Manual of Practical Medicine [6 ed.] 9352702387, 9789352702381

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MANUAL OF

PRACTICAL MEDICINE

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MANUAL OF

PRACTICAL MEDICINE Sixth Edition

R Alagappan MD FICP Formerly Director-Professor and Head Institute of Internal Medicine Madras Medical College and Senior Physician Government General Hospital Chennai, Tamil Nadu, India

The Health Sciences Publisher New Delhi | London | Panama

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Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected]

Overseas Offices J.P. Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44 20 3170 8910 Fax: +44 (0)20 3008 6180 Email: [email protected]

Jaypee-Highlights Medical Publishers Inc City of Knowledge, Bld. 235, 2nd Floor, Clayton Panama City, Panama Phone: +1 507-301-0496 Fax: +1 507-301-0499 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd 17/1-B Babar Road, Block-B, Shaymali Mohammadpur, Dhaka-1207 Bangladesh Mobile: +08801912003485 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd Bhotahity, Kathmandu Nepal Phone: +977-9741283608 Email: [email protected]

Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2018, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/ or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. The CD/DVD-ROM (if any) provided in the sealed envelope with this book is complimentary and free of cost. Not meant for sale. Inquiries for bulk sales may be solicited at: [email protected] Manual of Practical Medicine First Edition: 1998; Second Edition: 2002; Third Edition: 2007; Fourth Edition: 2011; Fifth Edition: 2014 Sixth Edition: 2018

ISBN 978-93-5270-238-1

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Dedicated to My beloved Wife

Dr R Gomathy MBBS DGO DMCH

for her patience and constant encouragement

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Preface to the Sixth Edition

I have the pleasure of introducing the sixth edition of Manual of Practical Medicine. The speed of increase of medical literature places an enormous strain on the editor in keeping up the size of the manual. The manual has grown in size and complexity, mirroring the growth in different fields of internal medicine. The basic principles of history taking and the clinical examination have not been changed. All the chapters have been revised and updated. A large number of diagrams and CT images have been incorporated for easy understanding. I place my sincere thanks and regards to Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Group President) and Miss Ritu Sharma (Director–Content Strategy) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India for their constant encouragement in updating this manual. I dedicate this edition to my beloved wife, Dr R Gomathy, whose love, affection, patience and constant encouragement helped me in many ways to bring out successfully several editions of this manual. I profusely thank the postgraduates in internal medicine, Dr Karthikeyan Subbian and Dr Jayaprakash Thangavel, for their devoted time consuming hard work in revising and updating this edition. They helped me a lot in obtaining many new diagrams and also in replacing some of the old images. I offer my heartfelt thanks to Dr KG Srinivasan, Consultant Radiologist of KGS Advanced MR, CT Scan and Ultrasound and Doppler Scan, for his generous contribution of MR, CT images to various chapters of this manual and a small write-up on CT PET scan. He is a role model to be emulated by everyone for the rare combination of qualities—wisdom, politeness and hard work. I do hope and wish that the sixth edition of this manual will be a good and complete guide for medical students and practicing physicians.

R Alagappan

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Preface to the First Edition

Medicine is an everchanging science. The vast clinical experience, the technological advancement in the field of investigatory modalities, tremendous explosion in the invention and addition of newer drugs in the field of pharmacology, and a wide variety of interventional therapeutic advancements have contributed to the voluminous growth of medical literature. Human brain cannot remember all the facts. It is impossible to learn, register, remember and to recall all the medical facts in the course of time-bound undergraduate and postgraduate medical education. It is the realisation of these difficulties that prompted me to write this manual. Hence, an earnest attempt has been made to merge the clinical methods and the principles of internal medicine and to present both in a condensed form. To keep the size of the volume compact and small, only certain important clinical topics are included in this manual. Even references are not included since high-tech reference system is available in all the good libraries. The manual will be of practical value to the medical students and practicing physicians with an emphasis not only on clinical methods, clinical features, various essential investigations, but also on the management of various important clinical disorders. I am deeply indebted to three of my postgraduate students Dr K Narayanasamy (MD), Dr Rajesh Bajaj (MD), and Dr S Sujatha (MD) who have helped me in preparation of the manuscript, computer and laser printing and up to the stage of submission to the publishers. But for their untiring efforts and hard work, the timely publication of this manual would not have been possible. I wish to acknowledge the contribution of my associates and colleagues in securing the clinical photographs, echocardiograms, X-rays, CT films, nuclear imaging photographs and computer line diagrams for this manual: C Lakshmikanthan, R Alagesan, P Thirumalai, K Kannan (Madurai), CU Velmurugendran, SG Krishnamoorthy, S Sethuraman, P Raja Sambandam, MA Muthusethupathy, P Soundarrajan, AS Natrajan, D Sivagnanasundaram, C Panchapakesa Rajendran, KR Suresh Bapu, Thirumoorthy and Hari Ramesh. I wish to thank my postgraduate students who did the proofreading of the entire manual. Last, but by no means the least, I wish to acknowledge the help and encouragement provided by the editorial department and the editorial staff of M/s Jaypee Brothers Medical Publishers, New Delhi, India for their kind cooperation in bringing out this manual. I do wish that this manual will be a good guide and primer to the internal medicine students and practicing physicians.

R Alagappan

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Contents 1. Introduction to Internal Medicine............ 1 •• History Taking  2 •• General Examination  4 ♦♦ Examination of the Skin  4 ♦♦ Hair 6 ♦♦ Face 8 ♦♦ Eyes 9 ♦♦ The Tongue  9 ♦♦ Characteristic Types of Facies  12 ♦♦ Constitution 12 ♦♦ Stature 13 ♦♦ State of Nutrition  16 ♦♦ Posture 17 ♦♦ Hands and Fingers  18 ♦♦ Feet and Toes  20 ♦♦ The Skin in Clinical Medicine  21 ♦♦ Nails in Clinical Medicine  23 •• Temperature 25 ♦♦ Normal Temperature Regulation in the Body  25 ♦♦ Factors Determining Rate of Heat Production  25 ♦♦ Fever 26 •• Pain 31 ♦♦ Chest Pain  31 ♦♦ Abdominal Pain  33 ♦♦ Pain due to Disorders of GIT  33 ♦♦ Renal Pain  35 ♦♦ Peripheral Vascular Pain Arterial Occlusion  35 ♦♦ Venous Pain  35 ♦♦ Neurogenic Claudication  35 •• Oedema 35 ♦♦ Aetiology and Types of Oedema  36 ♦♦ Pathophysiology of Oedema  36 ♦♦ Characteristic Features of Oedema of Various Aetiologies 36 •• Shock 38 ♦♦ Control of Arterial Blood Pressure  38 ♦♦ Control Mechanism  38 ♦♦ Classification 38 •• Fundamentals in Genetics   40 ♦♦ Normal Chromosome Number and Structure  41 ♦♦ Chromosomal Abnormalities  41 ♦♦ Single Gene Disorders  42 ♦♦ Mosaicism 43 ♦♦ Chimerism 43 ♦♦ Multifactorial or Polygenic Inheritance  43 ♦♦ Genomic Imprinting  44 ♦♦ Trinucleotide Repeat  44 ♦♦ Mitochondrial Disorders  44 ♦♦ Common Chromosomal Disorders  44 •• Immunology 45 ♦♦ The Immune System and the Basis of Immunity   45 ♦♦ Clinical Aspects of Immunology  46 ♦♦ Immunoglobulins   46 ♦♦ Disorders of Immunoglobulins  48 ♦♦ Immunodeficiency States  48 ♦♦ Hypersensitivity Reactions  49

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Histocompatibility Antigens  50 Transplant Rejection  50 Autoimmune Diseases  50 Immunology and Malignancy  50

2. Nutrition................................................... 51 •• Classification of Nutrients  52 ♦♦ Water 52 ♦♦ Macro-nutrients 52 •• Classification of Nutritional Disorders  53 ♦♦ Pathological Causes of Nutritional Disorders  54 ♦♦ Effects of Malnutrition  54 ♦♦ Protein–Energy Malnutrition  54 •• Vitamins 56 ♦♦ Vitamin A (Retinol)  56 ♦♦ Vitamin D  58 ♦♦ Vitamin E  60 ♦♦ Vitamin K  61 ♦♦ Thiamine (Vitamin B1) 61 ♦♦ Riboflavin (Vitamin B2) 62 ♦♦ Niacin (Nicotinic Acid and Nicotinamide)  62 ♦♦ Pyridoxine (Vitamin B6) 63 ♦♦ Biotin 63 ♦♦ Vitamin B12 and Folate  63 ♦♦ Vitamin C (Ascorbic Acid)  63 •• Inorganic Nutrients  65 ♦♦ Sodium 65 ♦♦ Potassium 65 ♦♦ Calcium 66 ♦♦ Phosphorus 66 ♦♦ Iron 67 ♦♦ Iodine 67 ♦♦ Zinc 67 ♦♦ Fluorine 67 ♦♦ Magnesium 68 ♦♦ Manganese 68 ♦♦ Copper   69 ♦♦ Cobalt 69 ♦♦ Nickel 69 ♦♦ Chromium 69 ♦♦ Selenium 69 •• Obesity 69 ♦♦ Types of Obesity  70 ♦♦ Aetiology 70 ♦♦ Pathology   71 ♦♦ Prognosis   71 •• Anorexia Nervosa and Bulimia  72 ♦♦ Anorexia Nervosa  72 ♦♦ Bulimia   72

3. Infectious Diseases.................................. 73 •• Bacterial Infections  74 ♦♦ Staphylococcal Infections  74 ♦♦ Streptococcal Infections  76 ♦♦ Meningococcal Meningitis  78 ♦♦ Gonococcal Infection  78

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x Manual of Practical Medicine ♦♦ Diphtheria 79 ♦♦ Tetanus 80 ♦♦ Botulism 81 ♦♦ Gas Gangrene (Clostridial Myonecrosis)  82 ♦♦ C. difficile Infection (Pseudomembranous Colitis)  82 ♦♦ Listeriosis 82 ♦♦ Anthrax 83 ♦♦ Haemophilus influenzae  84 ♦♦ Legionella (Legionnaires Disease)  84 ♦♦ Whooping Cough (Pertussis)  85 ♦♦ Gram-negative Enteric Bacteria  85 ♦♦ Escherichia coli  85 ♦♦ Campylobacter 86 ♦♦ Enteric Fever  86 ♦♦ Shigellosis: Bacillary Dysentery  88 ♦♦ Cholera 88 ♦♦ Brucellosis (Undulant Fever)  90 ♦♦ Plague 90 ♦♦ Helicobacter pylori  91 ♦♦ Anaerobic Infections  92 ♦♦ Nocardiosis 93 ♦♦ Atypical Mycobacteria  94 ♦♦ Extrapulmonary Tuberculosis  95 ♦♦ Leprosy (Hansen’s Disease)  96 ♦♦ Chancroid 98 ♦♦ Granuloma Inguinale  99 ♦♦ Chlamydial Infections  99 ♦♦ Mycoplasma Infections 102 •• Spirochetal Diseases  103 ♦♦ Syphilis 103 ♦♦ Yaws (Framboesia)  107 ♦♦ Endemic Syphilis (Bejel)  107 ♦♦ Pinta 107 ♦♦ Leptospirosis (Weil’s Disease)  107 ♦♦ Relapsing Fever  108 ♦♦ Rat-bite Fever  109 ♦♦ Lyme Borreliosis  109 •• Rickettsial Infections  110 ♦♦ Epidemic Louse-Borne Typhus  110 ♦♦ Endemic Flea-Borne Typhus (Murine Typhus)  110 ♦♦ Scrub Typhus (Tsutsugamushi Fever)   111 ♦♦ Rocky Mountain Spotted Fever  111 ♦♦ Rickettsialpox 111 ♦♦ Tick Typhus (Rickettsial Fever)  111 ♦♦ Ehrlichiosis and Anaplasmosis  111 ♦♦ Diagnosis of Rickettsial Infections  111 ♦♦ Q-Fever 111 ♦♦ Kawasaki Disease  112 •• Viral Diseases  112 ♦♦ Classification of Viral Disorders  112 ♦♦ Viral Infections and Cancer  113 ♦♦ Viral Pathogenesis  113 ♦♦ Immunity-Viral Diseases  113 ♦♦ Diagnostic Virology  113 ♦♦ Viral Respiratory Disorders  114 ♦♦ Parainfluenza 114 ♦♦ Influenza 114 ♦♦ Respiratory Syncytial Virus Infections  114 ♦♦ Herpes Virus Infections  115 ♦♦ Varicella Zoster Infections  117 ♦♦ Epstein-Barr Virus (HHV-4) and Infectious Mononucleosis 119 ♦♦ Cytomegalovirus 121

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Human Herpesviruses Types—6, 7 and 8  122 Human Papillomavirus and Parvovirus Infections  122 Parvovirus Infections  123 Variola (Small Pox)  124 Measles (Rubeola)   124 Rubella (German Measles)  125 Mumps 126 Poliomyelitis 126 Rabies 127 Dengue Fever (Break-bone Fever)  129 Yellow Fever  129 Japanese B Encephalitis  130 Chikungunya Virus Infection  130 Gastrointestinal Virus Infections  130 Hepatitis Viruses (A–E)  130 Coxsackie Virus Infections  130 Human Immunodeficiency Virus (HIV) Infection and Acquired Immunodeficiency Syndrome (AIDS)  132 •• Protozoal Infections  141 ♦♦ Malaria 141 ♦♦ Amoebiasis 146 ♦♦ Giardiasis 147 ♦♦ Cryptosporidiosis 148 ♦♦ Trichomoniasis 148 ♦♦ Balantidiasis 149 ♦♦ Isosporiasis 149 ♦♦ Leishmaniasis 149 ♦♦ Trypanosomiasis 151 ♦♦ Toxoplasmosis 154 ♦♦ Pneumocystis jiroveci  155 •• Helminthic Infestations  156 ♦♦ Classification of Helminths that Infest Humans  156 ♦♦ Ankylostomiasis (Hookworm)  156 ♦♦ Ascariasis 156 ♦♦ Strongyloidiasis 159 ♦♦ Enterobius Vermicularis (Threadworm or Pinworm) 160 ♦♦ Trichuris Trichiura (Whipworm)  161 ♦♦ Tissue-dwelling Human Nematodes  161 ♦♦ Lymphatic Filariasis  163 ♦♦ Tropical Pulmonary Eosinophilia  164 ♦♦ Loiasis 165 ♦♦ Onchocerciasis (River Blindness)  165 ♦♦ Dracunculiasis (Guinea Worm Infection)  166 ♦♦ Zoonotic Nematodes  166 ♦♦ Trichinosis (Trichinellosis)  166 ♦♦ Cutaneous Larva Migrans (CLM)  167 ♦♦ Trematodes (Flatworms/Flukes)  168 ♦♦ Schistosomiasis (Blood Flukes)  168 ♦♦ Hepatobiliary Flukes  170 ♦♦ Intestinal Flukes  170 ♦♦ Lung Flukes  170 ♦♦ Cestodes (Tapeworms)  170 ♦♦ Taenia Saginata  170 ♦♦ Taenia Solium and Cysticercosis   171 ♦♦ Echinococcosis 174 ♦♦ Hymenolepiasis Nana  175 ♦♦ Diphyllobothrium latum  175 •• Fungal Infections  176 ♦♦ Candidiasis 176 ♦♦ Histoplasmosis 178 ♦♦ Coccidioidomycosis 179

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Contents xi ♦♦ Pneumocystosis (Pneumocystis jiroveci Pneumonia) 180 ♦♦ Cryptococcosis 181 ♦♦ Aspergillosis 181 ♦♦ Mucormycosis (Zygomycosis/Phycomycosis)  183 ♦♦ Penicillium Marneffei Infections  184 ♦♦ Mycetoma (Maduromycosis and Actinomycetoma) 184 •• Immunisation Against Infectious Diseases  185 ♦♦ Milestones in Vaccine Evolution  185 ♦♦ Adult Immunisation  185

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4. Cardiovascular System.......................... 189 •• Symptoms and Signs  190 ♦♦ Dyspnoea 190 ♦♦ Angina Pectoris  191 ♦♦ Palpitation 192 ♦♦ Syncope 192 ♦♦ Cyanosis 193 ♦♦ Arterial Pulse  194 ♦♦ Blood Pressure  198 •• Examination of Neck Veins  201 ♦♦ Jugular Venous Pressure  201 ♦♦ Jugular Venous Pulse  202 •• General Examination  204 ♦♦ External Features of Cardiac Disease   204 ♦♦ Eyes in Cardiology  204 ♦♦ Inspection 205 ♦♦ Palpation 205 ♦♦ Percussion 208 ♦♦ Auscultation 208 ♦♦ Heart Sounds  209 ♦♦ Heart Murmurs  213 ♦♦ Dynamic Auscultation  217 •• Electrocardiogram 218 ♦♦ Electrical Axis  218 ♦♦ Left Atrial Enlargement  219 ♦♦ Right Atrial Enlargement  219 ♦♦ Left Ventricular Hypertrophy  219 ♦♦ Right Ventricular Hypertrophy  221 ♦♦ Biventricular Hypertrophy  222 ♦♦ Right Bundle Branch Block  222 ♦♦ Left Bundle Branch Block  222 ♦♦ Hemiblocks (Fascicular Blocks)  223 ♦♦ Bi-fascicular Block   223 ♦♦ Tri-fascicular Block  223 ♦♦ ECG in Coronary Artery Disease  224 ♦♦ ECG in Electrolyte Imbalance  226 ♦♦ ECG Changes with Drug Intoxication  228 ♦♦ ECG in Acute Pulmonary Embolism  229 ♦♦ ECG Features of COPD  229 ♦♦ ECG Features of Hypothermia  229 ♦♦ ECG in Various Arrhythmias  229 •• Congenital Heart Diseases  239 ♦♦ Classification of Congenital Heart Diseases  239 ♦♦ Cardiac Malposition   240 ♦♦ Cardiac Abnormalities with Various Genetic Disorders 243 ♦♦ Maternal Disease causing CHD  243 ♦♦ Atrial Septal Defect  244 ♦♦ Ventricular Septal Defect  245 ♦♦ Patent Ductus Arteriosus  247 ♦♦ Eisenmenger Syndrome  248

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Tetralogy of Fallot  249 Pulmonary Stenosis  252 Congenital Aortic Stenosis  253 Coarctation of the Aorta  254 Anomalous Pulmonary Venous Connection   256 Ebstein’s Anomaly  257 Complete Transposition of the Great Vessels (D-Transposition) 258 ♦♦ Congenitally Corrected Transposition of the Great Vessels 259 ♦♦ Truncus Arteriosus   259 ♦♦ Tricuspid Atresia  260 ♦♦ Congenital Complete Heart Block   260 ♦♦ Idiopathic Dilatation of the Pulmonary Artery   261 ♦♦ Congenital Abnormalities of the Coronary Arteries   261 ♦♦ Rheumatic Fever  262 Valvular Heart Disease  264 ♦♦ Mitral Stenosis (MS)  264 ♦♦ Mitral Regurgitation (MR)   268 ♦♦ Mitral Valve Prolapse Syndrome (MVPS)  270 ♦♦ Aortic Stenosis (AS)  271 ♦♦ Aortic Regurgitation (AR)   273 ♦♦ Tricuspid Stenosis (TS)  275 ♦♦ Tricuspid Regurgitation (TR)  277 ♦♦ Pulmonary Stenosis (PS)  277 ♦♦ Pulmonary Regurgitation (PR)  277 ♦♦ Infective Endocarditis (IE)  278 Cardiac Failure  281 ♦♦ Aetiology 282 ♦♦ Pathophysiology 282 ♦♦ Classification of Cardiac Failure High Output and Low Output Failure  282 ♦♦ Treatment of Cardiac Failure  284 Systemic Hypertension  290 ♦♦ Recommendations of the Eighth Joint National Committee (JNC 8)  290 ♦♦ Strategies in the usage of Antihypertensive Drugs  291 ♦♦ Causes of Isolated Systolic Hypertension  291 ♦♦ Factors Influencing Prognosis  292 ♦♦ Non-drug Therapy   293 ♦♦ Drug Therapy  293 ♦♦ Special Considerations in Antihypertensive Therapy 298 Acute Coronary Syndrome (ACS)  300 ♦♦ Unstable Angina  300 Myocardial Infarction (MI)  304 ♦♦ Incidence 304 ♦♦ Risk Factors  304 ♦♦ Symptoms 305 ♦♦ Signs 305 Myocarditis   312 ♦♦ Giant Cell Myocarditis  313 Cardiomyopathies 313 ♦♦ Dilated (Congestive) Cardiomyopathy   313 ♦♦ Tako Tsubo Cardiomyopathy  314 ♦♦ Arrhythmogenic Right Ventricular Dysplasia (ARVD) 314 ♦♦ Restrictive (Obliterative) Cardiomyopathy  314 ♦♦ Hypertrophic Obstructive Cardiomyopathy  315 ♦♦ Primary Cardiomyopathies  317 ♦♦ Secondary Cardiomyopathies  317 ♦♦ Peripartum Cardiomyopathy (PPCM)  317

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xii Manual of Practical Medicine •• Pericarditis 318 ♦♦ Aetiologic Classification   318 •• Cardiac Tamponade   320 ♦♦ Causes 320 •• Cardiac Arrest  320 ♦♦ Causes 320 ♦♦ Cardiopulmonary Resuscitation (Basic Life Support) 321 ♦♦ Cardioversion (DC Shock)  322 •• Cardiac Surgery  323 •• Cardiac Transplantation   323 ♦♦ Contraindications to Cardiac Transplantation  323

5. Respiratory System................................ 325 •• Anatomical Landmarks  326 •• Bronchopulmonary Segments  326 ♦♦ Borders of the Lung  326 ♦♦ Pleural Border  326 •• Pulmonary Circulation  327 •• Systemic Circulation (Bronchial Circulation)  327 •• Symptoms and Signs  327 ♦♦ Cough 327 ♦♦ Sputum 327 ♦♦ Haemoptysis 328 ♦♦ Dyspnoea 329 ♦♦ Chest Pain  330 •• General Examination  330 ♦♦ Clubbing   330 •• Examination of the Neck  332 ♦♦ Scalene Lymph Node  332 ♦♦ Significant Node  332 ♦♦ Lymphatic Drainage of the Lung and Pleura  332 ♦♦ Presence of Veins over the Chest Wall  333 •• External Manifestations of Respiratory Diseases  333 •• Examination of the Respiratory System  333 ♦♦ Inspection of Upper Respiratory Tract  333 ♦♦ Inspection of Lower Respiratory Tract  333 ♦♦ Position of Trachea  334 ♦♦ Position of Apex Beat  334 ♦♦ Symmetry of Chest  334 ♦♦ Chest Deformities  334 ♦♦ Spinal Deformity  335 ♦♦ Movement of the Chest  335 •• Palpation 337 ♦♦ Tracheal Tug-Oliver’s Sign  337 ♦♦ Inspiratory Tracheal Descent  337 ♦♦ Confirmation of Apical Impulse  337 ♦♦ Measurement of the Chest Expansion  338 ♦♦ Assessing Symmetry of Chest Expansion  338 ♦♦ Assessment of Anterior Thoracic Movement  338 ♦♦ Assessment of Posterior Thoracic Movement  338 ♦♦ Tenderness over the Chest Wall  339 ♦♦ Detection of Subcutaneous Emphysema  339 ♦♦ Tactile Fremitus  339 ♦♦ Friction Fremitus  339 ♦♦ Vocal Fremitus  339 •• Percussion of the Lung Fields  339 ♦♦ General Principles  339 ♦♦ Areas of Percussion  340 •• Auscultation 342 ♦♦ General Principles of Auscultation  342 ♦♦ Auscultatory Areas  342

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♦♦ Technique of Auscultation  342 ♦♦ Importance of Auscultation  342 ♦♦ Breath Sounds  342 ♦♦ Added Sounds  343 ♦♦ Voice Sounds  344 ♦♦ Miscellaneous Sounds  344 ♦♦ Other Features of Clinical Significance  345 ♦♦ Others 345 Cavity 346 ♦♦ Thick-walled Cavity  346 ♦♦ Thin-walled Cavity  346 Fibrosis 347 ♦♦ Types of Fibrosis  347 Investigations 347 ♦♦ Sputum Examination  347 ♦♦ Lung Function Tests  347 ♦♦ Bed Side Lung Function Tests  347 ♦♦ Spirometry 347 ♦♦ Lung Volume Estimation  348 ♦♦ Peak Expiratory Flow Rate  349 Chest X-ray  349 ♦♦ Causes of Bilateral Hilar Enlargement  349 ♦♦ Causes of Unilateral Hilar Enlargement  349 ♦♦ Unilateral Hypertransradiant Hemithorax  349 ♦♦ Hemithorax Opacity  349 ♦♦ Widespread Alveolar Opacities  350 ♦♦ Honeycomb Lung (Air Containing Cysts 0.5–2.0 cm in Diameter)  350 ♦♦ Miliary Mottling (0.5–2 mm Opacities)  350 ♦♦ Solitary Pulmonary Nodule   350 ♦♦ Multiple Medium Sized Pulmonary Nodules (5–10 mm)  351 ♦♦ Lung Cavities  351 ♦♦ Unilateral Elevated Hemidiaphragm  351 ♦♦ Bilateral Elevated Hemidiaphragm  351 CT Scan  352 Ultrasound Scan  352 MRI Scan  352 Gas Diffusion Capacity  352 ♦♦ Arterial Blood Gas Analysis  352 ♦♦ Ventilation-Perfusion Imaging  352 ♦♦ Pulmonary Angiography  352 ♦♦ Bronchoscopy 352 ♦♦ Pleural Aspiration and Percutaneous Pleural Biopsy  353 ♦♦ Oxygen Therapy   353 Respiratory Diseases  353 ♦♦ Classification of Respiratory Diseases  353 ♦♦ Bronchial Asthma  353 ♦♦ Obstructive Sleep Apnoea-Hypopnoea Syndrome (OSAHS) 358 ♦♦ Chronic Obstructive Pulmonary Disease (COPD)  360 ♦♦ Bronchiectasis 363 ♦♦ Cystic Fibrosis  366 ♦♦ Tuberculosis 368 ♦♦ Pneumonia 374 ♦♦ Lung Abscess  377 ♦♦ Pleural Effusion  378 ♦♦ Pneumothorax 383 ♦♦ Interstitial Lung Disease   384 ♦♦ Bronchogenic Carcinoma  385 ♦♦ Mediastinal Mass  387 ♦♦ Acute Respiratory Distress Syndrome (ARDS)  389

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Contents xiii ♦♦ Pulmonary Hypertension   392 ♦♦ Cor Pulmonale   395 ♦♦ Pulmonary Thromboembolism  396 •• Lung Transplantation  399 ♦♦ Indications 399 ♦♦ Types 399 ♦♦ Prognosis 399

6. Abdomen................................................ 401 •• Clinical Examination  402 ♦♦ Signs and Symptoms  402 ♦♦ General Examination  404 ♦♦ Signs of Liver Cell Failure  404 ♦♦ Regions of Abdomen  405 ♦♦ Inspection 405 ♦♦ Palpation 408 ♦♦ Percussion 411 ♦♦ Auscultation   413 ♦♦ Causes of Hepatomegaly  414 ♦♦ Causes of Painful Hepatomegaly   414 ♦♦ Causes of Pulsatile Liver  414 ♦♦ Causes of Splenomegaly  415 ♦♦ Causes of Hepatosplenomegaly  415 ♦♦ Causes of Hepatosplenomegaly + Lymphadenopathy   415 •• Gastrointestinal System  415 ♦♦ Dysphagia 415 ♦♦ Achalasia Cardia  418 ♦♦ Gastro-oesophageal Reflux Disease  418 ♦♦ Peptic Ulcer Disease  418 ♦♦ Zollinger-Ellison Syndrome  422 ♦♦ Endoscopy 422 ♦♦ Gastrointestinal Bleeding  422 ♦♦ Diarrhoea 424 ♦♦ Malabsorption 426 ♦♦ Tuberculosis of Abdomen  427 ♦♦ Inflammatory Bowel Disease  429 ♦♦ Irritable Bowel Syndrome   432 ♦♦ Ischaemic Colitis  433 ♦♦ Carcinoid Tumours   433 ♦♦ Gastric Ulcer and Malignancy  434 •• Hepatology and Pancreas  435 ♦♦ Hepatic Segments  435 ♦♦ Liver Function Tests  435 ♦♦ Jaundice 437 ♦♦ Congenital Jaundice  438 ♦♦ Familial Defects in Hepatic Excretory Function  440 ♦♦ HIV and the Liver  441 ♦♦ Pregnancy and the Liver  441 ♦♦ Viral Hepatitis  441 ♦♦ Chronic Hepatitis  444 ♦♦ Prevention of Hepatitis  447 ♦♦ Autoimmune Hepatitis  447 ♦♦ Polycystic Liver Disease  448 ♦♦ Liver Abscess  448 ♦♦ Amoebic Abscess  449 ♦♦ Steatosis 449 ♦♦ Nonalcoholic Fatty Liver Disease  449 ♦♦ Cirrhosis of Liver  450 ♦♦ Variceal Bleeding  455 ♦♦ Ascites 457 ♦♦ Fulminant Hepatic Failure  459 ♦♦ Hepatic Coma (Hepatic Encephalopathy)  460

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♦♦ Hepatorenal Syndrome  461 ♦♦ Hepatocellular Carcinoma (Hepatoma)  462 •• Metabolic Liver Disease  463 ♦♦ Wilson’s Disease  463 ♦♦ Haemochromatosis 465 ♦♦ Reye Syndrome (Fatty Liver with Encephalopathy) 466 ♦♦ Budd-Chiari Syndrome  466 ♦♦ Acute Pancreatitis   467 ♦♦ Chronic Pancreatitis   470 ♦♦ Tropical Pancreatitis  471 •• Liver Transplantation  471 ♦♦ Cadaver Donor Selection   471 ♦♦ Indications 471 ♦♦ Contraindications 472 ♦♦ Immunosuppression 472 ♦♦ Live Donor Transplantation   472 ♦♦ Auxiliary Liver Transplantation  472 ♦♦ Split Liver Transplantation  472 ♦♦ Bioartificial Liver  473 ♦♦ Success Rate  473 ♦♦ Molecular Adsorbent Recirculating System (MARS) 473

7. Haematology.......................................... 475 •• Haematopoiesis and Haematopoietic Growth Factors 476 ♦♦ Cell Divisions  476 ♦♦ Haematopoiesis 476 ♦♦ Normal Haematopoiesis  476 ♦♦ Antigen Designation—Cellular Distribution  477 ♦♦ Haematopoietic Stem Cells  477 ♦♦ Haematopoietic Stem Cell Differentiation  477 ♦♦ Nature of the Marrow Stem Cell  478 ♦♦ Stem Cell Diseases  478 ♦♦ Therapeutic Application of Stem Cells  478 ♦♦ Haematopoietic Growth Factors  478 ♦♦ Major Growth Factors  478 •• Normal Reference Values in Haematology  480 ♦♦ Absolute Reticulocyte Count  480 ♦♦ Reticulocyte Index  481 ♦♦ Peripheral Film Morphology  481 ♦♦ WBC Count  482 ♦♦ Erythrocyte Sedimentation Rate  482 ♦♦ Automated Full Blood Analysis  482 •• Anaemia 482 ♦♦ WHO Definition  482 ♦♦ Practical Classification of Anaemia  482 ♦♦ Classification of Anaemia (Based on Reticulocyte Index) 483 ♦♦ Symptoms and Signs  483 ♦♦ Iron Deficiency Anaemia  483 ♦♦ Megaloblastic Anaemia  486 ♦♦ Anaemia of Chronic Disease (ACD) (Sideropenic Anaemia, Simple Anaemia)  489 ♦♦ Haemolytic Anaemia  490 ♦♦ Hereditary Spherocytosis (HS)   491 ♦♦ Sickle Cell Disease  492 ♦♦ Thalassaemia 494 ♦♦ Pancytopenia 495 ♦♦ Aplastic Anaemia  495 •• Blood Transfusion  497 ♦♦ Indications   497 ♦♦ Manipulation of Blood Products  497

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xiv Manual of Practical Medicine •• Disorders of the White Cells  498 ♦♦ Neutrophils 498 ♦♦ Lymphocytes 498 ♦♦ Eosinophils 499 ♦♦ Monocytes 499 ♦♦ Basophils 500 •• Myeloproliferative Disorders  500 ♦♦ WHO Classification of Myeloid Leukemia   500 ♦♦ Polycythaemia Vera  500 ♦♦ Essential Thrombocythaemia (Primary Thrombocytosis) 502 ♦♦ Primary Myelosclerosis (Myelofibrosis)  503 ♦♦ Myelophthisic Anaemia  503 •• Haematological Malignancies  504 ♦♦ Lymphoid Malignancies  504 ♦♦ Leukaemias   504 ♦♦ Myelodysplastic and Preleukaemic Syndromes (MDS and PLS)  514 ♦♦ Lymphomas   515 •• Plasma Cell Dyscrasias  519 ♦♦ Plasma Cell Disorders   519 •• An Approach to Bleeding Disorders  522 ♦♦ History 522 ♦♦ Examination 522 ♦♦ Bleeding Disorders  524 ♦♦ Immune Thrombocytopenic Purpura (ITP)  524 ♦♦ Thrombotic Thrombocytopenic Purpura (TTP)  525 ♦♦ Haemolytic Uraemic Syndrome (HUS)  526 ♦♦ HIT—Heparin-induced Thrombocytopenia (White Clot Syndrome) 526 ♦♦ Disorder due to Deficiency of Clotting Factors  527 •• Bone Marrow Transplantation   529 ♦♦ Indications 529 ♦♦ Types of Bone Marrow Transplantation  530 ♦♦ Selection of the Donor  530 ♦♦ Preparation of the Patient  530 ♦♦ Marrow Aspiration and Infusion  530 ♦♦ Bone Marrow Transplantation (BMT) in Leukaemia 531 ♦♦ Autologous BMT  531 •• Haematopoietic Stem Cell Transplantation  531 ♦♦ Allogeneic Stem Cell Transplant  531 ♦♦ Autologous Stem Cell Transplant  531 ♦♦ Peripheral Blood Stem Cell Transplantation (PBSCT)  532

8. Nephrology............................................ 533 •• Urine Analysis  534 ♦♦ Methods of Collection of Urine Specimens  534 ♦♦ Dipstick Testing  534 ♦♦ Microscopic Analysis  534 ♦♦ Haematuria 534 ♦♦ Urinary Casts  535 ♦♦ Leucocytes in Urine  536 ♦♦ Renal Tubular Cells  536 ♦♦ Crystals 536 ♦♦ Proteinuria 536 ♦♦ Reducing Substances in Urine  538 ♦♦ 24-hour Urine Studies  538 ♦♦ Blood Tests for Evaluating Glomerular Disorders   539 ♦♦ Serum and Urine Protein Electrophoresis  539 ♦♦ Urine Eosinophils  539 ♦♦ Renal Ultrasonography  539

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♦♦ IV Urography  539 ♦♦ Radionuclide Scanning  539 ♦♦ MRI Imaging and Angiography  539 ♦♦ Creatinine Clearance (ClCr) 539 Urinary Tract Infection  539 ♦♦ Definitions 539 ♦♦ Risk Factors Associated with Urinary Tract Infection 540 ♦♦ Pathogenesis 540 ♦♦ Symptoms of UTI  540 ♦♦ Principles of Treatment of UTI  541 ♦♦ Recommendations for Use and Care of Urinary Catheters 541 ♦♦ Urinary Antiseptics  543 ♦♦ Prophylaxis for UTI  543 Glomerulopathies 543 ♦♦ Classification 543 ♦♦ Classification of Nephritic Syndrome Based on Complement Levels  543 ♦♦ HIV-associated Nephropathy  543 ♦♦ Nephrotic Syndrome  544 ♦♦ Glomerulonephritis 547 ♦♦ Alport Syndrome  549 ♦♦ Fanconi Syndrome  549 ♦♦ Chronic GN  550 ♦♦ Tubulointerstitial Disease of Kidney  550 ♦♦ Acute Interstitial Nephritis  551 ♦♦ Renal Biopsy—Indications  551 ♦♦ Contraindications to Renal Biopsy  551 ♦♦ Chronic Interstitial Nephritis  551 ♦♦ Polycystic Kidney Disease  551 Acute Kidney Injury/Acute Renal Failure (ARF)  552 ♦♦ Causes of ARF  553 ♦♦ Acute Tubular Necrosis  553 ♦♦ Renal Tubular Acidosis (RTA)  555 Chronic Kidney Disease  556 ♦♦ Chronic Renal Failure (CRF)  556 Dialysis 560 ♦♦ Haemodialysis (HD)  560 ♦♦ Haemofiltration 560 ♦♦ Intermittent Peritoneal Dialysis  560 ♦♦ Continuous Ambulatory Peritoneal Dialysis (CAPD) 560 Renal Transplantation  561 ♦♦ Rejection 561 ♦♦ Immunosuppressive Therapy in Renal Transplant­ation  561 Fluid and Electrolyte Imbalance  561 ♦♦ Sodium 561 ♦♦ Potassium 563 Acid-Base Balance and its Disorders  564 ♦♦ Definitions 565 ♦♦ Hydrogen Ion Homeostasis  565 ♦♦ Approach to Acid-Base Disorders  567

9. Nervous System..................................... 569 •• Higher Functions  570 ♦♦ Definitions 570 •• Examination of Higher Mental Functions  572 ♦♦ Consciousness 572 ♦♦ Causes of Coma  572 ♦♦ Approach to Coma  573 ♦♦ Appearance and Behaviour  577

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♦♦ Emotional State  577 ♦♦ Orientation 577 ♦♦ Handedness 577 ♦♦ General Intelligence  577 ♦♦ Memory 578 ♦♦ Perceptions 578 ♦♦ Visuospatial Functions  578 ♦♦ Sleep 579 ♦♦ Speech and Language  583 ♦♦ Cognitive Scales  588 Examination of the Cranial Nerves  589 ♦♦ First Cranial Nerve (Olfactory Nerve)  589 ♦♦ Second Cranial Nerve (Optic Nerve)  590 ♦♦ The Oculomotor (Third), Trochlear (Fourth), and Abducent (Sixth) Cranial Nerves  597 ♦♦ Fifth Cranial Nerve (Trigeminal Nerve)  605 ♦♦ Seventh Cranial Nerve (Facial Nerve)  607 ♦♦ The Eighth Cranial Nerve (Vestibulocochlear Nerve)  611 ♦♦ The Ninth and Tenth Cranial Nerves (Glossopharyngeal and Vagus Nerves)  615 ♦♦ Eleventh Cranial Nerve (Accessory Nerve)  615 ♦♦ The Twelfth Cranial Nerve (Hypoglossal Nerve)  617 Spinomotor System  617 ♦♦ Corticobulbar and Corticospinal (Pyramidal) System 618 ♦♦ Extrapyramidal System  619 ♦♦ Neuromuscular System (Lower Motor Neurons)  620 ♦♦ Cerebellum 640 Sensory System  643 ♦♦ Positive Phenomena  643 ♦♦ Negative Phenomena  643 ♦♦ Cutaneous Afferent Innervation  643 ♦♦ Sensory Pathways  644 ♦♦ Modalities of Sensation to be Tested  645 ♦♦ Arrangement of Sensory Fibres  645 ♦♦ Sensory Dermatomes  645 ♦♦ Proprioceptive Sensations  647 ♦♦ Vibration Sense  648 ♦♦ Muscle Sensitivity  648 ♦♦ Cortical Sensations  649 Epilepsy 652 ♦♦ Classification of Seizures  652 ♦♦ Precipitating Factors for Epilepsy  652 ♦♦ Causes 653 ♦♦ Age-related Causes of Seizures  653 ♦♦ Status Epilepticus  657 ♦♦ Epilepsy in Pregnant Women  659 ♦♦ Psychogenic Seizures  660 Neurocutaneous Syndromes  660 ♦♦ Neurofibromatosis 660 ♦♦ Tuberous Sclerosis  661 ♦♦ Von Hippel-Lindau Syndrome  661 ♦♦ Sturge-Weber Syndrome  661 ♦♦ Ataxia Telangiectasia  661 Cerebrovascular Disorders  662 ♦♦ Stroke 662 ♦♦ Young Stroke  669 ♦♦ Subclavian Steal Syndrome  673 ♦♦ Lacunar Infarction  673 ♦♦ Cortical Venous Thrombosis (Dural Sinus Thrombosis) 674 ♦♦ Intracerebral Haemorrhage (ICH)  675 ♦♦ Subarachnoid Haemorrhage (SAH)  678

•• Brain Death  681 ♦♦ Essential Neurological Signs  681 •• Headache 681 ♦♦ Pain Sensitive Structures  681 ♦♦ Pain Insensitive Structures  682 ♦♦ Mechanisms of Production of Headache  682 ♦♦ Headache Caused by Systemic Illness  682 •• Neoplastic Disease of the Central Nervous System  685 ♦♦ Spinal Cord Tumours (Excluding Secondaries)  685 ♦♦ Cerebral Tumours  685 ♦♦ Ring Enhancing Lesion—Differential Diagnosis  687 •• Movement Disorders  688 ♦♦ Classification 688 ♦♦ Parkinson’s Disease  688 ♦♦ Parkinsonism Plus Syndromes  691 •• Motor Neuron Disease  691 ♦♦ Genetic Classification  691 ♦♦ Amyotrophic Lateral Sclerosis  692 ♦♦ Progressive Muscular Atrophy (Predominant LMN Involvement) 692 ♦♦ Progressive Bulbar Palsy  693 ♦♦ Primary Lateral Sclerosis (Predominant UMN Involvement) 693 ♦♦ Pseudobulbar Palsy (UMN Fibres Corticobulbar Tracts) of Cranial Nerves  693 ♦♦ Variants of Motor Neuron Disease  693 ♦♦ Spinal Muscular Atrophy (SMA)  695 •• Ataxic Disorders (Cerebellar and Spinocerebellar)  695 ♦♦ Hereditary Ataxia  695 •• Congenital Ataxias  696 •• Ataxic Disorders with Known Metabolic or Other Causes 697 •• Ataxic Disorders of Unknown Aetiology of Early Onset 698 •• Ataxic Disorders of Unknown Aetiology of Late Onset 699 ♦♦ Multiple Sclerosis  702 ♦♦ Clinical Features not Suggestive of MS  704 ♦♦ Features that Differentiate MS from Other Demyelinating Disorders  704 ♦♦ Meningitis 706 ♦♦ Types of CNS TB  706 ♦♦ Complications of TB Meningitis  708 ♦♦ Corticosteroids in CNS Tuberculosis  708 ♦♦ Encephalitis 708 ♦♦ Slow Virus Disease  709 ♦♦ Autonomic Nervous System  712 ♦♦ Horner’s Syndrome  713 •• The Spine  713 ♦♦ Curvature Disorders  713 •• Spinal Cord  715 ♦♦ Vascular Syndromes of Spinal Cord  716 ♦♦ Spinal Cord Disorders  717 ♦♦ Traumatic Lesions of the Spinal Cord   718 ♦♦ Tuberculosis 718 ♦♦ Syphilis 719 ♦♦ Epidural Abscess  719 ♦♦ Epidural Haemorrhage and Haematomyelia 719 ♦♦ Cervical Spondylosis  720 ♦♦ Lumbar Canal Stenosis  721 ♦♦ Paraplegia 723 ♦♦ Syringomyelia 730

