power, flexibility, speed of reaction and motor correctness. FUNCTIONAL EVALUATION OF AN ATHLETE Unlike the usual medical consultation, an athlete needs an evaluation of his strength, flexibility, endurance, power and reaction time. These are parameters that are paramount for better performance rather than staying alive. The functional evaluation of an athlete is a complex task. It is not just sufficient to know about the functioning of the heart, lungs, nervous system and the peripheral circulatory system, but the functioning of the organism during muscular work of high intensity is also necessary. In addition, the movement and mechanical aspects required of the human machine during specific sports should also be studied. This calls for close cooperation between a physiologist and a biomechanics expert. Some of the parameters investigated during fitness testing of an athlete include cardiac frequency (at rest, during work and during recovery), oxygen consumption in relation to weight, oxygen pulse (VO2/cardiac frequency), pulmonary ventilation, respiratory quotient and lactic acid estimation. Muscular strength, flexibility, power, endurance, reaction time give an estimate of musculoskeletal and neuromuscular conditioning. Athletes are tested in a lab setting or ‘on the field’ environment. Testing a swimmer on a treadmill makes little sense and hence a variety of ergometers have been designed to simulate sports specific actions, the swimming fluke being an example. ‘THE ATHLETE’S HEART’ Chronic physiological overload causes an increase in the heart size, as well as increase in the heart’s range to perform and is as a result of physiological hypertrophy of the muscle mass (Linzbach) and of regulatory dilatation of both ventricles. This is in opposition to an increased heart size due to disease (myogenic dilatation) resulting from overload (pressure or volume) or primary myocardial damage. During the years of growth, between 14 and 18 years, endurance training results in a particularly rapid increase in heart size. Physicians unaware of the athlete’s heart are often responsible for declaring an athlete with a large heart as ‘unfit’. SPORTS THERAPY Remedial exercises have been used in treating ailments as diverse as osteoarthritis and osteoporosis, to hypertension and coronary artery disease, and to counteract the effects of ageing. Osteoarthritis needs non-load bearing exercises and

Obesity not caused by dysfunction of the endocrine system, the main cause seems to be decreased energy output together with excessive energy input. Even with a well-controlled diet it is difficult to lose weight. In order to come up with an exercise programme for an obese individual, it is important to evaluate how healthy the subject is and his or her residual physical capacity. This clinical and instrumental check-up should help the physician assess the cardiovascular, respiratory and musculoskeletal systems and gauge the percentage of body fat that needs to be reduced. It is also important at this stage to know the factors that would limit or hinder the training programme, e.g. presence of arthritis or asthma. A specific and personalised training routine can then be planned. The motivation and general psychological state of the obese patient must be considered to reduce the frequent phenomenon of ‘quitting’, which is often the basis of failures. Physical reconditioning of the obese must be programmed to improve body fat mass to lean tissue mass, reactivate muscles that have become hypotonic and hypotrophic due to disuse, restore physiological mobility of major joints and recondition cardiovascular and respiratory systems. The training programme can be divided into three major parts: First, rhythmic, low frequency and intensity callisthenic type exercises that will improve mobility. Once mobility is achieved, muscular conditioning through anti-gravitational stimulus like lifting light dumbbells or medicine balls. The second part is aimed at improving the efficiency of the cardiovascular, respiratory and musculoskeletal systems. Exercises are now based on ‘movement’ and have to be of ‘submaximal’ intensity where heart rate rises to 60% of theoretical maximum heart rate. Workloads should be progressively increased. For the obese, initially, instead of running or walking, cycling or swimming is recommended for weight loss. ‘Endurance’ sports activities can now be introduced for a sustained weight loss or maintenance programme. Thirdly, ’balanced training’ or ‘controlled’ exercise is fundamental to fitness and should be designed on a scientific basis. The importance of ‘rest’ cannot be over emphasised. Prescribing exercise is an art by itself. The type, intensity, duration and frequency of exercise are quantified. Periodic checks help in monitoring the progress or usefulness of exercise and help in subsequent modifications. Sports therapy is not used in isolation. It supplements other methods of treatment. Exercise can reduce drug dependence and dosage in the management of ailments like diabetes and hypertension. THE SCIENCE OF TRAINING Training, a systematic repetition of exercises, aims at achieving a better performance. Science has become increasingly important in the process of training and enables training to be more focused. General and specific elements of training have to be analysed separately. As an example, let us consider strength as one of the motor characteristics that needs to be developed. Various

methods of training contribute to different kinds of muscle strength. Isotonic or dynamic exercise result in lesser increase of strength but its effect lasts longer than the isometric type and it causes less co-ordination disturbances. Principles of Exercise Specificity ‘You get what you train for’, adaptation is specific to a stressor and the affect of a stressor is specific to an individual. The specific adaptation to imposed demand (SAID) principle is the cornerstone of athletic training. Thus, strength training will bring about greater changes in muscular strength than in cardiorespiratory fitness.

Sports Medicine

osteoporosis just the reverse. Aerobic exercise is used as a ‘fat burner’ in the management of obesity. ‘Endorphins’ liberated during exercises act as ‘stress busters’.

Overload Christensen in 1931 showed that training with a standard workload substantially lowered the heart rate; say 180 to 160 beats per minute. Further training of the same intensity did not modify this heart rate response, but if training was increased in severity, the original work could be completed with a slower heart rate, perhaps down to 140 beats per minute. Progressive increase could be in terms of extent (more km, repetitions) or intensity (more kg, faster runs) or in terms of density (shorter intervals of rest between exercises, repetitions, sets, units 2 to 3 per day) and so on. Reversibility ‘Effects of exercise are not permanent’. Just as regular exercise produces training, subsequent lack of exercise produces ‘detraining’. When either intensity, duration, frequency of exercise is reduced, the degree of adaptation brought about by the training load will gradually weaken. Strength losses are faster than mobility losses. Status improvements brought about by ‘special’ methods over a short term are lost quicker than those brought about by ‘slower’ methods over a longer term. If a limb is totally immobilised, the losses may be up to 5% per day. Cross transfer Some cross transfer effects of exercise do occur. Overloading one area will also put some extra stress on others as well. Although endurance running is not the ideal method for developing leg strength, a runner will have greater leg strength than someone who does not exercise at all. Repeated overstressing causes progressive fatigue Physical training is only one of the stressors that bombard the body everyday. Domestic and social life, career studies, institutional demands are all stressors and eventually add up to contributing to a fatigue state. Science has lent objectivity to training. Recent studies have made it possible to measure the limits of physical adaptability to sports training – maximum muscle power can be increased by 50%; aerobic power by 35% and anaerobic power by 60%. NUTRITIONAL ASPECTS: FOOD AND FLUID Dietary manipulations to increase carbohydrate loading are carried out by endurance athletes for increasing muscle glycogen stores two- or three-fold. While lack of certain foodstuffs may bring about a decrease in functional capacity, or even illness, it has yet to be proved that excessive consumption of foodstuffs will increase functional 2047

capacity. Most people over-estimate their dietary requirements. Overeating causes decreased performance and faster ageing than a well balanced diet. Seventy per cent of the human body is composed of water, most of which is contained inside cells. Heat and stress cause sweating. When sweating, fluid is drawn from this intracellular supply with resulting adverse effects on cell metabolism. Fluid loss becomes apparent when 1% to 2% of the body weight has been lost as sweat. When fluid loss amounts to 4% to 5% of the body weight the capacity for physical hard work is reduced by nearly 50%. During exercise in a hot environment, water loss can be considerable and can amount to 5 litre or more per hour. To maintain physical efficiency, fluid replenishment is necessary. Cooler fluids (25 to 30°C) are absorbed better than hot ones. Presence of glucose and other sugars retards this absorption. Up to 60% to 70% of a 400 mL draft of water leaves the stomach in 15 minutes while only 5% of a drink containing 10% sucrose leaves in the same time. For rapid absorptions, drinks should not contain more than 2.5% of carbohydrates. It is well known that sweat contains electrolytes in addition to water. However, the concentration of sodium and chloride in sweat is only about one-third that of plasma, so that relatively more water is lost than salt and sweating leaves body fluids more concentrated. Costill has suggested that electrolytes be replaced after exercise by drinking a glass of orange or tomato juice and by adding a little more salt to diet. Taking into account fluid absorption and stomach emptying times, it has been recommended that fluid replacement should be done by the athlete during less intense periods of exercise and less concentrated solutions should be drunk at more frequent intervals. The sensation of thirst is not an accurate guide when it comes to replacing fluid loss by sweat. Slaking one’s thirst generally provides only half the amount of fluid required. Anyone who indulges in strenuous physical activity is advised to drink considerably more than he thinks he needs. SPORTS INJURIES The only time the human body is called upon to surpass itself deliberately is during sports. An athlete gives ‘his heart out’, exercisers ‘go all out’, and in trying to overcome the physical, physiological and psychological limits, injuries do occur. A wide spectrum of sports injuries are seen from niggling sprains and career-threatening ligamentous tears to lifethreatening dislocations. Injury frequency has increased drastically with the development of professional and recreational sports activities. Speculations have been made about possible factors that may influence the occurrence of such injuries. Today’s athletes have increased the intensity and duration of training and that too in unfavourable environmental conditions. Exercising in groups where the fit and the unfit are clubbed together, like in an aerobics class, results in the uninitiated individual doing more than what the body can take.

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Sports injuries may be acute or chronic, ‘extrinsic’ or ‘intrinsic’. Extrinsic injuries are those caused by faulty surfaces, shoes, protective gear, sports apparatus or apparel and environmental factors. Intrinsic injuries which account for a majority of sports

injuries are a result of faults in body conditioning (through training) or technical errors (poor sports technique). Orthopaedic surgeons who are trained to tackle bones and joints are often inadequately exposed to soft tissue musculoskeletal injuries. Muscle injuries which by far account for most sports injuries are thus often underdiagnosed, missed and mistreated. Shin splints and tennis elbows are poorly understood and treated. A tennis elbow may be caused by faulty technique—using the wrist, elbow in front of the body or wrong grip size or just heavy balls. Treating all tennis elbows by pain relieving medication or a steroid injection without analysing the cause would be foolhardy. OVERUSE INJURIES A category of injury peculiar to the athlete is an overuse injury. Athletes often overuse and abuse their bodies due to the misconception amongst athletes and coaches that more is better. Overuse injuries do not immediately cripple the athlete. Repetitive exposure of tissue to low magnitude forces results in injury at the microscopic level. Repeated overload as in running or jumping are often associated with overload injuries to the lower extremity. In the running gait, a force in the range of 3 to 5 times the body weight ascends up the lower extremity at heel strike. This force behaves like a sound wave with a short duration (20 to 40 ms) with rapid dissipation. Considering an impact of 250% of the body-weight, a runner absorbs at ground contact 110 tons on each foot per mile. The forces for longer distances can be imagined, considering that a long distance runner who runs 100 miles per week plants each foot about 3 million times a year. Factors predisposing to overuse injuries can be intrinsic or extrinsic. Intrinsic causes would include malalignment (pronated feet, femoral anteversion), leg length discrepancy, muscular imbalances. Poor training methods (exercising to the point of pain), hill work, sloping or hard surfaces are extrinsic factors that can predispose to injury. Although the muscle tendon unit is the most commonly affected structure, even bone is not immune to overuse injury. Treatment Overuse injuries are treated by rest, relief of local inflammation, and the gradual reintroduction of controlled and protected activity. If the recurrence is to be prevented, it is also important to ensure that the future training load is controlled more carefully and adjusted more gradually. For example, changes from endurance running to sprinting, or from road to track, must be gradual. Shoes should be examined for the adequacy or arch support and heel-cushioning.The squash racket’s handle should be thickened to prevent further strains of the common extensor origin. The swimmer’s arm action should be analysed to reduce impingement of rotator cuff tendons on the coracoacromial arch. The road runner should be advised to interpose the occasional run on grass. DIRECT SOFT TISSUE TRAUMA Many sports put the participants at risk of direct trauma to muscle, tendon, ligament, and subcutaneous tissues by contact with the ground, the opponent, a ball or an opponent’s bat. Strict enforcement of the rules, a properly prepared playing surface, and tuition in the skills of the sport will prevent some of these injuries but they can never be avoided completely.

The prevention of bleeding depends on ice compression, and elevation (mnemonic ‘ICE’). The local application of cold for 10 to 20 minutes will induce vasoconstriction and has the added benefit of relieving pain. Venous hydrostatic pressure at the site of injury is reduced by elevation of the injured limb for 2 to 24 hours. Extravasation of blood is limited by a compression bandage applied immediately after the ice is removed, and maintained for 2 to 24 hours. Elevation is not only the simplest of the three measures to implement, it is probably also the most important and the most neglected. Recovery is faster if a nonsteroidal anti-inflammatory agent is administered, in full dosage, for 3 to 5 days after soft-tissue injury. Prompt orthopaedic advice should be obtained. Rehabilitation Absolute rest is usually inappropriate after the first 24 hours. Selective, graded and protected activity is preferred to immobilisation. Before return to competition can be permitted, balance and co-ordination skills must be relearned. STRESS FRACTURES The repeated application of stress to a bone may result in a ‘fatigue’ or ‘stress’, fracture. The most common sites are the tibia, the distal fibula, and second and third metatarsals. Femoral stress fractures are also seen. There is no history of acute trauma; there need not be any pain at rest. Initial radiographs may appear normal, and later may show callus formation. Radioisotope bone scan may be necessary to confirm the diagnosis. A simple bedside test is the sharp pain produced by insinuation of the suspect of the area of bone with a physiotherapist’s ultrasound applicator. Treatment Aims of treatment are to avoid complete fracture and allow the bone to heal. This requires temporary abstinence from the sport. Weight bearing should be avoided if it is painful. Strength and endurance should be maintained by isometric exercises and

by a change of activity like cycling or swimming (for metatarsal or fibular fracture). FRICTION SYNDROME Local inflammatory response to overuse may be evident with pain, swelling, discolouration, warmth, and palpable crepitations. Examination may reveal nothing. Re-examination immediately after a provocation test may be helpful.