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♦♦ Subacute Combined Degeneration (Posterolateral Sclerosis of the Spinal Cord)  731 ♦♦ Other Causes of Posterolateral Column Syndrome 732 Craniovertebral Junction (CVJ) Anomalies  732 ♦♦ Classification 732 Peripheral Neuropathy  735 ♦♦ Pathogenesis 735 ♦♦ Classification of Peripheral Neuropathy  735 ♦♦ Symptoms 736 ♦♦ Guillain-Barré Syndrome  738 ♦♦ Chronic Inflammatory Demyelinating Polyneuropathy 739 ♦♦ Hereditary Sensory Motor Neuropathy (Charcot-Marie Tooth Disease)  740 Polymyositis 741 ♦♦ Classification 741 Muscular Dystrophies  742 ♦♦ Classification 742 ♦♦ Mitochondrial Myopathy  744 Congenital Myopathies  744 ♦♦ Central Core Disease  744 ♦♦ Nemaline Myopathy  744 ♦♦ Centronuclear Myopathy  744 ♦♦ Myotonia Congenita (Thomson’s Disease)  745 ♦♦ Paramyotonia Congenita  745 ♦♦ Myasthenia Gravis  746 ♦♦ Myasthenic Syndrome (Eaton-Lambert Syndrome) 748

10. Endocrine and Metabolic Disorders..... 749 •• Hypothalamus and Pituitary Gland   750 ♦♦ Anatomy 750 ♦♦ Anterior Lobe  750 ♦♦ Neurohypophysis 750 •• Hypopituitarism 750 ♦♦ Aetiology 750 •• Hypersecretory Disorders of Anterior Pituitary   752 ♦♦ Acromegaly and Gigantism  752 ♦♦ Hyperprolactinaemia 755 ♦♦ Pituitary Tumours  756 ♦♦ Pituitary Hyperplasia  757 ♦♦ Empty Sella Syndrome  757 ♦♦ Craniopharyngioma 757 •• Disorder of the Neurohypophysis  757 ♦♦ Diabetes Insipidus  757 ♦♦ Syndrome of Inappropriate Antidiuretic Hormone Secretion 760 •• Thyroid Disorders  761 ♦♦ Anatomy and Physiology of Thyroid Gland  761 ♦♦ Hyperthyroidism   762 ♦♦ Hypothyroidism   767 ♦♦ Thyroiditis 770 ♦♦ Malignant Tumours of the Thyroid  773 ♦♦ Medullary Carcinoma  774 •• Disorders of Parathyroid Gland and Calcium and Phosphorus Metabolism  774 ♦♦ Anatomy and Physiology  774 ♦♦ Actions of Parathormone  774 ♦♦ Actions of Calcitonin  774 ♦♦ Parathormone Related Peptide (PTHrp)  775 ♦♦ Causes of Hypercalcaemia  775 ♦♦ Primary Hyperparathyroidism  776

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♦♦ Hypercalcaemia in Malignancy  778 ♦♦ Endocrine Causes of Hyperparathyroidism  778 ♦♦ Secondary Hyperparathyroidism (Increased PTH and Calcium may be Normal or Low)  778 ♦♦ Tertiary Hyperparathyroidism  778 ♦♦ Hypocalcaemic Disorder  778 Adrenal Glands  780 ♦♦ Anatomy and Physiology  780 ♦♦ Primary Hyperaldosteronism  780 ♦♦ Secondary Hyperaldosteronism  781 ♦♦ Cushing’s Syndrome   781 ♦♦ Adrenal Insufficiency   784 ♦♦ Adrenal Crisis  787 ♦♦ Phaeochromocytoma 788 ♦♦ Sexual Disorders  790 Diabetes Mellitus (DM)  792 ♦♦ Aetiologic Classification of Diabetes Mellitus   793 ♦♦ Risk Factors for Type 2 Diabetes Mellitus (Statistical Risk Disease) 794 ♦♦ Diagnosis 795 ♦♦ Insulin Therapy  795 ♦♦ Type 2 Diabetes Mellitus   802 ♦♦ Acute Complications of Diabetes  810 ♦♦ Long-term Complications of Diabetes  816 ♦♦ Diabetic Foot  823 ♦♦ Diabetic Nephropathy (DN)  824 ♦♦ Pregnancy and Diabetes   825 ♦♦ Surgery and Diabetes  827 ♦♦ Hypoglycaemia in Adults  828 ♦♦ Fed (Reactive) Hypoglycaemias  832 Hyperlipoproteinaemias   833 ♦♦ Structure 833 ♦♦ Classification of Lipoproteins and their Composition   833 Osteomalacia 838 ♦♦ Aetiology 838 Osteoporosis 839 ♦♦ Aetiology 839 ♦♦ Male Osteoporosis  841 ♦♦ Paget’s Disease  842

11. Connective Tissue Disorders................. 843 •• Arthritis 844 ♦♦ Approach to Musculoskeletal Pain  844 ♦♦ Classification 844 ♦♦ Rheumatoid Arthritis  844 ♦♦ Drug Therapy  849 ♦♦ Osteoarthritis (OA)  853 ♦♦ Spondyloarthropathy 853 ♦♦ Systemic Lupus Erythematosus (SLE)  857 ♦♦ Mixed Connective Tissue Disease   861 ♦♦ Progressive Systemic Sclerosis   862 ♦♦ Vasculitis Syndromes  865 ♦♦ Polyarteritis Nodosa  866 ♦♦ Churg-Strauss Disease (Allergic Angiitis or Granulomatosis)   868 ♦♦ Wegener’s Granulomatosis (WG)  868 ♦♦ Temporal Arteritis (Giant Cell Arteritis, Cranial Arteritis) 869 ♦♦ Takayasu’s Arteritis (Aortic Arch Syndrome)  870 ♦♦ Kawasaki Disease (Mucocutaneous Lymph Node Syndrome) 870 ♦♦ Behçet’s Syndrome  871

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Contents xvii ♦♦ Sjogren’s Syndrome (SS) (Autoimmune Exocrinopathy/ Autoimmune Epithelitis)  871 ♦♦ Antiphospholipid Antibody Syndrome (APS)  872

12. Oncology................................................ 875 •• Basic Concepts  876 ♦♦ Genes and Cancer  876 ♦♦ Tumour Suppressor Genes and Familial Cancers  876 ♦♦ Cell Biology of Cancer  876 •• Aetiology of Cancers  878 ♦♦ Carcinogens   878 •• Clinical Features of Cancer  880 ♦♦ General Features  880 ♦♦ Specific Clinical Features  881 ♦♦ Investigations 883 ♦♦ Diagnosis 884 ♦♦ Staging 884 ♦♦ Performance Status  885 ♦♦ Cancer Screening  885 ♦♦ Complications 886 ♦♦ Vaccination of Cancer Patients  886 •• Paraneoplastic Syndromes  887 ♦♦ Endocrine Syndromes  887 ♦♦ Haematologic Syndromes  888 ♦♦ Neurologic Syndromes  889 •• Oncologic Emergencies  890 ♦♦ Superior Vena Caval Obstruction  890 ♦♦ Increased Intracranial Pressure (Brain Metastasis)  891 ♦♦ Meningeal Carcinomatosis  891 ♦♦ Intracerebral Leucocytostasis (Ball’s Disease)  891 ♦♦ Seizures 891 ♦♦ Spinal Cord Compression  891 ♦♦ Malignant Effusions  892 ♦♦ Airway Obstruction  892 ♦♦ Haemoptysis 892 ♦♦ Intestinal Obstruction  893 ♦♦ Urinary Obstruction  893 ♦♦ Biliary Obstruction  893 ♦♦ Other Emergencies  893 •• Metastatic Cancer of Unknown Primary Site   894 ♦♦ Biologic Behaviour  894 ♦♦ Clinical Evaluation  895 ♦♦ Pathological Evaluation or Biopsy  895 •• Principles of Cancer Therapy   896 ♦♦ Surgery 896 ♦♦ Radiation Therapy  896 ♦♦ Chemotherapy 897 ♦♦ Therapy of Selected Cancers  905 •• Symptom Control in Severe Cancer   907 ♦♦ Pain 907 ♦♦ Nausea and Vomiting  907 ♦♦ Pruritus 908 ♦♦ Hiccup 908 ♦♦ Breathlessness 908 ♦♦ Cachexia/Anorexia 908 ♦♦ Constipation 908 ♦♦ Complications of Therapy  908 ♦♦ Late Effects of Cancer Therapy  910

13. Geriatric Medicine................................. 913 •• Ageing 914 ♦♦ Postulated Mechanisms for Ageing  914 ♦♦ Some Physiological Effects of Ageing  914

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Characteristics of Disease in Old Age  914 Giants of Geriatric Medicine  916 Principles of Management of Geriatric Problems  918 Drugs Cleared by the Kidney which should be Closely Monitored in the Elderly  919

14. Substance Abuse.................................... 921 •• Alcohol 922 ♦♦ Risk Factors for Alcoholic Liver Disease  922 ♦♦ Effect of Alcohol on Liver  922 ♦♦ Alcohol and Central Nervous System (CNS)  924 ♦♦ Tobacco Alcohol Amblyopia  925 ♦♦ Nutritional Deficiency Syndrome  925 ♦♦ Pregnancy and Alcohol   926 ♦♦ Gastrointestinal 926 ♦♦ Haematology 926 ♦♦ Cardiovascular System  926 ♦♦ Respiratory System  926 ♦♦ Genitourinary System  926 ♦♦ Bone 927 ♦♦ Endocrine 927 ♦♦ Skin 927 ♦♦ Alcohol and Malignancy   927 ♦♦ Alcohol and Lymphatic System  927 ♦♦ Alcohol and Drug Interactions  927 ♦♦ Psychological 927 ♦♦ Social 927 ♦♦ Alcoholic Coma  927 ♦♦ Alcohol Withdrawal  927 ♦♦ Alcohol Dependence—Drugs Used for Management 928 •• Smoking 928 ♦♦ Contents of Cigarette Smoke  928 ♦♦ Pharmacology of Cigarette Smoke  928 ♦♦ Characteristics of Smokers  929 ♦♦ Clinical Correlations  929 ♦♦ Passive Smoking  930 ♦♦ Smoking and Drugs  930 ♦♦ Types of Smoking  930 ♦♦ Cessation Process  931 ♦♦ Cessation Methods  931

15. Imaging Modalities in Internal Medicine................................... 933 •• X-ray 934 ♦♦ Chest Film  934 ♦♦ Plain Abdominal Film  934 ♦♦ Plain X-ray Skull  938 ♦♦ X-ray Hands  940 •• Contrast Studies  941 ♦♦ Intravenous Urography Pyelography (IVU or IVP)  941 ♦♦ Angiography 942 •• Radioisotope Scanning  942 ♦♦ Cardiac Scanning  942 ♦♦ Brain Scanning with 99mTc 942 ♦♦ Ventilation/Perfusion Scan (V/Q Scan)  943 ♦♦  99mTc Bone Scan  943 ♦♦ Renal Scan  943 ♦♦ Adrenal Scan  943 ♦♦ Hepatobiliary Scan  943 ♦♦ Thyroid Scan  943 ♦♦ White Cell Scan  943 ♦♦ Gallium-67 Scan  944

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♦♦ Positron Emission Tomography (PET)   944 ♦♦ Single Photon Emission Computed Tomography (SPECT) 944 Ultrasound 944 ♦♦ Abdominal Scan  944 Echocardiography 945 ♦♦ Thyroid Scan  947 ♦♦ Orbit and Eye  947 ♦♦ Large Veins and Arteries  947 ♦♦ Special Techniques  947 Computed Tomography (CT) Scan  947 ♦♦ CT Brain  947 ♦♦ CT Chest  948 CT Angiography  948 ♦♦ Benefits   950 ♦♦ Risks   951 ♦♦ CT Coronary Angiography  951 ♦♦ CT—Abdomen 951 Magnetic Resonance Imaging (MRI)   953 ♦♦ Advantages of MRI  954 ♦♦ Diffusion-weighted MRI  954 ♦♦ Disadvantages of MRI  955

16. Procedures............................................. 957 •• Pleural Aspiration  958 ♦♦ Indications for Pleural Aspiration  958 ♦♦ Indications for Therapeutic Aspiration  958 ♦♦ Site of Aspiration  958 ♦♦ Pleural Aspiration Needle  958 ♦♦ Procedure 958 •• Pleural Biopsy  958 •• Lumbar Puncture  959 ♦♦ Indications 959 ♦♦ Contraindications 959 ♦♦ Lumbar Puncture Needle  959 ♦♦ Procedure 959 •• Queckenstedt’s Test  960 ♦♦ Procedure 960 ♦♦ Cisternal Puncture  960 •• Pericardiocentesis 960 ♦♦ Indications 960 ♦♦ Needle 960 ♦♦ Procedure 960 ♦♦ Aftercare 961 •• Ascitic Fluid Aspiration (Paracentesis)  961 ♦♦ Indications 961 ♦♦ Procedure 961 ♦♦ Aftercare 962 •• Bone Marrow Aspiration  962 ♦♦ Indications 962 ♦♦ Contraindication 962 ♦♦ Needles 962 ♦♦ Procedure 962 •• Trephine Biopsy  963 •• Liver Biopsy  963 ♦♦ Indications 963

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♦♦ Contraindications 963 ♦♦ Liver Biopsy Needles  963 ♦♦ Procedure 963 ♦♦ Aftercare 964 Kidney Biopsy  964 ♦♦ Contraindications 964 ♦♦ Procedure 965 ♦♦ Aftercare and Complications  965 Setting up a Drip  965 ♦♦ Indications 965 ♦♦ Precautions 966 ♦♦ Procedure 966 Administration of Intravenous Cytotoxics   966 ♦♦ Procedure 966 ♦♦ Contraindications for Cytotoxic Therapy  967 ♦♦ Problems 967 Percutaneous Central Venous Cannulation   967 ♦♦ Procedure 967 ♦♦ Maintenance of Central Venous Cannulation  969 Passing a Nasogastric Tube  969 ♦♦ Procedure 969 ♦♦ Problems 969 ♦♦ Aftercare and Complications  969 Urethral Catheterisation  970 ♦♦ Indications 970 ♦♦ Contraindications 970 ♦♦ Choice of Catheters  970 ♦♦ Procedure 970 ♦♦ Problems 971 Arterial Puncture  971 ♦♦ Contraindications 971 ♦♦ Site of Puncture  971 ♦♦ Procedure 971 Tracheostomy   971 ♦♦ Indications 971 ♦♦ Types 971 ♦♦ Tracheostomy Tubes  972 ♦♦ Procedure 972 ♦♦ Postoperative Care  972 ♦♦ Removal of Tube  972 Endotracheal Intubation  972 ♦♦ Types 972 ♦♦ Procedure 973

Laboratory Reference Values............... 975 ♦♦ Serum Biochemistry  975 ♦♦ Serum Enzymes  975 ♦♦ Haematologic Values  976 ♦♦ Urine 976 ♦♦ Stool 976 ♦♦ Sweat 976 ♦♦ Hormones 976 •• Cerebrospinal Fluid  977

Index.......................................................................979

04-Jan-18 2:24:39 PM

CHAPTER

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Introduction to Internal Medicine

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Manual of Practical Medicine

HISTORY TAKING History taking is an art, which forms a vital part in approaching the patient’s problem, and arriving at a diagnosis. History taking helps to form a healthy doctorpatient relationship. It also builds up the patient’s confidence and trust in his doctor. Even before going into the patient’s complaints, important facts can be gained from the following data, asked as a routine from every patient, helping the consulting doctor to arrive at a most probable conclusion to the patient’s problems. z Name: Gives a clue to the country, state, and religion to which the patient may belong. z Age: Problems setting in at childhood are prob­ ably congenital in origin. Degenerative, neoplastic, and vascular disorders are more common in the middle aged or elderly. In women beyond the menopausal age group, the incidence of problems like ischaemic heart disease increases in equal proportion as that in their male counterparts. z Sex: Males are prone to inherit certain conditions transmitted as X-linked recessive diseases, e.g. haemo­ philia. They are more prone to develop conditions like IHD, bronchogenic carcinoma and decompensated liver disease, as they are habituated to smoking and consump­tion of alcohol, in larger numbers than their female counterparts. Females are more prone for developing autoimmune disorders like SLE, thyroid disorders, etc. z Religion: Jews practice circumcision soon after birth, and so development of carcinoma of penis is rare in them. Muslims do not consume alcohol, and so are less prone to develop problems related to its consumption, e.g. decom­pensated liver disease. Sikhs do not smoke and are less likely to develop problems related to smoking, e.g. carcinoma of lung. Certain sections of Hindus do not consume meat products and consume a high fibre diet and are therefore protected from developing carcinoma of the colon. z Address: People hailing from the urban region are prone to develop problems related to urbanisation like expo­ sure to constant stress and atmospheric pollut­ants (industrial and vehicular) and problems developing consequent to this, e.g. IHD, COPD, interstitial lung disease, etc. Inhabitants of mountains or hilly regions may develop problems like primary pulmonary hyper­ tension, may have a persistent patent ductus arteriosus (from childhood) or may be goitrous secondary to iodine deficiency. The particular place from which the patient hails may be endemic for certain diseases, e.g. fluorosis prevalent in certain pockets in Andhra Pradesh.

After having obtained the above details, the patient should be approached as follows: z Greet the patient, preferably by his name and start off the con­sultation with some general questions such as, “What can I do for you?,” or “How can I help you?,” or “What is the problem?” z The presenting of complaints: Allow the patient to tell his complaints in his own words. Do not put leading questions to the patient. The current complaints and their duration should be noted in a chronological order. z History of present illness: Allow the patient to elaborate on the story of his illness from its onset to its present state. Take care so as not to put any leading questions to the patient which may distort the patient’s history. The doctor may, however, interrupt the patient to ask for the presence of ‘positive’ or ‘negative’ symptoms pertaining to patient’s current problems. In analysis of the symptoms, it is important to consider the mode of onset of the illness (acute, subacute, or insi­dious) and the progression of the illness to the present state (gradually deteriorating, getting better, remaining the same or having remis­sions and exacerbations). A review of all the systems can be made by questioning the patient on the presence or absence of symptoms pertaining to a particular system. z History of previous illnesses: This should include all important previous illnesses, operations, or injuries that the patient might have suffered from birth onwards. The mode of delivery and the timing of attainment of the various developmental milestones in infancy may be important in some cases. It is always wise to be cautious while accepting readymade diag­nosis from the patient like ‘Typhoid fever,’ ‘Malaria,’ etc. unless the patient has records of the mentioned illness. Tactful enquiry about sexually transmitted diseases and its treatment, when this is considered of possible relevance to the patient’s problem, should be made. History of a previous single painless penile ulcer with associated painless masses over the inguinal regions, occurring 3 to 4 weeks after exposure to a commer­cial sex worker, which may have healed subse­quently with or without treatment with the formation of a residual papery or velvety scar over the penis indicates a previous affliction by syphilis. This is important, as syphilis in its tertiary form, later in life, can present with systemic manifesta­tions, e.g. aortic aneurysm and regurgitation, tabes dorsalis. History of white discharge per urethrum with associat­ed dysuria, 2 to 3 days after exposure to a commercial sex worker indicates gonorrhoea. This is important as gonorrhoea can later lead to gonococcal arthritis or urethral stricture.

Introduction to Internal Medicine z

z

z

z

The menstrual history: The following enquiries are made: — Age of menarche — Duration of each cycle — Regular or irregular cycles — Approximate volume of blood loss in each men­ strual cycle — Age of attainment of menopause — Post-menopausal bleeding. Obstetric history: The following enquiries are made: — Number of times the patient conceived. — Number of times pregnancy was carried to term — Number of abortions (spontaneous or therapeutic). — Number of living children, their ages and the age of the last child delivered. — The time interval between successive pregnancies/ abortions. — Mode of delivery (vaginal, forceps assisted, or caesarean). — Development of oedema legs, hypertension or seizures in the antenatal or postnatal period (seizure within 48 hours of delivery is due to preg­ nancy induced hypertension, beyond 48 hours may be due to cerebral sinus thrombosis). — Presence of impaired glucose tolerance in the course of pregnancy or history of having given birth to a large baby may give a clue to the presence of diabetes mellitus in the patient. Treatment history: This should include all pre­ vious medical and surgical treatment and also any medication that the patient may be continuing to take to the present date. Details of drugs taken, including analgesics, oral contracep­tives, psychotropic drugs and of previous surgery and radiotherapy are partic­ ularly important. It is important to find out if the patient had been allergic or had experienced any unto­ ward reactions to any medica­tion that he may have consumed previously, so that the same medication can be avoided in the patient in future and the patient is also appraised of the same. Knowledge of any current therapy that the patient may be on is necessary in order to avoid adverse drug reac­tions, when new drugs are introduced by the consulting doctor. Family history: Enquire about the presence of consan­ guinity in the patient’s parents, any disease states in the patient’s parents, brothers, sisters and close relatives (presence of disease states like HTN, DM, IHD in the above may make the patient more prone to develop a similar problem). It is prudent to record the state of health, important illnesses, the cause and age of death in any member of the patient’s family (may give a clue to the presence of HOCM, or development of IHD). Presence of a hereditary dis­order prevalent in

the family should be enquired for. Marital status of the patient and the number of children that the patient has should also be enquired for (infertility in a patient may give a clue to the presence of immotile cilia syndrome, cystic fibrosis or Young’s syndrome). z Social history: Enquire about the patient’s family life style, daily habits, and diet; about the nature of the patient’s work (hard work or sedentary), as this may help in rehabilitation of the patient; about the possi­bility of over crowding at home (over crowding aids in the spread of communicable diseases) and the sani­tation in and around the house; about the presence of pets in the house; about the use of alcohol (number of days in a week and also the quantity consumed each day), tobacco (whether chewed or smoked) and betel nut. An alcoholic consumes alcohol almost everyday and develops withdrawal symptoms on abstaining from alcohol. Smoking: Enquire about the number of cigarettes/ beedis smoked per day and the duration of smoking. This may be presented as: Pack years: Duration of smoking in years × Number of packets of cigarettes smoked/day, e.g. two packs of cigarettes smoked per day for twenty years constitutes 40 pack years (Risk for development of bronchogenic carcinoma increases when pack years exceed 40). Smoking index: It is the number of cigarettes or beedis smoked per day and its duration, e.g. the smoking index of a person smoking 20 cigarettes or beedis per day for 20 years is 400. Smoking index greater than 300 consti­tutes a risk factor for broncho­genic carcinoma. Chewing betel nut or tobacco is a habit common with people living in the rural areas, and this increas­es the risk of developing oral malignancies. Enquire about history of travel abroad or other places within the country, as it may give a clue to the import of a disease by the patient, endemic in the place visited. z Occupational history: Enquiry must be made on all previous and present occupation, as it may give a clue to the presence of an occupational disease in the patient and also to plan the rehabilitation, e.g. — Mesothelioma—exposure to asbestos. — Carcinoma of the urinary bladder—exposure to aromatic amines in dyestuff industry. — Silicosis—occurs in mine workers. On the other hand, the presence of a disease in an individual may make him unfit for his occupation by proving to be hazardous to him as well as to others, e.g. i. Salmonella infection or carrier state in food handlers. ii. Epilepsy in drivers of public transport vehicles.

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Manual of Practical Medicine

GENERAL EXAMINATION

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Examination of the Skin Pigmentation of the skin varies from dark skinned to fair individuals, depending on the race to which they belong. z Generalised absence of skin pigmentation occurs in albinism. Syndromes with features of albinism are: — Chédiak-Higashi syndrome (phagocyte defici­­ency disease). — Phenylketonuria (inborn error of amino acid meta­bolism). z Patchy absence of skin pigmentation may be due to vitiligo (Fig. 1.1). In the presence of vitiligo, suspect presence of DM or other autoimmune disorders in that patient. z Circumscribed hypopigmented lesions of the skin may occur in — Hansen’s disease (Tuberculoid or Borderline Tuber­culoid types). — Tinea versicolor. z Generalised hyperpigmentation of the skin is seen in — Haemochromatosis — Endocrine disorders „ Addison’s disease „ Cushing’s syndrome „ Ectopic ACTH production. z Patchy hyperpigmentation of the skin is seen in — Pellagra (in parts exposed to sunlight)

Fig. 1.1  Vitiligo

Porphyria Cutanea Tarda Scleroderma — Café au lait spots* (Fig. 1.2) — Chloasma — Butterfly rash over face in SLE — Acanthosis nigricans — Drugs—chlorpromazine, clofazimine, heavy metals like gold, bismuth — Fixed drug eruptions. Yellow pigmentation of the skin: — Jaundice (there is yellowish discolouration of the skin, mucous membranes, and the sclera seen through the bulbar conjunctiva. This usually occurs when the total serum bilirubin value has exceeded 2 mg/dl). — Carotenaemia (this occurs due to excessive inges­­­ tion of carotene. There is a yellowish discolour­­ ation of the skin and the mucous mem­brane, but there is no yellow discolouration of the sclera. — Lemon yellow discolouration of the skin can occur in long standing severe anaemia. Bluish discolouration: Bluish discolouration of the skin, mucous membranes and sclera can occur in the presence of cyanosis. In peripheral cyanosis, the bluish discolouration is seen only in the peripheries like the tips of the fingers and toes, tip of the nose and ear lobes. The sclera and the mucous membranes are not discoloured. In central cyanosis, the mucous membranes, e.g. the tongue, the lips, as —

z

z

Fig. 1.2  Café au lait macule

*Café au lait spots are macules, present in more than 90% of patients with neurofibromatosis (both types I and II). They appear as light brown round to ovoid macules, with smooth borders, often located over nerve trunks, their long axis being parallel to the underlying cutaneous nerve. Its presence is significant when 6 or more of these macules, each more than 1.5 cm in diameter, are present. Café au lait macules with irregular borders are present over the midline of the body and are seen in McCune-Albright syndrome (fibrous dysplasia).

Introduction to Internal Medicine well as the sclera and the peripheries show a bluish discolouration. Bluish dis­c olouration simulating cyanosis can be seen with methaemo­globinaemia and sulphaemo­globinaemia. z Ruddy complexion: This complexion, whereby the patient has a reddish hue with a tinge of bluish discolouration is seen in patients with polycythemia vera, in whom there is an increased haemoglobin concen­tration. z Pallor: This complexion, in which the patient appears pale, is seen over the skin, mucous mem­branes, lower palpebral conjunctiva, finger nails and palms of the hands, indicating that the patient has anaemia. Loss of the pigmentation of the palmar creases of the hands gives a clue that the Hb may be less than 7 gm% in that patient. z Look for the presence of macules, papules, vesicles, pustules or scars, which may suggest the presence of exanthematous fever. Segmental distribution of vesicles on an erythe­ matous base, on one-half of the body, suggests a diagnosis of herpes zoster. Herpes zoster involving many segments simultaneously suggests an immuno­ deficiency disorder in the patient, e.g. AIDS, DM. z Dermatographia: Firm stroking of the skin results in a red linear elevation followed by a wheal, sur­rounded by a diffuse pink flare. This occurs in patients with allergic predis­position and urticaria. Dermato­gra­phism is also seen in carcinoid syndrome. z Some other important skin markers to be looked for in order to get a clue to the diagnosis in a patient are: — Purplish striae over the lower, anterior abdom­inal wall in Cushing’s syndrome. — Erythema marginatum in rheumatic fever.

Fig. 1.3  Adenoma sebaceum

Purpuras, ecchymosis are seen in purpuras (ITP, Henoch-Schönlein purpura), coagulation defects, leukaemias. — Adenoma sebaceum (Fig. 1.3) Tuberous Shagreen patch (Fig. 1.4)     sclerosis Ash leaf macules — Haemangiomas present externally may also be pre­sent in the CNS. — Telangiectasia—seen in ataxia telangiectasia. Multiple telangiectasias are seen in Osler-RenduWeber syn­d rome in which AV mal­forma­tions are found in the lung, liver, CNS and mucous membranes. — Spider naevi in decompensated liver disease, SVC obstruction. — Palmar erythema in decompensated liver disease, chronic febrile illness, chronic leukae­­ mias, polycythaemia, rheumatoid arthritis, thyro­ toxicosis, chronic alcohol intake and may also be seen in physiological states like pregnancy. — Erythema nodosum (Fig. 1.5)—This is a non-specific skin marker and may be seen in conditions like pri­ mary complex, sarcoidosis and with certain drugs. — Multiple neurofibromas: von Recklinghausen’s disease. — Xanthomas—Hyperlipidaemia. — Malignant tumours of the skin—Squamous cell carci­n oma, basal cell carcinoma, malignant melanoma. — Pigmentation of the mucous membrane of the oral cavity may be seen in Addison’s disease, and also in Peutz-Jeghers syndrome (peri-oral pig­men­ tation and polyposis of colon). —

Fig. 1.4  Shagreen patch

}

Fig. 1.5  Erythema nodosum

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Manual of Practical Medicine —

—

—

—

A tuft of hair or a lipoma over the lower lumbar region in the back may indicate the presence of a spina bifida. Diabetes mellitus „ Necrobiosis lipoidica diabeticorum (papulo­ nodular lesions enlarging to form brownishyellow plaques with waxy surface over the front of legs), „ Diabetic dermopathy (dull red, oval, flattopped papules over both legs), „ Diabetic bullae (over legs, hands and feet bilaterally healing with atrophic scars), „ Diabetic rubeosis (flushed skin of face), „ Carotenoderma (yellowish tint of skin due to deposition of carotene), „ Granuloma annulare (papular lesion over central areas of body and flexures of neck, arm and thigh), „ Scleredema diabeticorum (diffuse, waxy, nonpitting induration of skin particularly over back of neck and upper trunk), „ Infections like furuncle, carbuncle, can­ didal parony­chia, balanoposthitis, intertrigo, vaginitis and recur­rent dermatophytosis. Chronic renal failure „ Uraemic frost, „ Erythema papulatum uraemicum (erythematous nodules over palms, soles and forearm), „ Generalised pruritus, „ Metastatic calcification, „ Kyrle’s disease (multiple discrete or confluent hyper­kera­totic follicular papules over lower extremities), „ Nail changes (half-half nail—proximal white and distal half pink, mees lines), „ Oral manifestations (coating of tongue, xero­ stomia, ulcerative stomatitis). Internal malignancy „ Acanthosis nigricans (Fig. 1.6) (adenocarcinoma of GIT), „ Palmo-plantar keratoderma (Ca bronchus and oeso­phagus), „ Necrolytic migratory erythema (glucagonoma), „ Pityriasis rotunda (hepatocellular Ca), „ Sign of Leser-Trelat (sudden eruption of intensly pruritic multiple seborrhoeic keratosis in Ca stomach), „ Migratory thrombophlebitis (Ca pancreas), „ Cutaneous hamartoma (Ca breast, thyroid, gastro­intestinal polyposis-cowdens disease).

Fig. 1.6  Acanthosis nigricans

Hair The scalp contains approximately 1,00,000 hairs. Each hair grows for about 1,000 days. Rate of hair loss per day is approximately 100 normally. Look for: z Presence and colour of scalp hair z Presence and distribution of hair over body (Second­ ary sexual character).

Stages of Hair Follicle Growth Racial characteristics of hair colour and texture are determined genetically. The growth of hair is cyclic. Secondary sexual male (14–15 years) and female (12–13 years) pattern of hair appear at puberty. Adrenal androgen decides the growth of pubic hair and it occurs even in the absence of gonadotrophin. There are three different types of hair: 1. Lanugo hairs: Fine long hairs covering the foetus and they are shed one month before full-term. 2. Vellus hairs: Fine short vellus hairs replace lanugo hairs. 3. Terminal hairs: They replace the vellus hairs on the scalp and the pubic vellus hairs are replaced by dark, curly hairs at the time of puberty. There are three phases of hair growth. The duration of these phases vary in different regions of the body. Axillary hair and facial hair in case of males grow 2 years after the appearance of pubic hair. The shape of hairs varies depending on the race. z Asians: Straight hair z Mongoloids: Sparse facial and body hair z Negroids: Curly hair z Europeans: Wavy hair.

Introduction to Internal Medicine Temporal recession and baldness are common in males and the process is androgen dependent. Temporal recession in female may suggest virilization. Frontal baldness is a marker for myotonic dystrophy and also seen in some cases of systemic lupus erythematosus. Phases of Hair Growth (Fig. 1.7) z

z

z

Anagen phase: It is the actively growing phase and in the case of scalp, it lasts for 3 to 5 years. Catagen phase: It is the conversion stage from active to resting and it lasts for a few weeks. Telogen phase: It is the resting stage lasting for a few months and is replaced by anagen phase.

The length of anagen phase determines the length of the hair. Normally 85% of scalp hairs are in anagen phase and the remaining 15% are in telogen phase. The anagen phase is shorter and the telogen phase is longer in eyebrows and sexually determined hair.

Fig. 1.8  Alopecia areata

Types of Alopecia (Loss of Hair) Cicatricial Alopecia z z z

z z z

z

Trauma Burns Infections: Folliculitis, herpes zoster, gumma, lupus vulgaris Morphea, lichen planus, sarcoidosis, DLE Cutaneous neoplasms: Basal cell Ca Drugs—mepacrine.

Non-cicatricial Alopecia z

z

z

Alopecia areata (Fig. 1.8) (most common): It is an autoimmune disease characterised by single or multiple areas of alopecia without inflammation. If it involves the whole of scalp it is called alopecia totalis and the whole of body is called alopecia universalis. It is associated with other autoimmune diseases like

z

z

z

SLE, vitiligo, autoimmune thyroi­ditis and autoimmune haemolytic anaemia. Physiologic: Androgenic alopecia is an autosomal dominant male pattern baldness. The early change is a bilateral frontal recession of the hairline. This pattern is usually familial. 5-alpha reductase inhibitor finasteride is useful in the treatment. Other causes are puberty, preg­nancy and neonatal period. Systemic diseases: SLE, hyperthyroidism, hypo­thyroi­ dism, acrodermatitis enteropathica, pernicious anaemia and Down’s syndrome. Infection: Moth eaten type in syphilis and fungal infections. Drugs: Antimetabolites, cytotoxics, heparin, carbi­ mazole, iodine, bismuth, vitamin A, allopurinol and amphetamines. Telogen effluvium: Systemic illness (typhoid, measles, pneumonia) post-partum and post-surgical. Radiation.

Fig. 1.7  Hair follicle growth stages

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Manual of Practical Medicine

Colour of Hair

z

White hair albinism (due to absence of pigment). Grey hair is a sign of ageing. Poliosis patchy loss of pigmentation of hair in the region of an adjoining vitiligo. Flag sign brownish discolouration of hair, with inter­ spersed normal colour of hair, is seen in protein energy malnutrition.

z

Wrinkling of Forehead z

z

Causes of Hypertrichosis (Excess Hair) z z z z z z z

Familial Sexual precocity Hypothyroidism Adrenal hyperplasia or neoplasm Virilising ovarian tumours (Fig. 1.9) Drugs (Androgens, Minoxidil) Hirsutism (male distribution of hair in females).

Decreased Body Hair Distribution (Loss of Secondary Sexual Character) This is seen in the following conditions: z Decompensated liver disease z Klinefelter’s syndrome z Bilateral testicular atrophy as seen in Hansen’s disease.

Rickets Thalassaemia. Bilateral wrinkling of the forehead is seen in anxiety states or in the presence of bilateral ptosis as in Myasthenia Gravis, bilateral third nerve palsy or bilateral Horner’s syndrome. Unilateral wrinkling of forehead is seen on the side of unilateral ptosis, as in unilateral third nerve palsy or Horner’s syndrome.

Absence of Wrinkling of Forehead z

z

Unilateral absence of wrinkling of forehead is seen in Bell’s palsy, on the affected side. Bilateral absence of wrinkling of forehead is seen in myotonic dystrophy and in hyperthy­roidism (Joffroy’s sign).

Hypertelorism This means the presence of wide spaced eyes. This is diagnosed when the inter inner canthal distance between the two eyes is more than half of the inter pupillary distance (Fig. 1.10).

Low Set Ears

Face Forehead Prominent Forehead This is seen in: Acromegaly z Chronic hydrocephalus z Frontal balding as seen in myotonic dystrophy z

Fig. 1.9  Virilisation

An imaginary horizontal line is drawn from the outer canthus of the eye to the pinna of the ear on the same side. Normally about 1/3rd of the total length of the pinna is seen above the line. If less than 1/3rd of the total length of the pinna is seen above the line in a patient, he is said to have low set ears. A prominent crease seen over the lobule of the pinna is a marker for development of ischaemic heart disease.

Fig. 1.10  Hypertelorism

Introduction to Internal Medicine

High Arched Palate

z

This is said to be present when the roof of the palate is not seen when the examiner’s eyes are kept at level with the patient’s upper incisor teeth, with the pa­tient’s mouth wide opened or 3 cm above an imaginary line joining the upper incisor teeth and uvula. It is also said to be present when the roof of the palate extends above an imaginary line drawn con­necting the two malar prominences.

Eyes Look for the following features when examining the patient’s eyes: z Ptosis (unilateral or bilateral) (Figs 1.11 and 1.12) z Pallor z Cyanosis z Icterus z Bitot’s spots (vitamin A deficiency) z Phlyctenular conjunctivitis (may give a clue to presence of PT) z Arcus senilis (gives a clue to the presence of athero­ sclerosis) (Fig. 1.13) z KF ring (Fig. 1.13) is seen in Wilson’s disease, primary bili­ary cirrhosis, cryptogenic cirrhosis, intraocular copper foreign body (uniocular KF ring), caro­tenaemia z Corneal opacities may be drug induced, e.g. Amiodarone or due to storage disorders z Cataract (early formation of cataract may be due to hypoparathyroidism, hyperparathyroidism, dia­betes mellitus or prolonged oral steroid intake) z Subconjunctival haemorrhage (may be seen in whooping cough or leptospirosis) z Corneal ulcers (seen in Bell’s palsy and in trigeminal nerve palsy) z Enlargement of the lacrimal glands (Sjögren’s syndrome)

z

Ectopia lentis (upward subluxation of lens may be seen in Marfan’s syndrome, whereas down­ward subluxation of the lens may be seen in homo­cystinuria) Blue sclera (Fig. 1.14).

Arcus senilis 1. Greyish white in colour 2. Present just internal to the limbus 3. A clear zone of iris seen in between the limbus and the ring 4. Due to deposition of calcium and lipids on the cornea 5. Seen in middle to old aged people 6. Its presence suggests a possible presence of atherosclerosis or hyperlipidaemia in the patient 7. It is a complete ring

8. It is seen well with the naked eye 9. It does not disappear at all

Fig. 1.12  Bilateral ptosis

No zone of iris seen in between limbus and the ring Due to deposition of copper on the Descemet’s membrane of the cornea Seen in the young Its presence suggests the presence of Wilson’s disease The ring is incomplete initially, appearing first in the superior aspect of the limbus, then progressing to appear in the temporal aspect, then inferiorly and finally medially Confirmation of its presence may require a slit-lamp examination It disappears with treatment, disappearance being in the same pattern as its appearance

The Tongue The tongue is often red with prominent papillae— fungiform papillae over the edges and the tip, filiform papillae over the centre, and the circumvallate papillae set in a wide ‘V’ shape with its apex pointing backwards separating the anterior 2/3 from posterior 1/3. The tongue aids in appreciating the various types of taste of food and also helps in the process of mastication. Note the colour, size, shape, coating, surface, mobility and local lesions.

A

Fig. 1.11  Unilateral ptosis

KF ring Yellowish green in colour Present on the limbus

B Figs 1.13  (A) Arcus senilis; (B) Kayser-Fleischer ring

Fig. 1.14  Blue sclera (Osteogenesis imperfecta)

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Manual of Practical Medicine Macroglossia Down’s syndrome z Acromegaly z Myxoedema z Amyloidosis z Angioedema z Tumours z

Microglossia Pseudobulbar palsy z Facial haemiatrophy z Marked dehydration z Starvation z

Colour (Fig. 1.15) Blue tongue—central cyanosis z Brown tongue — Uraemia — Acute liver necrosis z White tongue — Centrally coated (enteric fever) — Leukoplakia — Excessive furring z Scarlet red tongue—niacin deficiency z Dark red tongue — Polycythemia — Riboflavin deficiency z Black tongue — Melanoglossia — Bismuth — Iron — Antibiotics like penicillin z

z z

Slate blue tongue—haemochromatosis Abnormal pigmentation—brownish black tongue — Addison’s disease — Nelson’s syndrome — Peutz-Jeghers syndrome — Chronic cachexia — Malnutrition

Dryness of tongue Dehydration z Haemorrhage z Mouth breathing z Uraemia z Coma z Atropine/belladonna z Sjögren’s syndrome z

Ulcers Single z Tuberculosis z Carcinoma z Syphilis z Dental irritation. Multiple z Aphthous ulcers z Herpes z Secondary syphilis z Pemphigus z Chickenpox z Vitamin B deficiency. Recurrent z Aphthous ulcers z SLE z Coeliac disease z Behçet’s syndrome z Lichen planus z Pemphigus z Neutropenia.

Fissured Tongue (Scrotal) (Fig. 1.16) z z z z

Down’s syndrome Vitamin B deficiency Acromegaly Congenital malformation.

Geographic Tongue (Fig. 1.17)

Fig. 1.15  Pallor of tongue

Asymptomatic inflammatory condition with rapid loss and regrowth of filiform papillae leading to denuded red patches ‘wandering’ across the surface of the tongue—no clinical significance.

Introduction to Internal Medicine

Fig. 1.16  Fissured tongue

Fig. 1.18  Oral hairy leukoplakia

Fig. 1.17  Geographic tongue

Fig. 1.19  Black hairy tongue

Hairy Leukoplakia (Fig. 1.18) It is caused by EB virus and is typically seen in the lateral margin of the tongue and is diagnostic of AIDS.

Hairy Tongue (Fig. 1.19) Formation of keratin layer prior to desquamation can result in elongation of filiform papillae over the medial dorsal surface of the tongue.

Median Rhomboid Glossitis (Fig. 1.20) It is red due to depapillation of rhomboid area at the centre of the dorsum of the tongue with associated candidiasis. It is marker of immune deficiency disorders.

Fig. 1.20  Median rhomboid glossitis

Bald Tongue (Ironed Out Tongue)

Tongue in Neurology

It is due to the diffuse atrophy of the papillae. It is commonly seen in pellagra, xerostomia and iron/B12 deficiency disorders.

Fasciculation (fibrillation) within the tongue when lying in the oral cavity is a feature of motor neurone disease and

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Manual of Practical Medicine also occurs in syringomyelia. Wasting of half of the tongue is due to hypoglossal nerve palsy and it deviates to the same side on protrusion. Myotonia can be better demonstrated in the tongue in myotonic dystrophy. Spastic tongue is due to pseudo­bulbar palsy.

z

z

Characteristic Types of Facies (Fig. 1.21) z

z

z

z

z

z

z

z

z

z

z

z

z

z

Acromegalic facies: Prominent lower jaw, coarse features, large nose, lips, ears, prominent forehead and cheek bones and widespread teeth. Cushing’s syndrome: Rounded ‘moon face’ with excessive hair growth. Hypothyroid face: Puffy face with a dull expression with swollen eyelids and loss of hair over eyebrows. Hyperthyroid face: Anxious look with widely opened eyes with the upper and lower limbus seen, associated with infrequent blinking and absence of wrinkling of the forehead. Leonine facies: Seen in leprosy, and shows thickening of the skin and ear lobes with a flattened nasal bridge and loss of hair over the lateral aspect of eye­brows and eyelashes (madarosis). Elfin facies: This is seen in supravalvular aortic stenosis, or pulmonary artery stenosis (William’s syndrome). There is a presence of a wide mouth with large lips (pouting effect), widely spaced teeth, broad forehead, pointed chin, protruding ears and eyes set wide apart. Congenital pulmonary stenosis: A broad face with eyes set wide apart (moon face). Face in pneumonia: In lobar pneumonia, the alae nasi are over active, eyes bright and shiny, and herpetic lesions may be present over the angles of the mouth. Face in COPD: Anxious look with bluish discolour­ ation of lips, tip of the nose, ear lobes and breathing out through pursed lips. Face in nephrotic/nephritic syndrome: Face is puffy with periorbital oedema and pallor. Face in scleroderma: Skin over the face is taut and shiny. Patient finds difficulty in opening his mouth or to smile (microstomia). Face in SLE: Seen predominantly in women. There is a butterfly rash seen over the face encom­passing the upper cheeks and the nasal bridge. Erythema may be seen over the rash on exposure to sunlight. Face in Sjögren’s syndrome: There is enlargement of the lacrimal gland on both sides along with enlargement of the parotid and submandibular glands on both sides. Myasthenic facies: Bilateral ptosis with outward deviation of the eyes, wrinkling of the forehead and partially opened mouth.

z

z

z

z

Myotonic dystrophy: Bilateral ptosis with absence of wrinkling of the forehead, frontal baldness with absent sternomastoids and bilateral cataract. Pres­ence of a transverse smile is also charac­teristic of this condition. Parkinsonian face: Immobile, fixed and expres­sionless face with infrequent blinking of the eyes. Normal rate of blinking is about 20 per minute. In Parkinsonism, the rate of blinking is reduced to less than 10 per minute. On closing the eyes, fluttering of the eyelids is seen (blepharoclonus). In post-encephalitic parkinsonism, oculo­gyric crisis (tonic upward deviation of the eyes) may be seen. A jaw tremor may also be seen. Bell’s palsy: Absence of wrinkling of forehead on the side of the lesion, along with inability to close the eyes, and on attempting to do so the eyeball is seen to move upwards and outwards (Bell’s pheno­me­non). There is also loss of the naso-labial fold on the side of lesion and deviation of the angle of the mouth to the opposite healthy side on smiling. However, in long standing Bell’s palsy, when con­tra­ctures of the facial muscles develop, prominent nasolabial grooves may be seen on the affected side, creating confusion as to the side of lesion. Cirrhotic facies: Sunken cheeks and eyes with malar prominence and presence of bilaterally enlarged parotid glands (esp. in cirrhosis second­ a ry to alcoholism). Cretinoid face: Face is pale and has a stupid and dull look. Nose is broad and flattened. Lips are thick and separated by a large and fissured pro­truding tongue. Hair on eyebrows, eyelashes and scalp are scanty. Presence of prominent medial epicanthal folds and low set ears. Tabetic facies: Partial ptosis with wrinkling of forehead and unequal, small and irregular pupils.

Constitution Constitution indicates the body type or habitus. Human race can be classified into the following somatotypes.

Clinical Classification z

z z

Asthenic: Thin, long and underdeveloped body with long neck, flat chest and slender fingers. They have a vertical heart. They are prone to have neurasthenia and visceroptosis. Normosthenic: Normal average body build. Sthenic: Broad, short, fat neck, muscular chest and large stumpy fingers. They have horizontal heart.

Anthropometric Classification z

Endomorph: Soft, round contours with well-developed cutaneous tissues, and short stature.

Introduction to Internal Medicine

Fig. 1.21  Facies in medicine

z

z

Mesomorph: Wide, stocky, muscular individ­ual and normal stature. Ectomorph: Long narrow hands, long feet, shallow thorax, small waist and tall stature.

Stature Stature is total height measured from vertex of head to the soles of the feet. It is a sum total of upper segment

measurement (from vertex of head to the upper border of symphysis pubis) + lower segment measurement (from top of symphysis pubis to soles of the feet). Arm span: It is the distance between the tips of the middle fingers of the two hands, with both the arms held outstretched horizontally outwards from the body. z Normally the relationship between arm span and stature (height) varies according to age as follows:

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Manual of Practical Medicine Age a.  0–7 years b.  8–12 years c.  More than 12 years

z



Arm span minus height (in cm) –3  0 +1 (in females) +4 (in males)

The relationship between upper segment measure­ ment (from vertex to symphysis pubis) and lower segment measurement (from symphysis pubis to the heel) also varies with age as follows: Age a.  At birth b.  3 years c.  10 years d. Adult

Upper segment/lower segment 1.7 1.4 1.0 0.8

Stature > Arm Span z z

Adrenal cortex tumour Precocious puberty. This is because of early epiphyseal fusion.

Marfan’s syndrome

Homocystinuria

1. It is a connective tissue disorder

It is an inborn error of metabolism, due to lack of the enzyme cystathionine synthase, leading to an accumulation of homo­cystine and methionine and a deficiency of cystathionine and cystine

2. It is transmitted as an autosomal dominant trait

It is transmitted as an autosomal recessive trait

3.  Mental faculty normal

Mental defect is present

4.  Bones are normal

Osteoporosis is present

5. Mitral valve prolapse and dilatation of the aortic root and sinus of Valsalva may be present

Medial degeneration of the aorta and elastic arteries may be present

6. There is no predilection to development of thrombosis

Arterial and venous thrombosis can occur

7.  Superolateral subluxation of the Inferolateral subluxation of the lens lens

Skeletal Defects z

Arm Span > Stature

z z

z z z z z

Eunuchoidism Hypogonadism Marfan’s syndrome Homocystinuria Klinefelter’s syndrome.

This is because of delayed epiphyseal fusion. The dif­ference in measurement must be greater than five centimeters to be significant.

Upper Segment > Lower Segment z z

z

z

z z

Stature: Tall and thin (asthenic) Skull: Dolicocephalus High arched palate Chest and spine: Pectus carinatum, pectus exca­vatum, straight back syndrome, kyphosis, scoliosis Limbs: Long thin limbs and long thin fingers (Arachno­dactyly) Joint hypermobility and ligament laxity Feet: Pes planus, pes cavus, hallux valgus.

Wrist sign (Fig. 1.23): The patient with Marfan’s syndrome is able to enclose his wrist with the thumb and little finger of the other hand, and the digits will overlap. The little finger overlaps the thumb by at least 1 cm.

Adrenal cortex tumour Precocious puberty.

Lower Segment > Upper Segment z z z z z

Eunuchoidism Hypogonadism Homocystinuria Klinefelter’s syndrome Marfan’s syndrome.

Marfan’s Syndrome It is a syndrome comprising of the following tetrad: Familial (autosomal dominant) z Lens dislocation (upward) z Great vessel (aortic or pulmonary) dilatation or dissection (Fig. 1.22) z Long tubular bones. z

Fig. 1.22  Sinotubular ectasia and ballooning of aortic root

Introduction to Internal Medicine Cardiac Defects z z z z z z z z

Aneurysm of aorta Dissection of aorta Sinus of Valsalva aneurysm Aortic regurgitation Mitral or tricuspid valve prolapse syndrome Atrial septal defect (ostium secundum) Ventricular septal defect Dilatation of the pulmonary artery.

Pulmonary Defects z z

Fig. 1.23  Wrist sign

Cystic bronchiectasis Spontaneous pneumothorax.

Investigations z

z

Slit-lamp examination of the eyes for detection of ectopia lentis X-ray of the hands.

Metacarpal index (MCI): This is calculated by measur­ing the average length of the second, third, fourth and fifth metacarpals, and the average midwidth of the same. MCI =

average length of the four metacarpals average midwidth of the four metacarpals

If MCI is > 8.4, it indicates presence of Marfan’s syndrome (Normal MCI = 5.4 to 7.9).

Gigantism Fig. 1.24  Thumb sign

Thumb sign (Fig. 1.24): In a patient with Marfan’s syndrome, a part of the distal phalanx of the thumb is seen beyond the ulnar border of the hand, when a fist is formed with the thumb flexed, within the palm. Height and arm span: The patient is tall, the lower segment being more than the upper segment by at least 5 cm. The arm span is more than the height of the patient by at least 5 cm. Ocular Defects z z

z z z z z

Micro cornea Ectopia lentis (Bilateral upward and outward dis­location) Cataract Strabismus Myopia Retinal detachment Iridodonesis.

Gigantism is said to be present in an individual, when his height exceeds six feet, six inches. Types of Gigantism z

z

Hereditary (Primary or genetic): In this type, the body is perfectly proportioned. They are normal mentally, physically and sexually. Endocrine gigantism: The following types are seen: — Hyperpituitary gigantism: They are wellproportioned and have good physical and sexual development. — Eunuchoid gigantism: They are tall, lanky and long limbed individuals with infantile sex organs, e.g. Klinefelter’s syndrome.

Dwarfism Dwarfism is said to be present when there is a marked, permanent shortness of stature, with predicted adult height less than 4 standard deviations from the mean. An adult may be called a dwarf, if his height is less than 4 feet.

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Manual of Practical Medicine Classification of Short Stature

Short stature—Causes

Normal variant — Familial short stature — Constitutional growth delay — Racial. z Pathological — Proportionate Prenatal a. Intrauterine growth retardation b. Antenatal infection in mother (TORCH*, syphilis, AIDS) c. Antenatal consumption of alcohol, tobacco, heroin d. Chromosomal disorders (Down’s synd­rome, Turner’s syndrome). — Postnatal i. Malnutrition (Protein-energy malnutri­tion, ano­­rexia nervosa) ii. Endocrine disorders (growth hormone defi­ ciency, hypothyroidism, congenital adrenal hyperplasia, precocious puberty) iii. Cardiovascular disorders (cyanotic and acya­ no­tic congenital heart disease, early onset rheumatic heart disease) iv. Respiratory disorders (Kartagener’s syndrome, cystic lung disease, childhood asthma) v. Renal disorders (renal tubular acidosis, renal rickets, nephrotic syndrome, chronic pyelonephritis) vi. Blood disorders (chronic anaemia like thalas­ semia or sickle cell anaemia, leukaemia) vii. Psychosocial disorders (maternal depri­vation). — Disproportionate i. Rickets ii. Skeletal dysplasia (kyphosis, lordosis, scoliosis) iii. Defective bone formation (osteopetrosis, osteogene­sis imperfecta) iv. Defective cartilage growth (achondroplasia, multiple cartilagenous exostosis) v. Defective bone matrix (fibrous dysplasia) vi. Inborn errors of metabolism (mucopolysacch aridosis) vii. Calcium and phosphorus metabolism defects (hyper­phosphatemic rickets) viii. Mineral metabolism defects (Wilson’s disease, zinc deficiency).

1. Hereditary

Constitutionally small

2. Genetic

Down’s syndrome, Turner’s syndrome, achondro­ plasia

3. Nutritional

Intrauterine growth retardation, protein and energy deprivation, Rickets

4. Endocrine

Cretinism, hypopituitarism, craniopharyn­gioma

5. Alimentary

Malabsorption syndromes, Crohn’s disease, cystic fibrosis

z

6. Cardiorespiratory Congenital heart disease, suppurative lung disease 7. Locomotor

Severe scoliosis

8. Miscellaneous

Chronic wasting diseases including renal failure and biliary diseases

State of Nutrition The state of nutrition depends mainly on the distri­bution of adipose tissue in the body. On this basis individuals can be classified as normal, overweight (fat or obese) and under­weight. The state of nutrition can be assessed in the following ways: 2 z Ideal body weight (IBW) = 22.5 × (height in metres) In women, the ideal body weight is calculated as follows: 0.94 × 22.5 × (height in metres)2 If the body weight > 10% of IBW, the individual is overweight If the body weight > 20% of IBW, the individual is obese. z Body mass index (BMI) is calculated as follows: BMI = weight in kg/(height in metres)2 The normal range of BMI is 19–25 In males, it is 20–25 In females, it is 18–23 If BMI is between 25 and 30, the individual is over weight. If BMI > 30, the individual is obese. z

z

* Toxoplasmosis, other infections Rubella, Cytomegalovirus, Herpes simplex.

Grading of obesity Grade I if BMI 25–30 (overweight) Grade II if BMI 30–40 (obese) Grade III if BMI > 40 (very obese) The amount of subcutaneous fat can be estimated by measuring the skinfold thickness over the triceps, biceps, subscapular region and suprailiac region, by using a special pair of calipers. Equations and nomograms are available for conversion of skin fold thickness to body fat. (Normal triceps skin fold thickness: Adult males— 12.5 mm; Adult females—16.5 mm). Rough calculation of body weight (Broca’s index) can be done provided the height of the individual is >100 cm, and so is possible in adults only.

Introduction to Internal Medicine Height in cm – 100 = desired body weight (in kg). Height in inches = body weight (in kg).

Obesity A person is said to be obese, if his body weight > 20% of IBW and his BMI > 30. Types of Obesity  z

z

z

z

Generalised obesity: There is excess fat deposition uni­ formly throughout the body. Over eating is the most common cause. It is characterised by the pres­ence of a ‘double chin.’ Android obesity (Fig. 1.25A): It is a type of obesity, which is characterised by excess deposition of fat over the region of the waist. Gynoid obesity (Fig. 1.25B): It is a type of obesity, which is characterised by excess deposition of fat over the region of the hips and thighs. Superior or central type of obesity: In this type, there is excess fat deposition over face, neck and upper part of the trunk and the arms are thin. This is seen in Cushing’s syndrome.

Recent evidence suggests that regional distribution of fat may be of greater prognostic significance than absolute degree of obesity. This is assessed by measur­ing the hip: waist ratio. The hip measurement is taken by measuring at a level that gives the maximal measurement of the hip, over the buttocks. The waist is measured by taking a circumference that gives the narrowest measurement between the ribcage and the iliac crest.

A B Figs 1.25A and B  Pattern of obesity: (A) Android type (apple-shaped); (B) Gynoid type (pear-shaped)

Waist–hip ratio

Type of obesity

Prognosis

1.  0.8 or less

Pear-shaped obesity

Good

2.  0.9 or greater

Apple-shaped obesity

Greater risk of developing complications of obesity

Under Weight Adults are significantly under weight if their BMI is 18 or less. Causes for weight loss: z Malnutrition z Grief or depression z Thyrotoxicosis z Diabetes mellitus z Addison’s disease z Tuberculosis z HIV infection z Chronic bronchitis z CCF z Malignancy z Malabsorption syndromes z Anorexia nervosa (This is diagnosed when the weight of the patient is < 25% of his IBW).

Posture The position or attitude constantly assumed by a patient at rest or in motion is referred to as posture. The posture of a patient, when viewed from the side, may be characteristic enough to suggest a diagnosis. The various postures seen in clinical practice are: Postures seen when the patient is standing/sitting. — Vertical line seen in standing posture, when viewed from the side, is a good posture. — Standing posture, when it assumes a S-shaped curve, when viewed from the side, is a poor posture. — Asthenic posture: The normal curves of the spine are exaggerated. Seen in debility, wasting and in senility. — Parkinsonian posture: Universally flexed pos­ture. — Lordotic posture: There is an exaggerated lum­ bar lordosis. Seen in muscular dystrophy, due to proximal muscle weakness. It is also seen in bilateral hip problems. — Cerebellar posture: In lesions of the cerebellum or its connections, the patient stands with his feet wide apart, and is unable to maintain a steady posture when standing with both his feet placed close together. Patient is ataxic on sitting (trun­cal ataxia) when the vermis of the cerebel­lum is involved. — Posture in ankylosing spondylitis: There is loss of the lumbar lordosis, with an exaggeration of the upper thoracic kyphosis.

z

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Manual of Practical Medicine Catatonic posture: In this, the patient maintains a particular posture of the body and limb for hours together. This is seen in schizophrenia. z Postures seen when the patient is lying down: — Decerebrate posture: Extension of elbows and wrists, with pronation of the arms is seen. It suggests that the lesion is at the brainstem level, disconnecting the cerebral hemispheres from the brainstem. — Decorticate posture: Flexion of elbows and wrists, with supination of the arms is seen. It suggests severe bilateral hemispherical damage above the midbrain. — Hemiplegic posture: The patient lies on his back, with the cheek on the affected side blowing out with each expiration. The affected upper limb lies flaccidly by his side, and the affected lower limb is externally rotated. This picture is seen imme­diately after the onset of haemiplegia. In long standing haemiplegia, there may be loss of nasolabial fold of the face on the side of the paresis, with the affected upper limb in a flexed posture and the affected lower limb in an extended posture. — Opisthotonus: In this posture, the patient is arched up like a bow, with his heel and occiput in contact with the bed. This posture is seen in patients with tetanus and strychnine poisoning. — Lateral decubitus posture with curled up limbs to minimise the stretching of the meninges, is seen with meningitis or meningism. — Patient lying up with a back rest or cardiac rest suggests a possibility of the patient having CCF or COPD. — Patient sitting up and holding on to a support before him, in order to fix his shoulders, and having dyspnoea, suggests a diagnosis of bron­chial asthma. — Patient lying down still and „ Clutching his chest—anginal chest pain „ Shallow breathing, with minimal or no movement of the anterior abdominal wall—peritonitis. — Patient rolling about in the bed from side to side and „ Clutching his chest—Myocardial infarction. „ Holding his upper abdomen—Biliary colic. — Patient sitting up and bending forwards, may be seen in „ Pericarditis „ Pancreatitis as the pain caused by both these conditions is relieved by assuming this posture. — Prone posture: Patient preferring to lie in the prone position than in the supine position may be due

to the presence of an abdominal aortic aneurysm which may erode on the vertebra in the supine posture and cause back pain. On lying prone the aorta falls forward from the vertebra and the pain subsides.

—

Hands and Fingers Hands z

z

z

z

z

z

z

z

Cretinism: Square palm, short, fat and blunt fingers and short radius. Down’s syndrome: Short and thick hand. Short thumb arising at a level lower than normal from the palm with incurving of the distal phalanx of the little finger (clinodactyly) (Figs 1.26 and 1.27) and a single palmar crease is seen over the palm (Fig. 1.28). Acromegalic hand (Fig. 1.29): This is known as the ‘Paw hand’. It is a massive hand with fat, cylindri­cal, spatulate fingers with blunt tips and broad and square nails. Eunuchoidal hand: The hand is long and narrow and thin skinned, with delicate and tapering fingers. Marfan’s syndrome: The hand is long with taper­ing, spidery fingers (arachnodactyly). Pseudohypoparathyroidism: Short fourth and fifth metacarpals producing a ‘dimpling sign’ (knuckleknuckle-dimple-dimple sign). Holt-Oram syndrome: The thumb is hypoplastic and in the same plane as the rest of the fingers. Thumb may be triphalangeal. Fifth finger may be missing. There may be radioulnar synos­tosis. The radius may be absent. Dupuytren’s contracture (Fig. 1.30): This occurs due to fibro­sitis commonly involving the ulnar side of palmar aponeu­rosis. This causes thickening and contraction of the apo­neu­rosis. This initially affects the proximal

Fig. 1.26  Clinodactyly—Down’s syndrome

Introduction to Internal Medicine

Fig. 1.27  Feet in Down’s syndrome

Fig. 1.29  Acromegalic hand

Fig. 1.28  Simian crease

Fig. 1.30  Dupuytren’s contracture

and middle phalanx of the ring finger and later the little finger may be affected. It is seen in the following conditions: Idiopathic z Cirrhosis liver z Phenytoin therapy z People working with machines producing vibration z Intake of oral contraceptive pills. z

Fingers z



Polydactyly (Fig. 1.31): Supernumerary fingers Causes — Congenital — Familial

Associated with VSD Laurence-Moon-Biedl syndrome — Turner’s syndrome. Syndactyly (Fig. 1.32): Webbed fingers. May occur in normal indi­viduals or in those with, certain congenital abnormali­ties. It is seen in Poland’s syndrome (absent unilateral pectoralis major muscle with TOF). Arachnodactyly (Fig. 1.33): Spider fingers. These are long and thin fingers. Causes — Marfan’s syndrome — Hypogonadism — Hypopituitarism — Homocystinuria — Normal individuals. — —

z

z



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Manual of Practical Medicine

z

z

Fig. 1.31  Polydactyly

Fig. 1.33  Arachnodactyly

Fig. 1.32  Syndactyly

Fig. 1.34  Hypoplastic thumb—Fanconi’s anaemia

Absence of digits (Fig. 1.34): Absence of one or more fingers may be congenital. Thumb may be absent in Fanconi’s congenital aplastic anaemia. Sausage fingers: Thick and fleshy fingers seen in — Acromegaly — Myxoedema — Psoriatic arthropathy.

Genu Valgum (Knock Knees) Causes Congenital z Rickets. z

Large Feet It is seen in acromegaly.

Feet and Toes

Short and Broad Feet

Genu Varum (Bow Legs)

It is seen in achondroplasia.

Causes Rickets z Osteomalacia z Osteitis deformans (Paget’s disease) z Achondroplasia. z

“Rocker-bottom” Foot (Fig. 1.35) This is a severe type of flat foot with a protuberant heel. Seen in Trisomy-18 (Edward’s syndrome, which may be associated with PDA).

Introduction to Internal Medicine calcaneum to the lower most point of the heel pad soft tissue shadow. Heel pad thickness is said to be increased when It is more than 23 mm in males z It is more than 2l mm in females. z

Causes of Increased Heel Pad Thickness z z z z z z

Fig. 1.35  Rocker-bottom foot

Fig. 1.36  Pes cavus

Pes Cavus (Claw Foot) (Fig. 1.36) Causes Familial z Peroneal muscular atrophy z Friedreich’s ataxia z Syringomyelia z Spina bifida occulta z Anterior poliomyelitis. z

The Skin in Clinical Medicine The skin has three layers (Fig. 1.37). The epidermis forms the outer layer which consists of avascular epithelium. The tough fibroelastic dermis forms the middle layer which contains blood vessels, nerves, sebaceous and sweat glands and hair follicles. The hypodermis containing loose connective tissue and fat forms the inner layer. Ninety per cent of the epidermal cells are keratinocytes. They synthesise insoluble proteins, keratins. Keratins form the main component of impervious surface of the epidermis. The pigment melanin is synthesised from phenylalanine by melanocytes which are present in the basal layer of the epidermis. The skin is the largest organ of the human body. It weighs about 4 kg and it covers an area of 2 m2. The brown or black colour of the skin is due to melanin. The amount of melanin present is decided by hereditary factors and the environmental factors like exposure or withdrawal from ultraviolet light.

Functions of the Skin z z

z z

Clawed Toes It is seen in z Friedreich’s ataxia z Peroneal muscular atrophy.

z z

z

Heel Pad Thickness It is the distance measured in an X-ray film of the patient’s foot taken laterally from the lower most point of the

Acromegaly Myxoedema Obesity Peripheral oedema Infection or injury to heel Eptoin therapy.

z z z z

Protection: Physical, chemical, infection Thermoregulation: Blood vessels and eccrine sweat glands Homoeostasis of water, electrolytes and protein Lubrication and waterproofing: Sebum secreted by sebaceous glands Sensations: Specialised nerve endings Immunological: Lymphocytes, macrophages, Langerhans cells Synthesis of vitamin D by keratinocytes Body odour: Apocrine glands Protection and prising: Nails Calorie reserve: Subcutaneous fat Psychosocial: Cosmetic—skin, lips, hair, nails.

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Manual of Practical Medicine

Fig. 1.37  Structure of skin

Primary Skin Lesions Universal and symmetrical skin lesions favour the diagnosis of systemic disorder and focal asymmetrical lesions favour the diagnosis of local infection or allergy.

Terminology of Skin Lesions Macule: Altered colour Papule (Fig. 1.38): Elevated skin lesion—2 cm Nodule: Solid palpable lesion—>0.5 cm Vesicle (Fig. 1.39): Fluid filled blister—0.5 cm

Fig. 1.38  Papule

Pustule: Blister filled with pus Papilloma: Pedunculated projecting lesion Wheal: Elevated central white lesion with red margin Telangiectasia: Dilated small cutaneous blood vessel Petechiae (Fig. 1.41): Pinhead size macule of blood in the skin. Purpura: Larger petechiae—which do not blanch on pressure Ecchymosis (Fig. 1.42): Large extravasation of blood into the skin Haematoma: Swelling due to bleeding—collection of blood Erythema: Redness of the skin.

Fig. 1.39  Vesicle

Introduction to Internal Medicine

Distribution and Site of Skin Lesions Centrifugal: Smallpox, erythema multiforme, erythema nodosum Centripetal: Chickenpox, pityriasis rosea Flexor aspect: Atopic eczema Extensor aspect: Psoriasis.

Colour of the Skin

Fig. 1.40  Bullae

Fig. 1.41  Petechiae

Pallor: Anaemia, shock (due to peripheral vasoconstric­ tion), haemorrhage, intense emotion Increased pigmentation: Racial, sunburn, haemochromatosis, chronic arsenic poisoning Argyria, cachexia, Addison’s disease, pigmentation of nipples and areolae in pregnancy, pellagra, X-irradia­tion Generalised loss of pigmentation: Albinism Patchy loss of pigmentation: Vitiligo, a marker for many autoimmune disorders Localised loss of pigmentation: Piebaldism Erythema: Sunburn, exanthematous fevers, inflamma­tory lesions Flushing: Drugs like nicotinic acid Cyanosis: Central or peripheral cyanosis, conditions simulating cyanosis—methaemoglobinaemia Jaundice: Yellow colouration of the skin due to increased serum bilirubin, Conditions simulating jaundice-carotenaemia (sparing of sclera).

Skin Lesions as Markers for Systemic Disorders Erythema nodosum: Sarcoidosis, tuberculosis, connective tissue diseases, post-streptococcal infection, drugs Erythema marginatum: Rheumatic fever Pyoderma gangrenosum: Ulcerative colitis, rheumatoid arthritis Dermatitis herpetiformis: Gluten enteropathy Generalised purpura: ITP and other haematological disorders Dermatitis artefacta: Personality disorders—anxiety.

Nails in Clinical Medicine (Figs 1.43 and 1.44) Koilonychia (Fig. 1.45) Fig. 1.42  Ecchymosis

It is due to thinning and softening of the nail plate resulting in spoon-shaped nail.

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Manual of Practical Medicine

Fig. 1.43  Structure of the nail

Fig. 1.45  Koilonychia

Fig. 1.44  Structure of the nail (lateral view)

Fig. 1.46  Beau’s line

Causes z z z z z

z z z

Iron deficiency anaemia Haemochromatosis Raynaud’s syndrome Porphyria Occupational — Motor mechanics — Rickshaw pullers Ischaemic heart disease Syphilis Inherited—autosomal dominant.

Beau’s Line (Fig. 1.46) They are transverse ridges in the nail plate due to temporary alteration of nail growth rate. Causes z z

Acute febrile illness Pneumonia

z z z z

Exanthems—Measles, mumps Myocardial infarction, pulmonary infarction Childbirth Drug reaction.

Plummer Nail Onycholysis of the nail (rat bitten nail). Causes z z z z

Hypothyroidism, hyperthyroidism Raynaud’s disease Porphyria Photo-onycholysis—doxycycline, chlortetracycline and chlo­ram­phenicol.

Lindsay Nail (Fig. 1.47) It is characterised by proximal dull white portion and a distal pink or brown portion with a well-demarcated transverse line of separation.

Introduction to Internal Medicine

Fig. 1.47  Half-half nail (Lindsay nail)

Fig. 1.48  White nail

Cause Uraemia.

Fig. 1.49  Black nail

z z z

White Nail (Terry Nail) (Fig. 1.48) It is characterised by white colour in the nail bed than the nail plate. Causes z z z z z z

Anaemia Hypoalbuminaemia (cirrhosis, nephrosis) Diabetes mellitus CCF Rheumatoid arthritis Malignancy.

Red Nail z

Congestive cardiac failure.

Blue Nail z z

Wilson’s disease (Copper deposits) Silver deposits.

Black Nail (Fig. 1.49) z z z

Peutz-Jeghers syndrome Cushing’s syndrome Addison’s disease.

z

Normal Temperature Regulation in the Body Normally heat is being continuously produced in the body, and also is being lost continuously to the surround­ings. When the rate of heat production is equal to the rate of heat loss, the person is said to be in heat balance. But when there is a disturbance of equilibri­um between the two, then the body temperature may rise leading to fever, or may fall leading to hypo­thermia.

Factors Determining Rate of Heat Production z z z z

Basal metabolic rate of the body Muscle activity Effect of thyroid hormones Effect of epinephrine and norepinephrine.

Causes of Heat Loss from the Body

Yellow Nail Syndrome

The other associated features are: z Oedema of finger, ankle and face z Infection: Sinusitis, bronchitis, bronchiectasis, pleural effusion

Carcinoma of skin, larynx, endometrium Lymphoma Agammaglobulinaemia Psoriasis (Fig. 1.50).

TEMPERATURE

z

It is characterised by yellow finger and toe nails, clubbing and onycholysis.

Fig. 1.50  Nail pitting in psoriasis

z

z

z

Radiation: Loss of heat from the body in the form of infrared rays. Conduction: Heat is conducted from the body to the objects in contact with it, e.g. chair, bed, etc. Convection: Heat is lost from the body by the air currents surrounding it. Evaporation: Evaporation of water (sweat) from the body surface serves as an important protective mecha­ nism in reducing body temperature which may rise due

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Manual of Practical Medicine to environmental factors (hot weather). In heat stroke, sweating is impaired and so body core temperature rises to dangerous levels.

Fever It is an elevation of body temperature above the normal circadian variation as a result of the change in the thermoregulatory centre, located in the hypo­thalamus.

Maximum Normal Oral Temperature At 6.00 AM 37.0°C (98.6°F) At 6.00 PM 37.6°C (99.6°F) The normal diurnal variation is 1°F. The normal body temperature is more towards the evening because of increased BMR and increased skeletal muscle activity. Rectal temperature is 0.6°C (1°F) higher than oral temperature. Oral temperature is 0.6°C (1°F) higher than tempe­ra­ ture recorded in the axilla.

Physiological Variation of Temperature In a menstruating woman, the early morning tem­perature is subnormal in the two weeks preceding ovulation. At the time of ovulation, the temperature rises by about 0.6°C (1°F), and persists till men­struation occurs (due to thermogenic property of progesterone). Chill is a sensation of cold that occurs in most fevers. Rigor is a profound chill with piloerection (goose flesh) associated with teeth chattering and severe shivering. Chills or rigors occur when the thermo­stat, situated in the hypo­thalamus, is suddenly reset to a higher temperature due to presence of pyrogens. The body temperature then tends to rise to the newly reset level in the thermostat by conserving heat in the body by cutaneous vasoconstriction and involuntary contraction of skeletal muscles, expe­ rienced as chills or rigors. Chills or rigors may be commonly seen with bacterial, rickettsial, protozoal, influenzal infections. With every 1°F rise of temperature, above 100°F, the pulse rate increases by 10, the respiratory rate by 4, and BMR by 7. Oxygen consumption increases by 13%.

Fever with Relative Bradycardia z z z z z z

Typhoid fever Meningitis Viral fever (Influenza) Brucellosis Leptospirosis Drug induced fever.

Fever with Exanthems z z z

Rash appearing on first day of fever—Chicken pox. Rash appearing on fourth day of fever—Measles. Rash appearing on seventh day of fever—Typhoid.

Febrile Convulsions It occurs in infants and children less than 5 years old. Convulsions are common at temperatures more than 40°C. It may not be a sign of cerebral disease. Normal Febrile Hyperpyrexia Hypothermia

37°C to 37.6°C (98.6°F to 99.6°F) Above 37.8°C (100°F) >41°C (>106°F) < 35°C (< 95°F)

Patterns of Fever Continuous Fever (Fig. 1.51) The temperature remains elevated above normal without touching the baseline and the fluctuation does not exceed 0.6°C (1°F) (diurnal variation), e.g. lobar pneumonia, infective endocarditis, enteric fever. Remittent Fever (Fig. 1.52) The temperature fluctuation exceeds 0.6°C (1°F), but without touching the baseline. Intermittent Fever (Fig. 1.53) The elevated temperature touches the baseline in between. In hectic or septic type of intermittent fever, the diurnal variation is extremely large, as occurs in septicaemia. Quotidian fever is a hectic fever occurring daily. Relapsing Fever (Fig. 1.54) Febrile episodes are separated by normal temperature for more than one day, e.g. Borrelia infection, rat bite fever. z Tertian fever (Fig. 1.55) occurs on the first and third day, e.g. Plasmodium vivax, ovale, falciparum. z Quartan fever (Fig. 1.56) occurs on first and fourth day, e.g. Plasmodium malariae. z Pel-Ebstein fever is a type of fever lasting for 3 to 10 days followed by an afebrile period of 3 to 10 days, e.g. Hodgkins and other lymphomas. z Saddle back fever: Initially fever lasts for 2 to 3 days followed by a remission lasting for 2 days and the fever reappears and continues for 2 to 3 days, e.g. dengue fever. z Borrelia infection and rat bite fever: Both are associated with several days of fever followed by several days of afebrile period and then the cycle repeats. z Cyclic neutropenia: Cyclic neutropenia accompanied with fever occurs every 21 days.

Introduction to Internal Medicine

Fig. 1.51  Continuous fever

Fig. 1.53  Intermittent fever

Fig. 1.52  Remittent fever

Fig. 1.54  Quotidian fever

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Manual of Practical Medicine

Drug Fever z z z z

z

It is prolonged fever and may belong to any febrile pattern There is relative bradycardia and hypotension Pruritus, skin rash and arthralgia may occur It begins 1 to 3 weeks after the start of the drugs and persists 2 to 3 days after the drug is withdrawn Eosinophilia may be present.

Almost all drugs can produce fever. Important com­monly used drugs producing fever are: Sulphonamide Procainamide Penicillins Propylthiouracil Iodides Methyldopa Anti-TB drugs Anticonvulsants Digoxin does not cause drug fever. Infections without Fever z z z z

Elderly patients Newborn Chronic renal failure Patients on steroids.

Hyperpyrexia Fig. 1.55  Tertian fever

It is an elevation of body core temperature, above 41°C (106°F), due to inadequate dissipation of heat. It is a medical emergency, since they are prone for sudden cardiorespiratory arrest. Causes of Hyperpyrexia z z z z z

Pontine haemorrhage Rheumatic fever Meningococcal meningitis Septicaemia Cerebral malaria.

Treatment It is treated with parenteral anti-pyretics to set the elevated thermostat set point to a lower level. Physical cooling aids in reducing the body temperature. Chlor­ promazine is some­times helpful in reducing the body temperature. Causes of Hyperthermia without Elevated Resetting of Thermostat

Fig. 1.56  Quartan fever

Hyperthermia is characterised by an unchanged setting of the thermoregulatory centre with an uncontrolled increase in body temperature that exceeds body’s ability to lose heat. z Heat stroke z Malignant hyperthermia is an inherent abnor­ mality of skeletal muscle cell sarcoplasmic reticulum which

Introduction to Internal Medicine is unable to store calcium ion. There is an increase in the  intracellular myoplasmic calcium, lead­­ing to activation of myosin ATPase, which converts ATP to ADP + PO4 + heat thereby producing hyper­thermia. Hyperthermia is triggered by use of inhalation anaes­thetics (Halothane, Cyclopropane) and muscle relaxants (Succinylcholine). z Neuroleptic malignant syndrome is characterised by — Muscular rigidity — Autonomic dysregulation — Hyperthermia. Neuroleptic drugs like haloperidol, phenothia­ zines trigger the onset of symptoms. Treatment of the above mentioned hyperthermias is by with­drawal of the offending agents. Anti-pyretics are of no use as the thermostat is not reset to higher level. Physical cooling helps. Central muscle relaxant (Dantrolene sodium) is helpful in the last two conditions. Bromocriptine is help­ ful in treatment of neuroleptic malignant syndrome. z Drug induced: Amphetamines, MAO inhibitors, tricyclic antidepressants, atropine z Thyrotoxicosis z Pheochromocytoma z Hypothalamic fever z Serotonin syndrome: It is seen with selective serotonin uptake inhibitors—monoamine oxidase inhibitors and other seratonergic medications. It consists of hyperthermia, diarrhoea, tremor and myoclonus. z Central nervous system damage: It is common in cerebral haemorrhage, status epilepticus, and hypothalamic injury.

Fig. 1.57  Fever settles by crisis

Fever can Subside in the Following Ways Crisis (Fig. 1.57): Elevated temperature settles down to the baseline immediately after starting treatment. It may be accompanied by diaphoresis, diarrhoea or diuresis, e.g. pneumonia. Lysis (Fig. 1.58): Elevated temperature settles down to the base­line in a step ladder fashion, after starting treatment, e.g. typhoid fever.

Pyrexia of Unknown Origin (PUO) It is defined as a persistent temperature of more than 101.2°F (38.4°C) lasting for more than 3 weeks, and defying one week of evaluation (Petersdorf and Beeson). It may be classified as given below: z Low grade PUO — Exercise — Heavy meals — Essential hyperthermia — Psychogenic

Fig. 1.58  Fever settles by lysis

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Manual of Practical Medicine Excitement Pre-menstrual. High grade PUO — Factitious — Fabricated — Occupational — Eczema — Hypothalamic lesion — Drug — Metabolic — Periodic — Ichthyosis. — —

z

Durack and Street Classification of PUO z

z

z

z

Classic PUO: Differs from earlier definition only in duration of hospita­lisation—either 3 days in hospital or 3 outpatient visits without detection of cause or 1 week of intelligent and invasive ambulatory investigations. Nosocomial PUO: Temperature of ≥ 38.3°C developing on several occasions in a hospitalised patient in whom infection was not manifest or incubating on admission with 3 days of investigations including at least 2 days incubation of cultures. Neutropenic PUO: Temperature of ≥ 38.3°C on several occasions in a patient whose neutrophil count is less than 500/microlitre or is expected to fall in 1 to 2 days with 3 days of investigations including at least 2 days of incubation of cultures. HIV associated PUO: Temperature of ≥ 38.3°C on several occasions over a period of more than 4 weeks for outpatients or more than 3 days for inpatients with HIV, with 3 days of investi­gations including 2 days of incubation of cultures.

Fever in the Immunocompromised Immunocompromised state can be as a result of congenital immunodeficiency, HIV infection, iatrogenic immunosuppression induced by chemotherapy, radiation, immunosuppressive drugs including corticosteroids and transplantation. Metabolic abnormalities such as diabetes mellitus and undernutrition play a role. Neutropaenia, impaired T-cell/B-cell responses and impaired skin barrier due to catheters contribute to the cause of fever. Fever may result from infections or from non-infectious causes such as drugs, vasculitis and malignancy.

cultures. Broad spectrum β-lactam monotherapy is adequate and is equivalent to β-lactam—aminoglycoside combinations. If the fever does not subside in a week’s time, empirical antifungal therapy (Amphotericin B/ Caspofungin) should be added. Post-transplantation Fever It may be due to infections, or graft rejection, or graftversus-host disease as in bone marrow transplant patients. Post-transplantation Infections Solid Organ Recipients z z z

Bone Marrow Recipients z

z

z

Pre-engraftment (0–4 weeks)—bacterial, fungal and respiratory viral infections. Post-engraftment—CMV/PCP/moulds and other opportunistic infections. Late (> 100 days)—community acquired bacterial infections, shingles, CMV and PTLD.

Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated lymphoma that can complicate transplantation following EBV infection. Causes of PUO Infection 30–40% Malignancies 20–30% Collagen vascular disease 10–15% Miscellaneous 10–15% Malignancies associated with PUO z z z z z z

Hodgkin’s disease NHL Leukaemia (Preleukaemia and aleukaemia) Hepatoma Renal cell carcinoma Ca colon.

Important Investigations z

Neutropenic Fever They are prone for bacterial or fungal infections. In-dwelling catheters predispose to infections with gram-positive organisms. Empirical broad spectrum antimicrobial therapy should be commenced after taking necessary

0 to 1month bacterial or fungal infections 1 to 6 months CMV/PCP infections > 6 months community-acquired bacterial infections, shingles, cryptococcal infections, post-transplant lympho­proliferative disorders (PTLD).



ESR-platelet correlation: If ESR > 100 mm/hr with throm­bocytosis, think of — Tuberculosis — Malignancy — Connective tissue disease. ESR > 100 mm/hr without thrombocytosis, think of viral infections.

Introduction to Internal Medicine z

z z

z

z z

Elevated alkaline phosphatase — Biliary tract infections — Alcoholic hepatitis — Primary and secondaries of liver — Hypernephroma, lymphoma — Miliary tuberculosis — CMV infection. Blood culture Serological tests (4 fold rise significant). Useful in: — Enteric fever — Hepatitis — CMV infection — Tularaemia — Secondary syphilis — Brucellosis — Q-fever — Amoebiasis — HIV. Imaging techniques — Plain X-ray chest: In all patients with PUO, when initial X-ray chest is normal, a second X-ray must be taken after 3 weeks to rule out miliary tuber­ culosis (time taken for radiological opacity to appear). Mottling of < 0.5 mm is not detectable in X-ray. — Contrast films IVP in renal abscesses, tumours Barium meal in intrinsic bowel disease Oral cholecystogram Cholangiography. — Ultrasound: Excellent imaging is procured in thin individuals and poor imaging in obese indi­viduals. SOL in hepatobiliary tree of more than 1 cm and endo­carditic vegetation of more than 2 mm can be detected. — CT scan: It gives excellent imaging in obese patients also. SOL in liver of more than 1 cm and CNS lesion of more than 0.2 cm can be detected. — MRI: It gives best resolution of tissue planes of differing intensity. It has an advantage over CT scan when studying bone, brain, pelvis, spinal cord and thoracic large vessels. MRI is contra­indicated when metal clips are present. — MRI and CT scans are useless in diagnosing menin­­gitis. 99m Tc-sulphur colloid is — Radionuclide scans: used for scanning liver and spleen. 111Indium labelled leucocytes are used for detection of intraabdominal abscess. CSF study Bone marrow study.

Most PUOs are due to: Occult tuberculosis z Occult pus z Occult malignancies z Collagen vascular diseases. z

Ninety per cent of PUOs are diagnosed by proper evalua­ tion. The rest recover under a watchful non-interference. As the duration of fever increases the likelihood of infection as the cause of PUO is remote. Extra-pulmonary tuberculosis remains the leading diagnosable cause of PUO among infections.

Therapeutic Trial These are best avoided whenever possible. If insti­tuted, the drug should be specific for that certain condition. Examples include: z Aspirin in a possible case of juvenile rheumatoid arthritis z Antitubercular agents continued for 3 to 4 weeks in suspected occult tuberculosis z Antibiotics in a patient with suspected endocarditis awaiting culture report z Heparin for suspected pulmonary embolism z Corticosteroids for suspected giant-cell arteritis z Antitubercular or steroid therapy in a suspected case of granulomatous hepatitis.