Sports Medicine

Acute Treatment Much of the pain and disability resulting from soft-tissue trauma is not due to the injury itself but to bleeding in and around the damaged tissues. Extravasated blood causes pain and limitation of movement at first by a space-occupying effect, then by causing local inflammation. Later, rehabilitation is hindered by fibrotic adhesions. Acute management concentrates on preventing this sequence of events.

Treatment Nonsteroidal anti-inflammatory drugs, 1 to 2 weeks of relative rest, stretching, isometric exercises and gradual resumption of activity, are advocated. Local injection of steroids may be helpful, if the above measures fail. Surgical decompression is occasionally required. SUDDEN CARDIAC DEATH Sudden cardiac death during sports tends to attract the attention of the press but is in fact very rare. Although vigorous physical activity carries a transiently increased risk of sudden cardiac death, this is greatest in those who are habitually least active and are overweight than in those who are most active. Prevention Exercise electrocardiography has been advocated as a screening procedure for all middle age sportsmen. However, it is not a prerequisite for exercise training unless there are symptoms suggestive of myocardial ischaemia, strongly positive risk factors for coronary disease, a family history of premature sudden death or dysrhythmias, or a personal history of exercisedinduced syncope. Instead, anyone unaccustomed to vigorous exercise should be taught that its intensity should be at first modest and should increase gradually. The exercising person should also be taught to recognise symptoms of underlying cardiac disease and seek medical advice. TRAUMA AND VIRAL INFECTIONS Herpes simplex virus infection may occur due to abrasive contact during sport, especially between wrestlers or between rugby front-row forwards. Hepatitis B and HIV infection may occur as a result of contact of one player’s blood with another player’s broken skin. This may be seen in wrestling, rugby, judo and boxing. OTHER EXERCISE-INDUCED ABNORMALITIES These are amenorrhoea, iron deficiency anaemia and rhabdomyolysis.

2049

28.4 Significant advances in the area of clinical nutrition have occurred in the last decade. Healthcare professionals and the patients have appreciated the role of nutrition in promoting optimal health. This nutrition awareness has created the need for more and precise information on all aspects of nutrition and clinical dietetics related to patient care. This chapter primarily conveys information concerning the role of diet in few diseases and also gives diet plans for the same. The general principles of diet therapy are listed in Table 1. However, it is recommended that each patient must be assessed individually and a diet plan formulated considering his/her nutritional status, associated illnesses and various deficiencies that need to be corrected. Table 1: Guidelines to Good Dietetic Therapy Reach and maintain ideal body weight Be careful of serving sizes Avoid skipping meals Increase your daily activity Preserve lean body mass

DEVELOPING A NUTRITION PLAN Diet is the cornerstone in management of various diseases. To lose weight, for heart diseases or for diabetes, a few small changes in eating habits can make a big difference. Healthy eating does not have to be monotonous. The easiest approach to improve eating habits is to use the food pyramid as a guide (Figure 1).

Diet in Medical Diseases Siddharth N Shah especially with a structured exercise programme, which is a balance of energy intake versus energy expenditure. Dietary Guidelines for Obese Patients  Set realistic short-term and long-term goals.  Avoid fasting or feasting/skipping any meals.  Always eat breakfast with good choice of cereals.  Do not eat in between the meals. Have low calorie/high volume food items.  Avoid ready to eat food items, concentrated food items like sweets, fried items, etc.  Do not sleep immediately after eating.  Do not eat while watching television, opening refrigerator, cooking, serving or reading.  Thoroughly chew each and every morsel of food, remembering that it takes around 20 mins to realise satiety.  Avoid alcohol and follow dietary recommendations.  Physical exercise is a must to burn away, excessive fat. Principles of Diet Energy A low calorie balanced diet providing atleast 1,200 Kcal/day is considered safest and most effective for weight loss in majority of obese patients. Energy restriction below 800 to 1,000 Kcal/ day is not recommended as it may lead to deficiencies of other nutrients and also the body goes in a negative feedback of conserving energy (reducing BMR). A triad of a calorie restricted balanced diet, increased physical activity and control of associated illness and various deficiencies goes a long way to achieve and maintain weight loss. Unrealistic/very low calorie/ starvation diets may lead to yo-yo syndromes, gallstones, etc. Protein A normal intake of 1 g/kg ideal body weight (IBW) is recommended for tissue repair. Fats Fats in the diet should be restricted as they are concentrated sources of energy. Both visible and invisible fats should be restricted in the diet. A minimum level of 15 to 20 g visible fat should be maintained in the diet, to provide palatability and essential fatty acid requirement.

Figure 1: The food pyramid. Each section of the pyramid is a food group. The smaller the section, the less of that type of food one should eat.

OBESITY Obesity is a predisposing factor for various complications like atherosclerosis, diabetes mellitus, arthritis and high blood pressure. A diet low in calories and fat, and high in fibre is recommended. It is designed to provide less than the required 2050 energy by the body and use up the fat stores of the body,

Carbohydrates Simple carbohydrates should be avoided. Potatoes, sweet potatoes, yam, banana, rice should be used prudently. A diet high in fibre provides satiety and long-term compliance. Vitamins and minerals Multivitamin and mineral supplements may be advised because calorie-restricted diets may be inadequate in some nutrients. Extra salt in the diet causes retention of water in the body. Thus moderate salt restriction is helpful.

Fibre High fibre foods like green leafy vegetables and fruits can be included in the diet freely in the form of thoroughly washed vegetable salads (raw or boiled), unstrained-unseasoned soups. These foods give a sense of satiety and regulate bowel movements too.

Fat Each of these gives 90 Kcal. Two tsp of oil/ghee/vanaspati/3 tsp of butter. One can have 2 to 3 exchanges each day. Sugar Each of these gives 100 Kcal. Five tsp of sugar/jaggery/2 tsp of honey. One can have 1 to 2 exchanges each day.

Food exchanges A food exchange is a grouping of food items which are of approximately similar nutritive value; so as to enable one to plan and select meals with ease and convenience and also provide variety.

Meat Each of these provides 85 Kcal. One serving of meat/fish/poultry = ½ cup cooked curry/1 egg (boiled). Vegetarians may substitute meat exchange with an extra exchange of pulse or milk. One can have 1 exchange each day.

Cereals Each of these provides 100 Kcal. Two medium size dry chapatti = 1 cup roasted/plain rice flakes = 1 cup cooked rice = 1 cup rawa upma = 1 bread slice (large). One can have around 7 to 10 exchanges or servings daily, depending upon the requirement.

Free foods Black-coffee/tea, plain sodas, unsweetened lime juice, clear soups, thin buttermilk made from double skimmed milk curds, masala (without coconut or oil base), ginger, vinegar, gelatine (unsweetened), coriander, mint, garlic, mustard, bay leaf, cinnamon, nutmeg, pepper.

Pulses and legumes Each of these provides 100 Kcal. Two cups thin dal = 1 cup thick dal = ¾ cup cooked pulses = 1 big cup sambhar. One can have 2 to 3 exchanges each day.

A prudent diet, structured exercise programme (to preserve the lean body mass), a positive attitude, a determination to improve quality of life (QOL) remains the cornerstone of any diet programme. Weight loss programme can majorly (with the exception of genetic/physiologic causes) be termed as ‘lifestyle modification programme’.

Nuts and oilseeds Each of these provides 100 Kcal. Three-fourth cup grated fresh coconut = 1 handful of groundnuts/cashew nuts/sesame seeds/ almonds. Vegetables Each of these provides 25 to 30 Kcal Veg. A: 1 big cup of dark green leafy vegetables. Veg. B: three-fourth cup of any other vegetables like brinjal, beans, ladies finger. Veg. C: half cup root vegetables like potato, beet root, yam, sweet potato, etc. One can have 2 to 3 servings each day, depending on whether one is on a calorie diet and/or carbohydrate enriched/restricted diet plan. Fruits One fresh medium sized citrus fruit/half pulpy fruit supplies roughly 50 Kcals. One can have 2 to 3 exchanges each day. Fruits are best eaten as a mid-morning or a mid-evening snack rather than along with the meals. Milk and milk products Each of these gives 100 Kcal. One-cup cow’s milk/3/4th cup buffalos milk/1-cup curds/8 medium sized pieces of paneer, made from cow’s milk. One can have 2 or more exchanges each day.

Diet in Medical Diseases

Water Water is allowed in liberal quantity. Fluids like thin buttermilk, dal water, unstrained soups, sugar free lime-water provide variety in the fluid and also fill-up the stomach; thereby reducing subsequent meal intake.

DIABETES MELLITUS Diabetic diets need not a complete deviation from the normal diet. A traditional Indian diet can be made suitable for diabetics with few modifications in the nutrient intake based on age, sex, weight and physical activity. The diet is designed to improve blood glucose and lipid levels, encourage healthy eating patterns, promote consistent food intake and avoid undue starvation or overeating, thereby improving quality of life. In many ways, it is similar to a weight loss diet. Principles of Diet Energy The calculated calorie requirement should allow the patient to achieve and maintain ideal body weight (IBW) and the desired waist-hip ratio (WHR).The total calorie requirement is calculated based on the level of physical activity and an individual’s actual weight. Based on body weight, the following guidelines can be used for calculating the energy requirement of diabetic patients. For overweight person – 20 Kcal/kg/day IBW For ideal weight person – 25 to 30 Kcal/kg IBW For underweight person – 40 Kcal/kg/day IBW For pregnant diabetic woman – 30 to 35 Kcal/kg/day IBW The total daily intake of calories from the various macronutrients can be distributed as shown. 2051

Distribution of calories Carbohydrates should constitute 60% to 65% of total calories, proteins and fats 15% to 20% each. These can further be divided into meals, which can be small frequent meals, avoiding the load on pancreas and stimulating it to produce insulin in regular doses and intervals, or it can be modified to the lifestyle of the patient. Carbohydrates An Indian diet predominates in this nutrient. Diabetics need not restrict carbohydrates. Simply modifying the type of carbohydrates in the diet will help achieve euglycaemia. Simple carbohydrates obtained from honey, sugar, jaggery, sugarcane, jam, glucose, etc. are readily absorbed and are to be avoided completely. Complex carbohydrates, such as cereals, whole grains, dals, pulses, sprouts, fruits and vegetables do not raise blood sugar quickly. Glycaemic index (GI) and glycaemic load (GL) both should be taken into consideration. Proteins The recommended dietary allowance (RDA) for protein is 1 gm/kg IBW. Pregnant women, lactating women and children require more protein compared to an adult in order to meet their physiological needs. Skimmed milk and milk products (except cream, butter), dals and pulses, nuts, oilseeds, fish, egg, poultry and meat are rich sources of protein. Cereals are fair sources of protein. For Type 1 diabetic children 1 to 1.5 gm protein/kg IBW is recommended. ‘Lente’ carbohydrate provides a good quality protein in addition to complex carbohydrate. Fats Fats are concentrated source of energy. Excess of fat in the diet increases the risk of obesity, and the process of atherosclerosis. Visible fats like ghee, butter, vanaspati contain a high proportion of saturated fats, which tend to increase serum cholesterol levels. Vegetable fats, such as sunflower oil, safflower oil, and corn oil contain a high proportion of polyunsaturated fatty acids (PUFA), which are helpful for controlling cholesterol levels. Some amount of n3 to n6 ratio of fat that is derived from milk and milk products, egg, flesh foods, nuts and oilseeds are known as invisible fats. A diabetic diet should provide both visible and invisible fat in limited quantities. A diabetic patient can take 15 to 20 gm visible fat per day to meet EFA requirement and maintain palatability of the diet. Vitamins and minerals They both are essential for the body. Cereals, pulses, dals, milk, dark green leafy vegetables, fresh fruits, egg and fish are common sources of these nutrients. Fibre Dietary fibre is beneficial in Type 2 DM as well as Type 1 DM. Fibre present in vegetables, certain fruits, legumes and fenugreek seeds (methi seeds) are soluble in nature and is effective in controlling blood sugar and serum lipid levels. Insoluble fibre present in cereals and millets like ragi, jowar and bajra provides bulk and roughage inducing satiety and improves long-term blood glucose tolerance. Diet Plans The diet plan is given in the Table 2. 2052

The Glycaemic Index and Glycaemic Load The glycaemic index (GI) is a numerical system of measuring how fast a carbohydrate triggers a rise in circulating blood sugar. Foods are tested and compared to the standard food glucose. The GI of glucose and white bread is set at 100. GI =

Blood glucose area of test food

× 100

Blood glucose area of reference food

A list of carbohydrates with their glycaemic values is shown below. A GI of 70 or more is high, a GI of 56 to 69 inclusive is medium, and a GI of 55 or less is low. Food Simple sugars Glucose Honey Sucrose Fructose Cereal products Whole wheat Oat bran White bread Whole wheat bread Corn flakes Macaroni Rolled oats Puffed rice Puffed wheat White rice Brown rice Pulses Soya bean Green peas, dried Vegetables Sweet potato Yam Potato Corn Fruits Apple Orange Banana Grapes Raisins Milk and milk products Ice cream Yoghurt Whole milk Skim milk

Glycaemic index (GI) 85 to 111 32 to 87 55 to 68 12 to 25 67 42 to 75 67 to 87 52 to 87 80 64 66 132 110 50 to 64 66 to 87 15 to 20 39 to 54 44 to 78 74 74 to 97 37 to 62 39 35 to 51 46 to 70 25 56 to 60 52 14 to 23 11 to 40 32

The glycaemic load (GL), is a relatively new way to assess the impact of carbohydrate consumption. A GI value tells you only how rapidly a particular carbohydrate turns into sugar. It does not tell you how much of that carbohydrate is in

Meals

1,400 Kcal

1,600 Kcal

1,800 Kcal

2,000 Kcal

Breakfast

1-cup tea with ½ cup skimmed milk (no sugar). 1 slice of whole wheat bread (without butter or cheese) (preferably in the form of a sandwich) or 2 dry phulkas or 2 dry khakhras or 2 idlis (without coconut chutney) or 1 cup cooked vegetable upma/ roasted rice flake chiwda/sundal.

1-cup tea with ½ cup skimmed milk (no sugar). 2 slices of whole wheat bread (without butter or cheese) (preferably in the form of a sandwich) or 2 dry phulkas or 2 dry khakhras or 2 idlis (without coconut chutney) or 1 cup cooked vegetable upma/ roasted rice flake chiwda/sundal.

1-cup tea with ½ cup skimmed milk (no sugar). 3 slices of whole wheat bread (without butter or cheese) (preferably in the form of a sandwich) or 3 dry phulkas or 3 dry khakhras or 3 idlis with ½ cup sambhar (without coconut chutney) or 1 cup unsweetened corn flakes or 2 dosas (made on a non-stick pan) with rasam or 1 cup cooked vegetable upma/sundal.

1-cup tea with ½ cup milk (no sugar). 3 slices of whole wheat bread (without butter or cheese) (preferably in the form of a sandwich) or 3 dry phulkas or 3 dry khakhras or 3 idlis with ½ cup sambhar (without coconut chutney) or 1½ cup unsweetened corn flakes or 2 dosas (made on a non-stick pan) with rasam or 1½ cup cooked vegetable upma/sundal.

Mid-morning —

1-cup plain skimmed milk.

1-cup plain skimmed milk.

1-cup plain skimmed milk.

Lunch

1 bowl thoroughly washed raw vegetable salad/unseasoned vegetable soup 2 phulkas (without ghee).

1 bowl thoroughly washed raw vegetable salad/unseasoned vegetable soup 2 phulkas (without ghee). ½ cup cooked rice.

1 bowl thoroughly washed raw vegetable salad/unseasoned vegetable soup 3 phulkas (without ghee) ½ cup cooked rice.

1 bowl thoroughly washed raw vegetable salad/unseasoned vegetable soup 3 phulkas (without ghee) ½ cup cooked rice.

¾ cup dal or 1 cup sambhar or ½ cup lean non-veg (non-fried, without skin) curry or ½ cup sundal. ½ cup cooked vegetables. ½ cup skimmed milk curds. Restrict use of coconut/peanuts, sugar, jaggery, and fried non-veg.

¾ cup dal or 1 cup sambhar or ½ cup lean non-veg (non-fried, without skin) curry or ½ cup sundal. ½ cup cooked vegetables. ½ cup skimmed milk curds. Restrict use of coconut/peanuts, sugar, jaggery, and fried non-veg.

¾ cup dal or 1 cup sambhar or ½ cup lean non-veg (non-fried, without skin) curry or ½ cup sundal. ½ cup cooked vegetables. ½ cup skimmed milk curds. Restrict use of coconut/peanuts, sugar, jaggery, and fried non-veg.

¾ cup dal or 1 cup sambhar or ½ cup lean non-veg (non-fried, without skin) curry or ½ cup sundal. ½ cup cooked vegetables. ½ cup skimmed milk curds. Restrict use of coconut/peanuts, sugar, jaggery, and fried non-veg.

Evening

1-cup tea with ½ cup skimmed milk (no sugar). 1 cup roasted rice puffs (no sev or puri) or 2 Marie biscuits.

1-cup tea with ½ cup skimmed milk Same as breakfast (type and (no sugar). quantity) 1 plain whole wheat bread (no butter or cheese) or ¾ cup roasted rice flakes (no nuts) or 1 cup roasted rice puffs or 4 Marie biscuits.

Same as breakfast (type and quantity)

Dinner

Same quantity as lunch.

Same quantity as lunch.

Same quantity as lunch.

Same quantity as lunch.

Bed-time

1 medium fruit (except banana, chickoo, mango, custard apple).

1 medium fruit. (except banana, chickoo, mango, custard apple).

1-cup plain skimmed milk or 1 medium fruit (except banana, chickoo, mango, custard apple).

1-cup plain skimmed milk and 1 medium fruit (except banana, chickoo, mango, custard apple).

Total oil for the days cooking 2 to 3 tsp.

Total oil for the days cooking 2 to 3 tsp.

Total oil for the days cooking 4 tsp.

Total oil allowance for the days cooking 4 tsp.

a serving of a particular food. The amount of available carbohydrate in a specific food serving multiplied by the GI value is called the glycaemic load (GL) value of the food. You need to know both things to understand a food’s effect on blood sugar. The carbohydrate in watermelon, for example, has a high GI. But there is not a lot of it, so watermelon’s glycaemic load is relatively low. A GL of 20 or more is high, a GL of 11 to 19 inclusive is medium, and a GL of 10 or less is low. GOUT A diet low in fat and purine is advised to decrease elevated blood uric acid levels. Before imposing dietary restriction, factors inhibiting the excretion of the accumulated uric acid should be excluded, e.g. presence of alcohol, excess tannins, fat. A thorough assessment of the diet by a registered dietician/ medical nutrition therapist will help in estimating the sources

Diet in Medical Diseases

Table 2: Diet Plan in Diabetes Mellitus

of purine in patient. Increased amounts of fluid will help excrete the accumulated uric acids. Energy It should be adjusted to 500 Kcal below the normal requirement for overweight/obese patients. Care should however be taken to avoid very low calorie diets (VLCD). Exercise helps weight reduction. However, strenuous exercise (weight bearing) should be avoided. Similarly, fasting/low carbohydrates should be avoided as it precipitates a gouty attack due to ketosis. Carbohydrates Liberal use of fruits and vegetables is recommended. Use of soluble fibre is particularly helpful. Protein Organ meats and legumes are best avoided due to their high purine content. Skimmed milk and its products should be used liberally to meet the protein requirements. 2053

Fats A low fat diet will promote weight reduction and relieve symptoms of gout by facilitating urinary excretion of accumulated uric acid. Alcohol Alcohol consumption should be completely avoided as it may inhibit urinary excretion of urates. Fluid Liberal fluid intake in the form of thin buttermilk, vegetable soups, etc. will facilitate urinary excretion of accumulated uric acid and also prevent formation of calculi. However, avoid cold drinks, carbonated beverages, large amounts/strong decoctions of tea and coffee. Table 3 shows list of foods moderate to high in purine. Table 3: List of Foods Moderate to High in Purine Liver, kidney, shell fish, meat extracts – meat gravies, shrimp, sardine, soups with meat stock, chicken, ham, tuna fish, mushroom, mutton, crab, oyster, lobster Whole milk, cream, ice cream, cheese Sweetbread, bakers and brewer’s yeast Lentil, pulses Cauliflower, peas, spinach, mushrooms, brinjal and sometimes cabbage Chickoo and custard apple

PEPTIC ULCER The diet for chronic peptic ulcer disease is designed to restrict foods or beverages that may cause gastric irritation and/ or stimulate excessive gastric acid secretion. General recommendations for the diet are given in Table 4. Table 4: General Recommendations for the Diet in Peptic Ulcer Eat balanced meals in a day in a relaxed mood Avoid too hot or too cold foods Avoid spicy and strongly flavoured foods Avoid alcohol, caffeine containing beverages, cigarette smoking and tobacco chewing, spearmints and peppermints Good physical and emotional rest is essential Avoid fried foods

Fats Fats delay gastric emptying and also help in meeting the caloric requirement. Fats from fried snacks and sweets may be avoided, as they are difficult to digest, may cause nausea and aggravate the symptoms. Vitamins and minerals Deficiency may occur with self-imposed limitation of green leafy vegetables and other foods. Adequate vitamin C and iron is necessary for proper healing of ulcer. Fibre Fibrous foods, such as raw vegetables, leafy vegetables, fruits (with peel), irritate mucosal lining. Thus only soft cooked vegetables and fruits are allowed during flare-ups. pH of food Most foods are considerably less acidic than the inherent gastric pH. Therefore pH of a food prior to ingestion has little therapeutic implication except for patients with lesions of mouth/oesophagus. Alcohol Alcohol consumption causes mucosal lining damage and may worsen existing disease/interfere with the treatment of peptic ulcer. Miscellaneous Stimulants, e.g. coffee, caffeine, spices, stimulate acid secretion and may also reduce lower oesophageal sphincter pressure. Some bland diet may do well in acute flare-up. Aroma of cooked foods also stimulates acid secretion. Thus cooked food should be bland in taste and flavour. Spices, condiments, pickles, vinegar, chillies, garlic and onions are not permitted in the diet. LIVER DISEASES The diet advised must provide adequate calories and essential nutrients, including essential amino acids to prevent malnutrition and extensive liver damage. Diet in Infective Hepatitis A high protein, high carbohydrate, moderate fat diet is recommended.

Principles of Diet Energy Energy of 35 to 40 Kcals/kg is recommended, as these patients are generally malnourished due to the ‘so called’ dietary restriction. Malnutrition affects the rapidly dividing cells of the GIT and could affect healing.

Carbohydrates

Proteins Proteins have a buffering effect. Milk proteins are considered better compared to non-vegetarian foods as they do not irritate gastric mucosa or stimulate acid secretion. A good amount of protein in the range of 1.2 gm/kg IBW should be provided.

High protein diet helps to regenerate liver cells. 1.0 to 1.2 gms/ day is allowed in mild jaundice. Proteins may be restricted in decompensated liver disease and in case of increased conjugated bilirubin.

Carbohydrates Adequate amounts of simple carbohydrates should be given. Avoid food items with fibres. Soluble fibres should be 2054 encouraged to meet the daily fibre requirements.

Simple carbohydrates given in large quantities improve liver function by building adequate hepatic glycogen stores and prevent endogenous protein breakdown by their proteinsparing effect. Protein

Fats Fats make food palatable and also help to meet the essential fatty acid requirements. Fried foods may cause nausea. Vitamins and minerals Supplementation may be necessary to prevent imbalances.

Utmost hygienic condition should be observed in preparing and handling food. Cirrhosis of Liver It is important to consider the dry body weight of patient while calculating nutrient requirements. A high carbohydrate diet, moderate to high proteins (1.0 to 1.2 gm/kg dry body weight) carefully watching for signs of hepatic encephalopathy, moderate fats with supplementation of vitamins and minerals is recommended. HYPERTENSION Principles of diet are same as in healthy adult except for sodium restriction. An average Indian diet contains 10 to 15 gm of salt. Salt should be restricted to 4 to 5 gm/day as per follows: Guidelines for a Low Salt Diet Avoid using salt at the table. Do not add salt in chapatti, rice, curd, and salads. The diet can be made palatable by judicious use of garlic, ginger, mint, lemon, vinegar, jeera powder, mustard and black pepper. Low sodium salts are high in potassium and may be beneficial but should be used carefully in patients with an underlying renal problem. List of Foods High in Sodium Dairy products: butter, cheese, ice creams, etc. Ready to eat food items: canned foods, sauces, chutneys, ketchup, papad, pickles, salad dressings, mayonnaise, etc. Fried foods: chips, wafers, sev, chiwda and other fried snacks. Bakery products: salted biscuits, cakes, pastries, bread rolls, and khari biscuits Non-veg items: shellfish, dry fish, fried non-veg, non-veg gravies and organ meats. Baking powder, Ajinomoto. Salt restriction may not be compulsory for the patients receiving diuretic therapy. DASH diets (Dietary Approaches to Stop Hypertension) recommend the use of 5 to 7 servings of fruits and vegetables and helps by providing roughage, vitamins, minerals, and antioxidants. ISCHAEMIC HEART DISEASE Principles of Diet Carbohydrates Simple carbohydrates should be avoided as they contribute towards endogenous production of cholesterol and triglycerides. Energy Weight reduction/achieving IBW with a low calorie diet helps to relieve the extra burden on heart. Proteins A normal intake of 1 to 1.2 gm/kg IBW is suggested. Animal proteins should be best avoided/used judiciously with restrictions due to their high cholesterol content.

Fats Fat content should be restricted to lower the serum cholesterol levels. A vegetarian diet is helpful as it is low in fat, cholesterol and high in fibre. Rich sources of cholesterol Butter, cheese, cream, ghee, egg yolk, liver, red meats. Poor sources of cholesterol Egg white, fish, lean cuts of chicken, skimmed milk, cottage cheese (prepared from skimmed milk), vegetable oils, fruits, vegetables, whole grains.

Diet in Medical Diseases

Miscellaneous Alcohol should be avoided, as it is directly hepatotoxic.

Role of PUFA have been identified in prevention of heart disease. It is important to obtain right amount of different fatty acids in the diet and avoid excessive intake of any one kind.The desirable polyunsaturated fatty acids/saturated fatty acids (PUFA/SFA) ratio is about 0.8 to 1.0. Table 5 gives PUFA/SFA ratio of common fats. Although the ratio of PUFA:MUFA:SFA is controversial, the latest recommendation is 1:1.5:1. Table 5: Ratio of Polyunsaturated Fatty Acids to Saturated Fatty Acids of Common Fats Oil

PUFA/SFA ratio

Safflower oil Sunflower oil Corn oil Soybean oil Cotton-seed oil Sesame oil Peanut oil Coconut oil Butter

8.2 6.4 4.46 4.07 1.96 2.66 1.82 0.04 0.06

RENAL DISEASES Diet plays a central role in the management of kidney diseases. Principles of Diet in Glomerulonephritis In acute stages, an effort should be made to maintain fluid and electrolyte balance and provide sufficient non-protein calories. Energy Poor appetite may interfere with energy intake. The calorie intake can be increased up to RDA by use of jellies, sugar, butter, oil, desserts, etc. using the allotted amount of protein sources. Carbohydrates Simple carbohydrate diet like fruit juices with glucose, sweetened tea, etc. should constitute the main bulk of calories. Excessive sweets may however cause nausea. Protein Unless oliguria or renal failure develops, proteins are not restricted. Proteins are to counteract the loss of albumin in case albuminuria exists. The emphasis is upon proteins of high biological value especially egg and milk. The limitation placed on second-class protein needs restriction of dals, pulses, nuts, beans which are otherwise good sources of calories also.