PAIN Pain is an unpleasant sensation localised to a part of the body. Primary afferent nociceptors (pain recep­tors) are A-delta (small myelinated) and C (unmyeli­nated) fibres. Pain has to be analysed in the following way (Fig. 1.59): z Site z Character and severity z Duration z Frequency and periodicity z Radiation z Aggravating factors z Relieving factors z Associated factors.

Chest Pain Chest pain may be due to any of the following conditions.

Cardiac Causes z z

Angina pectoris Myocardial infarction

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Manual of Practical Medicine Pain in Acute Aortic Dissection The pain is of abrupt onset, reaches a peak rapidly and is felt in the centre of the chest and/or the back depending on the site of aneurysm. This pain lasts for many hours and is not aggravated by changes in position or respiration. It is associated with unequal or absent pulses.

Respiratory Causes Pleurisy. Pleural Pain

Fig. 1.59  Referred pain z z

Pericarditis Acute dissection of aorta.

Angina Pectoris It is a midline retrosternal constrictive, compressive or squeezing diffuse pain lasting for 3 to 15 minutes. It may radiate to either arm, either shoulder, jaw, back and upper abdomen. It is aggravated by exertion, heavy meal, emotion and is relieved by rest or nitrates. Usually the patient lies still. When there are no risk factors for ischaemic heart disease, precordial pain in a young individual or a fertile female is mostly non-ischaemic. Myocardial Infarction Pain in myocardial infarction (MI) is a similar anginal pain of spontaneous origin lasting for more than 30 minutes, but the inten­sity is very severe. In contrast to angina, this pain is not rapidly relieved by rest or coronary dilator drugs. It may be accompanied by autonomic disturbances like diapho­resis, nausea, hypotension and a feeling to defae­ cate. Patient is usually restless. Pericardial Pain It is a steady, substernal discomfort that mimics the pain of MI; it is worsened by lying down and is relieved by sitting and leaning forward. Often pain may be pleuritic, consequent to accompanying pleural inflam­mation.

It is a sharp, knife like, localised superficial pain, aggravated by deep inspiration and coughing due to stretching of the inflamed parietal pleura and is relieved by lying down on the affected side due to restricted movement of chest on the same side. In diaphragmatic pleurisy, pain arising from central tendinous portion of the diaphragm is felt characteri­ stically at the tip of the shoulder, trapezius ridge and the neck since the central part of diaphragm receives sensory supply from phrenic nerve (C3, 4, 5). Pain may radiate down to upper abdomen when peripheral part of diaphragmatic pleura (supplied by 6th to 12th intercostal nerves) is involved simulating acute abdomen.

Chest Wall Causes z z

Musculoskeletal pain Neuropathic pain.

Musculoskeletal Pain Costochondral and chondrosternal articulations are most common sites of anterior chest pain. Pain may be darting and lasts for a few seconds or it may be a dull ache enduring for hours or days. Tietze’s Syndrome Painful swelling of one or more costochondral articu­ lations, usually second or third. Neuropathic Pains Neuropathic pains have an unusual burning, tingling or electric shock like quality. Pain is triggered by very light touch and on examination, sensory deficit is characteri­ stically present in the corresponding der­matome, e.g. damage to peripheral nerves as in diabetic polyneuro­pathy or peripheral afferents as in herpes zoster.

GI Causes z z z

Reflux oesophagitis Hiatus hernia Oesophageal spasm.

Introduction to Internal Medicine Causes of Acute Chest Pain Disorder

Quality

Duration

Site of pain

Associated features

Angina

Compressing Squeezing

>2 and 30 min

Similar to angina

Unrelieved by nitrates Associated cardiac failure/arrhythmia

Aortic stenosis

Similar to angina

Recurrent episodes

Similar to angina

Late-peaking ESM with conduction to carotid arteries

Aortic dissection

Knife like tearing

Unrelenting painonset abrupt

Radiating to back between shoulder blades

Connective tissue disorder/ HTN/loss of peripheral pulse

Pericarditis

Sharp

Episodic or hours/days

Retrosternal

Relieved by sitting or leaning forward pericardial rub

Pulmonary embolism

Pleuritic

Abrupt Minutes to hours

Similar to angina or lateral

Tachycardia, dyspnoea, hypotension

Pulmonary hypertension

Variable

Compressing

Substernal

Raised JVP, oedema, dyspnoea, loud P2

Pneumonia/pleurisy

Pleuritic

Variable

Localised unilateral

Pleural rub, cough, crackles, dyspnoea

Pneumothorax

Pleuritic

Sudden onset-hours

Unilateral localised

Hyper-resonant note, decreased breath sounds, coin sound

GERD

Burning

10–60 min

Substernal epigastric

Post-prandial pain More on recumbency

Oesophageal spasm

Compressing or burning

2–20 min

Retrosternal

Simulates angina

Peptic ulcer

Burning

Prolonged

Epigastric

Relieved with food, antacids, H2 blockers, PP inhibitors

Gallbladder disorders

Compressing

Prolonged

Right hypochondrium

Pain follows food

Herpes zoster

Sharp/burning

Variable

Dermatomal distribution

Vesicular lesions over the affected segment

Musculoskeletal

Variable

Aching

Localised

Local tenderness, pain on movement

Psychological

Variable

Variable

Variable

Anxiety/depression

Abdominal Pain Some important causes: Inflammation of peritoneum z Mechanical obstruction to hollow viscera z Vascular disturbances z Abdominal wall causes (trauma or infection of muscles) z Distention of visceral surfaces (hepatic or renal capsules) z Referred pain from extra-abdominal sources (pneumonia, IHD, spine, genitalia) z Metabolic causes (DKA, porphyria, uraemia, etc.) z Neurogenic causes. z

Pain of diaphragmatic pleuritis is felt at right upper quadrant of abdomen. Referred pain from spine is characteristically intensi­fied by certain motions like coughing, sneezing or straining and is associated with hyperaesthesia over involved derma­tomes. Pain referred from testicles or seminal vesicles is accen­ tuated by slightest pressure on either of these organs. The abdominal discomfort is of dull aching character and is poorly localised.

Pain due to Disorders of GIT

Pain Referred to Abdomen

Oesophageal Pain

Possibility of intrathoracic disease must be considered in every patient with abdominal pain. Apparent abdo­m­i­nal muscle spasm caused by referred pain will diminish during inspiration whereas it is persistent throughout respiratory phases, if it is of abdominal origin.

This may be either due to oesophageal spasm or due to reflux oesophagitis. In case of oesophageal spasm, the pain is retrosternal and mimics anginal pain. In case of reflux oesophagitis, the pain is retrosternal and has a burning character, usually occurring about 1 hour after a meal.

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Peptic Ulcer Pain Duodenal ulcer It is often an episodic, recurrent epi­gastric pain described as sharp, burning or ill-defined. It charac­teristically occurs from 90 minutes to 3 hours after eating and awakens the patient from sleep. Pain is relieved by food, antacids or H2 blockers. Changes in character of pain suggests development of complications. Pain radiating to back Penetration of ulcer Pain aggravated by food and Gastric outlet   accompanied by vomiting   obstruction Abrupt, severe abdominal pain Perforation of ulcer When accompanied by coffee Ulcer bleed   ground vomitus and melena Some patients with duodenal ulcer have no symptoms. Gastric ulcer Epigastric pain, which is worsened by taking food and is relieved by vomiting. Relief with antacids is less consistent than that of duodenal ulcer pain.

Mechanical Small Bowel Obstruction In this condition, the colicky pain is mid abdominal which tends to be more severe in case of high obstruc­tion. Pain occurs in paroxysms and the patient is comfortable in between the pains. Borborygmi is heard during episodes of pain. Later, pain becomes less severe as the motility is impaired in the oedema­tous intestine. If there is strangulation of gut, pain is steady, severe, localised, without colicky nature. Pain of small bowel obstruction is accompanied by faeculent vomit­ ing, singultus and obstipation (No passage of faeces or gas).

Colonic Obstruction Colicky abdominal pain is of much less intensity, felt at any site over abdomen depending on the part of colon involved, e.g. hypogastric pain in sigmoid colonic involvement. Faeculent vomiting is rare; constipation progresses to obstipation.

Pain in Acute Appendicitis In the initial stages, pain is poorly localised in the periumbilical or epigastric region. As inflammation spreads, pain becomes somatic, more severe and is loca­­lised to right lower quadrant. Pain is accompanied by anorexia, nausea, vomiting and fever. Tenderness at McBurney’s point

(junction of medial 2/3 and lateral 1/3 of spinoumbilical line) is elicited later.

Acute Pancreatitis In acute pancreatitis, there is a severe, constant epi­gastric pain radiating to the back, lasting for 24 hours. Pain is aggravated by taking alcohol or fatty food and is relieved by sitting upright. Pain may be associated with vomiting, jaundice, paralytic ileus, gallstones, and shock. There is profound elevation of amylase levels.

Biliary Colic Acute distention of gallbladder causes pain in the right hypochondrium with radiation to the right, pos­te­rior region of thorax or to the tip of right scapula. Distention of common bile duct (CBD) causes pain in the epigastrium radiating to upper part of lumbar region. Murphy’s sign: In acute cholecystitis, the patient is asked to breathe in deeply and gallbladder is palpated in the usual way. At the height of inspiration, the breath is arrested with a gasp as the mass is felt.

Pain of Peritonitis It is a steady and aching pain located directly over inflam­ med area. The pain is accentuated by pressure or changes in tension of the peritoneum and hence the patient lies still. There is associated tonic muscle spasm. The intensity of pain is dependent on the type and amount of foreign substance to which the peri­toneal surfaces are exposed. If the peritonitis is due to perforation of a hollow abdo­ minal viscera, liver dullness is obliterated.

Superior Mesenteric Artery Occlusion It is a mild, continuous, diffuse pain present for 2 to 3 days before vascular collapse or peritonitis sets in. There is no tenderness or rigidity. Bloody diarrhoea may be present. In chronic mesenteric artery insufficiency, abdo­minal pain occurs after intake of food (abdominal angina).

Abdominal Wall Pain It is a constant, aching pain, aggravated by movement, prolonged standing and pressure. When muscles of other parts of the body are also involved, myositis should be considered.

Metabolic Causes of Abdominal Pain Whenever the cause of abdominal pain is obscure, one of the following metabolic causes must be considered.

Introduction to Internal Medicine z z z z z z

Diabetic ketoacidosis Porphyria Uraemia Lead colic Hyperlipidaemia C1 esterase deficiency.

Neurogenic Abdominal Pain Causalgic pain is of burning character and is limited to the distribution of peripheral nerve. Normal stimuli like touch can evoke this type of pain. There is no muscle spasm or change with respiration or food intake. Pain from spinal nerves or roots is of lancinating type. It may be caused by herpes zoster, arthritis, tumours, herniated nucleus pulposus, diabetes, syphi­lis. Pain is aggravated by movement of spine and is usually confined to a few dermatomes. Hyperaesthesia is common.

Psychogenic Abdominal Pain There is no relation to meals. Onset is usually at nights. There is no nausea or vomiting. There is no abdominal muscle spasm; even if present does not persist. There is no change with respiration. But restriction of depth of respiration occurs as a part of anxiety state.

Renal Pain Pain due to obstruction of urinary bladder causes a dull suprapubic pain of low intensity. Pain due to ureteric obstruction (intravesical por­ tion) is characterised by severe suprapubic and flank pain which radiates to genitalia and upper part of thigh. Obstruction of ureteropelvic junction causes pain at costovertebral angle, whereas obstruction of the remainder of the ureter is associated with flank pain which radiates from loin to groin.

Peripheral Vascular Pain Arterial Occlusion Intermittent Claudication Patient often complains that after walking a distance (claudication distance), the pain starts and on con­tinued walking the pain is aggravated and compels the patient to take rest. Pain disappears when the exercise stops.

Rest Pain This pain is continuous and aching in nature. This is due to ischaemic changes in the somatic nerves (cry of the dying nerves).

Venous Pain Venous pain may be due to:

Varicose Veins Pain felt in lower leg or whole of the leg according to the site of varicosities. Pain gets worse when the patient stands up for a long time and is relieved when he lies down. Pain of varicocele of testes is of similar charac­ter.

Venous Thrombosis Patient may have pain and swelling of leg (around ankle). Homan’s sign: Dorsiflexion of foot elicits pain in the calf. Moses’s sign: Squeezing of calf muscle from side to side elicits pain. In superficial thrombophlebitis, there is pain and tender­ness over superficial inflamed veins. The above manoeuvres may dislodge the thrombus resulting in pulmonary embolism.

Neurogenic Claudication Symptoms of dysfunction of cauda equina appear on walking or prolonged standing and are relieved by rest. This is due to lumbar canal stenosis which is made worse in middle age due to degenerative changes especially between L4 and L5 vertebrae. There is march of pain with paraesthesia and absent ankle jerk after exercise. Symptoms take 5 to 10 minutes to fade.

OEDEMA Oedema is a collection of excess fluid in the body inter­ stitium, from the intravascular compartment. Ascites Pathological collection of fluid in the peritoneal cavity Hydrothorax Pathological collection of fluid in the pleural cavity Anasarca Generalised oedema Pericardial effusion Pathological collection of fluid in the pericardial cavity. Normal Body Fluid Compartments Compartment

Volume (in litres)

Percentage lean body weight

1.  Total body water

42

60

2.  Extracellular water – Plasma – Interstitial

14 3–4 11

20 4–5 16

3.  Intracellular water

28

40

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Manual of Practical Medicine

Aetiology and Types of Oedema Generalised Oedema z z z z z z

Cardiac oedema Renal oedema Hepatic oedema Nutritional oedema Cyclic-premenstrual Idiopathic.

Localised Oedema z z z z

Venous oedema Lymphatic oedema Inflammatory oedema Allergic.

Fast Oedema This indicates oedema occurring in conditions causing hypoalbuminaemia. The oedema pits on pressure applica­ tion but disappears within 40 seconds of its application.

Slow Oedema (Fig. 1.60) This indicates oedema occurring in conditions causing congestion (CCF). The oedema pits on pressure appli­ cation but lasts for more than 1 minute.

Pathophysiology of Oedema (Fig. 1.61) Normal hydrostatic pressure at the arteriolar end of the capillary bed = 35 mm Hg. Normal hydrostatic pressure at the venular end of the capillary bed = 12 to 15 mm Hg. Oncotic pressure of plasma = 20 to 25 mm Hg.

Fig. 1.61  Pathophysiology of oedema

Normally, fluid volume in different compartments of the body is maintained by the normal Starling’s forces, mentioned above. z Hydrostatic pressure at the arteriolar end of the capillary tends to push the intravascular fluid into the interstitium. z The oncotic pressure at the venous end of the capil­ lary, maintained chiefly by body albumin, tends to remove fluid from the interstitium into the vascular compartment. The normal lymphatic flow carries the albumin, extruded from the intravascular compartment into the interstitium, back into the intravascular compart­ment, to maintain the normal oncotic pressure. Oedema may result when there is: Increase in hydrostatic pressure z Decrease in oncotic pressure z Obstruction to veins/lymphatic flow z Vascular wall injury (mechanical, thermal, chem­ical). z

Characteristic Features of Oedema of Various Aetiologies Cardiac Oedema The pathophysiology of this oedema is: Increased back pressure on the venous side of circulation leading to transudation of fluid into the interstitium. z Decreased intravascular volume leading to de­creased renal blood flow and thereby stimulation of the reninangiotensin mechanism. z Decreased intravascular volume leads to hyper­ osmolality of the blood, which in turn stimulates the osmoreceptors in the posterior pituitary to secrete antidiuretic hormone. This hormone stimu­lates the thirst mechanism and the patient consumes more water, which contributes to the oedema formation. z

Fig. 1.60  Pitting pedal oedema

Introduction to Internal Medicine z

In left sided cardiac failure there is accumulation of fluid in the lung interstitium leading to develop­ment of pulmonary oedema.

Cardiac oedema is a dependent oedema found over the ankles in ambulant patients, and over the sacrum in bed ridden patients.

Renal Oedema The pathophysiology of this oedema is: Primary increase in sodium and water retention by the kidneys (as in AGN). z Decrease in oncotic pressure due to increased loss of albumin in urine (as in nephrotic syndrome) z However, in CRF, oedema need not be present initially. In the last stage of CRF, oedema develops due to retention of sodium and water.

z

z

Renal oedema characteristically involves the loose con­ nective tissues, especially over the periorbital region, more prominent when the patient wakes up in the early morning, as the patient with renal oedema are able to lie down flat (comfortably).

Oedema Seen in Liver Disease The pathophysiology of this oedema is that the collection of fluid occurs characteristically first in the peritoneal cavity (Ascites), because of the follow­ing: z Increased portal venous pressure (Portal HTN). z Obliteration of the lymphatic drainage of the liver. z Hypoalbuminaemia (Due to impaired synthesis of albumin by the decompensated liver). z Decrease in the intravascular volume leading to activation of renin-angiotensin-aldosterone mecha­ nism and retention of salt and water. Decreased metabolism of aldosterone by the decompensated liver leads to secondary hyper­aldosteronism and increased retention of salt and water. z Tense ascites leads to increased intra-abdominal pressure thereby decreasing venous return from the lower limbs and hence development of pedal oedema.

Oedema of Nutritional Origin It is a generalised oedema. Causes of nutritional oedema are: z Decreased ingestion of proteins leading to hypoalbuminaemia and therefore oedema. z Thiamine deficiency leading to beriberi. Oedema in beriberi occurs because of the following: — Due to lack of thiamine, glucose is incom­ pletely metabolised and lactic and pyruvic acids

accu­ m u­ l ate, which causes peripheral vaso­ dilatation and transudation of fluid through the capillaries. — The resulting anaemia also contributes to the development of oedema. — Development of high output cardiac failure results in oedema. Oedema can occur on re-feeding after prolonged starvation due to: — Increased salt intake. — Increased release of insulin which acts directly on the renal tubules to increase sodium re-absorption.

Idiopathic Oedema Periodic episodes of oedema occurring exclusively in women. Diurnal variation of weight occurs with orthostatic retention of salt and water. This suggests an increase in capillary permeability on erect posture.

Cyclical or Pre-menstrual Oedema This oedema is due to sodium and water retention, secondary to excessive oestrogen stimulation.

Other Causes of Oedema z

z

Myxo-oedema (oedema typically located in pre-tibial region along with periorbital puffiness) Pregnancy.

Less Common Causes of Facial Oedema z z z

Myxo-oedema Allergic reaction Trichinosis.

Localised Oedema z

z

z

Venous oedema — Deep vein thrombosis — Thrombophlebitis — Varicose veins — SVC/IVC obstruction. Lymphatic oedema — Chronic lymphangitis — Resection of regional lymph nodes — Filariasis — Radiotherapy — Congenital (Milroy’s disease—congenital ab­sence of lymphatic tissue). Inflammatory/allergic causes — Cellulitis — Bee/wasp sting.

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Manual of Practical Medicine

Drugs Causing Oedema z z

z z z z z

z

and systemic vascular resistance. Cardiac output in turn is a pro­duct of stroke volume and heart rate. Stroke volume depends upon preload, afterload and myo­cardial contractility.

Non-steroidal anti-inflammatory drugs Arteriolar vasodilators — Minoxidil — Hydralazine — Clonidine — Alpha-methyl dopa — Guanethedine Calcium channel blockers Alpha-blockers Cyclosporin Growth hormone Steroidal hormones — Glucocorticoids — Anabolic steroids — Oestrogens — Progestins Immunotherapy — Interleukin-2 — Monoclonal antibody — OKT-3

Control Mechanism z z

z

z

z z z z

Release of vasodilator metabolites (adenosine) Release from endothelium of substances which relax (EDRF or nitric oxide) vascular smooth muscle Release from endothelium of substances which con­ tract (endothelin) vascular smooth muscle Autonomic nervous system (baroreceptor reflexes and vasomotor centre in the brainstem) Release of vasopressin Renin angiotensin aldosterone system Release of vasodilators (prostaglandins and kinins) Fluid and electrolyte balance.

Classification Cardiogenic Shock Myopathic z

SHOCK

z z

Shock may be defined as a state in which there is profound and widespread reduction in the effective delivery of oxygen and other nutrients to tissues leading to reversible, and if prolonged, to irreversible cellular injury. Acute circulatory failure, shock, low cardiac output states are various terms used to describe a clinical syndrome of hypotension, peripheral vasoconstriction, oliguria and often impaired consciousness.

Control of Arterial Blood Pressure

z

Acute MI Dilated cardiomyopathy Myocardial depression in septic shock Myocarditis.

Mechanical z z z

MR, VSD following MI Ventricular aneurysm LV outflow obstruction (AS, HOCM).

Electrical Arrhythmias Tachyarrhythmias (SVT, VT, VF) z Bradyarrhythmias (complete heart block—StokesAdams attacks) z Tachybradyarrhythmias (Sick sinus syndrome). z

Organ perfusion is dependent on an appropriate perfusion pressure which is determined by cardiac output

Classification of Shock Type of shock

Filling pressures

Cardiac output

Sys. vascular resistance

PCWP

Aetiologies

Cardiogenic

­↑

↓

­↑

↑ ­↑ ↑ or N ↓ or N

MI, cardiomyopathy, valvular heart disease, arrhythmias, acute VSD, MR RV infarct

Distributive (septic)

↓

­↑

↓

↓

Sepsis, anaphylaxis, toxic shock syndrome

Hypovolemic

↓

­↑ ↓

­↑

↓

Haemorrhage, hypovolemia

Obstructive

­ ­ (Proximal) ↑ ↓ (Distal)

↓

­↑

­↑

Pulmonary embolism tamponade, tension pneumothorax

Introduction to Internal Medicine

Extracardiac Obstructive Shock z z z z z

Pericardial tamponade Constrictive pericarditis Acute massive pulmonary embolism Severe pulmonary hypertension Coarctation of the aorta.

Oligemic Shock Fluid depletion (vomiting, diarrhoea, burns, sweating, fistulae, pancreatitis) Haemorrhage Internal: GIT perforation, splenic rupture, ectopic pregnancy z External: Trauma, fracture femur, etc. z

Distributive Shock z z z z z

Septic shock Toxins Anaphylaxis Neurogenic shock Endocrinologic shock.

Hypovolemic Shock Because of decreased blood volume, there is inade­quate ventricular filling, decreased preload and stroke volume. Cardiogenic Shock Systolic arterial pressure is < 80 mm Hg and cardiac index is < 1.8 L/min/m2. LV filling pressure is elevated. Common Causes MI (> 40% of LV involvement), myocarditis, following cardiac arrest or prolonged cardiac surgery. Cardiac Causes of Acute Circulatory Failure Endocardial Mitral valve disease Aortic valve disease Myocardial RV infarct LV infarct Cardiomyopathy Myocarditis Atrial arrhythmias Pericardial Tamponade Constrictive pericarditis Great vessels Aortic dissection Pulmonary embolism. Extracardiac Obstructive Shock There is inability of the ventricles to fill during dias­tole, markedly limiting stroke volume and ultimately the cardiac output.

Distributive Shock There is profound decrease in peripheral vascular resis­ tance by the release of histamine, kinins, pros­taglandins, lipid A, endorphins, TNF, IL-1 and IL-2. Some prostaglandins and leukotrienes produce vaso­constriction. Patient may suffer from more than one form of shock simultaneously.

Clinical Features Patients have hypotension (mean arterial BP 100 mm Hg. To maintain blood flow to organs which are vul­ nerable (kidneys, liver, brain and lungs). To maintain arterial blood lactate < 22 mmol/l.

Treatment z z

Maintenance of airway and ventilation is essential. Volume resuscitation should be done in all cases except in cardiogenic shock. — The pneumatic antishock garment (PASG) with sequential inflation of legs and abdominal com­ part­ments to 15–40 mm Hg may be useful in all types of shock except cardiogenic shock. It helps by increasing peripheral vascular resistance.

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Manual of Practical Medicine Trendelenburg’s position to aid venous return and cardiac index. — Fluid resuscitation by giving 500 ml bolus of normal saline with further infusions depending on BP and other parameters. Fresh frozen plasma or packed cells may be needed. Vasopressors — Dopamine is the pressor of first choice except in cyclic anti-depressant and phenothiazine over­doses (5 µg/kg/min if renal perfusion is impaired or 10 µg/kg/min when renal perfusion is ade­quate). — Norepinephrine given in a dose of 2 to 8 µg/ minute causes peripheral vasoconstriction and lesser chrono­tropic and inotropic response. — Dobutamine can be given in a dose of 1 to 10 µg/ kg/minute to increase cardiac output in a low cardiac output state. — Amrinone can be given by adding 500 mg to 150 ml of normal saline for a final volume of 250 ml. A loading dose of 0.75 mg/kg is given over 2 to 3 minutes, with infusion following at 5 to 10 µg/kg/minute. — Isoproterenol in a dose of 1 to 4 µg/minute can be tried only in atropine unresponsive bradycardia requiring pacemaker. Sodium bicarbonate should be given when pH falls less than 7.2. Inappropriate bicarbonate use may cause CNS acidosis and diminish peripheral tissue oxygenation. Antibiotics should be given empirically when sepsis is suspected, and glucocorticoids when adrenal insuffi­ciency is suspected (after drawing blood for basal cortisol). —

z

z

z

Cardiogenic Shock z z z

z

z

Oxygen Nitrates Intra-aortic balloon counter pulsation for salvaging reversibly damaged myocardium Thrombolytic therapy or CABG or PTCA to restore myocardial perfusion Vasopressors like dopamine or dobutamine or both.

Interruption of pathogenic sequence by i. Inhibition of endorphin receptors with naloxone ii. Inhibition of arachidonic acid metabolites iii. Human monoclonal antibody against lipid A, inhi­bitors of sepsis mediators like IL-1 and TNF-α.

z

Anaphylactic Shock Maintenance of airway. Epinephrine is the cornerstone of therapy. It is given in a dose of 0.3 to 0.5 mg (0.3–0.5 ml of 1:1,000 solution) SC and repeated twice at 20 minute intervals if necessary. It can be given intravenously (3–5 ml of 1:10,000 solution) or sublingually (0.5 ml of 1 : 1,000 solution) or via endotracheal tube (3–5 ml of 1 : 10,000 solution). z Volume expansion by crystalloid or colloid. z Inhaled beta-agonists to treat bronchospasm. z Aminophylline is used as a second line drug. z General measures to delay the absorption of the offending antigen. For orally ingested antigens, activated charcoal (50–100 g) with 1 to 2 g/kg (max­ i­mum 150 g) of sorbitol or 300 ml of magnesium citrate can be given. Emesis is not indicated. For injected antigens, slight constriction and local epinephrine injection at the affected site may be useful. z Antihistamines may shorten the duration of the reaction. For recurrent symptoms, H2 blockers may be useful. z Glucocorticoids (Hydrocortisone 100 mg IV every 6 hours) have no effect for 6 to 12 hours, but they may prevent recurrence or relapse of severe reactions. z Glucagon in a dose of 1 mg bolus followed by a drip of 1 mg/hour provides direct inotropic support for patients taking beta blockers. z Patients should be readmitted when there is relapse. z Patients requiring radiocontrast administration despite a previous reaction should receive predni­ sone, 50 mg PO q6h for 3 to 4 doses and diphenhy­ dramine, 50 mg PO 1 hour before the procedure. Cardiac resuscitative measures should be available. z z

Cardiac Tamponade z z

Inotropic agents (norepinephrine, dopamine) Pericardiocentesis.

Septic Shock z

z

Infection must be treated (antimicrobials, surgical drainage of pus or both) CVS monitoring and support

FUNDAMENTALS IN GENETICS Introduction Chromosomes are the carriers of inherent factors. They are situated in the nucleus of the cell. They are made up of double stranded deoxyribonucleic acid (DNA).

Introduction to Internal Medicine Pedigree chart (Fig. 1.62) is very useful to find out the mode of inheritance of various disorders. DNA are found only in the chromosomes and are double stranded helical structures, bound together by hydrogen bonds. It is made up of nucleic acid, a com­plex substance composed of long chains of molecules called nucleotides. Each nucleotide is composed of: z

z z

Nitrogenous bases Purines Adenine (A) & Guanine (G) Pyrimidines Cytosine (C) & Thymine (T) Sugar moiety Deoxyribose Phosphate molecule.

Genes are made up of DNA. The function of the genes is to provide exact information for synthesis of specific amino acid sequence of the protein they con­trol. The genetic code for this information is founded on triplet codons (the sequential nitrogenous bases for specific amino acids). Ribonucleic acid or RNA are mainly found in the nucleolus and cytoplasm. They contain uracil instead of thymine as pyrimidine base, pairing with adenine. The sugar moiety is ribose and they are single stranded. They form a conduit in the formation of the polypeptide chain, as coded by the gene for the specific protein.

Normal Chromosome Number and Structure There are 22 pairs of autosomes and 1 pair of sex chromosomes (XX in females and XY in males). The arrangement of chromosomes in pairs in dec­ reas­ing order of size, and numbered from 1 to 22 is known as Karyotyping of chromosomes. It represents the chromosomal constitution of a person. The chromosomes are divided into 7 groups, from A to G depending upon their size and position of the centromere (nipped-in narrow portion, where the chro­ matids meet) of the chromosome. Metacentric chromosome: The centromere is in the centre. Acrocentric chromosome: The centromere is close to one end. Submetacentric chromosome: The centromere is in intermediate position. Each chromosome has a short arm called ‘p’ (petit) and a long arm called ‘q.’ These arms are divided into regions, bands and sub-bands, numerically, e.g. 7q 21.2 means long arm of chromosome 7, region 2, band 1 and sub-band 2. The normal male has 46 XY chromosomal consti­tution. The normal female has 46 XX chromosomal consti­tution. Turner’s syndrome: When a sex chromosome has been lost it may result in chromosomal constitution of 45 XO. Klinefelter’s syndrome: When a sex chromosome has been added it may result in chromosomal constitution of 47 XXY. When a chromosome is added or deleted, a (+) or (–) sign is incorporated. Example: Down’s syndrome, in which an extra chro­­ mosome is added on chromosome 21, is indicated as 47, XY, +21. If part of short arm is missing on chromosome 5, it is indicated as 46, XY, 5p– (Cri-du-chat syndrome).

Chromosomal Abnormalities These can be divided into those which involve Autosomes z Sex chromosomes, which may in turn be due to either numerical (addition or loss of one or more chromosomes) or due to structural abnormalities. z

Numerical Chromosome Aberrations Autosomal Aneuploidy Fig. 1.62  Symbols used in pedigree chart

Aneuploidy means numerical gain or loss of one or few chromosomes.

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Manual of Practical Medicine Monosomy: It means loss of an autosome, and is incompatible with life as even one chromosome may carry many important genes. z Trisomy: It means addition of an autosome. Examples: Trisomy 21 (Down’s syndrome) 47, XY, +21 Trisomy 18 (Edward’s syndrome) 47, XY, +18 Trisomy 13 (Patau’s syndrome) 47, XY, +13 z Polyploidy: It means that the chromosome number is a multiple of 23, but exceeds the number 46. These are incompatible with life. Examples: Triploidy (69 chromosomes) Tetraploidy (92 chromosomes).

Autosomal Dominant Inheritance

Sex Chromosome Aneuploidy

Autosomal dominant traits may show variable expres­­ sion (variation in severity of the same genetic disorder). Sometimes a gene may not express itself (non-penetrance) and this explains apparent skipped gen­ e rations. Penetrance of a gene results in complete expression of the characteristics of the gene. There is 50% chance that the child of an affected parent will be affected.

z

These are more common than autosomal aneuploidy, with the exception of trisomy 21. This occurs as a result of non-disjunction (failure of homologous chromosomes to separate) during one of the meiotic divisions in oogenesis or spermatogenesis. If the number of X chromosomes added is more, there are higher chances of the presence of mental retardation. If the number of Y chromosomes added is more, the male is tall, aggressive in behaviour and often delin­quent. Structural Aberration of Chromosome These arise from chromosomal breakage. The abnor­ malities that occur may be z Deletion: A segment of chromosome is lost after breakage, e.g. Cri-du-chat syndrome (deletion of short arm of chromosome 5) 46, XY, 5p– z Translocation: There is aberrant rejoining of the broken segments, occurring on two chromosomes. There is, therefore an exchange of segments between two nonhomo­logous chromosomes, e.g. Down’s syndrome occur­ring due to translocation between chromosomes 14 and 21. Philadelphia chro­mo­some, an acquired transloca­tion occurring between chromosomes 9 and 22, is seen in patients with CML.

Single Gene Disorders These occur due to mutation (change in a gene) in either one or in a pair of homologous alleles at a single locus of the chromosome. Allele Homologous chromosome

Gene at a given locus Paired chromosomes

If the locus is on one of the 22 autosomes, it called autosomal (dominant or recessive) and if on X or Y chromosome, then it is called sex-linked (dominant or recessive).

Disorders inherited in this manner, manifest in a heterozygous state (i.e. people who have one normal and one mutant allele at the locus involved). • It is characterised by vertical transmission to subse­ quent generations. • Nearly always one parent is affected. • If the affected individual does not have an affected parent, it may be due to: a. Illegitimacy b. New mutation occurring in the germ cell of the unaf­fected parent c. Mild affection, and so disorder not detected in parent.

Examples: Achondroplasia z Facioscapulohumeral muscular dystrophy z Gilbert’s syndrome z Hereditary spherocytosis z Huntington’s chorea z Hyperlipoproteinaemia type II z Marfan’s syndrome z Myotonic dystrophy z Neurofibromatosis z Polycystic disease of the kidney z von Willebrand’s disease z Porphyria. z

Autosomal Recessive Inheritance These disorders manifest in the homozygous state (i.e. people who have two mutant alleles, one on each of the homologous chromosomes, one from each parent). z Heterozygous carriers of the single mutant allele are clinically normal. z Mating between two heterozygotes have a 25% chance of producing affected homozygote, 50% chance of heterozygote (clinically normal) and 25% chance of normal homozygote. z It is characterised by horizontal transmission with affected persons all in the same generation. z If an affected individual mates with the hetero­ zygote, then there is a 50% chance of producing an affected

Introduction to Internal Medicine child and 50% chance of producing a hetero­zygous (clinically normal) child.

Examples: — Albinism — Ataxia telangiectasia — Cystic fibrosis — Friedreich’s ataxia — Glycogen storage disorder — Limb girdle muscular dystrophy — Wilson’s disease.

X-linked Recessive Inheritance In these disorders, the mutant gene is carried on the X-chromosome. These disorders manifest only in the male and not in the female children (as the mutant gene on one X-chromosome is counteracted by the normal gene on the other X-chromosome. The absence of another normal X-chromosome in a male makes the disorder manifest in them). z A mother who is a carrier will have her daughters to be carriers and all her sons affected. z Very rarely, a woman can exhibit an X-linked recessive disorder when — She may have Turner’s syndrome (45, XO) — Testicular feminisation syndrome (XY sex chromo­ some constitution) — She may have had a mother as a carrier and an affected father — Normal father in whom mutation occurred in the X-chromosome and a carrier mother — Affected father and normal mother in whom mutation occurred in one transmitted X-chromo­some. — Manifesting heterozygote: This occurs as a result of random inactivation (Lyonization), by chances of the normal X-chromosome in most of the cells. Examples: Christmas disease z Duchenne’s muscular dystrophy z G-6-PD deficiency z Haemophilia z Nephrogenic diabetes insipidus. z

X-linked Dominant Inheritance This condition will manifest in females also (as the effect of the mutant gene on one X-chromosome cannot be counteracted by the normal gene on the homologous X-chromosome).

z

z

In this type of inheritance, the affected father transmits the disorder to all his daughters but to none of his sons. The affected mother may transmit the disorder to 50% of her children (males or females).

Example: Vitamin D resistant rickets.

Y-linked or Holandric Inheritance Only males are affected An affected male transmits the trait to all his sons but to none of his daughters. Examples: Hairy ears, Webbed toes.

z z

Mosaicism In this there is existence of different chromosomal patterns in the cells of the tissue of the same individual. Examples: Klinefelter’s syndrome showing a mosaicism of XX/XXXY, XY/XXY, XY/XXXY. Turner’s syndrome showing a mosaicism of XO/XXY, XO/XX, XO/XXX.

Chimerism This can occur when An ova is fertilised by sperms from two different indi­viduals z Exchange of cells via the placenta between two nonidentical twins. Examples: Ninety per cent of the male twin’s cells may have an XY chromo­some constitution, and 10% have an XX chromosome constitution, and most of his red cells may be of blood group A and a few red cells of group B. Ninety per cent of the female twin’s cells may have an XX chromo­some constitution, and 10% have an XY chromosome constitution, and most of her red cells may be of blood group B and a few red cells of group A. z

Multifactorial or Polygenic Inheritance In this form of inheritance, the manifestation of a disorder is due to the presence of multiple gene muta­tions. Characteristics transmitted by multifactorial inheritance are intelligence, stature, skin colour, finger printing and ocular refraction. This is due to an additive effect of the genes for a particular charac­teristic, e.g. a tall person has more genes for tall than for short stature. Certain disorders like hyper­tension, DM, IHD are transmitted in this way.

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Manual of Practical Medicine

Genomic Imprinting

Chromosome 3

This is a phenomenon in which there is gene inactivation on selected chromosomal regions leading to preferential expres­sion of an allele depending on its parental origin. Examples: z Wilms’ tumour—Chromosome 11 z Beckwith-Wiedemann syndrome—Chromosome 11 z Prader-Willi syndrome—Chromosome 15 z Angelman’s syndrome—Chromosome 15 z Duchenne’s dystrophy—X chromosome.

z

Trinucleotide Repeat

Chromosome 6

Several diseases are associated with an increase in the number of nucleotide repeats above a certain threshold. When repeat length increases from one generation to next, disease manifestations may worsen or be observed at an earlier age. This is referred to as ‘Phenomenon of anticipation.’ Examples: z Huntington’s disease z Spinocerebellar ataxia 1,2,3,6,7,8 and 12 z Friedreich’s ataxia z Fragile X syndrome z Dystrophia myotonica z X chromosomal spinobulbar muscular atrophy z Dentato Rubro Pallido Luysian atrophy.

Mitochondrial Disorders Mitochondrial gene is inherited through the maternal line. Hence all children from an affected mother will inherit the disease. Examples: z Mitochondrial encephalopathy with lactic acidosis and stroke like episodes z Myoclonic epilepsy with ragged red fibres z Neuropathy ataxia and retinitis pigmentosa z Lebers hereditary optic neuropathy z Chronic progressive external ophthalmoplegia z Kearns-Sayre syndrome.

Common Chromosomal Disorders Chromosome 1 z z z

Homocystinuria Hypokalaemic periodic paralysis Charcot-Marie-Tooth disease (type 1b)

Chromosome 2 z z

Alport syndrome (AR) Crigler-Najjar type 1

von Hippel-Lindau

Chromosome 4 z z z

Huntington’s disease ADPKD type II Abeta lipoproteinaemia

Chromosome 5 z z

z z z

Retinitis pigmentosa (AR) Werdnig-Hoffmann disease Haemochromatosis Ankylosing spondylitis Spinocerebellar ataxia 1

Chromosome 7 z z z

Cystic fibrosis Supravalvular AS MODY type II

Chromosome 9 z z z

Tuberous sclerosis (1) Hereditary haemorrhagic telangiectasia Nail patella syndrome

Chromosome 10 z z z

MEN IIa Refsums disease Congenital erythropoietic porphyria

Chromosome 11 z z z z z z

Sickle cell anaemia Thalassemia Wilms’ tumour Ataxia telangiectasia Hereditary angioedema MEN I

Chromosome 12 z z z

von Willebrand’s disease Phenylketonuria SCA 2

Chromosome 13 z z z

Wilson’s disease Osteosarcoma Retinoblastoma

Chromosome 15 z z

Marfan’s syndrome Angelman’s syndrome

Introduction to Internal Medicine Chromosome 16 z z z

ADPKD I Alpha thalassemia Tuberous sclerosis (2)

Chromosome 17 z z z z

Neurofibromatosis type 1 Charcot-Marie-Tooth disease type 1a Hyperkalaemic periodic paralysis Li-Fraumeni syndrome

Chromosome 18 z

Methaemoglobinaemia

Chromosome 19 z

Myotonic dystrophy

Chromosome 20 z

MODY type 1

Chromosome 21 z z

Amyotrophic lateral sclerosis Progressive myoclonic epilepsy

Chromosome 22 z

Neurofibromatosis type 2

Chromosome Y z

z z z z

Haemophilia A,B Colour blindness Alport syndrome Fabry’s disease Duchenne and Becker muscular dystrophy.

IMMUNOLOGY The Immune System and the Basis of Immunity The immune system is a part of body’s defence system, which protects it against noxious and harmful environ­ mental agents, as well as internal miscreants (neoplasia).

Primary Lymphoid Organs z z z

z z z z

Lymph nodes Spleen Tonsils Peyer’s patches.

Dispersed Immune Cells Immunocytes are dispersed between other cells, e.g. within the gut epithelium and lamina propria.

Migration of Lymphocytes There is one way traffic of T and B cells from primary lymphoid organs into the bloodstream and continuous recirculation of cells between the secondary lymphoid organs, tissues and bloodstream.

Cells Involved in Immunity Identification of cell types is by identifying CD (Cluster of differentiation) and other surface markers on lympho­cytes. This is valuable in the classification of lymphomas and its clinical diagnosis and also in research. CD can be tested using monoclonal antibodies. There are certain groups of cells for which no antibody is available to distinguish between them. But they can be identified only by functional characteristics.

Gonadal dysgenesis

Chromosome X z

Secondary Lymphoid Organs

Bone marrow Thymus Foetal liver.

Antigen Presenting Cells These are found in lymphoid organs and the skin. Their role is to present the antigen to lymphocytes in a particular way, to start off the immune response. They include: z Interdigitating cells in thymus z Langerhans’ cells of skin z Veiled cells in afferent lymph z Interdigitating cells in the T areas of lymph nodes z Follicular dendritic cells in B areas of lymph nodes z Macrophages and other non-immune cells (epi­thelial cells).

T-lymphocytes They are from stem cells of the bone marrow, which have matured under the influence of a hormone or factor produced by the epithelial cells of the thymus. T-cells perform immunoregulatory functions via their secreted products and act as effector cells capable of killing other cells. Given appropriate stimulation, T-cells proliferate and differentiate into many subsets.

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Manual of Practical Medicine Immune Regulatory T-cells z z

Helper T-cells (TH)—CD4 Suppressor T-cells (TS)—CD8

Effector T-cells z z

Cytotoxic (TC) cells—CD8 Mediators of delayed hypersensitivity (TDTH)—CD4

B-lymphocytes When appropriately stimulated, B-cells undergo prolif­ e­ration, maturation and differentiation to form plasma cells, which synthesize antibodies (immunoglobulins). Subsequently a clone of daughter cells are formed.

Neutrophil Polymorphs They are short-lived cells which are highly concen­trated in the bloodstream. But they can respond to chemotactic signals in the presence of tissue injury or infection. They marginate in the capillaries and move into the tissues where they can phagocytose and kill bacteria and other foreign materials.

Macrophages These are derived from bone marrow precursors which differentiate to monocytes and finally settle in the tissues as mature, mononuclear phagocytes, e.g. alveolar macrophages in lung, Kupffer cells of liver, brain microglial cells, kidney mesangial cells. Macrophages are capable of phagocytosis and killing of microorganisms. They also secrete cytokines and influence T-cells and other important cells. Aggregates of macrophages, granulomas are char­ ac­teristic of many chronic infections and idiopathic inflammatory diseases (TB, leprosy, sarcoidosis, Crohn’s disease).