2055

Fats Normal quantities are allowed as excretion of their end products do not depend on kidney function.

juices, coconut water, etc. may cause cardiac arrhythmias. Salts that are otherwise high in potassium should be avoided.

Sodium Sodium restriction to 1,000 mg is necessary with existing oedema, hypertension or oliguria.

Fluid Allowance depends on the hydration levels, previous day’s urine output, fever, vomiting, diarrhoea and high environmental temperature.

Fluid In oliguria, fluids are restricted to prevent further oedema. Allowance depends on the hydration levels, previous day’s urine output, fever, vomiting, diarrhoea and high environmental temperature. Diet in Chronic Renal Failure (Conservative Management) Efforts should be made to reduce the nitrogenous waste load on the kidneys. Knowledge of the usual dry body weight and proper assessment of the actual food quantity consumed by an experienced medical nutrition therapist is of utmost importance. Additionally, a good psychological and emotional support goes a long way in improving QOL. A summary of diet in various diseases is given in Table 6. Goals of Nutrition Care in the Management of ESRD  To prevent deficiency and maintain good nutrition status and growth, in cases of children through adequate protein, energy, vitamin and mineral intake. 





To control oedema and electrolyte imbalances by controlling sodium, potassium and fluid intake. To prevent/retard the development of renal osteodystrophy by controlling calcium, phosphorus and vitamin D intake. To enable the patient to eat a palatable, attractive diet that fits his/her lifestyle as much as possible; thereby improving QOL.

Energy 35 to 40 Kcals/kg dry present body weight; wherein carbohydrates and fats form the bulk. Non-protein cereals like arrowroot, sago, root-vegetables like potato, sweet potato, help to meet the requirement of non-protein, high-energy food items. Proteins Protein intake of 0.7 to 0.8 g/kg present dry body weight ensures meeting the patient’s requirement of daily basis. Reducing the protein further than this actually raises the serum creatinine levels due to tissue catabolism. Major amounts/portions of protein allowances should come from first class proteins (FCP), sources of which include milk and milk products, egg and nonvegetarian food items. Fats Moderate amounts of fat will give palatability and also add calories, in addition to meeting the EFA requirements. Sodium Salt restriction of 2 to 3 gm is usually recommended to maintain the electrolyte balance. Higher amounts may further aggravate hypertensive nephropathy changes. Potassium Moderate potassium in the diet, in the range of 1,500 to 2056 2,000 mg, is allowed. High potassium obtained through fruit

Enteral nutrition Enteral nutrition consists of provision of nutrients through a tube when oral intake is inadequate, for the purpose of maintaining or restoring nutrients status. It is given to all patients with ‘functioning GI tract’ who are unable to consume adequate amount of nutrients orally to meet their nutritional requirements. PRINCIPAL GOALS OF NUTRITION SUPPORT 

This is to support protein synthesis rather than suppress proteolysis. This will help to initiate the anabolic phase leading to patient’s convalescence.



Understand the body’s metabolic response to injury and illness.



Assess the nutritional status of the patient in order to decide whether nutritional intervention is indicated.



Determine the optimal route of nutrient intake.



Provide substrate (carbohydrates, proteins, fats, vitamins and minerals) for the ongoing metabolic functions.



Limit catabolism and maximise protein synthesis.



Bolster immune function and improve wound healing.



Improve cardiac and respiratory function by restoring glycogen stores in the cardiac and diaphragmatic muscles.



Correct acid-base and electrolyte disturbances.



Potentially modify the systemic inflammatory response.



Be aware of, anticipate and minimise feeding (technique of delivery and metabolic) related complications.



Understand the ability of total parenteral nutrition to serve as a drug vehicle and to help in the correction of metabolic derangements.



Confirm adequacy of nutrition support and response to support.

Although it is not known how long a hyper-metabolic patient can tolerate starvation, the loss of lean tissue that occurs in catabolic patients (20 to 40 gm N2) suggests that depletion to a critical level may occur in 7 days. The need for nutrition support is based on current status of the patient’s nutritional reserves and an estimate of the associated stress/severity of the underlying disease, with a heightened systemic response. Anticipated time delay before which the patient can resume feeds/normal diet. Nutritional Supplements It may not be always possible to meet the nutritional requirements of a patient, especially if the nutritional intake is poor or the catabolism is high. Artificial nutritional supplements

recommended that the portion of fats in artificial nutrition be increased for patients with either sepsis or non-septic critical illness. Care is taken to avoid essential fatty acid deficiency. Studies show that the peptide system is less affected than the free amino acid pathway in malnourished patients. Administration of peptides can thus prevent protein deficiency. Furthermore, due to the lower osmolality, peptide based formulas are better tolerated than amino acids. Trace elements, vitamins and minerals are also added in doses equivalent to RDA. Many supplements are available with immune boosters like glutamine and arginine.

Diet in Medical Diseases

available in the market are of great help during these times. There are a wide variety of disease specific nutritional supplements available. Carbohydrates may be provided as simple sugars or complex carbohydrates such as fibre. Most proprietary formulae are lactose and gluten free. Nutrition support in critically ill patients is aimed at preventing the negative effects of starvation during the course of disease and at minimising the negative effects of protein catabolism. Healthy, malnourished non-septic patients utilise mainly carbohydrates for energy production and convert excess glucose into fat. In contrast, patients with sepsis show an increase in oxygen consumption and utilise mainly stored fat to meet their energy requirements. The same effects are seen in a non-septic critically ill patient. Consequently, it is

In stress or catabolic states, a high protein, moderate carbohydrate, moderate fat with immuno-modulators is required.

Table 6: Diet in Various Diseases Disease condition

Energy (Kcals)

Carbohydrate (gm)

Proteins (gm)

Fats (gm)

Fibre (gm)

Salt (mg)

Exercise

Obesity

20 Kcals/kg IBW, not 2 contact with the patient years since last dose Women planning pregnancy One dose of Tdap, if not received previously Pregnant women who One dose of Td vaccine in the second received Td >10 years ago or third trimester Pregnant women who One dose of Tdap in the immediate received Td 2 to 10 years ago postpartum period Pregnant women Three doses of Td in the second or never immunised third trimester; first two doses at least 4 weeks apart, third dose 6 to 12 months after second dose Td = Tetanus toxoid, diptheria; Tdap = Tetanus toxoide, diphtheria, acellular pertussis.

Local reactions (generally erythema and induration with or without tenderness) are common after immunisation. Rare cases of Guillain-Barre syndrome have been reported after

Adult Immunisation RK Singal, AK Agarwal immunisation. A previous history of neurological illness, especially Guillain-Barre syndrome following administration of another vaccine, is a contraindication for immunisation. Table 2: Tetanus Immunisation Schedule for Adults Sustaining a Wound History of Tetanus Clean Minor Toxoid Doses Wound

All Other Wounds

Unknown or less than three doses Three or more doses

Tdap/Td

Tdap/Td, TIG

Tdap/Td if more than 10 years elapsed since last tetanus toxoid dose

Tdap/Td if more than 5 years have elapsed since the last tetanus toxoid dose

TIG = Tetanus immunoglobulin; Tdap = Tetanus toxoid, diphtheria, acellular pertussis; Td = Tetanus toxoid, diphtheria.

RABIES With a large population of unvaccinated stray dogs, rabies continues to be prevalent in India. The fact that no treatment is available for established disease and a fatal outcome is universal, highlights the importance of immunisation, the only effective preventive measure. The spread of rabies can best be prevented at a population level by vaccinating all stray and pet dogs. Pre-Exposure Prophylaxis It is recommended for high risk groups like veterinarians, laboratory personnel working with rabies virus, medical and paramedical personnel treating rabies patients, dog catchers, forest staff and zoo keepers. Post-Exposure Prophylaxis Depending on the severity of the exposure and categories of exposure, the recommended treatment for each is shown in Table 3. All exposures in the wild are category III exposures. Rodents are not reservoirs of rabies virus. Small rodents (e.g. squirrels, chipmunks, rats, mice, hamsters, guinea pigs, and gerbils) and lagomorphs (including rabbits and hares) are rarely infected with rabies and have not been known to transmit rabies to humans. Following exposure, wound care consists of washing the wound with soap and water while avoiding touching the wound with bare hands. Post-exposure immunisation can be discontinued if the animal is healthy after 10 days. Vaccines available in India include purified duck embryo, purified chick embryo, Vero cell (cell line from kidney epithelial cells of African Green monkey) derived and human diploid cell vaccine. Rabies immunoglobulin, used to provide passive protection, is available as a human and an equine preparation. Anaphylactic shock may occur following the administration of equine preparations. Skin testing should be performed before giving 2063

the injection by injecting 0.1 mL of equine rabies immunoglobulin, diluted 1:10 in saline, intradermally into the flexor surface of the forearm to raise a bleb of 3 mm diameter. An equal amount of saline is injected as control in the other forearm. After 15 minutes, an increase in diameter to >6 mm of wheal surrounded by flare is taken as a positive skin test. Table 3: Categories of Exposure and Recommended Treatment for Rabies Category I Touching, feeding of animals or licks on intact skin Recommendation: If history is reliable, no prophylaxis is indicated Category II Minor scratches or abrasions without bleeding or licks on broken skin and nibbling of uncovered skin Recommendation: Wound management and use of vaccine Category III Single or multiple transdermal bites, scratches or contamination of mucous membrane with saliva (i.e. licks), exposure to bats Recommendation: Wound management plus rabies immunoglobulin plus immunisation

Passive immunisation: It provides immediate protection to previously unvaccinated individuals. Human rabies immunoglobulin (HRIG) is used in a dose of 20 IU/kg (maximum 1,500 IU). If HRIG is not available, equine rabies immunoglobulin should be used in a dose of 40 IU/kg (maximum 3,000 IU). Rabies immunoglobulin should be infiltrated into and around the wounds; leftover immunoglobulin, if any, should be given intramuscularly at a site away from the site of vaccine administration. Passive immunisation is not indicated in individuals who have previously received the vaccine. Table 4: Recommended Dosage Schedule for Rabies Vaccine Situation

Dosing schedule

Pre-exposure prophylaxis

Days 0, 7, 28

Post-exposure prophylaxis (no prior immunisation) (Category II or III exposure)

Days 0, 3, 7, 14, 28 + RIG on day 0

Post-exposure prophylaxis – New CDC guidelines*

Days 0, 3, 7, 14 + RIG on day 0

Re-exposure after a full course of immunisation

Days 0, 3

Re-exposure after incomplete course of immunisation

Treat as if previously not vaccinated

RIG = Rabies immunoglobulin; Dose = 10 IU/kg of human RIG or 20 IU/kg of equine RIG infiltrated around the wound. Leftover RIG should be injected intramuscularly at a site away from that of vaccine administration. *CDC. Use of a reduced (4-Dose) vaccine schedule for post-exposure prophylaxis to prevent human rabies. Recommendations of the Advisory Committee on Immunisation Practices. MMWR Morb Mortal Wkly Rep 2010; 59(RR-2):1-9.

The vaccine is administered intramuscularly in the deltoid or in the anterolateral thigh. It should not be given in the gluteal region since the high fat content of this site retards vaccine uptake. Recommended dosage schedules are shown in Table 4. Bites sustained during sleep or those due to unidentified animals should presumptively be treated in India as if due to a possibly 2064 rabid animal. No consensus is available regarding the

management of bites due to wild rodents and treatment needs to be individualised. Rabies vaccines and rabies immunoglobulin are safe during pregnancy, lactation and in immunocompromised states including human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Minor reactions at the local site of injection and rare cases of anaphylaxis have been reported. Immunospuppresive drugs should be avoided during the course of immunisation. HEPATITIS B Hepatitis B and its complications like hepatic failure, cirrhosis and hepatocellular carcinoma account for significant morbidity and mortality. Hepatitis B immunisation remains the most effective measure to prevent hepatitis B virus (HBV) infection. Percutaneous or mucosal exposure can occur in injection-drug users; household contacts of persons with chronic HBV infection; health care workers; patients with chronic kidney or liver disease; HIV-positive patients; diseases where blood products or multiple blood transfusions are required, and patients undergoing major surgeries. Sexual exposure (homosexuals, promiscuous heterosexuals, commercial sex workers and sex partners of HBsAg-positive persons) may also be associated with transmission of the virus. Immunisation is indicated for all unvaccinated adults at risk for HBV infection and all adults seeking protection from HBV infection, including post-exposure prophylaxis. Hepatitis B vaccine, a recombinant DNA vaccine, is available as a single-antigen formulation and also in fixed combination with other vaccines. For immunocompetent adults, 20 µg of recombinant vaccine is administered at 0, 1, and 6 months as an intramuscular injection in the deltoid muscle using a 24 to 38 mm needle. Protective antibody levels, defined as anti-HBs antibody titers of 10 mIU/mL or higher, are seen in approximately 30% to 55% of healthy adults aged 90% after the third dose. Prevaccination Screening It is not cost-effective in India. It may be cost-effective in adult populations with a prevalence of HBV infection of >20%, such as household, sexual, and needle-sharing contacts of HBsAg-positive persons; HIV infected persons; injection drug users; men who have sex with men; patients with chronic liver disease (CLD) and endstage renal disease (ESRD). Prescreening requires testing for HBsAg, anti-HBs and anti-HBc. If HBsAg is positive or Anti-HBs titres are more than 10 mlU/mL, immunisation is not required. In those in whom both anti-HBc and anti-HBs are negative, immunisation should be administered. If Anti-HBc alone is positive, a test dose of the vaccine should be given and anti-HBs titers repeated after a month. Immunisation is required only in those who have titers of less than 10 mIU/mL at one month. If the vaccine schedule is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be separated by an interval of at least eight weeks. If only the third dose has been delayed, it should be administered as soon as possible. Post-Exposure Screening It is indicated in patients with ESRD, CLD, HIV infection, sex partners of HBsAg-positive persons, infants born to HBsAg-

Non-responders who are HBsAg and anti-HBc negative should receive a further full course of immunisation as fourth, fifth and sixth doses. Retesting should be done 1 to 2 months after the last dose. If there is no response, 40 µg of recombinant vaccine is administered at 0,1, and 6 months. For patients with chronic kidney disease (CKD) and other immunosuppressed patients, 40 µg of recombinant vaccine is administered at 0, 1, 2, and 6 months. A booster dose should be administered when anti-HBs levels decline to less than 10 mIU/mL (90% after the third dose

Testing for protective concentration of anti-HBs antibody (>10 mIU/mL) should be performed 1 to 2 months after the last dose of the vaccine series. Persons with >10 mIU/mL are considered to be immune. Immunocompetent persons have longterm protection and do not require further testing, however, immunocompromised persons might need annual testing to assess anti-HBs antibody levels. The level should be >100 mIU/mL in CKD patients

Pneumococcal Polysaccharide vaccine (23 valent polysaccharide vaccine)

Two weeks prior to 0.5 mL IM or s.c. elective splenectomy. One time revaccination with PPV after 5 years is recommended in patients with functional or anatomic asplenia

Single dose

0% to 66%

The scientific evidence for the efficacy of PPV has been a very controversial issue. Evidence for the efficacy of PPV in high-risk groups is lacking. In resource-limited settings, routine PPV vaccination is not recommended for healthy elderly (>65 years) and high-risk patients, such as those suffering from chronic organ failure, diabetes, nephritic syndrome, or HIV infection

Seasonal influenza [Trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV)]

Elderly, COPD, chronic pulmonary, renal or cardiac disease

TIV: 0.5 mL IM LAIV: 0.2 mL Intranasal

Annual, single dose

70%

Evidence insufficient for use in India

H1N1 Influenza [killed inactivated vaccine; live attenuated intranasal vaccine (LAIV)]

Pregnant women Health care workers Age 6 months to 24 years Age 25 to 64 years with high-risk medical conditions

Killed inactivated vaccine: 0.5 mL IM Live vaccine: 0.2 mL (half in each nostril)

Single dose

Above 90%

Do not give killed vaccine to those with egg allergy. Avoid LAIV in asthma

Typhoid (Injectable Vi polysaccharide vaccine; Live oral Ty21a vaccine)

All adolescents

Vi polysaccharide: 0.5 mL IM or s.c. Live Ty21a: 1 capsule, orally four doses on alternate days

Vi polysaccharide: Booster every 3 years.Ty21a: Repeat series once in 3 years

51% to 55%

Entire community during an outbreak

Cholera [Oral: Shanchol Lipopolysaccharide of formalin killed V. cholera (5 strains)]

Adults in endemic areas and during potential/actual outbreaks

300 to 600 IU of different strains

Two doses 1 to 6 weeks apart. Booster every second year

67%

Protective efficacy of 67% over two years in all age groups

Meningococcal (Polysaccharide – Bi- and Quadrivalent Conjugate)

Travellers, pilgrims Polysaccharide: and people 0.5 mL s.c. attending fairs and festivals. Health care personnel. Haj pilgrims administered a single dose of quadrivalent vaccine

Single dose

85% to 95%

Does not induce herd immunity; no effect on nasopharyngeal carriage. Safe in pregnancy and in HIV + patients

Contd... 2066

Vaccine

Target Population

Dose

Dosage Schedule

Protection Rate

Remarks

Japanese encephalitis (live-attenuated SA 14-14-2 vaccine)

1 to 15 years

0.5 mL s.c.

Single dose

90% to 100%

Recommended in adolescents

Yellow fever (live, attenuated virus preparation made from the 17D yellow fever virus strain)

Travellers visiting Africa and South America

0.5 mL s.c.

Single dose

95%

Protective antibodies develop 10 days following immunisation

Human papilloma virus (Bivalent HPV 16/ 18 vaccine; Quadrivalent HPV 6/11/16/18 vaccine)

Girls 10 to 12 years 0.5 mL IM Men 9 to 26 years to prevent genital warts

Bivalent: 0, 1, 6 months Quadrivalent: 0, 2, 6 months

97% to 100%

Immunise before sexual activity commences

Herpes zoster (lyophilised preparation of the Oka strain of live-attenuated varicella zoster virus (VZV))

Adults >60 years Chronic medical conditions with an increased risk of herpes zoster

Single dose

51%

Protect from light before reconstitution Use immediately to minimise loss of potency

0.65 mL s.c.

Adult Immunisation

Contd...

Note: Details of immunisation against tetanus and rabies are provided in Tables 1 to 4. s.c. = Subcutaneous; IM = Intramuscular. Live attenuated influenza vaccine, human papilloma virus vaccine and oral Ty21a typhoid vaccines varicella and herpes zoster vaccines are contraindicated during pregnancy. The safety of Japanese encephalitis vaccine and of yellow fever vaccine has not been established in pregnancy and their use should be avoided. All other vaccines may be safely administered to pregnant women. Booster doses are required only for hepatitis B (those with low anti-HBs titres), cholera (every 2nd year) and typhoid (every 3 years) immunisation.

The Vi polysaccharide vaccine is a subunit vaccine composed of purified Vi capsular polysaccharide from the Ty2 S. typhi strain and elicits a T-cell independent IgG response that is not boosted by additional doses. The target value for each single dose is about 25 μg of the antigen.The Vi vaccine is given as a single subcutaneous or intramuscular dose of 0.5 mL. A booster is recommended every three years. Both live oral Ty21a and Vi polysaccharide vaccines have an efficacy of 51% to 55% at three years and may be coadministered with other killed/live vaccines. Abdominal discomfort, nausea, vomiting, fever, headache and rash or urticaria have been reported in some patients after oral Ty21a vaccine administration. Vi polysaccharide immunisation can result in fever, headache and erythema or induration. The Ty21A vaccine should not be used during pregnancy. In HIV seropositive individuals with a CD4+ T-lymphocyte count >200/ mm3, both Ty21a and Vi vaccines can be administered. However, in HIV-seropositive individuals with a CD4+ T-lymphocyte count 99/min is a strong predictor of perioperative complications. Hence, all these points need to be considered, in addition to Goldman’s risk index, in predicting cardiovascular morbidity/mortality. Table 2: Modified Goldman’s Risk Index for Non-cardiac Surgery (Detsky’s modification) (Score >20 High Risk) Risk Factors

Risk Score

Coronary artery disease MI within 6 months MI more than 6 months old Angina class III Angina class IV Unstable angina within 3 months

10 5 10 20 10

Alveolar pulmonary oedema or signs of CCF Within 1 week Ever

10 5

Critical aortic stenosis

20

Arrhythmias Rhythm other than sinus or sinus plus Atrial premature beats >5 Greater than 5 ventricular premature beats

5 5

Poor general medical status PO2 50 mm Hg or Potassium 3 mg/dl or Abnormal SGOT or signs of chronic liver diseases or Bedridden state due to non-cardiac causes

5

Age >70 years

5

Emergency surgery

10

Table 3: Risk Class from the Goldman’s Risk Index Class

Scores

Mortality Rate

Class I Class II Class III Class IV

0 to 5 6 to 12 13 to 25 >26

6% 7% 20% 100%

In 1999, Lee et al. revised Goldman’s criteria for cardiac risk index and developed six independent predictors/variables which correlated with post-operative cardiac complications. Patients with more than 2 variables have a postoperative cardiac complication rate of ~10% and are considered to be high risk (Table 4).

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Table 4: Revised Goldman’s Criteria for Cardiac Risk Index LEE Variables 1. High risk type of surgery 2. Ischaemic heart disease (includes any of the following: history of myocardial infarction, history of a positive exercise test, current complaint of chest pain that is considered to be secondary to myocardial ischaemia, use of nitrate therapy, or electrocardiography with pathologic Q waves) 3. Congestive heart failure 4. History of cerebrovascular disease 5. Pre-operative treatment with insulin 6. Pre-operative serum creatinine >2 mg/dL LEE Criteria – Revised Cardiac Risk Index Number of variables 0 1 2 3

Risk of major post-operative cardiac complication 0.4% 0.9% 7% 11%

Major risk factors: control and stabilise before surgery  Unstable or severe angina  Recent MI  Decompensated HF  Significant arrhythmias  Severe valvular disease Intermediate risk factors  History of ischaemic heart disease  History of compensated or previous HF  History of cerebrovascular disease  Diabetes mellitus  Renal insufficiency Minor risk factors  Advanced age (greater than 70 years)  Abnormal ECG (LV hypertrophy, left bundle branch block, ST-T abnormalities)  Rhythm other than sinus  Uncontrolled systemic hypertension Elective Non-Cardiac Surgery and Anti-Platelet Therapy in Patients with Previous PCI Anticoagulants like subcutaneous fractionated or unfractionated heparin do not substitute the antiplatelet protection of thienopyridine and/or aspirin therapy in patients with bare-metal or drug-eluting stents undergoing non-cardiac surgery.

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Delay elective surgery until more than 1 year post drug-eluting stent placement (DES). In case it needs to be done, risk assessment with cardiologist for discontinuation of clopidogrel or ticlopidine for 5 days, or prasugrel for 7 days perioperatively is necessary. Proceed to surgery with aspirin or, if indicated, with dual antiplatelet therapy. If dual therapy or aspirin was discontinued give a single aspirin 325 mg dose immediately preoperative period and post-operatively continue aspirin and resume dual therapy as soon as feasible, preferably by 2nd/3rd day.

In patients who underwent balloon angioplasty only, delay surgery until more than 14 days post-balloon angioplasty. At more than 14 days proceed to surgery with aspirin. If aspirin therapy was discontinued, give a single aspirin 325 mg dose immediately pre-operatively and continue aspirin, postoperatively. In patients with Bare metal stents, delay surgery until more than 45 days (preferred; minimum 30 days) post bare-metal stent placement. However, if surgery needs to be done whether before or after 45 days risk assessment should be done with cardiologist for discontinuation of clopidogrel or ticlopidine for 5 days, or prasugrel for 7 days pre-operatively. Proceed to surgery with aspirin or, if indicated, with dual antiplatelet therapy. If dual therapy was discontinued give a single aspirin 325 mg dose immediately pre-operatively. Post-operatively continue aspirin and resume dual therapy as soon as feasible, preferably by 2nd/3rd day. Investigations in High Risk Cardiac Cases In high risk cases, ECG, Echocardiography for detection of LV dysfunction, stress testing, intraoperative cardiac monitoring for arrhythmias, ST-T changes and invasive haemodynamic monitoring, such as arterial pressure, central venous pressure, pulmonary wedge pressure for high risk cases scheduled for high risk surgeries. RISK OF PULMONARY COMPLICATIONS (PULMONARY RISK CASE) There is no risk score in pulmonology to predict complications. However, there are general risk factors which predict postoperative pulmonary complications (Table 5). Table 5: Pulmonary Risk Factors Age >70 years Obesity Smoking history Poor nutrition Antecedent respiratory infection Intrathoracic or upper abdominal surgery Prolonged anaesthesia time Poor general medical status Pre-existing pulmonary disease: Obstructive lung disease is a greater risk than restrictive lung disease

Anticipated Complications Minor complications These include bronchitis, tracheobronchitis, and exacerbation of COPD. Major complications These include atelectasis, pneumonia, respiratory failure, need for prolonged ventilatory therapy, and pulmonary embolism. Pre-operative Evaluation It includes detailed history, respiratory rate, presence of cyanosis, clubbing, oedema, presence of emphysema, rhonchi, increased forced expiratory time, absent or decreased tidal percussion (indicative of COPD),Scadding sign (in-drawing of suprasternal notch with each inspiration) and fine crepitations indicative of

healing. Insulin dependent diabetics have a higher risk of deep vein thrombosis.

Investigations for High Risk Care Chest radiograph, spirometry, FEV1/FVC and FEV1 reliably predict risk of complications. Peak expiratory flow rate (PEFR) measurements done serially may predict post-operative complications. Persistent hypercapnia on arterial blood gas analysis in a patient with COPD is associated with pulmonary morbidity. Sputum microbiological studies and ECG are needed in some patients.

Pre-Operative Evaluation Assess glycaemic status: Fasting and post-prandial blood sugar and HbA1c. If the HbA1c is >9%, insulin should be started. If above 12%, consideration should be given to improving control before elective surgery is undertaken. Assess cardiac risk by detailed history and cardiac risk score. Evidence of peripheral vascular disease may indirectly suggest co-existing coronary artery disease. Look for carotid bruits. Assess for cardiac autonomic neuropathy by electro-cardiogram for CAD and heart rate variability (HRV) after deep breathing. HRV of 180/ 110 mm Hg warrants to postpone the surgery. However, Stage I and Stage II hypertension with no additional cardiovascular disease risk, can proceed for surgery. Patients on ACE inhibitors or ARB may develop post-operative hypotension if volume depleted.

HOW MUCH SHOULD YOU INVESTIGATE A HEALTHY INDIVIDUAL? Who is a healthy individual? One who has no disease, does not smoke or consume alcohol, exercises regularly and has normal weight and nutrition is considered normal. If age is less than 40 years the investigations needed are haemoglobin and blood glucose. Haemoglobin, blood glucose, blood urea, and ECG are needed if age is between 40 and 50 years. The serum creatinine and chest radiograph are additional investigations to the previously mentioned tests in patients more than 60 years of age.