Natural Killer Cells (NK Cells) NK cells are large granular cells. They are important in resistance to viral infections and malignancy. Sur­ face molecule of a cell, altered by virus or cancerous transformation can be recognised by NK cells, which in turn engage the infected or altered cells and kill them.

Eosinophils They are metabolically very active and they contain granule mediators like, the toxic protein (eosinophilic major basic protein), histaminases, etc. which inactivate mast cell

products. They are attracted by factors released by T-cells, mast cells and basophils, e.g. eosinophilic chemotactic factor of anaphylaxis. They aid human host defences against worms, schistosoma and are also implicated in allergic diseases such as asthma.

Mast Cell Series Their granules contain many inflammatory and chemo­ tactic mediators. All have receptors for IgE and are degranulated when an allergen cross links to specific IgE molecules bound to the surface of the cell. Mast cells and basophils are involved in parasite immunity, allergic diseases and in delayed hyper­sensitivity reactions.

Cytokines Cytokines are cell regulatory molecules which are essential for the regulation of growth and differen­tiation of lympho­ haematopoietic and other cells. All these cells take part in immune response and bring about active immunity or immunological tolerance. The entry of ‘non-self’ antigens in the body triggers an immune response which includes: z Humoral immune response with specific antibody formation z Cell-mediated immunity with production of cyto­ toxic lymphocytes and the lymphokine secreting delayedtype T-cells z Establishment of immunological memory (for sec­ond­ ary response) z Specific immune unresponsiveness (immunologic tolerance).

Clinical Aspects of Immunology The immune system protects our body against exoge­nous substances, microbes and possibly tumours, but immune responses also damage normal host tissues and react to homologous antigens and sometimes to endo­genous antigens, the basis of autoimmune disorders. Disorders related to the immune system falls into three groups: 1. Hypersensitivity reactions 2. Autoimmunity 3. Immunodeficiency states.

Immunoglobulins There are five types of immunoglobulins namely, IgG, IgA, IgM, IgD and IgE.

Introduction to Internal Medicine Major Cytokines and their Biology Name

Major source

Main function

Interleukin-1a and b

B-cells, macrophages, large granular lymphocytes

Lymphocyte activation, macrophage activation, increased leucocyteendothelial adhesion, fever, acute phase protein synthesis

Interleukin-2 (T-cell growth factor)

Activated T-cells

Activation of T-cell cytotoxic responses and induction of non-MHC restricted cytotoxic lymphocytes

Interleukin-3

T-cells

Colony stimulating factors for cells of various lineages, stimulates production and renewal of the pluripotent stem cells

Interleukin-4

Activated T-cells, mast cells

Proliferation and differentiation of B-cells, expression of MHC class II antigens on resting B-cells, modulation of host immunity and inflammatory responses

Interleukin-5 or B-cell

T-cells

Potent eosinophil differentiation and activation factor, B-cells differentiation and antibody production

Interleukin-6

Lymphoid and nonlymphoid cells (monocytes, fibroblasts, transformed T-cells)

Mediation of inflammation and immune response, production of acute phase proteins, stimulating effect on haematopoietic stem cells, costimulant of IL-2 production

Interleukin-7

Bone marrow stromal cells

Growth and differentiating factor for T-cells, viability factor for immature and nonproliferating thymocytes

Interleukin-8

Produced by wide variety of cells on induction with IL-1, TNF, lipopolysaccharides, infectious agents

Chemotactic activating factor for neutrophils, T-cells and eosinophils

Interleukin-9

T helper cells

Acts synergistically with IL-4 to potentiate antibody production, stimulates erythroid colony formation and maturation of megakaryocytes

Interleukin-10

T-cells and B-cells

Potent immunosuppressant of macrophage function, downregulation of MHC class II antigen expression on macrophages and inhibits proinflammatory cytokines (IL-1, TNF, and IL-6)

Interleukin-11

Inflammatory mediator (stimulation of hepatic acute phase reactants), growth factor for megakaryocyte colonies, has synergistic effects on the growth factor activity of IL-3 and IL-4 on early haematopoietic progenitors

Interleukin-12

Macrophages and B-cells

Production of interferon gamma from T-cells and NK cells, differentiation of helper T-cells

Interferon-a and b

Leucocytes, fibroblasts

Antiviral, induces MHC class I antigens on cells

Interferon-g

T-cells, NK cells, fibroblasts

Induces MHC class II antigens, macrophage activation, ↑ endothelial celllymphocyte adhesion

Tumour necrosis factor (TNF-a, cachectin)

Macrophage, lymphocytes

Activation of cytotoxic cells, macrophages, granulocytes; ↑ leucocyteendothelial cell adhesion; cachexia

Tumour necrosis factor (TNF-b)

T-cells

Macrophage colony stimulating factor (M-CSF)

Stromal cells, macrophages and fibroblasts

Stimulates macrophage function and activation; ↑ expression of MHC class II antigen on macrophages

Granulocyte colonystimulating factor (G-CSF)

Stromal cells, monocytes macrophages, endothelial cells

↑­number of circulating granulocytes

 -do-

Granulocyte-macrophage Stromal cells, fibroblasts, T-cells and colony stimulating factor endothelial cells

Growth of progenitors for granulocytes, monocytes and erythrocytes; causes eosinophilia; enhances phagocytosis

Transforming growth factor (TGF)

Enhances fibrosis, neoangiogenesis; induces inflammation of mononuclear cell type

IgG IgG constitutes the major portion of Ig (70%). It is distributed equally between the blood and extracellu­lar fluids. IgG is the only immunoglobulin transported across

the placenta and it provides passively acquired immunity to the newborn during its early life. IgG participates in immunological reactions such as complement fixation, precipitation and neutralisation of toxins and viruses. It protects against infectious agents which are active

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Manual of Practical Medicine in blood and tissues. IgG suppresses the homologous antibody synthesis when passively administered and this property is utilised in the isoimmunisation of women by administration of anti-Rh (D) IgG during delivery. IgG is a late antibody and makes its appearance after IgM. There are four subclasses—IgG1, IgG2, IgG3 and IgG4.

Heavy Chain Disease

IgA

This is a condition in which there is formation of a gel or a precipitate on cooling the serum, which redis­solves on warming. Most cryoglobulins consist of either IgG, IgM or their mixed precipitates.

IgA constitutes 20% of total immunoglobulins. The major sites of IgA synthesis are gut mucosa and lamina propria of respiratory tract. Secretory IgA confers local immunity by forming an antibody paste and prevents infection by bacteria or virus and it also regulates commensals of gut.

This lymphoid neoplasia is characterised by the over production of the Fc portion of immunoglobulin heavy chains.

Cryoglobulinaemia

Immunodeficiency States Primary Immunodeficiency Disorders

IgM

Humoral Immunodeficiencies

It is a macromolecule which is predominantly intravas­ cular. It is the earliest immunoglobulin synthesised by the foetus from about 20 weeks of age. Presence of IgM in the foetus or newborn indicates intrauterine infection and its detection is useful in the diagnosis of congenital syphilis, toxoplasmosis and rubella. The isohaemagglutinins (anti-A, anti-B) and many other natural antibodies are IgM. Antibodies to typhoid ‘O’ antigen (endotoxin) and WR antibodies in syphilis are also of IgM class. IgM is responsible for protection against blood invasion by micro-organisms. IgM deficiency is often associated with septicaemias.

z

IgD It is helpful in the maturation and regulation of B-lymphocytes.

IgE It is necessary for immediate hypersensitivity reac­ tions and also useful in defence against helminths. IgE is produced in the linings of respiratory and intestinal tracts. Deficiency of IgE is associated with IgA deficiency in individuals with impaired immunity.

z z z

T-cell Immunodeficiencies z z

Light Chain Disease (Bence-Jones Proteins) This is found typically in multiple myeloma. This protein coagulates when urine is heated to 60°C and redissolves at 80°C in patients with myeloma. Multiple myeloma may affect plasma cells synthesising IgG, lgA, IgD or IgE.

DiGeorge syndrome Chronic mucocutaneous candidiasis.

Combined Immunodeficiencies z z z z z z z

Wiskott-Aldrich syndrome Nezelof’s syndrome Severe combined immunodeficiency Immunodeficiency with ataxia telangiectasia Immunodeficiency with lymphotoxins Immunodeficiency with thymoma Immunodeficiency with short limbed dwarfism.

Phagocytic Deficiency Diseases z z z z z z z

Disorders of Immunoglobulins

X-linked hypogammaglobulinaemia Transient hypogammaglobulinaemia of infancy Common variable, unclassifiable immunodeficiency Selective IgA deficiency.

z z

Job’s syndrome Chédiak-Higashi syndrome Lazy leucocyte syndrome Hyper IgA syndrome Myeloperoxidase deficiency Tuftsin deficiency Leucocyte G-6-PD deficiency Chronic granulomatous disease Schwachman’s disease.

Complement Deficiency Diseases z

Deficiency of a complement component — C deficiency causes recurrent pyogenic infec­tions 3 — C , C , C deficiency causes Neisserial infections 6 7 8 — C , C , C deficiency results in immune complex 1 2 4 like or lupus like disorders.

Introduction to Internal Medicine z

Deficiency of a complement inhibitor — Autosomal dominant C1 esterase inhibitor defi­ ciency (Hereditary angioedema).

Secondary Immunodeficiencies Causes z z z z

z z z z

Poor nutrition (proteins, calories, micronutrients) Old age Postoperative states (due to general anaesthesia) Loss of protective commensal gut bacteria (broad spec­trum antibiotics) Irradiation Cancer chemotherapy Immunosuppressive drugs Diseases like AIDS, lepromatous leprosy in later stages.

Hypersensitivity Reactions Type I Hypersensitivity (Anaphylactic, Reagin Dependent) This is mediated by IgE antibodies bound to mast cells and basophils formed in response to particular antigen (allergen). IgE protects against parasitic infections. Re-exposure of antigen in sensitised individuals results in release of primary and secondary mediators from mast cells due to degranulation. Systemic Anaphylaxis This occurs when an antigen is administered orally or parenterally. Even minute doses may induce shock in the appropriate host. Pruritus, urticaria, laryngeal oedema progressing to laryngeal obstruction shock and death within minutes can also result. Local Anaphylaxis It affects 10% of population and includes urticaria, angioedema, rhinitis, and atopic asthma.

Type II Hypersensitivity This reaction is mediated by antibody against intrinsic or extrinsic antigens adsorbed on the cell surface or on other tissue components. Complement Dependent Reactions Examples are: Transfusion reactions z Erythroblastosis fetalis z Autoimmune thrombocytopenia z Drug reactions z Goodpasture’s syndrome. z

Antibody Dependent Cell-mediated Cytotoxicity This reaction may be important for parasitic infections or tumours and may play a major role in graft rejection. Antireceptor Antibodies Examples are: Myasthenia gravis z Grave’s disease. z

Type III Hypersensitivity (Immune Complex-mediated) This is mediated by antigen-antibody complexes (immune complexes), which are formed either in the circulation or at the sites of antigen deposition. Anti­gens can be exogenous or endogenous. Systemic Immune Complex Disease Acute serum sickness: This is caused by administra­tion of large amounts of foreign serum (horse serum). About a week after inoculation, anti-horse serum anti­bodies are formed and react with foreign antigen to form circulat­ing immune complexes. Small immune complexes (antigen excess) deposit within capillary or arteriolar walls causing vasculitis. The affected tissues are renal glomeruli (causing glomerulonephritis), joints (arthritis), skin, heart and serosal surfaces. Large immune complexes (antibody excess) are cleared by phagocytes, ending the disease process. Immune complexes also aggregate platelets and acti­ vate factor XII, involving coagulation cascade and kinin systems. Local Immune Complex Disease (Arthus Reaction) This is a localised tissue vasculitis and necrosis due to focal formation or deposition of immune complex or planting of antigen in a tissue with immune complex formation in situ.

Type IV Hypersensitivity This reaction is induced by sensitised T-cells which on contact with the specific antigen, release lymphokines that cause biological effects on leucocytes, macro­phages and tissue cells. Two types of delayed hypersensitivity are: Tuberculin type (Developed in many infections with bacteria, fungi, viruses and parasites) z Contact dermatitis type (Resulting from skin contact with a variety of chemicals like nickel, chromium, drugs like penicillin and toileteries). z

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Manual of Practical Medicine

Histocompatibility Antigens

Acute Rejection

The most important of these antigens are grouped in the major histocompatibility complex (MHC) on short arm of chromo­some 6. It contains genes coding for ‘human leucocyte antigens’ (HLA).

It occurs within a few days after transplantation, after stopping immunosuppressive drugs.

Diseases Associated with HLA HLA antigen HLA B27 DR2 A3 B13 B8, DR3, DR4 B8, DR3

Diseases Ankylosing spondylitis Reiter’s disease Multiple sclerosis Haemochromatosis Psoriasis IDDM Addison’s disease Thyrotoxicosis Myasthenia gravis Coeliac disease

Class I Antigens These are present on all nucleated cells and platelets. They elicit antibodies in non-identical individuals. They bind only to those processed antigens which are synthesised endo­genously. MHC-I antigens present processed antigens to cytotoxic T-cells (CD 8). T-cell receptors recognise only antigen-MHC complexes. CD8 T-cells bind and kill only infected cells that bear self class I antigens (MHC restriction).

Class II Antigens MHC-II antigens are coded in the HLA-D region. These are characteristically confined to antigen present­ing cells. They typically bind and present exogenous antigens to CD4 T-cells (helper T-cells) and they also exhibit MHC restriction.

Class III Proteins Some components of the complement system (C2, C4, Bf) and some cytokines (TNF-α and β) are encoded within the MHC cluster. These are not histocom­patibility antigens.

Transplant Rejection Hyperacute Rejection When the recipient has been previously sensitised to antigens (following blood transfusion, previous preg­ nancy) in graft by developing antidonor IgM, IgG antibodies and comple­ment, hyperacute rejection sets in immediately within one to two days, i.e. imme­diately after revascularisation.

Chronic Rejection It occurs over months to years and is caused by several types of immune reaction.

Autoimmune Diseases If an individual mounts a significant immune response against his/her own body constituents as a result of a defect in immunological tolerance, secondary to some exogenous factors, e.g. virus, autoimmune disorders occur.

Organ Specific Disorders z z z z z z z z z z z z z z

Hashimoto’s thyroiditis Primary myxoedema Thyrotoxicosis Pernicious anaemia Autoimmune atrophic gastritis Autoimmune Addison’s disease Type I diabetes Goodpasture’s syndrome Myasthenia gravis Sympathetic ophthalmitis Autoimmune haemolytic anaemia Primary biliary cirrhosis Chronic active hepatitis Sjögren’s syndrome.

Non-organ Specific Disorders z z z z

Rheumatoid arthritis Dermatomyositis Progressive systemic sclerosis SLE.

Immunology and Malignancy Tumour Antigens These are present in malignant cells and induce immune response when the tumour is transplanted into syngenic animals. Such tumour specific antigens which induce rejection of tumour transplants in immun­ised hosts are termed ‘tumour specific trans­plantation antigens’ (TSTA). Second type of antigens are foetal antigens. These are found in embryonic cells and malignant cells and not in normal adult cells, e.g. Alfafetoprotein in hepatoma, carcinoembryonic antigen in colonic can­cers especially with metastasis. Occasionally found in alcoholic cirrhosis also. Inefficiency of immunological surveillance mecha­nism, as a result of ageing, congenital or iatrogenic immuno­­ deficiency may lead to increased incidence of cancer.

CHAPTER

2

Nutrition

Ch-2.indd 51

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52

Manual of Practical Medicine Balanced nutrition is essential to maintain health and to prevent diseases. We eat intermittently but the energy needs are continuous. Neurophysiologic mechanisms control appe­tite and eating behaviour. Energy needs of the body during feeding are met by the nutrients absorbed from gastrointestinal tract and at other times, body’s needs are met by the release of energy from stores. The excess amino acids, fatty acids and glucose are stored as proteins, triglycerides and glycogen. The above process is under the control of insulin. Nutrition plays a major role in causing certain systemic disorders: Coronary heart disease, diabetes mellitus, hypertension (excess lipids, obesity, sodium intake), renal stones, gall-stones, dental caries, and carcinomas of stomach, liver and large bowel. Either excess or poor nutrition can cause disease and diseases can cause malnutrition.

Macro-nutrients Carbohydrates—Energy Yielding Carbohydrates An average adult consumes 55 to 65% of calories as carbo­hydrates and they form the major source of energy. 200 gm of carbohydrate is required/day. 1 gm of carbohydrate yields 4 kilocalories (1 kcal = 4.184 kilo joules). Ketosis is likely to occur when the intake is less than 100 gm/day. Source of Carbohydrates zz

zz



CLASSIFICATION OF NUTRIENTS 1. Water 2. Macro-nutrients —— Carbohydrates „„ Energy yielding  Monosaccharides (glucose, fructose, ribose)  Disaccharides (lactose, maltose, sucrose)  Polysaccharides (starch) „„ Non-energy yielding  Dietary fibres —— Fats —— Proteins 3. Micro-nutrients —— Organic micro-nutrients Vitamins (not synthesised in the body) —— Inorganic micro-nutrients „„ Electrolytes (sodium, potassium, chlorine) „„ Minerals (calcium, phosphorus, iron, mag­ne­sium) „„ Trace elements (zinc, copper, iodine, sele­ nium, chromium and manganese).

Water Water accounts for 60 to 65% of the body weight (75% at birth and 50% in old age). Water is distributed between intra­ c ellular (40%) and extracellular (Plasma and interstitial fluid 20%) compartments. Daily water intake for an average adult will vary between 1 and 3 litres depending on the climate.

Ch-2.indd 52

Available as sugars—mono and disaccharides Intrinsic sugars—fruits and milk (good for health) Extrinsic sugars—cane sugar and beet-root sugar (dental caries) Available as polysaccharides—starch, glycogen Starch is available in cereals (wheat, rice, maize, etc.), roots (Potatoes and Cassava), plantains and legumes.

Glycaemic Index Two hours plasma curve after 50 gm of carbohydrate in a given food divided by a curve of 50 gm glucose in water. Glycaemic index is high for glucose, bread, and potatoes and low for legumes and whole grain cereals. Carbo­ hydrates with low glycaemic index are preferable for diabetic patients.

Non-energy Yielding Carbohydrates Dietary Fibre It is the natural packing of plant foods and not digested by human enzymes. They are of two types: 1. Water Soluble Fibres Oat bran, beans, pectin and guar gum. They act in upper GIT and induce early satiety, flatten glucose tolerance curve and decrease serum cholesterol. 2. Water Insoluble Fibres Wheat bran—hemicellulose of wheat because of increased water holding capacity increases the bulk of stool and prevents constipation, diverticulosis and cancer colon. Flatus formation is common with fibre diet. Daily requirement is 15 to 20 gm/day.

Fats An average adult consumes 30 to 40% of calories as fats. 1 gm of fat yields 9 kcal of energy. It is the cause for obesity in sedentary people.

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Nutrition There are three types of fats. zz Saturated fats: Ghee, palmitic acid, myristic acids— they increase plasma LDL and total cholesterol. They predispose to CAD. zz Monounsaturated fatty acids: Oleic acid zz Polyunsaturated fatty acids: Linoleic acid in plant seed oils and its derivatives—gamma linolenic acid, arachidonic acids are the essential fatty acids. They are precursors of prostaglandins, eicosanoids and they form part of the lipid membrane in all cells. The omega 3 series of polyunsaturated fatty acids occur in fish oil. By antagonising thromboxane A-2, they inhibit thrombosis. Their use is advocated to prevent hyper­ lipidaemia and CAD and to reduce triglycerides. Stage I Diet

Recommended Daily Protein Intake Clinical condition

Protein requirement (g/Kg)

Normal

0.8

Illness/Injury (Metabolic stress)

1.0–1.5

Acute renal failure

0.8–1.0

Haemodialysis

1.2–1.4

Peritoneal dialysis

1.3–1.5

Daily Energy Requirements Energy requirements depend on—age, sex, body weight, lactation, climate, (lower calories for tropical climate and higher calories for colder climate). Types of work

Males/kcals/d

Females/kcals/d

Rest

2000

1500

Light

2500

2000

Stage II Diet

Moderate

3000

2250

It is advocated in hyperlipidaemia when stage I diet fails to achieve the goal. It consists of 7% of each type of fat with daily intake of cholesterol less than 200 mg.

Heavy

3500

2500

Growing children, pregnant and lactating mother need more calories. Brain uses glucose at the rate 5 gm/hour (Preference for ketones when ketone levels are high).

Proteins

Balanced Diet

Proteins form the basic building units of tissue. They play the major role in the formation of enzymes and hormones and also in the transport mechanisms. Unlike carbohydrates and fats, no proteins are stored in the body. The amino acids in excess proteins are trans­aminated and the non-nitrogenous portion is stored as glycogen or fat. Protein requirements are highest during growth spurts— infancy and adolescence. (Protein requirement during these stages—1.5 to 2 gm/kg/day). There are 20 different amino acids of which 9 amino acids are essential—tryptophan, threonine, histidine, leucine, isoleucine, lysine, methionine + cysteine, phenylalanine + tyrosine and valine. They are essential for the synthesis of different proteins in the body. Proteins of animal origin—eggs, milk, meat—have higher biological value than the proteins of vegetable origin. An average adult requires 10 to 15% of total calories as proteins.

Balanced diet contains carbohydrates, protein, fat, mineral, vitamins and trace elements in adequate quantum and proportion in order to maintain good health.

It is advocated to prevent hyperlipidaemia and CAD. It consists of 10% of each type of fats with daily cholesterol less than 300 mg/day.

Ch-2.indd 53

It is equivalent to 1 gm/kg body weight.

CLASSIFICATION OF NUTRITIONAL DISORDERS zz

zz

zz

Under-nutrition: —— Quantitative deficiency „„ In children—marasmus „„ In adults—various forms of starvation, anorexia nervosa, bulimia, etc. Malnutrition: —— Qualitative deficiency „„ Protein deficiency—PCM or PEM „„ Vitamin D—rickets „„ Vitamin C—scurvy, etc. Excess nutrition: —— Quantitative—obesity

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Manual of Practical Medicine zz

zz

Excess nutrition: —— Qualitative– „„ Excess cholesterol—hyperlipidaemia „„ Excess vitamins—hypervitaminosis A, D, etc. Effect of toxins in food: Migraine, urticaria, coeliac disease, and lathyrism.

Pathological Causes of Nutritional Disorders zz



zz

zz

zz

zz

zz

Defective intake: It can be due to: —— Poor economic status —— Loss of appetite—excess coffee, tea, alcohol, smoking Systemic disorders—renal failure, liver cell failure Psychiatric disorders—depression, anorexia nervosa —— Persistent vomiting—organic obstruction, bulimia —— Food faddism —— Prolonged parenteral therapy. Defective digestion and absorption: —— Hypo or achlorhydria —— Various types of malabsorption syndromes (steatorrhoea, GJ) —— Prolonged use of antimicrobials. Defective utilisation: —— End organ failure—cardiac failure, hepatic failure, renal failure —— Severe systemic infections —— Malignancy of various organs. Excessive loss of nutrients: Protein losing enteropathy, nephrotic syndrome, enteric fistulas. Altered metabolism: —— Hyperthyroidism, diabetes mellitus, etc. —— Trauma, prolonged fever, malignancy, burns, and surgery. Increased requirements: —— Pregnancy and lactation —— Growth—infancy, childhood, adolescence.

Effects of Malnutrition zz

zz

zz zz

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Reduced inflammatory response (cellular and humoral) to infection Inability to cough due to muscle wasting, leading to pneumonia and bronchopneumonia Impaired wound healing Reduced haemopoiesis

zz zz zz zz

Prolonged drug metabolism Altered mental function Inadequate water intake—dehydration Bedsores and ulcers on pressure points.

Protein Energy Malnutrition It may be primary due to inadequate intake of protein (famine), or secondary due to defective intake, or digestion, or absorption, or altered metabolism and/or increased demand. The commonly associated illnesses with secondary protein energy malnutrition (PEM) are AIDS, CRF, inflammatory bowel disease, intestinal mal­absorp­tion, and malignancy.

PEM in Young Children There are two types of malnutrition: (i) Marasmus, (ii) Kwashiorkor and a combined form—marasmic-kwashiorkor. Marasmus Body weight is reduced below 60% of the WHO standard. Early weaning from breastfeeding and poor diet low in energy, protein and essential nutrients are the causes. Poor hygiene leading to gastroenteritis and further malnutrition.

Clinical Features zz

zz

zz

Child is wasted, with bone and skin with no sub­ cutaneous fat and poor muscle mass (Fig. 2.1). Gaseous distension of abdomen with diarrhoea can occur. In contrast to kwashiorkor, there is no oedema, skin or hair changes. There is no anorexia.

Kwashiorkor It is almost a pure form of protein malnutrition, occurring in the second year of life in a child weaned from breastfeeding on to a starchy diet with low protein. Secondary infection like-malaria, AGE, measles, etc. (increased protein requirement) further precipitate protein malnutrition.

Clinical Features (Fig. 2.2) zz zz zz

The child is apathetic, irritable and drowsy. Fairly intact subcutaneous fat and pitting oedema. The child is stunted and puberty is delayed.

Skin changes (Fig. 2.3): Maximal around napkin area— sym­m etrical–pigmented and thickened-Flaky paint mosaic like appearance with fissuring (Crazy pavement appearance). It is also seen over the areas of pressure and trauma.

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Nutrition and increased energy losses. Depletion of vitamins and minerals can also occur. Starvation induced undernutrition can be: zz Mild undernutrition: 80% of the standard weight or BMI 20 to 18. zz Moderate undernutrition: 70% of the standard weight or BMI 18 to 16. zz Severe undernutrition: Less than 70% of the standard weight or BMI less than 16.

Clinical Features zz zz zz

Fig. 2.1  Marasmus

Fig. 2.2  Kwashiorkor— generalised oedema

zz zz zz zz zz zz zz zz zz

Loss of weight and weakness Craving for food and intolerance to cold Nocturia and amenorrhoea Loss of libido and impotence Lax, dry skin with loss of turgor Loss of hair with thinning Muscle wasting and loss of subcutaneous fat Oedema with normal albumin level Subnormal temperature—bradycardia—hypotension Distended abdomen with diarrhoea Depression, introversion and loss of initiative Depressed tendon jerks and secondary infections.

Infections Associated with PEM zz zz zz

zz zz

Fig. 2.3  Skin changes kwashiorkor

Hair changes: The hair becomes thin, sparse, brownish and lusterless. They may fall-off and can easily be pulled. Partial correction leading to alternate bands of pigmentation and de-pigmentation of the hair. Pathology Acute protein depletion affecting liver, pancreas, and gut. Liver cannot synthesise albumin due to depletion of amino acids leading to hypoproteinaemia and oedema. There may be associated deficiency of vitamins and minerals. PEM can be mild or moderate or severe.

Ch-2.indd 55

Streptococcal and staphylococcal skin infections Gastroenteritis and gram-negative septicaemia Pulmonary tuberculosis, pneumonia and bronchopneumonia Helminthic infestations Viral infections like measles, herpes simplex.

Systemic Disorders in PEM PEM impairs the function of all organs. Gastrointestinal Tract Atrophy of intestinal villi—reduced quantity and quality of gastric, pancreatic and bile secretions, leading to malabsorp­tion. Cardiovascular System Atrophy and patchy necrosis, reduced myocardial mass and involvement of conduction system. Small heart with reduction in stroke volume and cardiac output.

PEM in Adults

Respiratory System

The primary form is more of undernutrition. It may be due to anorexia, insufficient food, increased demand

Atrophy of intercostal muscles and other muscles of respiration including diaphragm.

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Manual of Practical Medicine Decreased ventilatory derive—impaired lung function and vital capacity. Endocrine System Insulin, triiodothyronine and thyroxine levels are decreased and levels of growth hormone and cortisol are increased. These changes lead to increased catabolism of muscle protein and enhancement of lipolysis and gluconeo­ genesis. Primary gonadal dysfunction is common in adults. Immunologic Functions Impaired cell-mediated and humoral immunity. zz T and B lymphocyte functions impaired. zz Total lymphocyte count is decreased and there is delayed skin hypersensitivity (tuberculin test, etc.). zz Wound healing is delayed.

Investigations zz

zz

zz zz zz zz zz

Measure body weight, mid-arm circumference, and skin-fold thickness and calculate BMI. Blood: Hb, TC, DC, ESR—leucopenia, anaemia, thrombocytopenia, decreased Hb level and normal ESR. Serum proteins: Low albumin. Serum T3 and T4: Levels are decreased. Cortisol and growth hormone: Levels are increased. X-ray chest. ECG. Assessment of PEM Status

Tests Percentage of pre-morbid wt Percentage of ideal body wt Hand grip strength Serum albumin gm/l Serum transferrin gm/l Total lymphocyte/ml Delayed skin hypersensitivity Test (Tuberculin, etc.)

Moderate PEM 80–90 60–80 60–70 20–30 1–1.5 800–1200 5 mm

Severe PEM Less than 80 Less than 60 Less than 60 Less than 20 Less than 1 Less than 800 Less than 5 mm

Differentiation between Marasmus and Kwashiorkor Nutrient

Age Weight Appearance Weaning Oedema Skin and hair changes Anorexia and apathy Liver

Ch-2.indd 56

Marasmus Deficiency of proteins and calories and other nutrients Below 1 year Less than 60% Emaciated Early and abrupt Absent Mild

Kwashiorkor Protein deficiency

Absent

Present

Not enlarged

Fatty enlarged liver

1–4 years 60–80% Less degree of emaciation Late gradual Pitting oedema Marked

Management Good nursing, frequent feeding and prevention of intercurrent infections. Protein intake has to be increased—instead of normal 1 gm/kg—increase it to 2 to 3 gm/kg/day. Supplement vitamins and minerals. Correct hypothermia, hypogly­ caemia, hypokalae­m ia, dehydration, acidosis and electro­lyte imbalance. The National Institute of Nutrition, Hyderabad recom­mends an energy–protein rich mixture to treat PEM at home.

Whole wheat Bengal gram Groundnut Jaggery

— — — —

40 gm 16 gm 10 gm 20 gm

It supplies 330 calories and 11 gm of protein. This can be mixed with milk or water and can be taken 5 to 6 times/day. Prevention of PEM (UNICEF): Mnemonic—GOBI FFF G for growth monitoring O for oral re-hydration NaCl (3.5 gm) + NaHCO3 (2.5 gm) + KCl (1.5 gm) + glucose (20 gm) or sucrose (40 gm/L) of water. B for breastfeeding I for immunisation Against measles, diphtheria, mumps, tetanus, tuberculosis, and polio. F—Supplementary feeding F—Female child care F—Family welfare.

VITAMINS Vitamins are organic compounds in food, which are required in small amounts and are not synthesised in human body. They are classified into fat-soluble vitamins (A, D, E, and K) and water soluble vitamins (B and C). Fatsoluble vitamins are stored in liver and deficiency manifests only when stores are depleted. Excess intake of fat-soluble vitamins causes hyper­vitaminosis. Water-soluble vitamins are not stored and excreted in urine.

Vitamin A (Retinol) Vitamin A is found in foods of animal origin and the provitamin beta-carotene is present in plant tissues. It is

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57

Nutrition necessary for clear vision in dim-light and maintains the integrity of epithelial tissues. Sources: Liver, egg, chicken, butter, cereals, green leafy vegetables, carrots, yellow pumpkin, papaya, tomatoes, fish liver oils. Average daily requirement: 1000 µg. A dose of 1 µg is equivalent to 3 international units of vitamin A and 6 µg of carotenoids. Normal serum level is 20 µg/dl. Less than 10 µg/dl indicates deficiency.

Functions of Vitamin A Vision It provides the molecular basis for visual excitation in rods and cones. It induces differentiation of epithelial cells. In deficiency states mucous-secreting cells are replaced by keratin producing cells. It is required for growth and reproduction. Anti-infective vitamin—increased incidence of respiratory and gastrointestinal infections in deficient state. It has antioxidant activity. Vitamin A is required for reproduction, growth and maintenance of life. Skin-mucous membrane: Hyperkeratinisation of the epi­ thelium lining the follicles results in follicular hyperkeratosis or phrenoderma. An associated EFA deficiency aggravates this condition.

Causes of Deficiency zz zz zz zz zz

Intestinal malabsorption and malnutrition Defect in storage—liver disease Enhanced renal excretion—proteinuria Prolonged periods of total parenteral nutrition Increased demand—pregnancy.

X-3A — Corneal ulcer—< 1/3 of cornea involved X-3B —  Corneal ulcer—>1/3 of cornea involved—keratomalacia. zz Secondary X-N — Night blindness X-F — Xerophthalmic fundus X-S — Corneal scars

Treatment zz

zz

zz

Night blindness and xerosis—30,000 IU of vitamin A daily for one week. Corneal damage—medical emergency—20,000 IU/ kg/day of vitamin A for 5 days. Risk of vitamin A deficiency—2,00,000 IU orally for 2 days (Especially WHO develop measles).

Prevention In malnourished children—two oral doses of 2,00,000 IU or 1,00,000 IU/IM twice in a year.

Excess Carotenes Carotenaemia zz It is due to excessive intake of vitamin A precursors in foods, mainly carrots. zz It causes yellow colouration of skin including palms and soles. zz In contrast to jaundice, the sclerae are not involved and remains white. zz The serum is also yellow in colour. zz These changes disappear on omission of carrots. Vitamin A Toxicity Hypervitaminosis A is due to excessive intake of fish liver, polar bear liver or therapeutic over dose.

Clinical Features Night blindness: It is the earliest sign. Xerophthalmia: Dry thickened, pigmented bulbar conjunctiva with oval or triangular glistening white spots—Bitot’s spots (Fig. 2.4). Cornea become cloudy, soft (keratomalacia) and undergoes ulceration and necrosis. It leads to perforation, prolapse of the iris and endophthalmitis and ultimately blindness. zz zz

WHO Classification of Vitamin A Deficiency zz Primary X-1A — Conjunctival xerosis X-1B — Conjunctival xerosis + Bitot’s spots X-2 — Corneal xerosis

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Fig. 2.4  Bitot’s spot

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Manual of Practical Medicine Acute Toxicity Headache, nausea, vomiting, abdominal pains, dizziness, papilloedema, bulging fontanelle in infants and followed by generalised desquamation of skin in a few days.

Deficiency — 10 to 20 Severe deficiency — < 10

Chronic Toxicity zz Ingestion of 25,000 IU or more/day for a long time. zz Bone and joint pains, hyperostoses, hair loss, dry and fissured lips. zz Benign intracranial hypertension, pruritus, weight loss and hepatosplenomegaly. zz Recovery is usual, both in acute and chronic toxicity on discontinuing vitamin A.

zz

Vitamin D

Predisposing Factors for Vitamin D Deficiency zz

zz zz zz zz zz

Causes of Vitamin D Deficiency zz

zz

Vitamin D is essential for the metabolism of calcium and phosphorus and for the formation of bone. It enhances the absorption of above minerals from the gut, their mobilisation from bone and re-absorption of phosphorus and calcium from the kidneys. Vitamin D is not a vitamin but a hormone. Dietary supplements are not required when adequately exposed to sunlight.

People with darker skin Maximum hours spent in indoors People who cover their entire body Thinner skin in old age Breastfed infants without vitamin D supplementation Pregnant women People who are obese.

zz zz



Intestinal malabsorption—pancreatic insufficiency, coeliac disease, biliary tract obstruction. Kidney disease—impaired production of D3. Lack of exposure to sunlight. Defective metabolism—either due to renal disorders or drugs like phenytoin, rifampin. In children it causes rickets and in adults osteo­malacia.

There are two forms of vitamin D: 1. Vitamin D2 (calciferol or ergocalciferol) is obtained by ultraviolet irradiation of plant origin ergosterol. 2. Vitamin D3—cholecalciferol is formed from 7-dehydro­ cholesterol present in the epidermal cells of skin by exposure to sunlight. Dietary Sources Fish liver oil, eggs, liver, milk, cheese, butter. Daily Requirements Pre-school children — 10 microgram (400 IU/day) Children and adults — 5 microgram (200 IU/day) Pregnancy and lactation — 10 microgram (400 IU/day)

Metabolism (Fig. 2.5) Vitamin D2 and D3 are identical in potency and generally referred as vitamins D. First hydroxylation takes place in liver and 25-hydroxy vitamin D is formed. It is further hydroxylated in kidney into the most active 1,25 dihydroxycholecalciferol {1,25(DH2)D3} or (calcitriol).

Vitamin D3 Status – 25 (OH) D Level (ng/ml) Normal Insufficiency

Ch-2.indd 58

— >30 — 21 to 29

Fig. 2.5  Vitamin D metabolism

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Nutrition

Vitamin D—Role in Systemic Disorders Emerging evidence in the past decade has implicated the potential role of vitamin D in various chronic systemic disorders and bodily functions. Vitamin D deficiency is now considered as a risk factor for cardiovascular disease and metabolic syndrome. Vitamin D deficiency plays a role in the following systemic disorders: zz Autoimmune disorders —— Rheumatoid arthritis —— Inflammatory bowel disorders —— Type 1 diabetes mellitus —— Systemic lupus erythematosis —— Psoriasis zz Cardiovascular disorders —— Hypertension —— Coronary artery disease —— Cardiomyopathy —— Congestive heart failure —— Sudden cardiac death —— Coronary calcifications —— Peripheral vascular disease zz Endocrine and metabolism —— Primary hyperparathyroidism —— Type 1 and 2 diabetes mellitus —— Metabolic syndrome zz Haematopoietic system —— Anaemia —— Leukaemia zz Infections —— Childhood asthma —— Recurrent upper respiratory infections —— Tuberculosis zz Musculoskeletal system —— Rickets and osteomalacia —— Osteoporosis and fractures —— Myopathy —— Fibromyalgia zz Malignancies —— Breast cancer —— Colon cancer —— Ovarian cancer —— Pancreatic cancer —— Prostate cancer zz Nervous system —— Multiple sclerosis —— Stroke —— Headache zz Psychiatric disorders —— Depression —— Mood swings zz Reproductive system —— Dysmenorrhoea

Ch-2.indd 59

—— ——

PCOD Gestational diabetes

Rickets zz zz

Age incidence 1 to 2 years. Delayed milestones except speech, irritability, and prominent abdomen.

Skeletal Manifestations zz

zz

zz zz zz

In less than 1 year—craniotabes-abnormal softening of the skull in the occipital region. In children 1 year or more—‘hot cross bun’ appearance due to frontal and parietal bossing. Larger head and delayed closure of anterior fontanelle. Delayed dentition with defective enamel. Permanent teeth also show defective hypoplastic enamel with grooving, and pitting with high risk of caries.

Rachitic rosary: Costochondral junctions are enlarged and beaded. Pigeon chest: Forward projection of sternum. Harrison’s sulcus: A horizontal groove along the attachment of diaphragm due to contraction pulling the softened bony cage. Spine: Kyphosis, scoliosis and lordosis. Limbs: Widened epiphyses of wrists and ankles (Fig. 2.6) bending of long bones femur, tibia, fibula—resulting in knock knees and coxa vara (Fig. 2.7). General manifestations: Hepatosplenomegaly, tetany, con­ vul­sions, and frequent respiratory infections. Hypophosphataemic rickets: Either familial inherited or acquired renal tubular defects leading to defective renal tubular re-absorption of phosphates.

Fig. 2.6  Rickets—widening of wrist joints

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60

Manual of Practical Medicine zz zz



Defective matrix synthesis: Fibrogenesis imperfecta Miscellaneous: Aluminium bone disease Parenteral alimentation

Management zz

zz

zz

Fig. 2.7  Rickets—bow legs

Investigations zz zz zz zz

Hypophosphataemia Hypocalcaemia Raised serum alkaline phosphatase Radiological features: Widened (flaring) and irregular (fraying) of distal ends of long bones with cupping. Decreased density and increased trabecula­tions of shafts with subperiosteal osteoid formation giving a double contour appearance to the shaft.

zz

Hypervitaminosis D It causes hypercalcaemia. It is due to excess vitamin D intake.

Osteomalacia

Clinical Features

Adults manifest with defective mineralisation of newly formed matrix. It manifests with bone pain, severe malaise, proximal muscle weakness, difficulty in climbing stairs, getting up from sitting position and waddling gait. Bone and muscular tenderness on pressure and associated pseudofractures and fractures of ribs and pelvis are common.

zz

Radiological Features Pseudo-fractures: Linear zones of decalcification along the course of major arteries (Milkman’s line and Looser’s zones). Common Sites Pubic rami, ischium, neck of the femur, ribs and vertebrae “Cod-fish”—vertebrae: Compression causing widening of intervertebral space produces biconcave vertebrae. Vitamin D resistant rickets is due to defective tubular clearance of phosphates. Osteomalacia with normal calcium, phosphate, and vitamin D: zz Primary non-mineralisation defect: Hereditary—fluoride therapy

Ch-2.indd 60

zz

Vitamin D deficiency can be corrected by daily intake of 2,000 IU or 60,000 IU once a month. Rapid correction can be done by giving 60,000 IU weekly once for 4 to 6 weeks followed by once a month schedule. Twenty-five to fifty microgram (1000–2000 IU) of vitamin D, along with 500 to 1000 mg of calcium daily are sufficient for both rickets and osteomalacia. Duration of therapy: 6 to 12 weeks may be required or 40,000 IU/IM injections once in two weeks. Three to four injections are required. Recurrence can be prevented by daily intake of 400 IU of vitamin D. If osteomalacia is due to renal disease give alfacalcidol 1 µg/day PO and adjust the dose according to plasma calcium. Monitor plasma calcium. Otherwise treatment of osteomalacia is similar to rickets.

zz

Constipation, nausea, vomiting, drowsiness and renal damage. Metastatic calcification—kidneys, lungs, gastric mucosa, soft tissues and arteries.

Prevention Serum calcium level should be monitored regularly for patients on high dose vitamin D therapy. When serum calcium raises above 10.5 mg/dl, vitamin D should be stopped.

Vitamin E Alpha tocopherol is the most potent of the 8 naturally occurring substances with vitamin E activity. It is one of the main fat-soluble antioxidants in addition to carotenoids. It prevents oxidation of PUFA—polyunsaturated fatty acids in cell membranes by free radicals. It reduces atherogenesis. Daily requirement: For men — 10 mg For women — 5 mg

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Nutrition Sources:

Vitamin K Excess



It blocks the effects of oral anticoagulants. In pregnant women, it can cause jaundice in the newborn.

Vegetable oils, whole-grain cereals, nuts.

Deficiency: It occurs in intestinal malabsorption. Deficiency result in decreased proprioceptive and vibra­tory sensation due to posterior column degene­ration, areflexia, gaze paraesis, and gait disturbance. It produces haemolytic anaemia and retrolental fibroplasia in premature infants. Vitamin E excess: Headache, malaise, and hypertension. In premature infants parenteral vitamin E therapy may result in ascites, hepatosplenomegaly, cholestatic jaundice, azotaemia and thrombocytopenia. In patients on oral anticoagulants vitamin E excess can antagonize vitamin K and prolong prothrombin time and potentiate the action of anticoagulants.

Vitamin K Vitamin K 1 is present in green leafy vegetables and vitamin K2, which is synthesised by intestinal bacteria. It is a coagulant vitamin required for synthesis of unusual amino acid—gamma carboxyglutamic acid (Gla) which is essential for the production of four coagulation factors—II, VII, IX, and X. Daily requirement: 80 microgram/day.

zz

Sources: zz Leafy vegetables and liver. Deficiency: zz Newborn—haemorrhagic disease of the newborn is due to: —— Defective transfer of vitamin K from mother to foetus —— Lack of bacteria in the intestine —— Breast milk contain little of the vitamin zz Obstructive jaundice—defective absorption of vitamin K due to lack of bile. It may result in bleeding during biliary surgery. zz Anticoagulant therapy—warfarin, etc. act by antagonising vitamin K. zz Prolonged antibiotic therapy—by eliminating bacteria from the gut—reduced synthesis of vitamin K.

Management When prothrombin time is prolonged, give vitamin K 10 mg IM for 3 to 5 days till prothrombin time is normal.

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Thiamine (Vitamin B1) Thiamine functions as the co-enzyme, thiamine pyrophosphate. It plays a major role in Kreb’s cycle. In the absence of vitamin B1, cells cannot metabolise glucose aerobically. Brain is totally dependent on glucose for energy and so nervous system is affected early in thiamine deficiency. The total body content is 30 mg. It is essential for the metabolism of carbohydrates and in its absence pyruvic and lactic acids accumulate, which produces vaso­ dilatation and increase in cardiac output. Daily requirement: 1 to 2 mg/day. Dietary sources: Outer layer of cereals like rice, wheat, millets, pulses, nuts, yeast. Causes of deficiency: zz Defective absorption—alcoholism, folate deficiency, chronic malnutrition zz Excess loss—diarrhoea, diuretic therapy, peritoneal dialysis, haemodialysis zz Increased requirement—pregnancy, lactation, thyrotoxi­cosis, prolonged fever. Benfothiamine (S-benzoil thiamine-o-monophosphate): It is a fat-soluble derivative of thiamine. It prevents the formation of advanced glycation end products in diabetes mellitus. It is particularly useful in diabetic neuropathy and retinopathy.

Clinical Features It causes either cardiac involvement (Wet beriberi) or nervous system involvement (Dry beriberi). Cardiac Manifestations They are due to: zz High output state due to peripheral vasodilatation zz Oedema due to retention of sodium and water zz Biventricular failure Prominent signs are—raised jugular venous pulse, tachycardia, cyanosis, cardiomegaly, hepatomegaly, oedema, etc. Neurological Manifestations zz Peripheral neuropathy—distal, symmetrical impair­ ment of sensory, motor, and reflex function.

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Manual of Practical Medicine zz

zz

Wernicke’s encephalopathy—(cerebral beriberi)— global confusion, vomiting, nystagmus, ophthalmo­ plegia, fever, ataxia, coma. Korsakoff’s syndrome—impaired ability to learn, retro­g rade amnesia, confabulation (amnestic— confabulatory syndrome).

Investigations Low blood thiamine level, raised pyruvate and lactate levels. Low blood or erythrocyte transketolase activity, which increases by more than 15% after administration of thiamine, is diagnostic.

Management • Dramatic improvement in 48 hours in cardiac type of beriberi and the recovery is slow in neurological beriberi. • The memory disorder takes longer time to improve and certain degree of memory impairment may persist. • Thiamine 50 mg IM/IV for 1 to 2 weeks followed by oral therapy.

Riboflavin (Vitamin B2)

Causes of deficiency: zz Chronic small intestinal disorders zz Alcoholics zz Food habit—high intake of maize or millet (sorghum, jowar).

Pellagra

It is in the form of co-enzymes and takes part in various oxidation-reduction reactions.

Chronic wasting disease with signs of dementia, diarrhoea and dermatitis.

Daily requirement: 1 to 2 mg/day.

Skin changes: Erythema, vesiculation, cracking, exudation, crusting with ulceration.

Dietary sources: Milk, cheese, butter, liver, kidney, meat, whole cereals, legumes and green leafy vegetables. Causes of deficiency: Malnutrition, malabsorption and dialysis.

Clinical Manifestations Sore throat, glossitis, aphthous ulcers (Fig. 2.8), angular stomatitis, cheilosis, seborrhoeic dermatitis, normochromic anaemia.

Management Tablet riboflavin 5 mg tid.

Niacin (Nicotinic Acid and Nicotinamide) Limited amount is synthesised in the body from the essential amino acid—tryptophan (60 mg of tryptophan yields 1 mg of nicotinamide). Daily requirement: 15 to 20 mg/day. Dietary sources: Whole cereals, pulses, nuts, meat, fish, liver, kidney yeast and coffee.

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Fig. 2.8  Aphthous ulcer

Dermatitis is bilateral, symmetrical, in the form of hyper­ keratosis, hyperpigmentation, and desquamation mostly on exposed parts of the body to sunlight and is due to photosensitivity (Dermatitis in the neck—Casal’s collar). Diarrhoea: Widespread involvement of mucosa—glossitis, stomatitis, achlorhydria. Dementia: Fatigue, insomnia, apathy, confusion, disorien­ tation, hallucination, loss of memory and organic psychosis. Other signs: Tachycardia, cyanosis, cardiomegaly, hepato­ megaly, oedema, etc.

Management Nicotinamide 100 mg tid PO or 100 mg IM/IV for 2 weeks followed by niacin 10 mg od. Niacin excess Large doses once used for treatment of hypercholes­ terolaemia, etc. induce release of histamine resulting in severe flushing, pruritus, gastrointestinal disturbances, and hepatic toxicity with cholestatic jaundice, acanthosis nigricans. Asthma can be precipitated.

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Nutrition

Pyridoxine (Vitamin B6)

Vitamin B12 and Folate

It is available in three forms—Pyridoxine, pyridoxal phos­ phates, and pyridoxamine. It acts as a co-factor for many enzymes. Required for protein and fat metabo­lism. It is required for synthesis of haem precursors and for synthesis of GABA in brain—gamma amino butyric acid—a neuronal inhibitor and prevents convulsions.

The metabolism of these vitamins is dealt with in detail in the chapter on haematology.

Daily requirement: 1 to 2 mg/day. Dietary sources: Whole grain cereals, vegetables, yeast, meat, liver. Deficiency: Deficiency is rare. Many drugs act as pyridoxine antagonists and cause deficiency, e.g. INH, cycloserine, penicillamine, hydralazine, oral contraceptive pills.

Clinical Features zz zz

Glossitis, angular stomatitis, cheilosis, and neuropathy. In certain genetic disorders, pyridoxine metabolism is abnormal, and in those infants pyridoxine deficiency causes convulsions and later sideroblastic anaemia.

Management Many drug-induced antagonism of pyridoxine can be prevented by 30 mg of pyridoxine supplementation/day. However, high doses 100 mg/day is required in penicillamine therapy. Pyridoxine excess Perioral numbness, peripheral neuropathy, ataxia, clumsiness of hands and feet. Pyridoxine can antagonise levodopa, phenytoin, and barbiturates.

Biotin It functions as a co-factor in carboxylases. Daily requirement: 50 to 100 microgram/day. Causes of deficiency: zz Prolonged consumption raw egg whites—which binds biotin and prevents absorption from the gut. zz Prolonged parenteral nutrition. zz Biotinidase deficiency.

Clinical Features Perioral dermatitis, conjunctivitis, alopecia, ataxia, para­ es­thesias, seborrhoeic dermatitis, developmental delay.

Management Biotin 100 microgram/day.

Ch-2.indd 63

Vitamin B12 Salient Features: zz Daily requirement is 1 microgram zz It is present only in animal products zz Milk is the only source for vegetarians zz Vegans are at risk of deficiency zz The store of B 12 in liver can last for five years zz Vitamin B deficiency causes megaloblastic anaemia 12 and neurological degeneration zz It is required for the integrity of myelin zz Deficiency causes uneven demyelination zz It causes peripheral neuropathy, sub-acute combined degeneration of the spinal cord, optic atrophy and cerebral manifestations in the form of dementia.

Folic Acid Folic acid is very essential to prevent neural tube defects, which develops during the first four weeks after conception. Imperfect closure of neural tube results in three major congenital defects: zz Spina bifida zz Anencephaly zz Encephalocele. Folate is directly involved in DNA and RNA synthesis. Women planning pregnancy and throughout pregnancy should consume diet rich in folate. Folic acid 5 mg/day should be given during pregnancy.

Vitamin C (Ascorbic Acid) Most animals can synthesise ascorbic acid from glucose but humans cannot. Only L-ascorbic acid and dehydro-ascorbic acid have anti-scorbutic activity. The D-ascorbic acid and other analogues have no antiscorbutic activity.

Functions of Vitamin C By hydroxylation of proline to hydroxyproline: zz It promotes collagen formation. It aids in the production of supporting tissues of mesenchyma such as osteoid, dentine, collagen, and intercellular cement substance of capillaries. zz It enhances the iron absorption from the intestine.

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64

Manual of Practical Medicine Vitamin C helps in the synthesis of bile acids from cholesterol. zz It enhances the functions of reticuloendothelial system. Phagocytic action of leucocytes and the formation of antibodies have been improved by vitamin C. zz It helps in hydroxylation of tryptophan to serotonin. zz By stimulating the growth of intestinal flora, it augments the synthesis of vitamin B complex. zz Formation of nitroso-amines (powerful carcinogens) is prevented. As an antioxidant it reduces the risk for cancer formation. Antioxidant vitamins are vitamins A, C and E. zz Vitamin C is concentrated in adrenal cortex (160 mg/100 gm tissue) and in the lens of the eyes. It has some role in adrenal steroidogenesis and in preventing cataract formation. zz It reduces folic acid to tetrahydrofolic acid (THFA). In combination with folic acid, it helps in the maturation of RBC. zz

Sources Indian gooseberry (700 mg/100 g), guava (300 mg/100 g) green leafy vegetables, potatoes, meat (kidney, liver) fish, fruits. Partial loss of vitamin C in fruits and vegetables when stored unprocessed. It is partially preserved by processing (boiling, freezing, steaming, pressure-cooking and canning). Requirement 50 to 100 mg/day. Causes of Deficiency zz zz

zz

Poverty, famine, malnutrition, elderly living alone Increased demand—pregnancy, lactation, thyrotoxicosis Decreased absorption—malabsorption syndromes.

Clinical Features Vitamin C deficiency results in scurvy.

Scurvy This disease is caused by vitamin C deficiency. It occurs in areas of urban poverty. Infancy and Childhood zz

zz

Ch-2.indd 64

Painful swelling over the long bones due to subperiosteal haemorrhage Gingivitis, swollen, spongy gums if teeth have erupted

zz

zz zz zz zz

zz zz

Easy bleeding from scurvy buds, i.e. papillae in between the teeth Finally, the teeth are lost Lassitude, anorexia and pain in limbs Epiphyseal separation is common Inward sinking of sternum with sharp elevation of costochondral junctions (scorbutic rosary) Purpura and ecchymoses may appear in the skin Painful joint swelling due to haemorrhage into the joint cavities.

Common sites of haemorrhages: Retrobulbar, subarachnoid and intracerebral. Normocytic normochromic anaemia is common. Adults zz zz zz

zz zz zz zz zz zz

zz

zz

Total body content of vitamin C is 1.5 gm Gum involvement occurs only in people with teeth Swollen, spongy gums with increased friability, bleeding, secondary infection and loosening of the teeth Perifollicular hyperkeratosis with haemorrhage Haemorrhage into the muscles of the arms and legs Haemorrhage into the joints and in the nail-beds Petechial haemorrhages in the viscera and ecchymoses Delayed wound healing Other clinical manifestations are icterus, oedema, fever, convulsions and hypotension Vitamin C deficiency causes normochromic normocytic anaemia Associated nutritional folate deficiency can result in macrocytic/megaloblastic anaemia.

Investigations zz zz zz zz

Low ascorbic acid level in platelets and plasma. Elevated serum bilirubin value. Abnormal capillary fragility. Classical X-ray changes of bones.

Management zz zz

Scurvy is potentially fatal. 100 mg of vitamin C tid until a total dose of 4 gm has been administered and then followed by 100 mg od.

Hypervitaminosis C Large doses interfere with the absorption of B12 resulting in anaemia. Large amount of iron may be absorbed leading to haemochromatosis. Excess amount of oxalate crystals is passed in the urine, which may precipitate oxalate stone formation.

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Nutrition

INORGANIC NUTRIENTS

Causes zz

Fourteen minerals are essential for life. They are sodium, potassium, calcium, magnesium, iron, iodine, copper, zinc, cobalt, phosphorus, sulphur, chromium, selenium, and fluorine.

zz zz zz zz zz

Sodium It is the main electrolyte in extracellular fluid (Plasma and interstitial fluid). Along with chlorides, it determines osmo­lality of extracellular fluid.

Source Common salt—sodium chloride, small amounts in milk and vegetables.

zz

Clinical Features Altered mental status, twitching, seizures and coma. When serum level exceeds 160 mEq/L—it dehydrates cerebral vessels and causes ruptures of cerebral vessels— leading to permanent neurological deficit.

Management

Requirement

zz

1 to 2 gm/day but average intake by Indians—10 to 12 gm/day.

zz

Hyponatraemia

zz

Serum sodium level less than 130 mEq/L. Causes zz

zz

zz

zz zz zz

Extrarenal losses: Vomiting, diarrhoea, sweating, pancreatitis, burns, peritonitis Renal losses: Diuretics, salt losing nephropathy, ARF, CRF, renal injury, renal tubular acidosis Dilutional hyponatraemia: Increase in total body water content nephrosis, cirrhosis and CCF SIADH–Syndrome of inappropriate ADH secretion Addison’s disease Hypothyroidism.

Clinical Features Confusion, anorexia, lethargy, cramps dehydration. When the sodium level falls below 120 mEq/L—seizures, hemiparesis, and coma.

Management zz zz zz zz

Ch-2.indd 65

Hypovolemic patients—normal saline Dilutional hyponatraemia—water restriction SIADH—Water restriction + demeclocycline. Serum level below 120 mEq/L—hypertonic saline infusion.

Primary aldosteronism Cushing’s syndrome Congenital adrenal hyperplasia Hypertonic saline infusion Hypertonic haemodialysis/peritoneal dialysis Haemoconcentration due to excessive fluid loss— vomiting, diarrhoea, diuretics, etc. Diabetes insipidus (central type and nephrogenic).

Hypovolemic hypernatremia (haemoconcentration) —— Normal saline followed by 0.45% saline Hypervolemic hypernatraemia —— Loop diuretics, hypotonic fluids or dialysis Central diabetes insipidus —— Desmopressin

Potassium Potassium is mainly present in the intracellular compartment. Oral intake and renal excretion maintain the extracellular potassium balance. Acidosis shifts potassium out of cells and alkalosis shifts potassium into the cell. It maintains the intracellular osmotic pressure. Extra­ cel­lular potassium level plays a major role in skeletal and cardiac muscle activities. Normal serum value: 3.5 to 4.5 mEq/L.

Sources Banana, orange, lime, apple, pineapple, almond, beans, dates, yam, potato, and tender coconut water. It maintains the intracellular osmotic pressure. Extracellular potassium level plays a major role in skeletal and cardiac muscle activities.

Daily Requirement 3 to 4 gm/day.

Hypokalaemia When the serum level falls below 3.5 mEq/L.

Hypernatraemia

Causes

When the serum sodium is elevated above 150 mEq/L.

zz

GIT—loss due to vomiting diarrhoea, fistulae

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Manual of Practical Medicine zz

zz zz zz

Renal—diuretics, metabolic alkalosis, renal tubular acidosis Primary aldosteronism Cushing’s syndrome Drugs—insulin and glucocorticoids.

Clinical Features zz zz zz

zz

Muscle weakness, ileus, and polyuria. ECG—‘U’ wave, prolonged Q-T interval, flat or inverted. T-wave and premature beats. Hypokalaemia predisposes to digitalis toxicity. In severe hypokalaemia—flaccid paralysis and cardiac arrest.

Management zz

zz

Potassium rich dietary supplements or potassium chloride in liquid form. In severe hypokalaemia—KCl 20 to 40 mEq/hour IV with cardiac monitoring.

Hyperkalaemia When the serum level exceeds 5.5 mEq/L. Causes zz zz zz zz

zz zz

Acute and chronic renal failure Addison’s disease Hypoaldosteronism Shift of potassium from tissues acidosis, crush injuries, internal bleeding, blood transfusion. Drugs—potassium sparing diuretics, ACE inhibitors Pseudohyperkalaemia—due to increased cell destruction—haemolysis, thrombocytosis, and leukocytosis.

Clinical Features zz zz

Conduction disturbances and various arrhythmias. ECG—Peaked T-waves in pre-cordial leads-absent P-wave and wide QRS.

Management zz zz zz zz zz

Furosemide 40 mg IV Calcium gluconate 10 ml 10% IV Insulin + glucose to shift the potassium into the cells. NaHCO3 to correct acidosis. Haemodialysis.

Calcium The total calcium in human body is 1 to 1.5 kg, of which 99% is in bone and 1% is in extracellular fluid. The major quantum of calcium is used in the formation of bone

Ch-2.indd 66

and teeth. Calcium is essential for transmission of nerve impulses and muscle contraction. It serves as intra­cellular messenger of different hormones. It takes part in blood coagulation. Normal serum value: 9 to 11 mg/dl.

Daily Requirements zz zz zz

Adults—500 mg Pregnant and lactating women—1200 mg Post-menopausal women—1200 to 1500 mg.

Dietary Sources Milk, cheese, yogurt, eggs, fish eaten with bone, almonds and peanuts, leafy vegetables and dried fruits. 100 cc of milk contains 100 mg of calcium. Calcium is absorbed actively from jejunum and passively from ileum. Acidic pH, vitamin D, and presence of protein enhances absorption of calcium. Eighty per cent of calcium taken is lost in stool and some amount is also lost in the urine, and that is the cause for negative balance when the calcium is consumed in small quantum. The metabolism of calcium is intimately related to vitamin D, parathyroid hormone and calcitonin.

Phosphorus Total body phosphorus is about 1 gm. Similar to calcium 80% is present in bone and teeth and 10% in muscles. It plays a major role in the formation of bone, teeth, production of energy phosphate compounds such as ATP, CTP, GTP, DNA and RNA synthesis and acts as buffer system in blood. Normal serum level: 3 to 4 mg/dl.

Dietary Sources Milk, cheese, eggs, cereals, meat. Eighty per cent of ingested phosphorus is absorbed in jejunum and the serum level is controlled by the excretory function of the kidney. Fifteen per cent is excreted in the urine and the remaining 85% are reabsorbed in the proximal tubule and so its level goes up in renal failure. Antacid aluminium hydroxide prevents its absorption.

Hypophosphataemia It occurs in hyperparathyroidism and rickets. It causes muscle weakness, anorexia, malaise and bone pains. Dietary deficiency is rare and hyper­phosphataemia does not produce any adverse symptoms. However, in the presence of hypercalcaemia, hyperphos­phataemia can lead to metastatic calcification.

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Nutrition

Iron The total body iron content is 4 gm. Sixty per cent of that is present in haemoglobin. It is used in erythropoiesis. Normal serum level: 80 to 120 µgm/dl.

Daily Requirement zz zz zz zz

For males—1 mg For females—2 mg Pregnant/lactating women—3 mg. Only 10% of consumed iron are absorbed in duodenum and upper jejunum and so, the daily intake has to be 10, 20 and 30 mg respectively for the above categories.

Dietary Sources Green leafy vegetables, fruits, onions, cereals, pulses, jaggery, grapes, dates, animal foods like meat, liver, fish, kidney, egg yolk. Food rich in vitamin C enhances absorption of iron.

Iron Deficiency Iron deficiency causes microcytic hypochromic anaemia.

Iron Excess Siderosis denotes excessive deposition of iron in various sites like liver, pancreas leading to cirrhosis, DM.

Zinc It acts as a co-factor for a number of enzymes. It improves appetite, wound healing, and sense of well-being. Zinc deficiency causes thymic atrophy. Insulin in the stored form in beta cells of pancreas contains zinc but not when released. Normal serum value: 100 µgm/dl.

Daily Requirement 5 to 10 mg/day.

Dietary Sources

150 to 200 µgm/day.

Grains, beans, nuts, cheese, meat and shellfish. Plasma zinc is lowered in acute myocardial infarction, infections, and malignancies. Patients on prolonged IV alimentation (zinc free) may develop acute zinc deficiency leading to diarrhoea, mental apathy, and eczema around mouth and loss of hair (Fig. 2.9). Chronic zinc deficiency leads to dwarfism and hypo­ gonadism and ophthalmoplegia. Secondary zinc deficiency is seen in alcoholism and poorly controlled diabetes mellitus.

Dietary Source

Fluorine

Seawater, salt, sea-fish, vegetables and milk. Iodine deficiency is common in mountainous terrains such as Alps and Himalayas—endemic thyroid goitres are common.

It plays a major role in the prevention of dental caries. The safe limit of fluorine is 1 part per million in water (1 PPM).

Prevention

Source

Fortification of common salt with potassium iodide. Iodized poppy seed oil 1 to 2 ml IM injection will protect the individual against iodine deficiency for 5 years.

Soft water contains no fluoride. Hard water contains fluoride and sometimes to the tune of toxic level—10 PPM. Sea-fish and tea when taken frequently can contribute as

Iodine It is required for the synthesis of thyroid hormones. Total body iodine content is 30 mg and 80% of it is in thyroid. Normal serum level: 5 to 10 µgm/dl.

Daily Requirement

Ch-2.indd 67

Fig. 2.9  Acrodermatitis enteropathica (zinc deficiency)

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Manual of Practical Medicine much as 3 mg/day. Fluoride level more than 2 PPM can cause loss of appetite, AGE, and loss of weight. Fluoride level more than 5 PPM causes mottling of enamel and discolouration of teeth. Fluoride level more than 10 PPM causes osteo­sclerosis, increase in bone density and calcification of ligaments (Fluorosis in certain endemic areas).

Prevention of Caries When fluorine level is low, addition of traces of fluoride—1 PPM to the public waters supplies.

Daily Requirement 300 mg/day.

Sources Cereals, beans, leafy vegetables and fish. It is an activator of many enzymes and deficiency causes neuromuscular irritability, tremors and carpo­ pedal spasm. Chronic diarrhoea, chronic alcoholism and cirrhosis cause deficiency. Increased magnesium level causes renal damage.

Manganese

Magnesium Total body magnesium is 20 gm and 75% of it is complexed with calcium in bone. Normal serum level: 2 to 3 mg/dl.

Total body content is 15 mg and maximum quantum is in liver. It is an activator of many enzymes, stimulates bone growth and cholesterol synthesis and also takes part in glucose metabolism.

Vitamins and Trace Minerals – Requirement/day – Deficiency-induced Disorders Nutrient Vitamin A (Retinol)

Intake/day 5000 IU

Vitamin B1 (Thiamine)

1–2 mg

Vitamin B2 (Riboflavin)

1–2 mg

Vitamin B3 (Niacin) Vitamin B5 (Pantothenic acid) Vitamin B6 (Pyridoxine)

15–20 mg 5–10 mg 12 mg

Vitamin B7 (Biotin) 100–200 µg Vitamin B9 (Folic acid) 400 µg Vitamin B12 (Cobalamin) 5 µg Vitamin C (Ascorbic acid) Vitamin D (Ergocalciferol) Vitamin E (Alpha tocopherol) Vitamin K (Phyloquinone) Chromium Zinc

100 mg

Copper

2 mg

Manganese

1.5 mg

Selenium

100–200 µg

Iodine Iron

150 µg 10–15 mg

Molybdenum

Ch-2.indd 68

400 IU 10–15 IU 80 µg 30–200 µg 15 mg

Deficiency-induced disorders Xerophthalmia, Bitot’s spots, night blindness, keratomalacia, follicular hyperkeratosis, immune dysfunction, impaired embryonic development Peripheral neuropathy, beriberi, cardiomegaly with or without failure, fatigue, ophthalmoplegia,wernicke’s encephalopathy Angular stomatitis, sore tongue and mouth (Magenta tongue), cheilosis, seborrhoeic dermatitis, eye irritation Pellagra (Dermatitis, diarrhoea, dementia), sore mouth and tongue Weakness, fatigue, paraesthesias, tenderness of heels and feet Cheilosis, glossitis, seborrhoeic dermatitis, peripheral neuropathy, convulsions, hypochromic anaemia Alopecia, seborrhoeic dermatitis, myalgia, seizures, hyperaesthesia Megaloblastic anaemia, glossitis, diarrhoea, increased homocysteine Megaloblastic anaemia, decreased vibratory and position sense, ataxia, paraesthesias, dementia, diarrhoea Gingival inflammation and bleeding, purpura, petechiae, ecchymosis, scurvy, weakness, depression, joint effusion, poor wound healing Rickets-skeletal deformity-rachitic rosary, bowed legs, osteomalacia, osteoporosis, bone pain, muscle weakness, tetany Neuropathy, abnormal clotting, retinopathy, haemolysis, spinocerebellar ataxia

Evaluation Serum retinol RBC transketolase activity RBC glutathione reductase activity Urinary N-methyl-nicotinamide Urinary pantothenic acid Plasma pyridoxal phosphate Plasma biotin Serum folic acid RBC folic acid Serum cobalamin, serum methylmalonic acid Plasma ascorbic acid, Leukocyte ascorbic acid Serum 25 hydroxy-vitamin D Serum tocopherol, Total lipid-TGL:TC Prothrombin time Serum chromium Plasma zinc

Easy bruising/bleeding Glucose intolerance, peripheral neuropathy, encephalopathy Impaired taste and smell, alopecia, dermatitis (acro-orificial lesion) hypogonadism, delayed sexual maturation, growth retardation, dementia Anaemia, neutropenia, osteoporosis, defective keratinisation and Serum copper pigmentation of hair Plasma ceruloplasmin Dementia, dermatitis, hypercholesterolaemia, impaired growth and Serum manganese skeletal development Cardiomyopathy, muscle weakness Serum selenium, blood glutathione—Peroxidase activity Hypothyroidism, goitre TSH, urine iodine Hypochromic microcytic anaemia, impaired congenital development, Serum iron,total iron binding pre-mature labor, increased peri-natal and maternal mortality capacity, serum ferritin Severe neurological abnormalities

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Nutrition

Source Nuts and tea-leaves.

Daily Requirement 5 mg/day.

Copper Total body copper is 100 mg and it is present in muscles, bone, liver, kidney, brain, heart and hair. It is present in many enzymes including cytochrome oxidase and ceruloplasmin. Normal serum value: Ceruloplasmin 25 to 50 mg/dl and its equivalent amount of copper is 3 to 5 µgm.

Daily Requirement 2 to 3 mg/day.

Source Dairy products, cereals, meat, and nuts. Copper containing ceruloplasmin helps in iron transport and in the formation of haemoglobin. Copper deficiency causes iron deficiency anaemia and low ceruloplasmin causes Wilson’s hepatolenticular degeneration due to copper deposition.

Cobalt

Dietary Modifications—Diet Therapy Types of diet Low protein High carbohydrate Low simple sugar Low energy High energy Small feedings Low fat

Low fat and low cholesterol High fibre Low fibre Low sodium Low potassium High potassium High calcium Low phosphorus Low oxalate Gluten free

Disorders Chronic renal failure, nephrotic syn­drome, hepatic encephalopathy 70% of kcal—Athletes Post-gastrectomy state, lactose into­lerance Obesity, hypertension Undernourished Gastroesophageal reflux Steatorrhoea, gastroesophageal reflux, acute hepatic, gallbladder or pancreatic disorders, colon, prostate and breast cancers Hyperlipidaemia and coronary heart disease Hyperlipidaemia, diabetes mellitus Crohn’s disease, regional enteritis, ulcera­ tive colitis Hypertension, congestive cardiac failure ascites, chronic renal failure Chronic renal failure, hyper­kalaemia Diuretic therapy, hypokalaemia Osteoporosis Renal failure Renal stones Coeliac disease

Vitamin B12 contains cobalt. Cobalt stimulates production of erythropoietin.

OBESITY

Nickel

As per the state of nutrition, the individuals can be classified as normal, overweight and underweight.

It is present in certain enzymes like arginase and carboxylases. Nickel content of the hair—male 1 PPM and female 4 PPM. Some chocolate preparations contain nickel.

Chromium Total body content of chromium is 6 mg and this level decreases with age. Cooking in stainless steel containers improves the chromium of food. Chromium deficiency causes glucose intolerance. Chro­mium improves receptor binding of insulin. Tobacco contains large amount of chromium and the carcinogenic effect of tobacco is linked to chromium. (bronchogenic carcinoma).

Selenium By its intracellular antioxidant effect, it protects tissues and cell membrane against peroxidation and because of this property, it is considered to have anticancer activity (? human cancer). Selenium deficiency causes cardiomyopathy, and myopathy.

Ch-2.indd 69

Selenium excess causes alopecia, abnormal nails, emotional lability, and lassitude and garlic odour to breathe.

The state of nutrition can be assessed in the following ways: 2 zz Ideal body weight (IBW): IBW = 22.5 × (height in metres) Overweight — More than 10% of IBW Underweight — Less than 20% of IBW Obesity — More than 20% of IBW 2 zz Body mass index: BMI = Weight in kg/(height in metres) BMI — In males—20 to 25 In females—18 to 23 Overweight — BMI is between 25 and 30 Underweight — For males—BMI below 18 For females—BMI below 16 Obesity — BMI is more than 30 Grading of obesity: Grade I: BMI—25 to 30 (overweight) Grade II: BMI—30 to 40 (obese) Grade III: BMI—more than 40 (gross obesity) zz Skin-fold thickness: It can be estimated by using special pair of calipers over the triceps, biceps, subscapular and suprailiac region. Normal triceps skin-fold thickness:

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70

Manual of Practical Medicine Adult males—12.5 mm Adult females—16.5 mm zz Rough calculation of body weight in an adult (Broca’s index): Height in inches = weight in kg Height in cm - 100 = desired body weight in kg. zz Waist-hip ratio: —— Waist-hip ratio is useful to assess the prognosis in a case of obesity. —— Waist-measurement of narrowest segment between ribcage and iliac crest.

zz



„„

„„

zz

zz

Hip-maximal measurement of the hip over the buttocks: Waist-hip ratio 0.8 or less 0.9 or more



„„

Type of obesity Pear-shaped obesity Apple-shaped obesity

Prognosis Good Increased morbidity

Apple-shaped obesity is nothing but abdominal obesity, which is associated with hyperlipidaemia, insulin resistance, diabetes mellitus and coronary artery disease. Waist circumference: Waist circumference alone is enough to assess the prognosis in obesity. Waist Circumference—Morbidity Risk Sex Male Female

Moderate More than 94 cm (37”) More than 80 cm (32”)

High More than 102 cm (40”) More than 88 cm (35”)

Types of Obesity zz

zz zz

zz

Generalised obesity: Uniform deposition of excess fat throughout the body. Android obesity: Excess deposition of fat over the waist. Gynoid obesity: Excess deposition of fat over the hips and thighs. Superior or central type of obesity: Excess deposi­tion of fat over the face, neck, and upper part of the trunk and the limbs are thin—Cushing’s syndrome.

Aetiology zz

zz

zz

Ch-2.indd 70

Excess energy intake: With excess feeding, excess calories are stored in adipose tissue. Decreased energy expenditure: Physical activity is less in the obese than in the lean. Behavioural changes: —— High fat intake results in obesity. —— High fat diets do not switch-off appetite. —— Little is used for energy expenditure and is mostly stored. „„ Frequent snacks in between standard meals.

zz

Consumption of energy dense foods—sweets, ice-cream, soft-drinks Alcohol—it provides energy and stimulates appetite. Smoking—energy expenditure is more in smokers and their appetite is lost. Most of the smokers are lean. Giving up smoking induces fall in expenditure and increases food intake.

Age Physical activity is decreased with aging. Familial and genetic factors —— They play a major role. —— More than 20 genes and 12 chromosomes have been implicated in obesity. „„ Lipoprotein lipase: This enzyme is synthesised in adipocytes. It induces obesity by causing deposition of fat calories in adipose tissue. „„ Leptin: This hormone is produced by adipose tissue. It acts at the level of hypothalamus to suppress appetite. Elevated levels of leptin are seen in obesity similar to elevated insulin levels in type 2 diabetes mellitus obese. Exact role of leptin in obesity is not known. Leptin/leptin receptor: Mutation prevents leptin from delivering satiety signal. „„ Pre-opiomelanocortin: Mutation prevents synthesis of MSH and satiety signal. „„ Ag RP: Overexpression inhibits signal via MC4R. Secondary obesity due to endocrine causes —— Hypothalamic disorders: Froehlich’s syndrome Laurence-Moon-Biedl syndrome—obesity, hypo­ go­na­dism, over eating, visual impairment due to retinitis pigmentosa, etc. —— Hypothyroidism: Decreased metabolic rate with obesity. —— Cushing’s disease: Moon facies with central obesity. —— Insulinoma: Some of them are obese. It is due to increa­­sed calorie intake secondary to recurrent hypoglycaemia.

Factors increasing appetite

Factors decreasing appetite

•  Neuropeptide Y (NPY): Synthesised in arcuate nucleus of hypothalamus— appetite stimulant and reduces sympathetic output and energy expenditure

Leptin gene is in chromosome 7q 31.3. Synthesised in adipose tissue—decreases appetite and increases energy expenditure

•  Melanin concentrating hormone (MCH)

Melanocyte stimulating hormone (α-MSH)

•  Agouti related peptide (AgRP)

Coccaine amphetamine related transcript (CART)

•  Orexin

GLP-1 (Glucagon like peptide 1)

•  Endocannabinoid

Serotonin

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Nutrition

Pathology

zz

In obesity, the adipocytes number and size are increased in middle age resulting in obesity. With excess calorie intake the number and size can increase at any age. However, weight reduction causes reduction in size of adipocytes and the number does not decrease. Fat is deposited throughout the body, around internal organs, omentum, and in the intramuscular spaces. There is expan­sion of lean body mass with increased size of kidneys, heart, liver and skeletal muscles. There is fatty infiltration of liver.

zz

Drugs

zz

Complications zz zz zz zz zz zz zz zz

zz

zz

zz

zz

zz

Drugs can cause increase in body weight, e.g. corticosteroids, tricyclic antidepressants, valproate, sulphonylureas, contra­ceptives.

zz

zz

Hyperlipidaemias Hypertension Diabetes mellitus type 2 Insulin resistance Atherosclerosis Coronary artery disease Cerebrovascular strokes due to hypertension Osteoarthrosis of knees, hip, foot, and spine Varicose veins, deep vein thrombosis, pulmonary embolism Gallstones

Ventral and hiatal hernias Hypoventilation syndrome (Pickwickian synd­rome)— hypercapnia, hypoxia, cyanosis, poly­cy­thae­mia, pul­ monary hypertension, chronic cor pulmonale. Infertility, hirsutism Pregnancy—neural tube defects, pre-eclampsia, gesta­tional diabetes, pre-term labour, increased perinatal mor­tality. Cancers—gallbladder, colon, prostate In post-menopausal women—breast, ovary, endo­metrium Adrenal function—plasma cortisol levels are increased. Psychological—depression Skin—abnormal skin folds—fungal and bacterial infec­tions—Striae formation—chafing of skin of the thighs and axillae.

Prognosis Mortality rate is 25% higher if a person is 25% over weight and 50% higher if the person is 40% overweight. Sustained 10 kg reduction of weight in obese—Benefits: zz It causes a fall of 10 mm Hg systolic and 20 mm Hg diastolic blood pressure. zz 30% increase in exercise tolerance. zz 30% reduction in DM related mortality. zz Risk of developing DM is 50% less. zz 50% fall in obesity related cancer deaths. zz 10% increase in HDL cholesterol and 10% fall in total cholesterol. zz There is also 15 to 20% fall in LDL and triglycerides.

Syndromes of Obesity with Hypogonadism and Mental Retardation

Ch-2.indd 71

Feature

Prader-Willi

Laurence-Moon-Biedl

Ahlstrom

Cohen

Carpenter

Inheritance

Sporadic

Autosomal-recessive

Autosomal-recessive

Autosomal-recessive

Autosomal-recessive

Stature

Short

Normal/rarely short

Normal/rarely short

Short/tall

Normal

Obesity

Generalised

Generalised

Truncal

Truncal

Truncal and gluteal

Onset

Early 1–2 years

Early 1–2 years

Early 1–2 years

5 years

Craniofacies

Narrow bi-frontal diameter, almond shaped eyes, V-shaped mouth, higharched palate

No typical features

No typical features

High nasal bridge, higharched palate Open mouth, short-philtrum

Acrocephaly, flat nasal bridge, high-arched palate

Limbs

Small hands and feet, hypotonia

Polydactyly

Normal

Narrow hands and feet, hypotonia

Polydactyly, syndactyly, genu valgum

Gonads

Hypogonadism

Hypogonadism

Hypogonadism Not in females

Normal/hypogonadism

Hypogonadism

Other features

Enamel hypoplasia, nasal speech, hyperphagia

Mentation

Retardation

Dysplastic ears Delayed puberty Normal

Normal

Retardation

Retardation

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Manual of Practical Medicine Management Diet Moderate reduction in energy intake—500 to 600 calories less than the energy expenditures of the individual. Fat intake must be reduced. Avoid frequent snacks and diets with concentrated sugars. Complex carbohydrates with enough protein with adequate amount of fibre, vitamins and minerals are advised, e.g. for 1000 kcal diet-complex carbohydrate 100 gm, protein 40 to 50 gm, fat 30 gm. The aim of diet restriction is to reduce weight by 1 kg/week. Exercise Brisk walking 40 metres a day or cycling or swimming or games depending upon the individuals choice. Energy Expenditure during Exercise Mild exercise: Sitting 80 kcal/hour Standing 120 kcal/hour. Moderate exercise: Fast walking 3.75 mph—250 kcal/hour Swimming—250 kcal/hour Tennis—350 kcal/hour. Vigorous exercise: Cycling 10 mph—600 kcal/hour Running 10 mph—800 kcal/hour. Drug therapy Indications: BMI > 30 kg/m2 Or BMI > 27 kg/m2 + obesity related diseases. zz Centrally acting anorexiants: Sibutramine was the only FDA approved drug, but withdrawn in 2010 due to increased risk of non-fatal MI and stroke. It reduces calorie intake by acting on ventromedial and lateral hypothalamic regions. zz Peripherally acting drugs: Orlistat: It inhibits pancreatic and gastric lipase. Dose: 120 mg tid. Adverse effects: It causes fatty/oily stools, flatus, faecal urgency and deficiency of fat soluble vitamins. Psyllium mucilloid controls GI side effects. Supplement fat soluble vitamins. zz Endocannabinoid system: Rimonobant: It is a cannabinoid receptor 1 antagonist. It is withdrawn in 2009 due to neurologic and psychiatric side effects. zz Drugs under trial: —— Bupropion (dopamine and norepinephrine reuptake inhibitor) + Naltrexone (opioid antagonist). —— Bupropion + Zonisamide (Anticonvulsant that has serotonergic and dopaminergic activity. —— Lorcaserin: It is a 5HT 2c receptor antagonist. Very Low Calorie Diets Total intake of calories less than 800 kcal/day and total starvation diet are advised only under medical supervision.

Ch-2.indd 72

Surgery It is advised only when BMI is more than 40 and failure with strict diet restriction and drug therapy. zz Vertical banded gastroplasty—to reduce the volume of stomach zz Gastric bypass zz Gastric balloon—reduces the volume of stomach zz Wiring the jaws—allows only fluid diet zz Intestinal bypass—jejunoileal bypass induces malabsorption.

ANOREXIA NERVOSA AND BULIMIA Two important eating disorders seen in young females because of fear of becoming fat. The exact aetiology is not known, and most investigators favour psychiatric aetiology. The syndromes can overlap.

Anorexia Nervosa Weight loss of 25% or more of original body weight in the absence of organic disease.

Bulimia Recurrent episodes of binge eating with vomiting and to lose weight they use laxatives, diuretics and do vigorous exercise. Diagnostic Criteria and Clinical Manifestations Anorexia nervosa Female Below 25 years Restriction of diet Uncommon Weight loss more than 25% wasted Ritualised exercise Usual Amenorrhoea 100% CVS: (bradycardia hypotension) Common Skin: (hirsutism carotenaemia, dryness) Common Hypothermia Common Oedema +/– Complications Hypokalaemia Cardiac arrhythmias Oesophageal/gastric rupture —

Sex Age incidence Cause of weight loss Binge eating Appearance

Bulimia Female Young females Vomiting Common Fairly normal Rare 50% Uncommon Uncommon Uncommon +/– Hypokalaemia Cardiac arrhythmias Common

Above two eating disorders are diagnosed only on clinical grounds. No specific diagnostic laboratory tests exist.

Management zz zz

There is no specific treatment. The benefits of psychiatric intervention are marginal. Hospi­­ta­lise the anorexia nervosa patients and treat sympto­matically. Ryle’s tube feeding and at times total parenteral nutrition. For bulimia, hospitalisation is not required, except for the management of complications. Advised to consume small quantum of feeds to prevent gastric and oesophageal rupture.

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C H AInfectious P T E RDiseases

73

Infectious Diseases

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BACTERIAL INFECTIONS Staphylococcal Infections There are 33 species of staphylococci (Staphyle—bunch of grapes). Coagulase-positive Staphylococcus aureus is the most virulent form. Coagulase-negative staphylococci are less virulent. S. aureus forms part of normal human flora. They colonize in anterior nares, axilla, perineum, oropharynx, vagina and toe-webs. 25 to 50% is healthy carriers.

A1

A2

Predisposing Factors zz zz zz zz zz zz zz

zz zz zz

Diabetes mellitus HIV infection IV drug abuse Chronic haemodialysis Skin diseases Wounds (trauma, surgery, burns, IV lines) Presence of foreign materials (catheters, AV shunts, prosthetic valves, orthopaedic prosthesis) Breach in the mucosal lining—viral infections Impaired immune status Impaired leucocyte function—quantitative or qualitative.

Clinical Features (Figs 3.1A and B) zz

zz zz

zz zz zz zz

zz zz

S. aureus usually causes localized infections resulting in abscess formation and at times bacteraemia resulting in haematogenous spread. Skin: Boils, styes, carbuncles, folliculitis, furuncles. Respiratory system: Pneumonia, lung abscess, empyema. Cardiac: Endocarditis, myocarditis, pericarditis. CNS: Meningitis, brain abscess. Bone and joint: Osteomyelitis, septic arthritis. Intestinal: Enterocolitis resulting in abdominal colic and diarrhoea. Bloodstream: Septicaemia, metastatic abscesses. Multisystem: Toxic shock syndrome.

A3

Fig. 3.1A  (A1) Staphylococcal folliculitis; (A2) Sycosis barbae; (A3) Furuncle (boil); (A4) Scalded skin syndrome

Treatment zz

zz

zz

zz

zz

zz

Investigations zz

zz

zz

Ch-3A.indd 74

Gram’s stain and microscopic examination of tissue— gram-positive cocci in clusters (Fig. 3.2) Culture of infected material and blood—positive blood culture indicates bacteraemia Serology is not useful for the diagnosis of staphylococcal infections.