Recommendations The patient should continue his antihypertensive drug even on the day of surgery with a sip of water and continue the same post-operatively after resumption of oral feeds. Only diuretics need to be stopped 24 to 48 hours prior to surgery. Patients on diuretics need a serum potassium check before surgery. Acute uncontrolled perioperative hypertension can be controlled with sodium nitroprusside, nitroglycerine, hydralazine, diazoxide or labetalol injection. Beta blockers appear to be particularly attractive agents for the treatment of pre-operative high blood pressure. Beta-blockers effectively modulate blood pressure fluctuations; reduce perioperative coronary ischaemic episodes, post-operative atrial fibrillation, and other cardiovascular complications. Drugs like sublingual

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However, the situation in India may be totally different. Routine chest radiograph may uncover common diseases like tuberculosis. Eosinophil count is also important as tropical pulmonary eosinophilia, which is common in India, may predispose to bronchospasm during intubation. Elective surgery needs postponement in the event of a recent respiratory infection. RECOMMENDED READINGS 1.

ACC/AHA 2007 Guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. Circulation 2007; 116:e418-500.

2.

Adhikari P, Abey A. Risk factors for postoperative complications in sixty diabetic patients. Int J Diabetes for developing countries 2004; 24(4):115-9.

3.

Adhikari PMR, Mohanty A, Kalpana S, Pereira P. Postoperative pulmonary complications in fifty high risk cases. Karnatak J Med Sci 1998; 1:14-9.

4.

Breslon MJ, Miller CF, Rogers MC. Perioperative Management; 2nd Ed. Washington DC: Mosby; 1990.

28.9

Law and Medicine NK Grover

INTRODUCTION The practice of Medicine involves not only scientific and technical knowledge, but also social, ethical and moral issues. The chosen person for delivery of health care—‘the doctor’ is perceived by society that he should be able to deliver a comprehensive range of healthcare activities, social work responsibilities and they would seek a ‘Friend, Philosopher and Guide’ in the doctor. The concept of health care has evolved to mean a comprehensive scheme, which promotes good health, prevents ill health, cures the sick and rehabilitates the disadvantages. This is a scheme which involves interaction amongst economic upliftment, public health, health education, targeted prevention and cure. Attempts to match the range and extent of health care to available resources constitute a yet unresolved ethical dilemma. The phenomenal advances in medical practice in recent times have elevated medical practise from its empirical avenues to a precision technology which has increased the cost very significantly. Failure to appreciate this qualitative change has led to the ethical dilemmas in doctors and the society in modern times.

CONSENT This is the crux and pivot which allows a doctor to manage illness in an appropriate manner. The consent is implied in outdoor consultation, for indoor treatment for any intervention or operation, it has to be taken in writing. It is an ethical and legal requirement and an essential obligation on the part of treating doctors, not obtaining a valid consent amounts to breach of duty. It should be as informed as possible, in the language patient understands and always properly documented. To give valid consent, a patient should be in sound state of mind, above the age of 18 years and put his signatures/thumb impression duly witnessed. Further consent today is the key to ‘defence of doctor’. Special situations like serious patients require high risk or special or explicit consent. However, in emergency and life-threatening situations, the treatment cannot be withheld for want of consent. Special situations like unknown, unconscious patient or patient with insane mind require special avenues to tide over the issue of informed consent. In cases of infants and children consent may be given by the parent or guardian.

There has been a significant change in the relationship between the patients and the physicians, from that of the ‘Prime Healer Equivalent to God’ to a mere ‘Service Provider’ in the present era. But the practice of medicine is guided by the principle ‘Primun non nocere’ at least do no harm to the patient.

PATIENT’S CHARTER Since enactment of Consumer Protection Act (1986) and its Amendment in 1993, the Central Consumer Protection Council (CCPC) in 1994, developed a ‘Health and Patients Charter’ which was notified by Government of India in February 1996. Some of its important features are:

DOCTOR-PATIENT RELATIONSHIP Doctors have always enjoyed respect much more than any other professional—a friend, philosopher, guide and even revered as ‘Next only to God’ because they have served to mitigate illness and promote health. The cornerstone of the doctor-patient relationship has been confidence, faith and trust which have gradually been eroded. The social position of doctor has changed to that of a service provider with obligation to inform and perform ‘consented treatment’. This has happened due to many reasons like high tech, high cost medicine, rise in consumerism, increasing expectation of society and western influence where ‘liability litigation’ is order of the day.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

The doctor-patient relationship has many moral, ethical and legal aspects while the relation has conventionally been fiduciary or trustee in nature. In today’s era it has taken the shape of legal contract with many obligations. British Medical Association recommends healthy relationship between the two based on the concept of ‘partnership and collaborative efforts’ arrived by frank conversation, communication, consideration and consent. Such process allows patient to choose his preference and line of treatment with the guidance of physician leading to informed consent and shift of responsibility of outcome of disease and treatment of patient to some extent onto the patient in addition to treating doctor.

The practitioners of medicine and institutions providing health care are obliged to respect patient’s rights and privileges. Hospitals have similarly been made responsible with extra obligations like ‘Right of Access’ to all health facilities without any discrimination of sex, religion, caste or economic status. Emergency care, proper record keeping, patient safety protocol, standard of care, proper disposal of medical waste, etc. have specific guidelines and laws. Their preservation/destruction/ certification and the medico-legal aspects require full understanding of responsibility by medical professionals. Hence doctors should carefully follow the stipulated rules to avoid any litigation in future.

Right to Healthcare and Humane Treatment Right to Choice of Care Right to Acceptable Safety Right to Adequate Information Right to Consent and Refusal Right to Confidentiality Right to Redressal of Grievances Right to Health Education Right to Participation and Representation Right to Healthy Environment

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MEDICAL ETHICS Medical Council of India (MCI), a statutory body, was established in 1934 and re-enacted as MCI Act (1956) by the Parliament, Government of India. It is vested with powers to regulate and maintain standard of medical education, permissible standard of medical ethics and provision of penalties in the event of any violation of Code. Code of Medical Ethics was revised in 1970 and amended in December 2009 where it has enunciated doctorpharmaceutical industry relationship in addition to existing ethical norms. Each doctor has to abide by this. MCI was superseded by the Board of Governors vide Indian Medical Council Amendment Ordinance 2010 vide Government of India Gazette Notification No. 2 of 2010 dated 15th May, 2010 to improve its functioning and tide over some of the alleged irregularities like nepotism, favouritism and financial irregularities. MEDICAL NEGLIGENCE ‘Negligence has been defined as omission to do something which a reasonable man guided by ordinary considerations would do or doing something which a reasonable and prudent man would not do’ (Black’s Law Dictionary). The word ‘Negligence’ under Legal Glossary (Govt. of India) means want of attention to what ought to be done or looked after, lack of proper care in doing something which a reasonable professional guided by considerations which ordinarily regulate the conduct of human affairs would do or not doing something which a prudent and reasonable man would not do. The British and Indian courts have repeatedly upheld this principle that conditions must be fulfilled to prove and have been enunciated by established latest judgments of Supreme Court of India. The medical negligence arises only when you owe a duty. There is dereliction (breach) of that duty and damage (harm, complication or death) occurs which is ‘directly attributable’ to treatment given to the patient and not a mischance or complication which is well documented. Types of Medical Negligence Negligence has many manifestations, e.g. it may be active, passive, comparative, collateral, concurrent, continued, contributory, hazardous, gross, wilful, reckless and even criminal depending on the circumstances. Ordinarily, medical negligence is tried under Civil Laws, Laws of Contract, Tort or Consumer Protection Act, but in India it has criminal liability also.

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Civil Laws Governing Medical Negligence and Laws of Contracts When a doctor accepts or undertakes to treat a patient, in legal sense he is entering into a contract with the patient to render services adequately but not entering into any contract for curing the patient. He undertakes to use best of his skills and knowledge at all steps in diagnosis, treatment, administration of medicines, surgery and postoperative care, etc.This obligation is further augmented by law, commonly known as ‘Law of Torts’. In Law of Torts, ‘Tort’ can be defined as ‘Breach of Legal Duty’ which is independent of contract and this breach entails damages. For medical professionals domain of ‘Specific Tort’ covers professional negligence. The patient can file a suit for damages/compensation by taking recourse to law of contract as well as Torts in Civil Courts.

Consumer Protection Act To overcome the issue of cost and time taken by Civil Courts to settle the medical liability cases, Government of India promulgated a simple legal remedy ‘Consumer Protection Act (1986)’. This Act provides for settlements of medical negligence suits and award compensation by Three Tier Redressal Mechanism, i.e. Forum at District level, State level, National Consumer Redressal Commission. Finally, Appellate Tribunal can also entertain cases directly where the financial stakes are high. After the National Commission one can only appeal to the Supreme Court. Criminal Medical Negligence There is very thin line of margin which can bring medical negligence within the ambit of criminality and attach liability under penal laws. To be so, negligence must be grave, gross, intended or wilful and with total disregard to the life of patient and doctor should have acted in haste without due care or without a valid consent. Supreme Court has clarified that medical negligence will ordinarily be charged under Section 304A of IPC. This is a bailable offence and if proved draws up to 2 years of rigorous imprisonment and fine or both. OTHER ACTS OF MEDICAL NEGLIGENCE Besides the Indian Penal Code (1860), there are certain specific Acts which deal with the medical negligence in so far as the criminal liability is concerned and these are briefly discussed hereinafter. Medical Termination of Pregnancy Act, 1971 It provides that pregnancy can be terminated by a registered medical practitioner, on fulfilment of certain conditions. Under the provisions of this Act, a pregnant woman who has attained the age of 18 years pregnancy can be terminated with her due consent. In case of a woman who has not attained the age of 18 years or who has attained the age of 18 years and is a lunatic, pregnancy cannot be terminated except with written consent of her guardian. Under Section 4, MTP has to be done by a registered medical professional who is qualified to carry out this procedure and also at a place which is recognised and duly registered for medical termination of pregnancy. The Pre-Natal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, 1994 The Act provides for the regulations of prenatal diagnostic test or techniques for the purpose of detecting the sex of unborn child and its misuse which may lead to female foeticide. Any medical geneticist, gynaecologist, registered medical practitioner or any person who owns a genetic counselling centre or genetic laboratory or a genetic clinic or is employed therein, renders his professional and technical services and who contravenes any of the provision of the Act or Rules shall be punishable with imprisonment for a term up to 3 years which may extend to five years and with fine of 50,000/-. The offence, under this Act, is cognizable, non-bailable and noncompoundable. Registration of Births and Deaths Act, 1969 The Act provides that every birth has to be registered with the Government and similarly every death has also to be

The Transplantation of Human Organs Act, 1994 The Act provides for the regulation of removal, storage and transplantation of human organs for therapeutic purposes and for prevention of commercial dealing in human organs and matters concerned with or incidental thereto. The Act provides punishment for removal of human organ without authority (Section 18). Section 19 deals with punishment for commercial dealings in human organs. Section 20 deals with residuary offences which have not been provided in other sections of the Act. Article 21 of the Constitution of India, provides as under: No person shall be deprived of his life or personal liberty except according to procedure established by Law. The Courts while interpreting Article 21, have held that Article 21 (One of the Fundamental Rights guaranteed by the Constitution), cannot be given a meaningful interpretation unless the Right to Life covers the real meaning of the word ‘life’, which includes right to proper health, which includes treatment as well. The courts have severely punished the doctors who have failed to provide First Aid or proper treatment for various reasons including want of money, etc. The courts have given a very broad perspective to Article 21 of the Constitution vis-à-vis the medical profession and have applied the dictum of Fundamental Right. Reference here is made of guidelines laid in RN Katara Public interest litigation wherein Supreme Court has laid that every doctor is obliged to provide treatment in emergency. General Principles of Handling Case of Medical Negligence These have been lucidly and elaborately explained in the decision of Three Judge Bench of Supreme Court in Jacob Mathew versus State of Punjab and other (2005). Further Justice Markandey Katju in his famous judgment in Supreme Court (Sep 2009), has analysed and described various aspects of medical negligence and cautioned that merely because a complaint has been made that a treatment has been unsuccessful or caused mishap, doctors should not be harassed. Medical professionals operate in a sphere where success cannot be achieved in every case. Very often success and failure depend upon factors beyond the professional’s control. The judgment has clearly laid down the procedure in the event of complaint of medical negligence against doctor/ hospital whether in District/State/National Consumer Forum or Civil or Criminal Court. The complaint has to be referred to competent doctor/committee of doctors specialised in the field. Only when found by experts that there is a prima facie case of medical negligence, should notice be issued to doctor/ hospital. He further warned the police officials not to arrest or harass doctor. He emphasised the courts and consumers to base their opinion on the reports, findings of experts in medical science and must not substitute their own views over those of specialist. INDIAN PENAL CODE 1960 Some clauses relevant to the medical profession are: Section 304A IPC—Causing Death by Negligence Whoever causes the death of any person by doing any rash or negligent act not amounting to culpable homicide shall be

punished with imprisonment of either description for a term which may extend to 2 years or with fine or with both. Section 304 IPC—Punishment for Culpable Homicide not Amounting to Murder Whoever commits culpable homicide not amounting to murder shall be punished with imprisonment for life or imprisonment of either description for a term which may extend to 10 years and shall also be liable to fine if the act by which the death is caused is done with the intention of causing death or of causing such bodily injury as is likely to cause death, or with imprisonment of either description for a term which may extend to 10 years or with fine or with both, if the act is done with the knowledge that it is likely to cause death but without any intention to cause death or to cause such bodily injury as is likely to cause death.

Law and Medicine

registered. If not implemented then any professional or organisation who does not comply or who refuses to issue a certificate with effect to the same can be punished as per law.

Sections 312-316 of IPC Sections 312-316 of the Indian Penal Code (IPC) deal with miscarriage and death of an unborn child and depending on the severity and intention with which the crime is committed, the penalties range from 7 years to life imprisonment for 14 years and fine. Section 312—Causing Miscarriage Whoever voluntarily causes a woman with child to miscarry shall, if such miscarriage is not caused in good faith for the purpose of saving the life of the woman, be punished with imprisonment of either description for a term which may extend to 3 years or with fine or with both and if the woman be quick with child, shall be punished with imprisonment of either description for a term which may extend to 7 years and shall also be liable to fine. Section 313 of IPC—Causing Miscarriage without Woman’s Consent Whoever commits the offence defined in the preceding section without the consent of the woman, whether the woman is quick with child or not, shall be punished with imprisonment for life or with imprisonment of either description for a term which may extend to 10 years and shall also be liable to fine. Section 314 of IPC—Death caused by Act done with Intent to Cause Miscarriage Whoever, with intent to cause miscarriage of woman with child, does any act which causes the death of such woman, shall be punished with imprisonment of either description for a term which may extend to 10 years and shall also be liable to fine. But if act is done without the consent of woman, shall be punished either with imprisonment for life or with the punishment above mentioned. Section 315 of IPC—Act done with Intent to Prevent Child being Born Alive or to Cause it to Die after Birth Whoever, before the birth of any child, does any act with the intention of thereby preventing that child from being born alive or causing it to die after its birth and does by such prevent that child from being born alive, or causes it to die after its birth, shall, if such act be not caused in good faith for the purpose of saving the life of the mother, be punished with imprisonment of either description for a term which may extend to 10 years or with fine or with both. 2075

Section 316 of IPC—Causing Death of Quick Unborn Child by Act Amounting to Culpable Homicide Whoever does any act under such circumstances, that if he thereby caused death he would be guilty of culpable homicide, and does by such act cause the death of a quick unborn child, shall be punished with imprisonment of either description for a term which may extend to 10 years and shall also be liable to fine. THE DRUGS AND COSMETICS ACT The laws relating to drugs are called the Drugs and Cosmetics Act. They deal with various aspects of manufacture, sale, supply and distribution of drugs including fixation of prices. The Drugs and Cosmetics Act 1950 (26 of 1950) The first Act was promulgated in the year 1940. It was amended in the year 1950 and is now known as the Drugs and Cosmetics Act 1950 (26 of 1950). It provides for the control of the sale, supply and distribution of drugs. Drug Controller of India (Ministry of Health), Government of India is responsible for regulation, import and introduction of new drugs as well as permission for drug trials in India. There is a provision for fixing of prices and maximum quantities which can be held or sold. The Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954 This Act briefly deals with the control of advertisement and in certain cases deals with prohibiting advertisement of certain drugs for magic treatment of certain diseases and disorders. This also lays down the prohibition of misleading advertisement relating to drugs. CONCLUSION The subject of ethics, civil, criminal laws governing medical negligence and practice of medicine is vast. Some areas like

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Medicolegal Cases, Autopsy/Postmortem, Research and Drug Trials, Quality Assurance, Nursing Home Act, Shop and Establishments Act, Patient Safety Concerns, Disposal of Medical Waste are important areas which need detailed discussion but are not covered in this chapter. But it is the responsibility of doctor to know about these rules and regulations so that he can always be on right side of law. We now know that there are a plethora of rules, laws, regulating medical practise and medical negligence the profession need not fear in their practice. The law has always been considerate to the medical profession while dealing with medical negligence and takes due consideration of the circumstances, facility and infrastructure available to the doctor. The courts have always maintained that doctors have to provide due care with diligence and it is not expected of him to provide the very best which a brilliant doctor may offer but the basic which a ordinary doctor ought to know. The Supreme Court has opined that doctor can only be prosecuted if there is ‘gross medical negligence’. Similarly, the courts have observed an increase in frivolous and vexatious litigations. To avoid these, reverse fines have also been imposed on litigants. Definite guidelines are enunciated to protect the dignity and physical safety of doctors and the paramedical staff working with them. RECOMMENDED READINGS 1.

Bag RK. Law of Medical Negligence and Compensation, Publication Eastern Law House, 1996. Tapas Kumar Koley, Medical Negligence and the Law in India; Oxford University Press; 2010.

2.

Munjal YP. ‘Legal Issues in Medicine’. API Textbook of Medicine; 7th Ed. pp. 1486-1487

28.10

Travel Medicine Yash Pal Munjal

INTRODUCTION AND DEFINITION ‘Travel medicine’ has gained considerable importance and understanding because of the phenomenal increase in the people travelling across the globe. According to estimates by World Tourism Organisation, international tourist arrivals worldwide during 2010 were approximately one billion and it will escalate to 1.6 billion by the year 2020. Travel is associated with health hazards. It is estimated that 20% to 70% of the travelling population reports a health problem, 1% to 5% seek medical attention and 0.1% to 1% need acute emergency medical care and evacuation. It is estimated that one person in every 100,000 dies due to one reason or the other. Accidents contribute significantly to morbidity and mortality. This has led to the development and progress in ‘Travel medicine’.

They should carry with them a ‘first aid kit’ so that they can attend to themselves in an emergency. The contents of the basic medical kit (first aid items) are adhesive tape, antiseptic wound cleanser or soap, bandages, scissors, safety pins, emollient (lubricant) eye drops, insect repellent, insect bite treatment, antihistamine tablets, oral rehydration salts, antidiarrhoeal medication and common antibiotics which the traveller can use himself in case of diarrhoea, infections of the skin and soft tissue, respiratory and urinary tract along with antimalarial medication, antibacterial ointment, antifungal powder and insecticide besides adequate supplies of condoms and oral contraceptives. Special precaution has to be taken for travellers at the extreme of ages, pregnancy and associated disability. Some of the specific issues are discussed in the following paragraphs.

Travel medicine is an inter-disciplinary speciality concerned not only with the prevention of infectious diseases during travel but also the personal safety of the travellers and avoidance of risks. It also provides information about avoiding health risk to the places and the people where the sick individual is visiting. The Travel Medicine may be considered in the following broad heads:

SPECIFIC ADVICE

PRE TRAVEL—GENERAL ADVICE Any person travelling outside the frontiers of his/her country should seek advice from doctors trained in this speciality or the speciality clinics dealing with travel medicine.This advice ideally should be sought about 8 to 12 weeks before the date of travel and in cases where the travel is planned at the last moment even just before the visit is undertaken. The doctor must understand the following factors if he has to give useful and coherent advice to the travellers:  Mode of transport  Destination(s) – demography, disease profile of the country and places to be visited  Duration and season of travel  Purpose of travel  Standards of accommodation and food hygiene  Behaviour of the traveller  Underlying health of the traveller Traveller should be prepared for any eventuality—changes in the travel plans, loss of money, baggage and documents. Therefore, it is suggested that the individual should take an extra supply of medication for about two weeks. A duplicate copy of all the documents should be in the baggage including passport and related documents, detailed history of vaccination and prescription from the doctor, eye glasses and a small telephone directory of numbers for insurance and credit card replacements. A copy of such documents may also be kept at home which can be accessed easily by a relative or friend. Every traveller should preferably have a health travel insurance, and must understand clearly the extent to which travel related reimbursement is permissible and expenditure can be incurred.

Accidents Accidents are one of the major causes of disability and mortality. This gets compounded with the varying‘On Road Travelling Norms’ followed in other countries. Drinking and driving should not be mixed. The traveller should not drive a particular type of vehicle which he is not conversant with. It is also advisable to have protective gear especially while riding two-wheeler transport. Animal Exposure Exposure to animals at places of travel can increase the risk of zoonotic diseases as well as rabies. Rabies is endemic in some under-developed countries and the traveller is advised not to engage contact with unfamiliar animals. Rabies exposure prophylaxis may be useful for travellers who are on long visits to some of the endemic areas. Medicinal Interactions The traveller should be conversant with all the drugs which he is carrying and any drug—drug interaction thereof. It is useful to remember that antacids and antidiarrhoeal drugs frequently interfere with the absorption of other medications. While purchasing extra supplies in other countries, be careful with regard to quality of drugs.Therefore, always purchase medicines from a good quality store and get a receipt. Sexually Transmitted Diseases Travellers become uninhibited during vacations abroad when they may engage themselves in unprotected sexual activity. Therefore, it is important that they carry with them good quality and adequate supplies of condoms while travelling. Women should carry oral contraceptive pills. STD organisms are antibiotic resistant in some of the countries, therefore absolute care and protection is a must. Exposure to Ultraviolet Radiation In tropical countries, or at high altitude, the sun exposure can be more intense than expected. Travellers should use broad 2077

spectrum sun screen creams with UVA and UVB protection. Tetracycline and ciprofloxacin which are often recommended for travellers’ diarrhoea or malaria prophylaxis can cause suninduced rashes. In addition, sun glasses may be useful. Swimming Travellers are advised to undertake swimming only in hygienic and chlorinated pools because the other waters may be contaminated with bacteria from sewer or industrial waste, etc. Travellers must note about the risk of schistosomiasis in the area. If the traveller is bathing in questionable sources of water he should dry up vigorously and as rapidly as possible. Protection of feet must be ensured. High Altitude Travelling to places where the altitude is above 10,000 feet may cause acute mountain sickness. This usually presents with dizziness, headache, fever, chills or vomiting. Severe illness includes high altitude pulmonary oedema, confusion and extreme lethargy (high altitude cerebral oedema). The travellers are advised to travel at high levels slowly, acclimatise themselves to high altitudes and should not undertake strenuous activity. Use of alcohol and tobacco should be significantly reduced. For minor sickness acetazolamide can be used. Rest and acclimatisation may relieve discomfort. If extreme symptoms appear, traveller must be evacuated to lower levels as quickly as possible. Arthropod-Borne Diseases This can be a reason for morbidity and prolonged sickness. A bite by an insect or reptile may cause pain or inflammation at the site of the bite or sting. Certain generalised reactions are known due to the venom injected or allergic reaction. Moreover arthropods can transmit serious potentially lifethreatening diseases including malaria, yellow fever, dengue haemorrhagic fever, filariasis (mosquitoes), viral encephalitides (mosquitoes, ticks), onchocerciasis (black flies), leishmaniasis (sand flies), African trypanosomiasis (tsetse flies), American trypanosomiasis or Chagas diseases (reduvid or kissing bug), plague and tungiasis (fleas), typhus (fleas, lice, ticks) and relapsing fever (lice and ticks). Arthropods vary according to different geographical conditions. Vaccines are available to protect individuals against some of these illnesses. Therefore, it is preferable to use them but the advice must be tailored to the geographical area to be visited. Following precautions and preventive steps can be helpful:  Avoid walking in the countryside especially in the evening. Always wear light coloured long sleeved shirts and long pants with preferably gum boots. Wear footwear at all times and always shake footwear before wearing.  Use insect repellents, bed nets and good camps.  Sleep in air-conditioned or well-screened rooms or under bed nets in areas where arthropod borne diseases are present.  Prior to sleeping, spray the room/net with anti-insecticide spray. The net should be of good quality and should cover the bed on all sides. 2078  Avoid perfumes, scented creams, lotion, etc.

Malaria Travellers visiting countries which are considered malarial zones are advised to take prophylactic treatment. This treatment has to be based on the type of Plasmodia and their resistance patterns in the area of travel. The broad outline for prophylaxis is given in the Table 1. Table 1: Medications and Regimes for Malaria (Prevention) Name of Drug

Dose

Side-effects

Chloroquine Phosphate (Chloroquine sensitive areas)

Paediatric dose: 5 mg per kg per week Adult: 500 mg once a week Start 1 week before travel and continue 4 weeks after travel every week on same day of the week

Side effects are uncommon and could be dizziness, headache, nausea and vomiting Can exacerbate psoriasis Discontinue medicine if visual changes occur

*Mefloquine (Areas with Chloroquine resistance)

Paediatric dose: 5 mg per kg if weight is less than15 kg Adult: 250 mg once a week Start 1 to 2 weeks before travel and continue 4 weeks after the travel. Take it after the travel. Take it after food and with plenty of water.

Dizziness, vomiting, anxiety, restlessness, ectopics. May exacerbate already existing psychiatric disturbances or depression. Can trigger and interact with anti-epileptic and cardiac drugs. Do not use in major psychiatric disorders, seizure disorders and cardiac conduction defects.

*Doxycycline Hyclate

100 mg/dL Start 1 to 2 days before travel and continue 4 after the travel

It can cause skin rashes and an intense burn with exposure to sun weeks (use extra sun screen) and vaginitis in women. Do not take with milk products or antacids. Do not use in children below 8 years, pregnant women and nursing mothers.

*Atovaquone/ Weight based for children Proguanil 250 mg/100 mg/dL beginning 1 to 2 days before and discontinue 7 days after. Take with food or milk

*Chloroquine Phosphate + Proguanil

Side effects are uncommon Can cause severe or uncontrolled vomiting, diarrhoea, fever, nausea, stomach pain, loss of appetite, dark urine, clay coloured stools, jaundice or mouth sores. Do not use in renal failure, pregnancy or nursing mothers. Use with caution in patients with liver disease

Same as above Same as above This combination may be started 1 to 2 days before entering and continued for 4 weeks after arrival

* Useful in resistant P. falciparum.

Traveller’s Diarrhoea Traveller’s diarrhoea has been defined as the occurrence of three or more loose stools each day or any number of loose stools accompanied by abdominal cramps, fever, vomiting occurring among travellers usually from developed to developing countries. It affects 20% to 70% of travellers when travel is confined to 2 weeks or less. Developing countries of Asia, Africa and Latin America are high risk areas. Intermediate risk areas are Caribbean Islands, Israel, Southern Europe, South Africa and China while North America, Europe, Japan and Australia are low risk areas.