A4

zz

zz

zz

zz

Penicillin remains the drug of choice against the susceptible strains Therapy is problematic because of beta-lactamase production by Staphylococcus aureus which destroys many antibiotics Semi-synthetic penicillinase-resistant penicillins (SPRPs) such as oxacillin and nafcillin (1–2 gm IV 4-6th hourly), flucloxacillin (500 mg QID IV), cloxacillin and cephalosporins are effective against penicillin- resistant and methicillin sensitive Staphylococcus aureus (MSSA) isolates Methicillin resistant Staphylococcus aureus (MRSA) are resistant to all SPRPs as well as to all cephalosporins except fifth-generation cephalosporin – ceftaroline. Ceftaroline – 600 mg IV BD is useful against MRSA and VRSA and daptomycin resistant strains Vancomycin 1 gm IV BD and daptomycin (4–6 mg/kg IV OD) are effective against MRSA infections Linezolid (600 mg PO/IV BD) is used against VRSA Tedizolid – new oxazolidinone – 200 mg OD oral / IV is as effective as linezolid Other recently approved drugs are quinupristin, dalfopristin, telavancin, dalbavancin and tigecycline Surgical intervention is essential for suppurative and necrotizing lesions Duration of therapy for uncomplicated infections is 1–2 weeks and for complicated infections 4–8 weeks.

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Infectious Diseases

Staphylococcal Toxin-mediated Diseases zz

zz

Staphylococcal food poisoning: It is caused by ingestion contaminated food with staphylococcal enterotoxin resulting in nausea, vomiting, abdominal cramps and diarrhoea—treatment is supportive. Staphylococcal scalded skin syndrome (SSSS): It is caused by epidermolytic toxins of S. aureus—extensive erythema followed by bullous desquamation— newborns and children are affected.

Toxic Shock Syndrome

Fig. 3.1B  Infections caused by Staphylococcus aureus

Toxic shock syndrome (TSS) is a life-threatening systemic disease caused by exotoxin superantigens produced by Staphylococcus aureus or group A β-haemolytic streptococcal (GABHS) tissue infections. zz Diagnostic testing–Blood cultures are usually negative. Creatine phosphokinase (CPK) is often elevated. Detection of antibodies against toxic shock syndrome toxin-1 (TSST-1) is helpful and it indicates protection against recurrence zz Clinical features are—fever, myalgias, weakness, vomiting, diarrhoea, altered mental status and hypotension with evolving multiorgan failure zz The mainstay of therapy is reversal of hypotension zz Treat group A β-haemolytic streptococcal infection with penicillin G 4 million U IV q4h + clindamycin 900 mg IV q8h + single dose of immunoglobulin IV 2 gm/kg. Clindamycin is added to decrease toxin production zz Treat Staphylococcus aureus with oxacillin 2 gm IV q4h or vancomycin 1 gm IV q12h or linezolid zz The role of glucocorticoids in treating TSS is uncertain.

Coagulase-negative Staphylococci

Fig. 3.2  Staphylococcus aureus: Gram-positive cocci— Grape-like clusters

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This group includes S. epidermidis, S. hominis, S. warneri, S. saprophyticus, S. saccharolyticus and S. cohnii. They cause infections of intravascular and prosthetic devices and wound infections following surgery. They are commonly resistant to beta-lactams and many other antibiotics. Infections involving bone or prosthetic valve should be treated with a combination regimen of vancomycin 1 gm IV and rifampin 300 mg PO bid along with gentamycin 1 mg/kg IV tid for a period of six weeks especially in cases of methicillin-resistant strains.

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Streptococcal Infections Streptococci are nasopharyngeal and gut commensals. They are gram-positive and appear in chains (Fig. 3.3). Beta-haemolytic streptococci produce clear zone of haemolysis and alpha-haemolytic streptococci produce a greenish zone around the haemolysis on blood agar. Lancefield’s group A, B, C and G deals with betahaemolytic streptococci. Alpha-haemolytic includes S. viridans group (S. mitis, S. sanguis, S. mutans, S. salivarius) and Strep. pneumoniae. Lancefield’s group D includes non-haemolytic streptococci—S. bovis and enterococci (E. faecalis and faecium).

Investigations zz zz zz

Complications zz

zz

Pyogenic streptococci: It includes Lancefield’s group A, B, C and G.

β-haemolytic group A (S. pyogenes) They cause the following infections: zz Skin and soft tissue infections: Erysipelas, impetigo, necrotizing fasciitis zz Streptococcal toxic shock syndrome zz Puerperal sepsis zz Pharyngitis and tonsillitis: It clinically manifests as abrupt onset of sore throat (strep throat) with fever, pain on swallowing and cervical adenopathy. The pharynx, soft palate and tonsils are red and oedematous. zz Scarlet fever: Erythrogenic toxin may cause scarlet fever in susceptible individuals. Diffuse erythematous rash occurs which blanches on pressure—most intense in the groin and axilla—fades in 7 days with desquamation—facial flushing circumoral pallor and strawberry tongue—“sand-paper” texture of the skin due to occlusion of the sweat glands—the above clinical picture clinches the diagnosis of scarlet fever.

Leucocytosis with neutrophil predominance Repeated throat culture Detection of streptococcal antigen by rapid diagno­ stic tests

Suppurative: The clinical manifestations include sinusitis, otitis media, mastoiditis, peritonsillar abscess, and suppuration of cervical lymph nodes. Non-suppurative: —— Rheumatic fever—1 to 4 weeks after pharyngitis —— Glomerulonephritis—following nephritogenic strain of streptococcal group A infection (types 2, 4, 12, 49, 60).

Treatment Choose any one of the following antibiotics: Penicillin and its derivatives still remains the drug of choice. zz Benzathine penicillin G 1.2 million units single dose IM. zz Cephalosporins—any generation zz Macrolides—erythromycin 500 mg qid or azithromycin 500 mg od for 5 to 7 days. zz Clindamycin 300 mg bid for 7 to 10 days. zz

β-haemolytic group B (S. agalactiae) They cause neonatal infections including meningitis. Female pelvic infections—chorio-amnionitis, endometri­ tis, cystitis, pyelonephritis and septicaemia are common. They are sensitive to penicillins and cephalosporins. For meningitis gentamycin 1 mg/kg tid is added to penicillin. Vancomycin can also be used.

β-haemolytic group C and G They cause cellulitis and septicaemia. The treatment is similar.

α, β- or non-haemolytic group D streptococci (S. bovis) They cause endocarditis in association with bowel neoplasia or cirrhosis.

Enterococcal infections: (Previous Lancefield’s group D enterococci) Fig. 3.3  Streptococcus pyogenes: Gram-positive cocci— Arranged in chain

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Enterococcus faecalis and Enterococcus faecium cause wound infections, urinary tract infections, endocarditis and bacteraemia.

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Infectious Diseases They can be treated with penicillin/gentamycin/ vancomycin. Vancomycin-resistant strains can be treated with quinpristin/dalfopristin/linezolid.

Pneumococci (α-Haemolytic Optochinsensitive—S. pneumoniae) (Fig. 3.4) S. pneumoniae otherwise known as pneumococci are gram-positive diplococci which cause pneumonia, endocarditis, meningitis, otitis media, spontaneous bacterial peritonitis and septicaemia. It causes community acquired pyogenic bacterial pneumonia. Predisposing Factors � � � � � � �

Alcoholism Bronchial asthma HIV infection Sickle cell disease Splenectomy Haematological disorders Advanced age.

Clinical Features High fever, productive cough, rigor, pleuritic chest pain, dyspnoea and clinical signs of consolidation.

Investigations zz zz zz zz zz

Blood count, urea, sugar, creatinine Sputum for Gram stain Blood culture and sputum culture X-ray chest PA and lateral views A rapid urinary antigen test for S. pneumoniae.

Complications Pleural effusion, pericarditis, myocarditis, endocarditis, arthritis, meningitis, heart failure.

Treatment Choose any one of the following antibiotics. Benzyl penicillin 2 million units 4th hourly IV zz Amoxicillin 500 mg tid zz Azithromycin 250 mg bid zz Clarithromycin 500 mg bid zz Fluoroquinolones/cephalosporins can be given zz Vancomycin 1 gm bid Duration of therapy is for 1 to 2 weeks and for endo­ carditis 4 weeks. zz

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Fig. 3.4  Streptococcus pneumoniae: Flame-shaped or lanceolate appearance

Pneumococcal Meningitis It presents with fever, headache, altered mental status and clinical signs of meningitis. Gram-positive diplococci on Gram stain of CSF is confirmatory. Meningitis can be treated either with benzyl penicillin 40 lakhs units qid or ceftriaxone 2 gm IV bid plus vancomycin 15 mg/kg bid for 10 to 14 days. Dexamethasone 10 mg IV qid should be given immediately before or concomitantly with the first dose of antibiotic and continued for 4 days. Short course of dexamethasone reduces the morbidity and mortality. Pneumococcal Vaccine 23-valent pneumovax—0.5 ml SC. If at risk revaccinate after 6 years. The vaccine is indicated in the following conditions: >65 years old zz Chronic heart disease zz Chronic lung disease zz Chronic renal disease zz Diabetes mellitus zz Splenectomy or asplenia zz Sickle cell disease zz Coeliac disease zz Post-organ transplant status zz Immunosuppressive therapy zz HIV. zz

Contraindication—pregnancy and lactation.

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Meningococcal Meningitis It is caused by non-motile, aerobic, gram-negative diplococci (with contiguous sides flattened) Neisseria meningitidis (Fig. 3.5). Five out of nine serogroups— A, B, C, Y and W-135 are highly pathogenic. They are normal commensals in the nasopharynx of human beings. Infection is transmitted by droplets. The incubation period is 3 to 5 days. It reaches the CNS through the perineural sheath of olfactory nerve and multiplies in CSF. It reaches the bloodstream through submucosa of respiratory tract.

Clinical Features Fever, headache, vomiting, convulsions, delirium Neck stiffness with positive Kernig and Brudzinski signs zz Petechial rash of skin and mucous membrane zz Purulent CSF with gram-negative intracellular and extracellular diplococci zz Culture of CSF, blood, or petechial aspiration confirms the diagnosis. Neck stiffness may not be present in infants and elderly. Disseminated intravascular coagulation is an important complication in seriously ill toxic patients. zz zz

Prevention Prevention is by a single quadrivalent (A, C, Y and W135) vaccine 0.5 ml SC. Chemoprophylaxis is advocated for eliminating nasopharyngeal meningococci in carriers by any one of the following antibiotics:

zz zz zz zz zz

Rifampin 600 mg bid for two days Ciprofloxacin 500 mg single dose Ofloxacin 400 mg single dose Azithromycin 500 mg single dose Ceftriaxone 250 mg IM single dose.

Treatment Death from meningococcal disease is commonly due to hypovolemic shock (meningococcemia) or occasionally due to raised intracranial pressure (meningococcal meningitis) zz The antibiotic of choice is either ceftriaxone (75–100 mg/kg/day in two divided doses and not to exceed 4 gm/day) Or cefotaxime (200 mg/kg/day in four divided doses and not to exceed 8 gm/day) IV for 7 days zz Other supportive measures are—fluid replacement, effective ventilation, fresh frozen plasma zz Glucocorticoid is indicated for patients who have refractory shock in association with impaired adrenal gland responsiveness. zz

Gonococcal Infection Gonorrhoea is a common sexually transmitted infection caused by gram-negative intracellular diplococci Neisseria gonorrhoeae. The incubation period is 2 to 7 days.

Clinical Features zz

zz

zz

zz

zz

Profuse purulent urethral discharge with dysuria (Fig. 3.6) Men: Epididymitis, prostatitis, periurethral inflam­ mation, and proctitis—chronic infection may lead to urethral strictures Women: Cervicitis with purulent discharge, vaginitis, salpingitis, and proctitis—in pregnancy, it may cause premature birth, salpingitis, endometritis, puerperal sepsis and ophthalmia neonatorum for the newborn Disseminated disease with fever, rash, tenosynovitis, arthritis Rectal gonorrhoea due to anal intercourse and pharyn­geal gonorrhoea due to orogenital sex.

Diagnosis

Fig. 3.5  Neisseria meningiococci: Arranged in pairs, adjacent sides are flat

Ch-3A.indd 78

Gram-negative intracellular diplococci (Fig. 3.7) seen in smear/culture from urethra, cervix, rectum or pharynx confirms the diagnosis. DNA probes and PCR have 95% sensitivity and specificity.

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Infectious Diseases

Diphtheria (Fig. 3.8) Diphtheria is an acute infectious disease caused by grampositive Corynebacterium diphtheriae. It is not an invasive organism (no bacteremia). The incubation period is 2 to 7 days. Infection spreads through droplets or direct contact of the lesion.

Clinical Features zz

zz

Fig. 3.6  Gonococcal urethritis

zz

zz

Nasal diphtheria: As evidenced by rhinorrhoea— foul smelling discharge—excoriation, membrane formation, ulceration Tonsillar and pharyngeal diphtheria: Low grade fever, sore throat, white or grey adherent membrane with difficulty in peeling and results in bleeding— covering the pharynx or tonsils or soft palate—with cervical lymphadenitis and soft tissue oedema (bull neck) Laryngeal diphtheria: Downward extension of pharyngeal membrane causing hoarseness of voice, laryngeal obstruction and stridor—emergency tracheostomy to prevent mortality Infection at other sites: Cutaneous, non-healing ulcer with sharp border with adherent grey membrane— ulcerative conjunctivitis, aural diphtheria, ulcerative vulvovaginitis.

Diagnosis

Fig. 3.7  Neisseria gonococci: Kidney-shaped arranged in pairs

Throat swab or swab from the infected site and culture confirms the diagnosis. To prevent the high rate of mortality statistics the treatment immediately and do not wait for culture report.

Treatment zz

zz

zz

zz

zz

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Uncomplicated gonorrhoea: Single dose of any one drug is effective—ciprofloxacin 500 mg PO or ceftriaxone 125 mg IM or cefixime 400 mg PO or spectinomycin 2 gm IM. Other drugs used are: Any one drug can be given as single dose–Azithromycin 1 gm PO, ceftizoxime 500 mg IM, cefotaxime 500 mg IM, cefotetan 1 gm IM + probenecid 1 gm PO, cefoxitin 2 gm IM + probenecid 1 gm PO Complicated disseminated gonorrhoea: Ceftriaxone 1 gm IV/IM od for 7 days or spectinomycin 2 gm IM bid for 7 days. Gonococcal conjunctivitis: Ceftriazone 1 gm IM single dose. Gonococcal meningitis and endocarditis: Ceftriazone 1–2 gm IV BD – 14 days for meningitis and 4 weeks for endocarditis.

Fig. 3.8  Corynebacterium diphtheriae: Gram-positive bacilli— Chinese-letter appearance

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Manual of Practical Medicine Complications zz zz

zz

zz

Laryngeal obstruction and respiratory distress Myocarditis—muffled heart sounds, murmurs, con­ duction defects, various types of arrhythmias, such as cardiac failure, dilated cardiomyopathy. All these occur during the second week. Neurological complications occur in the second or third week. Paralysis of soft palate with nasal dys­arthria, oculomotor and ciliary paralysis with strabismus and loss of accommodation—paralysis of diaphragm and limbs simulating GuillainBarré syndrome (purely motor)—involvement of vasomotor centre with tachycardia, hypotension. Other complications—pneumonia, renal failure, encephalitis, cerebral infarction, pulmonary embolism.

Tetanus (Fig. 3.9) Tetanus is caused by powerful neurotoxin—tetano­ spasmin, an exotoxin elaborated by gram-positive Clostridium tetani characterised by increased muscle tone and spasm. Tetanus occurs in several clinical forms, including generalised, neonatal and localised disease.

Clinical Features zz

zz

Prevention

zz

DPT vaccine is advised at the age of 6, 10, 14 weeks and a booster at 18 months. The next booster consisting of diphtheria and tetanus toxoid (DT) is given at the age of 5 years.

zz

zz

Treatment Anti-diphtheritic serum (ADS) is administered as IV infusion over one hour to neutralize the toxin. zz Mild cases—20,000 to 40,000 units. zz Moderate lesions—40,000 to 60,000 units. zz Severe lesions—80,000 to 100,000 units. zz Antibiotics are used to prevent transmission to susceptible contacts, also to prevent toxin production and to reduce the severity of local infection zz Procaine penicillin G, 600,000 U IM q12h (12,500 – 25,000 U/kg IM q12h for children) until the patient can swallow comfortably; then oral penicillin V 125250 mg qid for a total period of 14 days zz Alternative antibiotics for patients allergic to penicillin are—erythromycin, rifampin or clindamycin zz If culture remains positive at the end of 2 weeks course, additional 10 days therapy is required zz Prophylaxis to contacts—Single dose of benzathine penicillin G IM (1.2 million units for persons ≥6 years of age or 600,000 units for children 70 years yy Incubation period 140 mm Hg yy Severe disease or spasms yy Temperature >38.5°C

yy Younger age, premature birth yy Incubation period 4 neutrophils /oil immersion field and no gonococci in pyuria Gram’s stain with >4 neutrophils/oil immersion field— no gonococci

Cervicitis Salpingitis

Mucopurulent cervical discharge, bleeding Lower abdominal pain Adnexal tenderness Masses, cervical motion tenderness Dysuria and frequency Mucopurulent cervicitis

Cervical mucus Gram’s stain >20 Neutrophils C. trachomatis always present in salpingitis

Rectal pain, tenesmus Discharge, bleeding History of anorectal intercourse NGU, arthritis, typical skin lesions Conjunctivitis

Negative gonococcal culture In rectal Gram’s stain—at least one neutrophil/field

Primary lesion Regional adenopathy proctitis

None

Purulent conjunctival discharge within 3 weeks of delivery Staccato cough, diffuse rales, interstitial infiltrates

Gram’s stain and culture negative for gonococci, pneumo and staphylo and Haemophilus spp. organisms None

Men

Urethritis

Sterile pyuria with negative urine culture

Adults—either sex Proctitis

Reiter’s syndrome LGV Neonates Conjunctivitis Infant pneumonia

Chlamydophila psittaci— Psittacosis (Ornithosis) Psittacosis is acquired from contacts with birds (parrots, parakeets, pigeons, chickens, ducks). Psittacosis is caused by C. psittaci. It is almost always transmitted to humans by the respiratory route. After entry it spreads via the bloodstream and localise in the pulmonary alveoli, reticuloendothelial cells of liver and spleen. The incubation period is 1 to 2 weeks.

Clinical Features zz zz

zz

zz zz

Severe headache, with chills and fever. Initially dry, nonproductive cough, and later small amount of mucoid or bloody sputum—the physical signs of pneumonitis is less prominent than X-ray findings as in mycoplasmal pneumonias A faint macular rash (Horder’s spots) resembling the rose spots of typhoid fever may appear Pneumonitis with splenomegaly suggests the diagnosis Chest pain, pleural effusion, myocarditis, pericarditis, and endocarditis mild gastroenteritis have all been reported.

Diagnosis zz

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Isolation of C. psittaci from cultures.

Gram’s stain >4 neutrophil/oil Immersion field and lack of gonococci indicative of NGU

zz

The antibodies appear during the second week— rising titer of complement-fixing antibodies or immunofluorescence are useful.

Treatment Tetracycline 500 mg qid for 2 to 3 weeks or doxycycline 100 mg bid or erythromycin 500 mg qid for 2 to 3 weeks are effective.

Chlamydophila pneumoniae Infections Infections begins in late childhood, it peaks in early adulthood and continue throughout adult life. C. pneumoniae can be grown in a variety of cell cultures, but very difficult.

Clinical Features zz

zz

zz

The clinical spectrum includes pharyngitis, sinusitis, bronchitis, and pneumonitis—pneumonitis resembles that of mycoplasmal pneumonia with a few clinical signs The organisms have been recovered from in culture from atheromatous plaque—it accelerates atherosclerosis and incidence of myocardial infarction— antimicrobial therapy reduces the cardiac events Diagnosis is by culture and serology. Cellular culture is difficult and the serology does not easily differentiate the strains of chlamydiae.

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Manual of Practical Medicine Treatment Tetracycline 500 mg qid or erythromycin 500 mg qid or levofloxacin 500 mg od or moxifloxacin 400 mg od for 10 to 14 days are effective.

Mycoplasma Infections Mycoplasmas are the smallest free-living organisms. They lack cell wall that results in cellular pleomorphism and are resistant to cell wall active antimicrobial agents such as penicillins and cephalosporins. Mycoplasma pneumoniae causes ‘atypical pneumonia’. Human infections are caused by two main genera— Mycoplasma and Ureaplasma. M. hominis causes cervicitis, vaginitis, pelvic inflammatory disease, and conjunctivitis in men and sepsis in neonates. M. orale, and M. salivarium cause periodontal disease. Ureaplasma consists of two species—U. parvum and U. urealyticum.

Clinical Features zz zz

zz

zz

zz

zz

zz

Infection is acquired by inhalation of aerosols. The incubation period is considerably longer—2 to 3 weeks. Headache, fever, prolonged cough causing chest muscle soreness. Ear pain due to bullous myringitis—blisters on the tympanic membrane is a unique but uncommon manifestation. A very few physical signs despite striking radiographic abnormalities. X-ray chest shows reticulonodular or interstitial infiltration primarily involving lower lobes. 1 : 64. Specific antibodies can be detected by ELISA, immuno­ fluorescence or complement fixation but there is delay. Nucleic acid amplification test is useful to confirm the diagnosis.

Treatment Although symptoms are alleviated by antimicrobial treatment, the organisms are not eradicated. Culture positivity may persist for many months despite clinically effective antimicrobial therapy. The treatment has to be continued for 2 to 3 weeks. Ceftriaxone 1 gm IV or cefotaxime 1 gm tid or azithromycin 500 mg od are drugs used to treat the hospitalised patients. The following drugs are used to treat the ambulatory patients: Doxycycline 100 mg bid or erythromycin 500 mg qid or clarithromycin 500 mg bid or azithromycin 500 mg od or levofloxacin 500 mg od or moxifloxacin 400 mg od or gemifloxacin 320 mg od are all effective.

Genital Mycoplasmas Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum are the most prevalent genital Mycoplasmas. Infants may become colonised during passage through a colonised birth canal. Neonatal colonisation does not persist. After puberty, colonisation occurs mainly as a result of sexual activity. Women have somewhat higher rates of colonisation than men. They are highly prevalent among healthy people. The following infections are caused by them: zz Nongonococcal urethritis zz Epididymitis and prostatitis zz Pelvic inflammatory disease zz Disorders of reproduction—antisperm antibodies and male infertility. Nucleic acid amplification test such as PCR are useful for diagnosis.

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Infectious Diseases Treatment Doxycycline 100 mg bid for 7 days or azithromycin 1 gm od are useful or erythromycin 500 mg qid for 2 weeks is effective.

About one-third of untreated latent stage patients enter the tertiary stage. The common lesions that occur in this destructive stage are—gumma, cardiovascular syphilis and neurosyphilis.

Clinical Features

Syphilis is a sexually transmitted chronic systemic infection caused by Treponema pallidum. After an incubation period of 3 to 6 weeks, a primary lesion appears. Primary lesion is often associated with regional lymphadenopathy. The secondary stage with generalised parenchymal, constitutional, and symmetrical mucocutaneous lesions and generalized lymphadenopathy appears 6 weeks to 6 months after the primary lesion. Secondary lesions subside within 6 weeks and the disease enters the latent stage lasting for years or decades. About one-third of untreated cases enter the tertiary stage characterised by progressive destructive mucocutaneous, musculoskeletal, or parenchymal lesions.

Primary syphilis (Fig. 3.27) The typical lesion of primary chancre begins as a single painless papule at the site of inoculation, most frequently located on the penis, labia, cervix, or anorectal region. Multiple primary lesions may appear in HIV patients. zz Papule ulcerates and the ulcer has well-defined rolled indurated margin, with a characteristic cartilaginous consistency on palpation of the edge and base of the ulcer. zz Regional lymphadenopathy: Usually bilateral inguinal and appear within one week of primary lesion and the nodes are firm, nonsuppurative and painless. The primary lesion heals within 4 to 6 weeks, but lymphadenopathy may persist for months zz Fluid expressed from the primary chancre contains T. pallidum as seen by darkfield microscopy or immunofluorescence.

Pathogenesis

zz

SPIROCHETAL DISEASES Syphilis

T. pallidum is a thin spiral organism and cannot be cultured in vitro. Nearly all cases of syphilis are acquired by sexual contact with infectious lesions—chancre, mucocutaneous lesions, and condylomata lata. Less common modes of transmission include nonsexual personal contact, infection in utero, blood transfusion and organ transplantation. T. pallidum penetrates intact mucous membranes or microscopic abrasions in skin and within a few hours enters the lymphatics and bloodstream to produce systemic infection and metastatic foci long before the appearance of a primary lesion. Blood of incubating patient is infectious. The incubation period is 3 weeks. The incubation period rarely exceeds 6 weeks. The primary lesion appears at the site of inoculation and heals spontaneously within 4 to 6 weeks. There is perivascular infiltration, chiefly by CD4+ and CD8+ T-lymphocytes, plasma cells and macrophages with capillary endothelial proliferation. The primary lesion heals spontaneously within 6 weeks. The secondary stage with systemic involvement and constitutional symptoms appear 6 weeks to 6 months time after the primary lesion. The T. pallidum are found in many tissues, blood, aqueous humor of the eye, and CSF. Secondary stage subsides within six weeks and the patient enters the early latent stage. At the end of the first year they enter the late latent stage.

Ch-3A.indd 103

zz

Secondary syphilis (Fig. 3.28) Constitutional symptoms that accompany or precede secondary syphilis are—sore throat, malaise, head­ ache, anorexia, fever, weight loss, meningismus. Acute meningitis may occur in 1 to 2% of cases. zz Generalised red or pink, nonpruritic, discrete maculo­papular rash appear on the trunk, proximal extremities and later involve the palms and soles. zz In warm, moist, intertriginous areas (scrotum, vulva, perianal region) papules enlarge to produce broad, moist, pink, highly infectious lesions—condylomata lata (weeping papules). zz Mucous membrane lesions: Painless silver-grey erosions surrounded by a red periphery—involve the oral or genital mucousa. zz Involvement of hair follicles can result in patchy alopecia of scalp hair, eyebrows, and beard. zz There is generalised nontender lymphadelopathy. zz Less common complications: Hepatitis, gastritis, proctitis, osteitis, arthritis zz Ocular involvement: Optic neuritis, pupillary abnor­ malities, iritis, uveitis, and presence of T. pallidum in aqueous humor zz Renal involvement: Acute nephrotic syndrome or haemorrhagic glomerulonephritis zz Many treponemes can be seen in moist lesions by immunofluorescence or darkfield microscopy. zz Serologic tests are positive.

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Manual of Practical Medicine zz

Remission occurs in two-thirds of cases and the remaining one-third enters the tertiary phase if left untreated.

Tertiary (Late) Syphilis zz

zz zz

This stage may occur at any time after secondary syphilis, even after years of latency, and is rarely seen in modern antibiotic era. This usually occurs after 2 years of latency Patients are noninfectious There are gummas involving many organs.

Late Benign Syphilis (Gumma) Fig. 3.27  Primary syphilitic chancre

Gummas are solitary lesions ranging from microscopic to several centimeters in diameter. It is a granulomatous inflammation with central area of necrosis due to endarteritis obliterans. T. pallidum has been recovered from these lesions. The commonly involved organs are—skin, skeletal system (usually long bones), nose (saddle-nose), palate (perforation), parotid glands, brain, thyroid gland, stomach, liver (hepar lobatum), breasts, pancreas, kidneys, testes, scalp, forehead, buttocks, presternal supraclavicular, and pretibial regions. The skin lesions manifest as nodules and that ulcerates to form punched-out lesions, with granulomatous base, which is covered with adherent yellow-white slough (washleather).

Cardiovascular Syphilis zz

Fig. 3.28  Mucous patch lesion of secondary syphilis

Early Latent Syphilis zz zz

zz zz

The period is limited to the first year after infection. The diagnosis is suspected on the basis of history of primary or secondary lesions or history of exposure to syphilis or delivery of an infant with congenital syphilis Relapse occurs in 25% of untreated cases Positive serological tests with normal CSF and absence of clinical manifestations of syphilis.

Late Latent (Hidden) Syphilis zz zz

zz

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The period that covers after one year of infection History of syphilis with inadequate treatment with no clinical signs Positive serologic tests for syphilis

zz

zz

zz

It appears 10 to 40 years after infection and is attributed to endarteritis obliterans of vasa vasorum, which provides blood supply to large vessels. It results in uncomplicated aortitis, saccular aneurysm of ascending aorta, aortic regurgitation, and coronary ostial stenosis. Syphilitic aneurysms usually saccular, rarely fusiform and do not lead to dissection. Only one in ten of aortic aneurysm of syphilitic origin involves the abdominal aorta. Linear calcification of ascending aorta on X-ray chest confirms the diagnosis of syphilitic aortitis.

Neurosyphilis zz

Asymptomatic neurosyphilis:The patients lack neurologic symptoms and signs, but who have CSF abnormalities in the form of mononuclear pleocytosis, increased protein and positive VDRL test.

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Infectious Diseases zz

zz

zz

zz

Meningeal syphilis: It involves either the brain or the spinal cord within or 6 months) or relapsing. Patient presents with myalgias, prostration, and relative bradycardia and rarely fever with skin rash. Myocarditis, pericarditis, meningitis, encephalitis, orchitis. Hepatitis, acute renal injury may occur. Culture negative endocarditis and vasculitis leading aortic aneurysm are other presentations of Q-fever.

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Manual of Practical Medicine Treatment zz zz

zz

Doxycycline 100 mg bid for 14 days. Even if left untreated the mortality rate is usually low, except in the presence of endocarditis. Endocarditis should be treated with doxycycline 200 mg od + oral hydroxychloroquine 600 mg; day for 2 years.

Kawasaki Disease It is a multisystemic disease. It is also known as “muco­ cutaneous lymph node syndrome.” It occurs in children between the ages of 3 months to 5 years. Rarely adults can also be affected. Several infectious agents (coronavirus, parvovirus, bocavirus, CMV, Yersinia pseudotuberculosis, meningo­ coccus) bacterial super-antigens, and genetic polymor­ phisms in components of the immune system (interleukin 10 and 18) are currently implicated in its pathogenesis. It results in a vasculitis characterised by the infiltration of vessel wall with mononuclear cells and later by IgA secreting plasma cells causing destruction of media and aneurysm formation.

Clinical Features The patients present with bilateral conjunctivitis, injected pharynx, erythematous lips, strawberry tongue, erythema of palms and soles, induration of the hands and feet, and Beau lines of the nails. Coronary vessel arteritis with myocardial infarction occurs in children above the age of 6 years or below 1 year. Coronary artery aneurysms and fistulas occur. Arteritis affecting extremity vessels with peripheral gangrene are also recorded.

Treatment zz

zz

zz

zz

zz

zz

zz

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IVIG (2 gm/kg over 10–12 hours) is given within the first 10 days of illness. IVIG should be given even if they present later. Aspirin should be started—100 mg/kg/day (not to exceed total 4 gm) in 4 divided doses until the patient is afebrile for 48 hours and then reduced to 5 mg/kg/ day until markers of inflammation normalize. If fever persists after 36 hours after the initial IVIG (no other cause for fever) second dose of IVIG should be given. If the disease persists after the second dose, methylprednisolone 30 mg/kg/day for period of 3 days should follow. Other options for refractory cases are TNF blockers (infliximab), cyclophosphamide, methotrexate, and plasmapheresis. Warfarin with low dose aspirin should be given for aneurysms larger than 8 mm in diameter. CABG and even cardiac transplant when needed.

VIRAL DISEASES Viruses are nucleic acids—double or single stranded DNA or RNA, packaged within a protein capsid with or without an envelope. Viruses are obligate intracellular parasites: they can replicate only within cells since their nucleic acids do not encode the many enzymes necessary for protein, carbohydrate, and lipid metabolism and for the generation of high-energy phosphates. They live only inside the host cells of bacteria, plant, invertebrates and vertebrates. They are invisible under light microscope. Electron microscope is essential to magnify the viral structure, size and shape. Some are precisely geometrical (Icosahedron) while others are pleomorphic either globular or filamentous. The viral genes express inside host cell and hijack the metabolic pathways and chemical components for synthesising progeny viruses. Hundreds or thousands of progeny may be produced from a single virus infected cell.

Classification of Viral Disorders DNA Viruses Double-stranded DNA Papovavirus Papilloma virus: Human warts JC virus: Progressive multifocal leucoen­cephalo­pathy (PML) zz Adenovirus: More than 30 serotypes; 10% of viral respiratory disease and 7% of viral meningitis zz Human herpes viruses—alpha (neurotropic), beta (epitheliotropic) gamma (lymphotropic) Herpes simplex virus (HSV 1 and 2)–(HHV 1 and HHV 2) Herpes (varicella) zoster virus (HHV 3) Epstein-Barr virus (EBV) (HHV 4): Infectious mononucleosis (glandular fever), Burkitt’s lymphoma, nasopharyngeal carcinoma Cytomegalovirus (CMV) (HHV 5) Herpes virus 6 and 7 (HHV 6 and HHV 7) roseola infantum and post-transplant problems like CMV Herpes virus 8 (HHV 8): Kaposi’s sarcoma zz Pox viruses —— Variola—smallpox (eradicated in 1979) —— Vaccinia—cowpox —— Orf—cutaneous pustules (caught from sheep) —— Molluscum contagiosum—pearly umbilica­ t ed papules zz Hepatitis B virus. Single-stranded DNA zz Erythrovirus (Parvovirus): Erythema infectio­s um— slapped cheek appearance, aplastic crises. zz

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RNA Viruses Double-stranded RNA Reovirus, e.g. Rotavirus—infantile gastroenteritis

zz

Positive single stranded RNA Picornavirus —— Rhinovirus—common cold—>90 serotypes „„ Enteroviruses—leading cause of meningoencephalitis/acute flaccid paralysis  Coxsackie A—meningitis, gastroenteritis  Coxsackie B—pericarditis, Bornholm disease  Hepatitis A virus  Echovirus—30% of viral meningitis  Enterovirus (EV 71)—hand, foot, and mouth disease.  Poliovirus zz Coronavirus zz Togavirus —— Rubella —— Alphavirus —— Flavivirus „„ Yellow fever „„ Dengue fever „„ Hepatitis C

EBV induced B cell malignancies can emerge. EBV also induces nasopharyngeal carcinoma, Persistent HTLV-I infection causes T cell lymphoma or leukaemia. Kaposi’s sarcoma-associated herpesvirus (KSHV also known as HHV-8) can cause Kaposi’s sarcoma.

zz

Negative single stranded RNA zz Orthomyxovirus—influenza A, B, C zz Paramyxovirus —— Parainfluenza —— Mumps —— Measles —— Respiratory syncytial virus zz Arenavirus —— Lassa fever —— Some viral haemorrhagic fevers —— Lymphocytic-choriomeningitis virus (LCM) zz Rhabdovirus—rabies zz Bunyavirus—some viral haemorrhagic fevers Retroviruses—(enveloped RNA viruses using reverse transcriptase to make DNA) zz Human immunodeficiency virus—HIV-1 and HIV-2 zz Human T-lymphotropic virus —— HTLV-I causes adult T-cell leukaemia/lymphoma —— HTLV-II causes tropical spastic paraparesis.

Viral Infections and Cancer Persistent viral infection is estimated to be the root cause of as many as 20% of human malignancies. Chronic HBV and HCV infections of liver predispose to hepatocellular carcinoma. Cervical carcinoma is caused by persistent infection with high-risk HPV strain. When humans are immunosuppressed by post-transplantation medications,

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Viral Pathogenesis Many viruses infect only humans (anthroponotic), others infect humans and animals and some infections are vectorborne. Most common viral infections are spread by direct contact, by ingestion of contaminated water or food, or by inhalation of aerosolised particles. Infection begins on epithelial or mucosal surface and spreads into surrounding tissues. After that they enter the lymphatics, bloodstream and neural circuits. Viruses cause disease on account of invasion of different cells in tissues and organs. The cells have virus receptors to which they get attached. When viruses cause organ based diseases, they are said to be tropic to those organs—neurotropic, hepatotropic (HAV, HBV, HCV, HEV).

Immunity-Viral Diseases Immunity to viral infection is typical of that of obligatory intracellular infections. Immunity can be either antibody mediated which protects from disease upon subsequent exposure or cell-mediated immunity which is operative in infections that spread internally through cell to cell contact. Vaccines using attenuated, inactivated, subunit extraction, or genetically engineered viral proteins can prevent infection. By effective vaccination smallpox was totally eradicated from earth. Measles, rubella, poliomyelitis, mumps, hepatitis, papilloma, JE, and rabies have been controlled effectively.

Diagnostic Virology Rising titers of antibody to virus specific antigens between acute and convalescent phase sera and a shift from IgM to IgG antibodies are generally accepted as diagnostic of acute viral infection. A >4 fold rise in IgG antibody concentration when acute and convalescent phase serum samples are analysed at the same time is diagnostic. zz IF and haemagglutination assays are useful. zz ELISAs can be sensitive and automated. zz Western blots require individual evaluation and are difficult to quantitate or automate. zz Virus isolation in short-term culture with immune detection by staining the culture with a monoclonal antibody to a specific viral protein.

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Manual of Practical Medicine zz

zz

zz

Viruses can be persistently or intermittently colonise normal human mucosal surfaces—herpes virus in saliva or positive CMV in normal urine—hence isolation virus does not establish the cause. Isolation of virus from blood, CSF and tissue are often diagnostic. Detection of nucleic acids does not indicate virus induced disease.

Viral Respiratory Disorders Common cold is caused by rhinovirus, coronavirus and adenovirus. Contamination with infected droplets spreads the infection. The common symptoms are rhinorrhea, sneezing, sore throat, headache, malaise, body pain and fever. Illness is self-limiting and lasts for 4 to 7 days. Treatment is symptomatic—warm saline gargles, analgesics, nasal decongestants and codeine for cough. Complications are sinusitis, bronchitis and pneumonia.

droplets and direct contact. The virus replicates in a few hours and spreads to the adjacent tissues.

Clinical Features The common symptoms are fever, sore throat, myalgias, arthralgias, frontal headache, ocular pain, and photophobia. Chest examination reveals a few rhonchi and crepitations in mild cases and in severe cases diffuse coarse crepitations, and dyspnoea with cyanosis. X-ray chest shows patchy infiltrations or areas of consolidation. Reye’s syndrome is a known complication of Influenza-B and it manifests by the onset of nausea, vomiting, lethargy, confusion, seizure and coma (avoid aspirin). Hepatomegaly may occur along with elevated liver enzymes. Myocarditis, pericarditis, encephalitis, Guillain-Barre syndrome and transverse myelitis are a few complications.

Treatment

Parainfluenza

zz

There are four types of parainfluenza viruses—type 1 causes croup and type 3 causes pneumonia and type 2 and 4 cause mild infections. Infection spreads through infected droplets and direct contact. Children have coryza, fever, sore throat, change in voice and croupy cough. Treatment is with antipyretics, steam inhalation, and for severe bronchiolitis/pneumonia—hospitalisation and oxygen if needed.

zz

Influenza (Figs 3.32A and B) Influenza is a RNA virus which includes A, B, and C types. It occurs in epidemics. Infection spreads through infected

zz

Amantadine 200 mg/day for 5 days. Symptomatic therapy and treat the complications. Influenza vaccine (inactive virus) is recommended to individuals at high risk—those on immunosuppressants and with end-organ failure.

Respiratory Syncytial Virus Infections It is a single-stranded RNA virus. It is the important cause of acute respiratory tract viral infections in infants and children. The infection spreads by infected droplets (large particle aerosols from sneezes) and by direct contact— hand-to-eye, hand-to-nose following hand contact with infected secretions. The infection starts as URTI and ends up with LRTI in a few days time. Chest auscultation reveals

A B Figs 3.32A and B  (A) Influenza—electron microscopy. Long arrow—helical nucleocapsid with segmented RNA; short arrow—spikes (hemagglutinin and neuraminidase) proteins on envelope; (B) Diagrammatic presentation

Ch-3A.indd 114

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115

Infectious Diseases diffuse rhonchi and coarse crackles over both lung fields. Chest radiography reveals hyperinflation with flattened diaphragm or patchy infiltration involving upper lobes or right middle lobe. Bone marrow transplant patients prior to marrow engraftment are at high risk for pneumonia and death.

Diagnosis Confirmation of diagnosis is by antigen detection by immunofluorescence or enzyme immunoassay methods or viral culture from a sterile collection of nasal washing or trachea-bronchial aspirate.

Treatment No specific treatment is available. Supportive treatments include oxygen, inhaled bronchodilators, inhaled ribavirin and mechanical ventilation if need be.

Herpes Virus Infections (Fig. 3.33) Herpes simplex viruses—HSV-1, HSV-2; (Herpesvirus hominis)—produce a wide variety of infections involving mucocutaneous surfaces, CNS and visceral organs. Infection with HSV-1 is acquired more frequently and earlier than HSV-2. More than 90% of adults have antibodies to HSV-1 by the 5th decade of life. Most individuals acquire HSV-1 infection before the 3rd decade of life. Antibodies to HSV-2 are usually detected after puberty in 20% of the population. HSV enters through the mucosal surfaces or abraded skin sites. On entry they replicate in cells of the epidermis and dermis. After sufficient replication, they enter into the neuronal cell—travel intra-axonally to reach the sensory and autonomic ganglia. They establish latent infection

Fig. 3.33  Herpes virus

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in the nerve ganglia. Primary infection is followed by episodes of reactivation throughout life. Both subtypes HSV-1 and HSV-2 can cause orofacial and genital infections. HSV-1 predominantly causes cutaneous, oropharyngeal, Bell’s palsy and ocular infections whereas HSV-2 causes genital herpes. Disseminated disease and frequent recurrences are common in immunocompromised individuals. Dormant HSV in ganglion cells may be reactivated resulting in recurrent attacks throughout life, most often in association with acute medical illness, menstruation, mechanical trauma, immunosuppression, mental stress, and exposure to ultraviolet light. However, the frequency of reactivation of infection is influenced by the anatomic site and virus type. Genital HSV-2 infection is twice as likely to reactivate and recurs 10 times more frequently than genital HSV-1 infection. Conversely, oral-labial HSV-1 infection recurs more frequently than oral-labial HSV-2 infection.

Oral-Facial Infections (Fig. 3.34) HSV-1 pharyngitis and gingivostomatitis usually result from primary infection, whereas reactivation with centrifugal spread of virus causes recurrent herpes labialis. Clinical signs and symptoms include fever, malaise, myalgias, difficulty in eating due to pain, and cervical adenopathy. Lesions may involve the soft and hard palate, gingiva, tongue, lip, facial area, buccal mucosa, posterior pharynx, and tonsillar pillars. Orallabial HSV follows trigeminal nerve root decompression, and dental extraction. Patients with atopic eczema may develop severe oral-facial HSV infection (Eczema herpeticum) HSV-1 and varicella-zoster virus (VZV) have been implicated in the aetiology of Bell’s palsy—flaccid paralysis of the mandibular portion of the facial nerve.