Prevention  Drink safe water.  Avoid uncooked cold food which is not boiled or steaming hot.  Avoid food from street vendors  The safe beverages include: 1. Boiled water beverages—tea or coffee. 2. Carbonated bottled drinks (keep in mind that large intake of mineral water can cause mild diarrhoea from the cathartic effect of the minerals). 3. Canned/boxed fruit juices. 4. Bottled/canned alcohol containing beverages—beer or wine in moderation. Recommendations for water treatment include the following:  Boil and cool water before drinking.  Use iodine tablets as directed. Be careful if using for pregnant women as it may interfere with foetal development.  Use chlorine dioxide tablets as directed.  Use a portable water filter available at Sports Goods Stores or General Stores. Several versions of portable UV light sources are available including litre water bottles with UV light or filters built in. Treatment Initial treatment should consist of using binders like bismuth and/or loperamide. In case it is severe and associated with fever, antibiotics may be used. If not controlled and/or associated with fever treat like any other acute infective diarrhoea. Vaccinations for Travellers Vaccinations for people travelling abroad are generally safe. The advice regarding vaccination varies according to the geographical area to be visited. All vaccinations for travellers are listed in Table 2. The details about the dosage and frequency of immunisation are given in the Chapter on ‘Adult Immunisation’ (Chapter 7, Section 28). Pregnant Traveller Pregnant women have a less effective immune response which makes them more vulnerable to have severe or potentially fatal complications from infections, such as malaria, typhoid fever

and amoebiasis. The pregnant traveller should get current and specific advice from experts who can contribute significantly to her safety, health and her future new born. Civil aircrafts do not allow travel beyond 36 weeks of pregnancy. Table 2: Vaccinations for Travellers Category

Vaccine

Routine Vaccination

Diphtheria, Tetanus and Pertussis Hepatitis B Haemophilus influenzae Type B Human Papillomavirusa Influenzab Measles, Mumps and Rubella

Pneumococcal Disease Poliomyelitis Rotavirusa

Cholera Hepatitis Ad

Rabies Tick-Borne encephalitis Typhoid Fever Yellow Feverd

Selective use for travellers

Japanese Encephalitisd Meningococcal Diseased Required Vaccination

**Yellow Fever (See Country List)

Travel Medicine

Incidence is highest among very young (40%) presumably owing to increased contamination and decreased immunity. Incidence is high in the 15 to 29 years age group (29%), perhaps owing to adventurous style travel and the ingestion of higher volume of potentially contaminated food. Unpeeled fruits, uncooked vegetables (salads) and cooked meals that have been stored at inadequate temperatures or cooked at insufficient temperatures are believed to be main source of enteric pathogens for travellers. Onset of diarrhoea is usually within the first week of travel. Duration of illness usually is short and self limiting to 24 hours in 20%, 2 to 7 days in 14% to 16% and 1 week or longer in 20% of cases. The average individual will experience four loose stools associated with abdominal cramps in 20% to 60% of cases, bloody stools (15%), fever (10%) and vomiting (10%). Clinical characteristics of illness are related to organisms responsible.

Tuberculosisc Varicella

Meningococcal Disease and Polio (required for Saudi Arabia specially for Haj pilgrims)

** It is applicable in certain countries to consult. a. These vaccines are currently being introduced in some countries. b. Routine for certain groups and risk factors, selective for general travellers. c. No longer routine in most industrialised countries. d. These vaccines are also included in the routine immunisation programme in several countries.

Avian Flu The travellers going to areas affected by H5N1 virus must have received seasonal influenza vaccine. They should avoid all direct contact with birds including domestic poultry or touching surfaces contaminated with poultry secretions. All food from poultry including eggs should be cooked thoroughly. Egg yolk should not be liquid or runny. Seek immediate medical help if affected with fever, cough, rhinorrhoea, difficulty in breathing, etc. SOME OTHER TRAVEL RELATED COMMON AILMENTS Jet Lag ‘Jet lag’ is a syndrome consisting of symptoms, such as fatigue, weakness, drowsiness and irritability. It is caused by disruption of circadian cycle. Various unproven but widely recommended measures include increased hydration, exercising (i.e. walking in the plane), administration of melatonin and administration of short acting hypnotics. Diet and nutrition play an important role in the management of jet lag. High carbohydrates and protein diet is advocated. Alcohol and caffeine should be used in moderation. Motion Sickness It is caused by travelling and consists of pallour, cold sweating, nausea and vomiting. The drugs with a proven record of safety and efficacy are scopolamine, antihistamines (dimenhydrinate, meclizine) and dextroamphetamine. Of these drugs, the transdermal scopolamine patch is the most effective with less side effects. 2079

Table 3A: Insulin Adjustment Schedule – Eastbound Travel Across Six or More Time Zones Dose Schedule

Day of Departure

First Morning at Destination

10 hr after Morning Dose

Second Day

Single dose schedule

Usual dose of Insulin

Two-thirds of usual insulin dose

Test blood glucose. Give remaining onethird a.m. dose if glucose is >240 mg/dL

Usual dose

Double dose schedule

Usual a.m. and p.m. doses of insulin

Two-thirds of a.m. dose

Test blood glucose. Give usual evening dose and remaining one-third morning dose if glucose >240 mg/dL

Usual two doses

Table 3B: Insulin Adjustment Schedule – Westbound Travel Across Six or More Time Zones Dose Schedule

Day of Departure

Test Blood Glucose 18 hr after a.m. Dose

First Morning Destination

Single dose schedule

Usual Insulin dose

One-third of usual morning insulin dose followed by snack or meal if blood glucose is >240 mg/dl

Usual dose of insulin

Double dose schedule

Usual a.m. and p.m. dose (10 to 12 hours after the morning dose)

As above

Usual two doses of insulin

Travel for Operated Patients During ascent in air travel there is expansion of gases in body cavities to the tune of about 25%. It is important that at least 10 days should have elapsed between any intrathoracic or intraabdominal surgery before flying. Similarly, minor dental procedures like root canal therapy or fillings are advised to wait for approximately 24 hours before flying. Pulmonary Disease The presence of chronic pulmonary disease, such as bronchitis, emphysema and asthma may limit their pulmonary gas exchange. Such conditions could become exacerbated even within the pressurised cabin of an airline. The cabin pressures maintained within commercial airline do not necessarily conform to those occurring at sea level. In these patients, pulmonary function should be maximised to maintain the best FEV1 possible by continuing bronchodilators and corticosteroid therapy before and during flights. If the traveller is unable to tolerate the lowered cabin pressure, request for supplemental oxygen should be made. Cardiac Disease Most of the in-flight deaths are caused by cardiac problems, such as myocardial infarction or cardiac arrest. The emergency medical kit of airlines is generally inadequate. The availability of external defibrillator on the airlines and resuscitation skills among flight attendants may avert approximately 50% of these deaths, which occur due to ventricular fibrillation. Further cardiac patients should carry all medications, a copy of the recent ECG and those with pacemakers should carry ECG performed with and without pacemaker activation. Diabetes Mellitus All diabetics should carry medications, syringes, needles and snacks with them. They must carry a card mentioning their physician’s name, telephone number, type and dose of insulin/

2080

other medication used. Tables 3A and B show the changes in dose schedule during east or west bound travel. SPECIAL HEALTH CONSIDERATIONS FOR TRAVELLERS WITH CHRONIC DISEASES The following broad principles must be kept in mind for advising travellers with chronic diseases. Asses status of disease and management to be followed during travel. Medical Examination after Travel It is advisable for all the travellers to have a medical examination on their return, if especially they have an existing chronic disease, such as COPD, diabetes mellitus, chronic respiratory disease or on anticoagulants. If they develop any sickness following their return home or they had been treated for any illness during travel especially malaria or any serious infectious disease or patients who have travelled for more than 3 months in a developing country should have medical examination. Again, it is pertinent to note that the traveller should provide adequate information about the place, duration of visit, pre-travel infection and malaria prophylaxis. Malaria may be considered an emergency especially if a person develops fever on his return and must be reported as well as proper consultation taken from the doctor. CONCLUSION Travel is undertaken for leisure, business, visiting family and relatives. Therefore, it is imperative that one must stay healthy and the traveller should get vaccinated, examined, and get medical insurance done before travelling to a particular country. He must see the Official Site for any ongoing raging or infective epidemic and demographic disease profile. Post travel medical examination is equally important as pre-travel medical advice. RECOMMENDED READINGS 1.

Health Information for International Travel (CDC: edition 2010, http:// wwwn.cdc.gov/travel/contentYellowBook.aspx).

2.

International Travel and Health (WHO: edition 2011, www.who.int/ith).

28.11

Nanotechnology and Nanomedicine

INTRODUCTION The word ‘nano’ is derived from the Latin word which means ‘dwarf’. The prefix ‘nano’ refers to one-billionth. When applied to linear measurement, a nanometer is one-billionth of a meter. The term nanotechnology is now used to refer to the creation of new objects with nano-scale dimensions between 1 and 100 nanometers. The width of a DNA molecule is approximately 2.5 nm. Most proteins are in the range of 1 to 15 or 20 nm. The width of cell membranes is in the range of 6 to 10 nm. Nanotechnology was first predicted by Nobel Laureate Richard Feynman in 1959. The 1012 cells in the human body themselves are very complex and efficient nano-machines and chemists and biochemists have been working at the nanoscale for some time without using the ‘nano’ lable. Most research in molecular biology already takes place on a nanoscale. Most areas of nanoscience aim to learn from biological nanosystems. The invention of light microscope (1632) allowing magnification × 400 diameters, apart from revealing microorganisms, opened the vista of study of living matter at micrometer size establishing the cell as a unit of life, and specific cell types for specific functions and the concept of cellular pathology. The invention of electron microscope by Ernest Ruska in 1931 (Nobel Prize 1986) allowing magnification X 12,000 diameters, and freeztech EM (X 95,000 diameter) led to the identification of subcellular organelles— lysosomes, peroxisomes, Golgi apparatus, endoplasmic reticulum, mitochondria and nuclear components chromosomes, and the concept of lysosomal, mitochondrial and chromosomal disorders. In the brain, EM revealed the synaptic vesicles (300 to 600 Å) which store neurotransmitters and microtubules as conveyors of a two way traffic between a nerve cell body and its dendrons and axons (one Angstrom is 10 nm). The invention of the scanning tunneling microscope in 1981 by Binig and Rohrer (Nobel Prize 1986) allowed the measurement of and manipulation of individual atoms on a surface. Scanning probe microscopes now extensively used in bio-scientific research are so sensitive that they can detect differences in one base pair in DNA hybridisation. Nanoscale oligonucleotide arrays for gene expression research encompassing the entire human genome on a single chip eliminates the need for labeling DNA strands which simplifies the process of diagnosis. Another Nobel Prize winning breakthrough in nanoscience was the discovery of spherical buckminister fullerenes by Kroto et al. in 1985— compounds containing 60 atoms of carbon arranged in a lattice of hexagonal and pentagonal specific connections sometimes likened to the surface of a soccer ball. The C60 fullerenes are 1 nanometer in diameter. Fullerenes have captured the imagination of pharmaceutical research for a number of their unique properties as drugs or components of targeted drug delivery (Table 1).

Ramchandra D Lele Some years after the discovery of fullerenes, carbon nanotubes or basically open-ended buckyballs were invented, which led to numerous potential scientific and commercial applications including novel display units for computers. Some nanotubes have superconducting properties which are utilised in the new generations of computer systems and electric transmission systems. Beyond biology, there is enormous interest in nanotechnology. The properties of nanoscale objects and material are quite different from the properties of the same chemical materials created with larger dimensions, as a result of the fundamental principles of quantum physics. Strength, electrical conductivity melting point, colour, and optical and magnetic properties are all potentially affected (Thrall 2004). There is growing interest in the use of biomolecules as components in electrical circuits and computing systems to permit further miniaturisations with increased computational capacity. The feasibility of using DNA hybridisation to solve complex mathematical problems has been demonstrated at a proof-concept level. DNA is more than just the secret of life. DNA is now a versatile component of nanoscopic structures and devices. DNA molecules of long length can be made with a sequence of building blocks chosen at will, enabling us to take new paths not yet taken by Nature. Researchers at Mc Gill University Chemistry Department Montreal have created the first examples of DNA nanotubes that encapsulate and load cargo and then release it rapidly and completely when a specific external DNA strand is added. DNA machines with moving parts are employed as nanomechanical sensors, switches and tweezers as well as more elaborate robotic functions. Nanorobots could actually be programmed to repair specific diseased chromosomes in cells or for delivery of Si RNA. Scientists have developed methods for detecting micro RNA from living cells as potential therapeutics for silencing cancer and disease-related genes. Nanotechnology is the art and science of manipulating individual atoms to create useful materials and devices on a scale of 1 to 100 nanometers (10–9) and to create miniature systems with novel functionality, such as nanorobots. Nanomaterials are biomaterials used, for example, in orthopaedic or dental implants or as scaffolds for tissue engineered products. Their surface modifications or coding greatly enhance the biocompatibility. These materials can be subclassified into nanocrystalline and nanostructured materials. Nanocrystalline materials are used in drug encapsulation, bone replacement, prostheses, e.g. artificial limbs, facial prosthetics, neuroprosthetics and implants. Super paramagnetic iron oxides (SPIOs) also known as monocrystalline iron oxide nano particles (MIONs) have shown 2081

Table 1: Nanotechnology Relevant to Medicine Nanotechnology Nanomaterials Nanocrystalline Nanostructured Polymer Nanoparticles 10 mm Dendrimers 1.5 nm Micelles 10 to 100 Drug-Conjugates Non-polymer Carbon nanotubules 1 to 100 nm Metallic nanoparticles