Fig. 3.34  Herpes labialis

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Genital Infections (Figs 3.35A and B) Pain, itching, dysuria, vaginal and urethral discharge along with inguinal adenopathy are common manifestations. Widely spaced bilateral lesions of the external genitalia are common in females. Lesions may be present in varying stages—vesicles, pustules, painful erythematous ulcers over the glans penis, shaft of the penis, cervix, and urethra. Both HSV-1 and HSV-2 can cause symptomatic rectal and perianal infections. HSV proctitis is usually associated with rectal intercourse. Extensive perianal herpetic lesions and HSV proctitis are common in HIV patients.

Herpetic Whitlow Inoculation of HSV through abraded skin surface of the finger results in HSV infection as evidenced by fever, oedema, erythema, vesicular/pustular lesions of fingertip and localized tenderness of the infected finger. Lymphadenitis involving epitrochlear and axillary lymph nodes are common.

Herpes Gladiatorum HSV infection of thorax, ears, face and hands have been described among wrestlers. Transmission of HSV is facilitated by the trauma.

Eye Infections HSV keratitis with characteristic dendritic lesions of the cornea is the commonest cause of corneal blindness. Pain, blurred vision, chemosis, and conjunctivitis are common symptoms. Do not use topical glucocorticoids which may aggravate the lesion with penetration into deeper tissues. Topical antiviral treatment and IFN therapy hastens healing. Disseminated HSV disease can cause chorioretinitis.

Central and Peripheral Nervous System Infections HSV is the most common cause of acute sporadic viral encephalitis. The pathogenesis varies in young children and adults. Primary HSV infection may result in encephalitis by spread of the virus from periphery through the olfactory bulb. Reactivation of latent HSV-1 infection in trigeminal or autonomic nerve roots affecting the CNS is another mechanism in adults. HSV-1 spreads centripetally from the cranial nerve ganglia to the frontal and temporal lobes. Acute necrotising encephalitis of HSV affects the temporal lobe. It presents with fever, headache, vomiting, seizures, dysphasia, memory loss, and hallucinations. The mortality is high if left untreated. HSV can cause lymphocytic meningitis. Autonomic nervous system dysfunction, especially of the sacral region occurs with both HSV and VZV infections in the form of numbness, tingling involving buttocks/ perineal areas, urinary retention, constipation, impotence and CSF pleocytosis. Guillain-Barre syndrome, transverse myelitis, Bell’s palsy, cranial polyneuritis, sensory impairment involving trigeminal nerve distribution, and vestibular dysfunction have been reported.

Visceral Infections Oesophagus: Multiple organ involvement may result from HSV viraemia. It can affect lungs, oesophagus and liver. Direct extension of oral-pharyngeal infection of HSV may result in HSV oesophagitis. Reactivation of HSV latent focus results in the spread of infection via vagus nerve to the oesophagus. The symptoms are odynophagia, dysphagia, retrosternal pain, and weight loss. Multiple oval ulcerations on an erythematous base appear over the distal end of oesophagus. Lungs: HSV pneumonitis is uncommon. It occurs in immunosuppressed individuals as focal necrotising pneumonitis. It can result from haematogenous spread during viraemia or as a result of direct extension from herpetic tracheo-bronchitis. The mortality is very high. Secondary infections are common. HSV has been isolated from the lower respiratory tract of persons with ARDS and prolonged intubation. Liver: HSV is an uncommon cause of hepatitis. It may present with fever, enlarged liver, elevated liver enzymes, leukopenia and DIC.

Diagnosis zz

A B Figs 3.35A and B  Herpes genitalis. (A) Vesicles; (B) Vesicles have ruptured-erosion

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zz

Make a clinical diagnosis. Tzanck preparation—staining of scrapings from the base of the lesion to detect giant cells and intranuclear inclusions of HSV infection.

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Infectious Diseases zz

zz

Acute- and convalescent-phase serum to demonstrate seroconversion and four-fold rise in titer of antibodies. Detection of virus, viral antigen, viral DNA from the scrapings of the lesions confirm the diagnosis by PCR.

Treatment Infections in immunocompetent patients: 1. Genital herpes: —— First episode: Acyclovir 400 mg tid or valacyclovir 1 gm bid or famciclovir 250 mg bid PO for 7 to 14 days or in severe cases/aseptic meningitis give acyclovir 5 mg/kg/tid for 5 days. —— Symptomatic recurrent genital herpes: Acyclovir 800 mg PO for 2 days or valacyclovir 500 mg bid PO for 3 days or famciclovir 750 mg bid or 1500 mg od PO for one day. —— Suppression of recurrent genital herpes: Acyclovir 200 mg qid/400 mg bid/800 mg od PO or famciclovir 250 mg bid or valacyclovir 500 mg od PO or patients with > 9 episodes/year valacyclovir 1 gm od PO continuous. 2. Oral-labial HSV infection: —— First episode: Acyclovir 200 mg qid or famciclovir 250 mg bid or valacyclovir 1 gm bid PO for 10 days. —— Recurrent episodes: Famciclovir 750 mg bid or 1500 mg od or Valacyclovir 2 gm od or 1 gm bid PO single day therapy with topical pencyclovir/ acyclovir cream several applications/day. —— Suppression of reactivation of oral-labial HSV: Oral acyclovir 400 mg bid for 10 days. 3. Surgical prophylaxis for oral/genital HSV infection: (skin laser therapy/nerve root decompression/ lumbar disc surgery) Acyclovir 5 mg/kg tid IV or 800 mg bid PO or valacyclovir 500 mg bid or famciclovir 250 mg bid PO for 10 days (initiate therapy 2 days before). 4. Herpetic whitlow: Acyclovir 200 mg 5 times/day PO for 10 days. 5. HSV proctitis: Oral acyclovir 400 mg 5 times /day. 6. Herpetic eye infections: Topical acyclovir/penciclovir/vidarabine/idoxuridine/trifluorothymidine and interferon are all beneficial. Topical steroids worsen disease. Infections in immunosuppressed patients: Acute symptomatic first/recurrent episodes: Acyclovir 5 mg/kg tid/day IV or acyclovir 400 mg qid PO or famciclovir 500 mg tid or valacyclovir 500 mg bid PO for 7 to 14 days is effective.

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Suppression of reactivation disease (genital or orallabial): Acyclovir 5 mg/kg tid or valacyclovir 500 mg bid or acyclovir 400 to 800 mg 3 to 5 times/ day PO— prevents recurrences during the 30-day period following transplantation. In HIV infected persons, acyclovir 400 to 800 mg bid or valacyclovir 500 mg bid or famciclovir 500 mg bid PO is effective in reducing clinical and subclinical reactivations of HSV. CNS HSV infections HSV encephalitis/aseptic meningitis: Acyclovir 10 mg/kg tid or 30 mg/kg/day—slow IV infusion. Neonatal HSV infections Acyclovir 20 mg/kg tid/day PO for 21 days. Visceral HSV infections HSV oesophagitis and pneumonitis: Acyclovir 15 mg/ kg/day IV for 10 days. In milder cases oral therapy with valacyclovir or famciclovir is effective. Disseminated HSV infections Acyclovir 5 mg/kg tid/day—adjustments for renal insufficiency may be needed. Erythema multiforme associated with HSV 500 mg bid acyclovir 400 mg bid or valacyclovir 500 mg bid PO for six months will suppress the recurrence rate of HSV. Bell’s palsy Valacyclovir 1 gm od/day for 5 days PO (but not acyclovir) along with prednisolone 25 mg bid PO for 10 days is beneficial if started within 7 days of onset. Acyclovir resistant HSV infections Foscarnet 40 mg/kg tid IV/day should be given until lesions heal.

Varicella Zoster Infections Varicella zoster virus (VZV) is HHV-3. Disease manifes­ tations include chickenpox (varicella) and shingles (herpes zoster). Chickenpox is a disease of childhood. Humans are the only reservoir of VZV. Transmission occurs by the respiratory route and subsequent replication of the virus presumably in the nasopharynx leads to seeding of the reticuloendothelial system and viraemia. The VZV infects dorsal root ganglia during chickenpox, where it remains latent until reactivated. The incidence and severity of the herpes zoster (shingles) increase with the age due to an age related decline in immunity against VZV. More than 50% of patients in whom herpes zoster develops are older than 60 years.

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Chickenpox

Complications

The virus is endemic in the population at large. However, it becomes epidemic periodically. Children between the ages of 5 and 10 years are commonly affected. The incubation period is 10 to 20 days. The patients are highly infectious 48 hours before the appearance of rashes and remain so throughout illness and until all vesicles are crusted.

Varicella pneumonia is the most serious complication. Productive cough with haemoptysis, pleuritic chest pain, dyspnoea and cyanosis as a result of interstitial pneumonitis are common. Aseptic meningitis, encephalitis, transverse myelitis, and Guillain-Barré syndrome are some of the CNS complications. Other complications are corneal lesions, myocarditis, hepatitis, glomerulonephritis, arthritis, Reye’s syndrome, and bleeding diathesis.

Clinical Features (Fig. 3.36) Patients develop a prodrome 1 to 2 days before the onset of exanthem with fever, and malaise. The skin lesions— the hallmark of the infection—include maculopapules, vesicles, pustules and scabs in various stages (pleomor­ phism) of evolution. New crops of lesions may erupt for 1 to 5 days. The skin lesions on erythematous base are ‘on’ the skin rather than ‘in’ the skin (dew drop on rose petal). These lesions evolve from macule to vesicle over hours to days, appear on the trunk and face and rapidly spread to other parts of the body. The lesions are also seen over the pharynx and vagina. In immunocompromised patients the lesions are numerous and haemorrhagic and take long time to heal. The common complication of varicella is secondary bacterial superinfection of the skin by Streptococcus pyogenes or Staphylococcus aureus. Skin infection results from excoriation of lesions after scratching. CNS involvement in the form of meningeal inflammation and cerebellar ataxia appear 3 weeks after the onset of the rash and rarely develops in the pre-eruptive phase. The CSF reveals lymphocytosis and increased protein levels.

Perinatal Varicella The mortality rate is high because the newborn has neither received transplacental antibodies nor has a mature immune system. The newborn is at risk for disseminated disease. This happens when maternal varicella develops one week before or within 48 hours after delivery.

Congenital Varicella When mother gets infected during the first or second trimesters of pregnancy varicella carries a small risk of congenital malformations—cicatricial lesions of an extremity (limb hypoplasia), growth retardation, microphthalmia, cataracts, chorioretinitis, deafness, and cerebrocortical atrophy. Diagnosis zz zz

zz zz zz

Varicella is a clinical diagnosis. Tzanck smear of skin lesions for giant cells and inclusion bodies. Four-fold rise in antibody titer. PCR for VZV—vesicular fluid. Immunofluorescent detection of antibodies to VZV membrane antigens, the fluorescent antibody to membrane antigen (FAMA) and ELISA are sensitive.

Treatment zz zz zz

zz

zz zz

Fig. 3.36  Chickenpox pleomorphism

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Patients with varicella should be isolated. Good hygiene includes daily bathing and soaks. Close cropping of finger nails to avoid scratching of the lesions along with antipruritic drugs— antihistamines and calamine lotion. Acyclovir 800 mg PO five times daily for one week. For children below 12 years of age—acyclovir 20 mg/ kg PO qid. Valacyclovir/famciclovir are also effective. Immunocompromised/disseminated disese—acyclovir 10 mg/kg tid IV infusion for 7 days.

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Infectious Diseases Prevention zz

zz

zz

Varicella vaccine: Universal childhood vaccination against varicella is effective. A single dose is adequate for children, whereas adults require two doses. For children the first dose is given at 12 to 15 months and the second dose at 5/6 years. In adults the second dose is given 4 to 6 weeks later. Varicella-zoster immune globulin (VZIG) should be given within 4 days of the exposure. The following are a few indications for VZIG: 1. Exposure to person with chickenpox or herpes zoster. 2. Newborn infant whose mother has chickenpox 3. Immunocompromised susceptible children 4. Susceptible pregnant women 5. Hospitalised premature infants. Antiviral therapy as prophylaxis—individuals who are at high risk, who are not eligible for vaccine or who are beyond the window period of 4 days after direct contact. Acyclovir/famciclovir/valacyclovir can be used.

Herpes Zoster (Fig. 3.37) Herpes zoster (shingles) results from reactivation of latent VZV from dorsal root ganglia. It occurs at all ages, but common after the age of 60 years. Recurrent herpes zoster is exceedingly rare except in immunocompromised hosts, especially those with HIV. It is a unilateral vesicular eruption confined to a single dermatome. Multiple dermatomes are involved in immunocompromised pesons. It is often associated with severe pain. T3 to L3 dermatomes are commonly involved. Zoster-associated pain is a continuum of pain from the onset of erythe­matous maculopapular rash to the resolution. Pain in the dermatome may precede

lesions by 3 days. The total duration of the disease from maculopapule to vesicle and pustule is 7 to 10 days. When trigeminal nerve is involved, lesions may appear on the face, mouth, eye, and tongue. Zoster ophthalmicus can result in blindness if left untreated. Ramsay Hunt syndrome: It presents with pain and vesicles in the external auditory canal, loss of taste sensation in the anterior two-thirds of the tongue and ipsilateral facial palsy. The most debilitating complication of herpes zoster is pain associated with neuritis and postherpetic neuralgia. Neuralgia is uncommon in young individuals, but more common beyond the age of 50 years. Hypo- or hyperaesthesia is common in the affected dermatome. CNS involvement in the form of meningitis, meningo­ encephalitis with altered CSF chemistry (pleocytosis, increased protein), transverse myelitis and granulomatous angitis with contralateral hemiplegia can occur. Immunocompromised patients are prone for cutaneous and visceral dissemination in the form of pneumonitis, hepatitis, meningoencephalitis and other serious complications.

Treatment zz

zz

zz

zz

zz

In uncomplicated herpes zoster, acyclovir 800 mg orally 5 times daily or valacyclovir 1 gm tid PO for 7 to 10 days. In disseminated lesions intravenous acyclovir 10 mg/kg tid for 7 days. Use atropine along with topical pencyclovir/ acyclovir application and immediate referral to ophthalmologist. For post-herpetic neuralgia—the following drugs are used—analgesics ranging from non-narcotic to narcotic derivatives, and drugs such as gabapentin, pregabalin, carbamazepine, phenytoin, valproate, tricyclic anti­d epressants such as amitriptyline hydrochloride, fluphenazine, lidocaine patches, ethylchloride spray, capsaicin cream, and stellate ganglion blocks. A live attenuated vaccine against herpes zoster given at the age of 60 years has shown promising results.

Epstein-Barr Virus (HHV-4) and Infectious Mononucleosis

Fig. 3.37  Herpes zoster

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Epstein-Barr virus is human herpes virus 4 (HHV-4). EBV is the cause of heterophile positive infectious mononucleosis (IM). IM is characterised by sore throat, fever, malaise, lymphadenopathy and atypical lymphocytosis. EBV

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Manual of Practical Medicine is transmitted by salivary secretions. The virus infects epithelial cells of oropharynx and salivary glands. They infect the lymphocytes in the tonsillar crypts directly. The virus spreads through the bloodstream. EBV infection of B-lymphocytes cause proliferation of T-cells (atypical mononuclear cells) which are cytotoxic to EBV infected cells.

Clinical Features EBV infection in infants and young children present as pharyngitis/tonsillitis. In contrast, 75% of CMV infections in adolescents present as IM. The incubation period is 4 to 6 weeks. In the prodromal period (1–2 weeks) patients present with fatigue, malaise, and myalgia followed by fever, sore throat, and lymphadenopathy. Posterior cervical group is commonly involved or it may be generalized lymphadenopathy. The nodes are discrete, tender and not fixed. Splenomegaly is more prominent during the second and third week. Five per cent of cases develop papular rash over the arms and trunk. Erythema nodosum and erythema multiforme have been described.

Complications Most cases of IM are self-limited. CNS—meningitis, ence­ pha­litis, cerebellar ataxia, acute hemiplegia, psychosis, bilateral VIIth nerve palsy, Guillain-Barré syndrome, acute transverse myelitis and peripheral neuropathy. Hepatitis with elevated liver enzymes, autoimmune and hypertrophy of lymphoid tissue resulting in upper airway obstruction can occur. Nonspecific antibody responses may include— rheumatoid factor, antinuclear antibodies, antismooth muscle antibodies, antiplatelet antibodies and cryoglo­bulins. IM has been associated with red-cell aplasia, granulocytopaenia, thrombocytopaenia, pancytopaenia, autoimmune haemolytic anaemia, haemophagocytic syndrome and splenic rupture. Other rare complications are myocarditis, pericarditis, pneumonitis, interstitial nephritis, and vasculitis.

Diagnosis zz

zz

zz

zz zz

Leukocytosis during the 2nd or 3rd week of illness with lymphocytosis. More than 10% of lymphocytes are atypical. Atypical lymphocytes (Fig. 3.38) are nothing but enlarged lymphocytes with abundant cytoplasm, large irregular nuclei, vacuoles, and indentations of the cell membrane. These may occur in other viral infections—CMV, HIV, parvovirus, dengue and typhus, leukaemia, lymphoma, drug hypersensitivity, and lead poison. Heterophile antibody tests (Monospot and Paul-Bunnel tests): Heterophile antibodies develop in 90% of patients in the 3rd week and disappearing after 3 months ( 1 year.

Variola (Small Pox) (Fig. 3.41) It is caused by variola virus. The incubation period was 1 to 2 weeks. It presented with high fever, headache, and prostration. The rash centrifugal in distribution characterized by the uniform progression from macule to pustule and heals by scarring. The complications were keratitis, blindness, pneumonitis, encephalitis and bacterial superinfections. The mortality was very high. Effective vaccination led to its global elimination by 1979 and routine vaccination stopped in 1985.

Fig. 3.41  Small pox

Measles (Rubeola) (Fig. 3.42) Measles is caused by measles virus (RNA virus). It is seen in early childhood. Measles is highly contagious and spreads by droplet spray during prodromal stage. Virus is shed in nasopharyngeal secretion, blood and urine.

Fig. 3.42  Irregular maculopapular rash—measles

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Infectious Diseases Complications zz

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Postinfectious encephalomyelitis—vomiting, con­ vulsions, coma, and neurological deficits—occurs in 0.1% of cases. Guillain-Barré syndrome, cerebral thrombophlebitis and hemiplegia have been reported. Subacute sclerosing panencephalitis (SSPE): It is a very late CNS complication 5 to 15 years after the infection. The measles virus acts as a ‘slow virus’ to produce degenerative CNS disease years after the initial infection. SSPE primarily affects children and very rarely develops in adults. The clinical manifestations are—personality changes, developmental retardation, dementia, myoclonic jerks cerebellar ataxia and various degree of motor disabilities. Measles virus has been isolated from the brain tissue of these patients. There is a high titer of measles specific antibodies in their serum and CSF. EEG shows ‘suppression burst episodes’ in myoclonic stage. CT/ MRI reveals variable cortical atrophy and ventricular enlargement with focal or multifocal lesions in white matter. Treatment is symptomatic and supportive. Respiratory system complications are—bron­chiolitis, bronchopneumonia, pneumonia, bronchiectasis, empyema, mediastinal emphysema and exacerbation of pulmonary tuberculosis. Otitis media and cervical adenitis are common. Conjunctivitis, keratitis and retrobulbar neuritis have been documented. Measles produces temporary anergy to cell mediated skin tests. Diarrhoea and protein losing enteropathy can occur in malnourished children.

Diagnosis zz zz zz

zz

Diagnosis is mostly clinical. Detection of measles specific IgM antibodies. Diagnostic seroconversion or four fold rise of IgG in paired sera. Isolation of virus by tissue culture.

Treatment zz zz zz zz

There is no specific antiviral therapy. Adequate intake of fluids and good nutrition. Vitamin A supplementation if needed Antimicrobials for secondary infection.

zz

Rubella (German Measles) Rubella is a systemic disease caused by a togavirus transmitted by inhalation of infective droplets. The incubation period is 2 to 3 weeks. The importance of rubella lies in its teratogenic effect on the foetus.

Clinical Features zz

zz

zz

zz

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MMR vaccine at the age of 9 months and second dose at the age of 4 to 6 years. Measles vaccine is contraindicated in pregnancy, children with primary immune deficiency, untreated tuberculosis, malignancy, organtransplant and those on immunosuppression.

No prodrome in children, but mild prodrome in adults presenting in the form of fever, malaise and coryza. Posterior cervical and post-auricular lymphadenopathy 5 to 7 days before the rash. Fine maculopapular rash of 3 days duration, appears on the face and then spreading to the trunk and extremities. Hepatitis, encephalitis, and thrombocytopaenia are some complications. Risk of Congenital Malformation in Rubella Infection

Stage of gestation

Likely % of congenital malformations

1–2 months

70–80% chance of illness, multiple defects spontaneous abortion

3 months

30–35% chance of illness, usually a single defect deafness, cataract, glaucoma, mental retardation pulmonary stenosis, patent ductus arteriosus

4 months

10% risk of congenital defects—commonly deafness

> 5 months

Occasional deafness

Diagnosis zz

zz zz

Detection of rubella IgM in serum or by IgG seroconversion Four fold increase in titer of IgG antibody Isolation of virus.

Treatment zz zz

Prevention zz

Post-exposure prophylaxis: Children should be vaccinated with MMR within 72 hours after exposure. Immunocompromised children, children with malig­ nancy and patients with AIDS should be given 0.5 ml of immunoglobin (maximum 15 ml) IM irres­pec­tive of immunity status within 6 days after exposure.

zz

zz

Treatment is symptomatic and supportive. Confirmation of rubella in the expectant mother raises the question of therapeutic abortion, an alternative to be considered in the light of personal, religious, legal and other factors. All women of child-bearing age should be tested for rubella and vaccinated if seronegative. Prevention is better and MMR must be given to all children.

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Mumps

Diagnosis

Mumps is a paramyxoviral systemic disease spread by respiratory droplets and is characterised by swelling of the parotid salivary glands. The incubation period is 2 to 3 weeks. It is infectious in the initial 4 days and infectivity occurs via saliva and urine. Mumps is more serious in adults than in children.

zz

Clinical Features (Fig. 3.43) Classical tender parotid enlargement develops within 48 hours of prodromal symptoms. Parotid enlargement is unilateral in 25% of cases and bilateral in the remaining 75% of cases. Other salivary glands (submaxillary and sublingual) are involved in 10% of cases. Fever and malaise are very minimal. The orifice of Stensen duct is red and swollen. Trismus may occur.

Complications zz

zz

zz

zz

zz

Meningitis: Meningitis presenting with high fever, neck stiffness, headache along with CSF lymphocytic pleocytosis can occur in 10% of cases. Orchitis: It develops one week after the onset of parotitis in about 25% of post-pubertal men, but sterility is rare. Testicular swelling and tenderness is unilateral 75% of cases. Testicular atrophy may occur. Pancreatitis: Upper abdominal pain, nausea, vomiting suggests pancreatitis. Mumps is the leading cause of pancreatitis in children. Oophoritis: Lower abdominal pain and ovarian enlargement suggests oophoritis in 5% of postpubertal women. Rare complications: They include encephalitis, Guillain-Barré syndrome, cerebellar ataxia, facial palsy, acute transverse myelitis, thyroiditis, hepatitis, neuritis, priapism, testicular infarction, myocarditis, nephritis and migratory arthralgias.

zz zz

zz

The diagnosis is usually clinical Serology for mumps specific IgM IgG seroconversion—four fold rise in titer IgG in paired sera Virus detection by PCR in urine, saliva or CSF.

Treatment zz zz

zz

Treatment is symptomatic and supportive. Orchitis: Support the testes with suspensory bandage. NSAIDs are useful. If the pain is not relieved inject locally into the spermatic cord at the external inguinal ring with10 ml of 1% procaine solution. Hydrocortisone sodium succinate 100 mg IV followed by 20 mg qid orally for three days. Interferon alfa 2b may be useful in preventing testicular atrophy. Prevention is by MMR vaccine.

Poliomyelitis Poliomyelitis virus, an enterovirus, is present in throat washings and stool. Excretion of virus may last for many weeks after infection (excretion starts one week before the onset of illness and persists for 4 to 6 weeks after the illness). The human being is the only reservoir of polio virus. There are three distinct serotypes of poliovirus 1, 2, and 3. The incubation period is 10 days. Infection is highly contagious. The virus is transmitted through the faeco-oral route, especially during the first week of the disease. Disease with type 2 in particular is on the verge of extinction.

Pathogenesis The virus multiplies in the mucosa of nasopharynx, intestinal tract and adjoining lymphoid tissue, stimulating the secretion of IgA antibodies which provide local immunity. IgM and IgG antibodies are present in the blood. The immunity is type specific. Infection by one type does not confer immunity against the other types. In 95% of cases the infection is ‘subclinical’ without any symptoms. They shed the virus in stool and they transmit the infection to healthy individuals.

Clinical Features

Fig. 3.43  Mumps—parotid enlargement

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1. Abortive poliomyelitis (Minor illness): There is viraemia in 5% of infected cases. The symptoms are fever, headache, vomiting, diarrhoea/constipation, and sore throat lasting 2 to 3 days. This entity is suspected clinically only during an epidemic. They completely recover.

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Infectious Diseases 2. Non-paralytic poliomyelitis: About 1% of infections present with symptoms and signs of meningeal irritation and muscle spasm without paralysis. This disease is indistinguishable from aseptic meningitis produced by other viruses. They recover completely. 3. Paralytic poliomyelitis: Paralytic poliomyelitis represents 0.1% of all poliomyelitis cases. The incidence is higher when the infection is acquired later in life. They present with fever, nuchal pain, backache and pain and tenderness in muscles. Tremor, muscle weakness, constipation and ileus may occur. Paralysis may occur at any time during the febrile period. Paralytic poliomyelitis is divided into two forms—1. Spinal poliomyelitis and 2. Bulbar poliomyelitis. Spinal poliomyelitis: Lower limb involvement is very common and muscle involvement is asymmetrical. Proximal muscles of the lower limbs are frequently involved. Flaccid paralysis is the most obvious clinical manifestation. Paralysis of the shoulder girdle often precedes intercostal and diaphragmatic paralysis, which leads to decreased chest expansion and decreased vital capacity. In severe cases intercostal, abdominal and trunk muscles are involved. The superficial and deep reflexes in affected limbs are absent. Fasciculations and muscle twitchings may be seen transiently. In 20% of cases bladder may be involved. Bulbar poliomyelitis: It is more common in adults.They present with the weakness of muscles supplied by the lower cranial nerves especially IX and X and of the respiratory and vasomotor centre. The symptoms include facial weakness, dysphagia, dysphonia, nasal voice, weakness of trapezius and sternocleidomastoid muscles, difficulty in chewing and swallowing and regurgitation of fluids through the nose. Respiratory paralysis may lead to hypoventilation and hypoxia resulting in lethargy or coma. Vasomotor centre disturbance results in blood pressure and heart rate changes. Convulsions are rare.

zz zz

Serology is not useful for diagnosis. CSF—pressure is normal, protein normal or mildly elevated, glucose not affected and WBC < 500/mcl with predominant lymphocytosis.

Treatment zz

zz

zz zz

Absolute bed rest in the first few days to reduce the rate of paralysis. Comfortable polio bed—firm mattress, footboard, sponge rubber pads, or rolls, sandbags and light splints. Pay attention to constipation and retention of urine. Intensive care unit for respiratory failure.

Prevention zz

zz

zz

Trivalent oral live poliovirus vaccine (OPV): Four doses are recommended (At birth, 6, 10, and 14 weeks). Inactivated polio vaccine (IPV): It has no risk of vaccine associated paralysis. Three doses of vaccine (6, 10, and 14 weeks) gives 95% protection. Pulse polio immunisation: All children less than 5 years of age are immunised on national immunisation days with two doses of OPV spaced about one month apart regardless of their previous immunisation status.

Rabies (Fig. 3.44) Rabies is a fatal disease and is transmitted by the infected saliva. More than 90% of human cases are due to infected dog bites. Either by bite or licking on the abraded skin or mucous membrane may result in infection. The virus cannot enter through intact skin. Street virus is the natural virus present in rabid animals. The following animals are reservoir of rabies—wolves, foxes, raccoons, shunks,

Complications Urinary tract infection, atelectasis, pneumonia, myocardi­ tis, paralytic ileus, gastric dilatation and pulmonary oedema may occur. Respiratory failure may result from: 1. Paralysis of respiratory muscles 2. Airway obstruction as a result of cranial nerve involvement 3. Lesions of respiratory centre.

Diagnosis zz

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Virus isolation is the confirmative diagnostic test. Virus can be isolated from stool, rectal swab and CSF (PCR).

Fig. 3.44  Rhabdovirus—electron microscopy—bullet shaped

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Manual of Practical Medicine jackals and vampire bat. Infected dog can infect cat and other domestic species. Inhalation of rabies virus aerosol in bat-infected caves can infect man. Transmission occurs through grafting of infected cornea and organ transplant. Respiratory secretions, urine, tears containing virus do not spread the infection.

Pathogenesis Virus multiplies locally in the muscle cells and through motor end plates it reaches the peripheral nerves and then dorsal root ganglion. The virus migrates centripetally towards CNS and replicates massively and then moves centrifugally to reach various organs including salivary glands. Viraemia is rare. Wide spread infection occurs in the brainstem, hippocampus, cerebellum and basal ganglia. Negri bodies can be seen within the cytoplasm of nerve cells in rabid animals.

Diagnosis zz

zz

zz

zz

Treatment zz

zz

Clinical Features The incubation period is 9 to 90 days (days to months to years). Face, head, and neck bites which are close to CNS have a shorter incubation period. The prodromal symptoms consist of fever, malaise, headache, nausea, vomiting, anxiety, insomnia, restlessness, pain and paraethesias over the site of bite wound. The CNS involvement with the stage of excitement is seen 1 week after the prodrome. The CNS involvement may be either “encephalitic” (Furious) or “paralytic”(Dumb). Furious rabies: 80% of cases are encephalitic and they present with delirium, a stage of excitement alternating with calm periods, painful laryngeal spasm on attempting to drink—hydrophobia—autonomic stimulation leading to hypersalivation, and seizures. In the later stages a wide number of stimuli such as strong light, noise and even suggestion of water induce laryngeal spasm with violent contraction of diaphragm and other inspiratory muscles. Babinski’s reflex is positive.

Isolation of virus confirms diagnosis. Virus culture is positive in the first week from saliva, throat swab, eye swab and CSF. Fluorescent antibody test to detect antigen in skin biopsies taken from the hairy area of the nape of the neck is positive in 75% of cases. Antirabies antibody detection in blood confirms the diagnosis. Demonstration of Negri bodies in the brain of the infected animal (Fig. 3.45).

Intensive care with attention to the airway, maintenance of oxygenation, and control of seizures. Milwaukee protocol: The induction of coma by ketamine, midazolam, and supplemental barbiturates along with the use of amantadine and ribavirin was reportedly helpful. There are six documented surviving cases.

Prevention zz zz

Immunization of household dogs and cats. Vaccine: There are three types of vaccine: 1. Purified chick embryo cell vaccine (PCECV), 2. Purified vero cell rabies vaccine (PVRV), 3. Human diploid cell vaccine (HDCV). For post-exposure prophylaxis— Human rabies immunoglobulin (HRIG) 20 IU/ kg— infiltrate at the site of bite and the remaining amount as IM and rabies vaccine on days 0, 3, 7, 14, and 28. Some advocate an optional dose on day 90.

Dumb rabies: In the less common paralytic form, an acute ascending paralysis resembling Guillain-Barré syndrome predominates with relative sparing of higher cortical function initially. Paraplegia or hemiplegia may occur. They have fever and sweat profusely. The stage of excitement is absent. Deep reflexes are absent. Later both the forms progress to autonomic dysfunction, coma and death within a few days after the onset of symptoms. Rabies in dogs: They do not suffer from hydrophobic syndrome. Infected dogs with change in temperament run amok biting anything in its way. The bark is altered. They die in five days time, but some live as carriers.

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Fig. 3.45  Rabies—Negri body

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Infectious Diseases zz

zz

zz

In patients with history of past vaccination, the need for HRIG is eliminated, but post-exposure vaccination is still required. Pre-exposure prophylaxis with three injections of HDCV 1 ml IM over the deltoid muscle on days 0, 7, 21 or 28. Wound treatment: Thorough cleansing, debridement, and repeated flushing of wound with soap and water are important. Do not suture the wound. Give HRIG in addition to rabies vaccination.

Diagnosis zz

zz zz

Treatment zz zz

Dengue Fever (Break-bone Fever) (Fig. 3.46) Dengue fever is due to a flavivirus transmitted by the bite of the Aedes mosquito. There are four serotypes. The incubation period is 7 to 10 days.

Clinical Features A prodromal period of two days with malaise and head­ ache, followed by sudden onset of high fever, chills, severe myalgias, arthralgias, backache, headache, generali­zed body pain (break-bone fever), pain on eye move­ment, lacrimation, anorexia, nausea, vomiting, relative bradycardia, lymphadenopathy, prostration and depression are some of the clinical manifestations of dengue fever. The fever is one of biphasic type—3 to 4 days of fever followed by remission for 2 to 3 days and recurrence (saddle-back). The rash is also biphasic—macular rash in the first 2 days, which is evanescent followed by maculopapular rash that spreads centrifugally sparing the palms and soles. Dengue haemorrhagic fever (DHF): It is a severe form of dengue fever that affects children living in endemic area. It presents with leukopaenia and thrombocytopaenia 20%, pleural effusion, ascites, and hypoalbuminaemia. Dengue shock syndrome (DSS): It is a complication of dengue haemorrhagic fever presenting with signs of circulatory failure as evidenced by tachycardia, narrow pulse pressure - 1 episode in a year Pulmonary tuberculosis—apical or miliary.

Subgroup A: Constitutional Disease zz zz zz

Prolonged fever > 1 month. Unexplained weight loss > 10% of the baseline. Chronic diarrhoea—more than 1 month.

zz zz

Behavioural Problems zz zz

zz zz zz zz

zz

zz

Primary HIV infection leading to inflammatory, demyelinating, or degenerative type of lesion. Aseptic meningitis occurs during seroconversion stage and late stages of the disease. VII, VIII and occasionally V cranial nerves are affected.

AIDS Dementia Complex zz zz zz

Ch-3A.indd 134

Two-thirds of HIV patients are affected. Patient is alert throughout the course of illness. Decline in cognitive function—impaired ability to concentrate, increased forgetfulness, difficulty in performing complex tasks leading to dementia.

Apathy, lack of initiative, vegetative state. CT/MRI reveals cerebral atrophy and cortical thinning with dilatation of the ventricles. Seizures in HIV infected patients. 50% of cases are due to AIDS dementia complex. 25% of cases are due to cerebral toxoplasmosis. Rest of the 25% of cases are due to cryptococcal meningitis, CNS lymphoma, and multifocal leukoencephalopathy.

Spinal Cord Lesions zz

zz zz

Vacuolar myelopathy similar to sub-acute combined degeneration of B12 deficiency—posterior and lateral columns—with increased tone, extensor plantar response, gait disturbance, bowel and bladder involve­ment. Dorsal column involvement with pure sensory ataxia. Paraesthesias/dysaesthesia of lower limbs.

Peripheral Neuropathies zz zz

zz

zz

Occur at all stages of illness. Demyelinating neuropathy similar to infective polyneuritis with proximal muscle weakness, areflexia, and minimal sensory deficit. Mononeuritis multiplex—individual peripheral nerves are affected as in diabetes mellitus. Distal symmetrical painful polyneuropathy.

Myopathy zz

zz

Subgroup B: Neurologic Disease

Motor problems—unsteady gait, poor balance. Spinal cord involvement with increased tone, exaggerated deep tendon reflexes, bowel and bladder incontinence.

Myalgias and proximal muscle weakness are common in HIV. Prolonged zidovudine therapy can cause myopathy.

Subgroup C: Secondary Infections Eighty per cent of HIV patients die of secondary infections. Greater incidence when the CD4+ T cell count falls below 200/µl. Protozoal Infections Pneumocystis jiroveci zz zz zz zz

It causes pneumonia. It presents with fever and non-productive cough. Typical clinical signs and X-ray findings are absent. Clinical suspicion for all AIDS patients when CD4 count falls below 200/µl.

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Diagnosis by demonstrating the organism in sputum, bronchoalveolar lavage, transbronchial biopsy or open lung biopsy.

Extrapulmonary Manifestations They are otitis, retinitis, thyroiditis, vasculitis, intestinal obstruction, lymphadenopathy, visceral and bone marrow involvement, and ascites. Management of Pneumocystis jiroveci Infection zz

zz

Trimethoprim/sulfamethoxazole 15 to 20 mg/kg/day PO or IV or TMP 20 mg/kg/day PO + dapsone 100 mg od PO or clindamycin 600 mg qid PO + primaquine 15 mg od PO or pentamidine 3 to 4 mg/kg/day IV or pentamidine 300 mg/day aerosol. Duration of treatment—21 days.

Entamoeba histolytica and Giardia lamblia zz

Management zz

zz zz

Toxoplasmosis of brain is most common secondary infection of CNS. 20% of AIDS patient develop this infection. It occurs in very late stage of AIDS when CD4+ count falls below 100/µl.

Clinical Features zz

zz

It manifests with fever, headache, focal neurological deficit such as seizure, aphasia, hemiparesis and coma. CT—multiple ring enhancing lesions.

Mycobacterium avium Complex and M. intracellulare zz zz

zz

Isospora belli zz

zz

TMP/SMX 10 mg/kg/day PO for ten days and then half of the dose for three months.

Cryptosporidia and Microsporidia zz

Both can cause diarrhoea and dysentery.

Management zz

Ch-3A.indd 135

Metronidazole 400 mg tid for 7 to 10 days.

It is easy to treat and it responds to INH, rifampin and ethambutol. Other atypical mycobacterial infections do not respond to therapy.

Mycobacterium tuberculosis zz

zz

zz

zz

It occurs early in the course of HIV infection. In the early phase they respond to conventional three drug therapy—nine months. Disseminated tuberculosis is more common with low CD4 counts. PPD skin test > 5 mm induration is taken as positive in patients with HIV infection. Emerging problem is multi-drug resistant (MDR) tuberculosis. Pulmonary TB—bilateral involvement, lower lobe involvement, and high sputum negativity are common.

Other Bacterial Infections zz

It causes diarrhoea.

Management

Ethambutol 15 mg/kg/day od + Clofazimine 100 mg od + Cifrofloxacin 750 mg od + Azithromycin or Clarithromycin for life.

M. kansasii Infection zz

Management Sulfadiazine 1 to 2 gm qid PO + pyrimethamine 25 to 100 mg qid or clindamycin 300 to 900 mg PO or 300 mg IV tid + pyrimethamine 25 to 100 mg qid or atovaquone 250 mg qid + pyrimethamine. Duration of treatment—life long.

It occurs when CD4+ count falls below 100/µl. Disseminated lesions are common and bone marrow aspiration is diagnostic.

Management zz

zz

zz

Metronidazole 400 mg tid for 10 days.

Bacterial Infections

Toxoplasma gondii zz

Both can cause diarrhoea and dysentery.

zz

zz

Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus can cause pulmonary and other infections. Enteric pathogens Salmonella, Shigella and Campylo­ bacter can cause gastroenteritis. Treponema pallidum can co-exist or infect the HIV infected patients. The incidence of neurosyphilis is high.

Fungal Infections Candida zz

Candida infection of posterior oro-pharynx, gingivallabial margins and vagina occur early in the course of HIV infection.

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Manual of Practical Medicine zz

zz

Candida infections of oesophagus, trachea, bronchus and lungs occur late in the course of HIV infection when the CD4+ T cell count falls below 100/µl. Iatrogenic causes such as indwelling catheters, broad spectrum antimicrobials, and drug-induced neutropaenia predispose to invasive disease.

Management zz zz

Fluconazole 200 mg od PO for 14 days. Amphotericin B 0.25 mg/kg/day IV for 10 days.

Cryptococcus neoformans zz zz zz zz zz

It causes CNS and pulmonary infections. Symptoms like fever, headache, vomiting occur. Meningeal signs with seizure occur in meningitis. MRI shows multiple ring-enhancing lesions. Cough, haemoptysis and dyspnoea occur with pulmonary infections.

Herpes Simplex Virus zz

zz zz

Management Acyclovir 200 mg five times daily PO or 5 mg/kg tid IV for 14 days. Herpes Zoster Virus zz

zz zz

India ink preparation of CSF is diagnostic. Detection of cryptococcal antigen in the blood or CSF. Culture and isolation: Blood, CSF, sputum, bone marrow.

Histoplasmosis zz

zz

Lung infection and disseminated lesions are caused by Histoplasma capsulatum and are common in endemic areas. Amphotericin and itraconazole are useful in the management.

Acyclovir 800 mg PO five times daily or 10 mg/kg IV tid for 14 days.

Epstein-Barr Virus (EBV) zz

zz

Management Amphotericin B 0.3 mg/kg/day IV + Flucytosine 150 mg/kg/day PO for 6 weeks followed by fluconazole 100 mg od for life.

Extremely painful, recurrent lesions involving several dermatomes and bilateral involvement crossing the midline are common in HIV infected patients.

Management zz

Investigations zz

Recurrent lesions occur over the orolabial, genital, and perianal areas. Painful ulceration with beefy-red colour is common. It causes painful keratitis, iritis, in contrast to painless CMV choroidoretinitis.

It is the causative agent of infectious mononucleosis, lymphoma, and oral hairy leucoplakia (OHL) OHL is seen in the lateral aspect of the tongue which cannot be scraped in contrast to candida lesion.

JC Virus zz

zz zz

It causes progressive multifocal leukoencephalopathy (PML). It involves cerebrum, cerebellum and brainstem. Signs: Aphasia, visual field defects, ataxia, hemiparesis, sensory deficit.

Human Papillomavirus zz

It causes cervical and anal carcinoma.

Viral Infections

Hepatitis B, C, and D

Cytomegalovirus (CMV)

zz

zz zz zz

zz

95% of HIV infected patients are sero-positive for CMV. It causes retinitis, oesophagitis, and colitis. It induces painless progressive loss of vision—usually bilateral. Disseminated CMV lesions occur when the CD4 + T cell count fall < 100/µl—eyes, CNS, liver, mouth, gut, adrenals and lungs.

Management Gancyclovir 5 mg/kg bid for 14 days followed by od dosage for life or foscarnet 60 mg/kg tid for 14 days followed by 90 mg/kg once daily IV for life.

Ch-3A.indd 136

These infections are also common in HIV infected patients.

Subgroup D: Secondary Neoplasms Kaposi’s Sarcoma zz zz zz

zz

zz zz

It is an uncommon neoplasm before AIDS. It is linked with human herpes virus-8 (HHV-8). The skin, mouth, hard palate, penis and lower limbs are common sites. It consists of multiple vascular nodules (vascular origin). Size of the lesion varies from a few mm to several cm. The colour of the lesion is reddish purple or brown.

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Infectious Diseases zz

zz

Other organs involved—lymph nodes, liver, spleen, GIT, and lungs. It never involves brain.

Management zz

zz

zz

Single/limited number of lesion: Radiation/ cryotherapy and intralesional vinblastine. Extensive lesion, non-life threatening: Single agent chemotherapy—vinblastine/bleomycin/interferon α if CD4 + T cell count falls below 100/µl. Life-threatening: Combination chemotherapy with bleomycin, doxorubicin and vinblastine; radiation.

Lymphoma zz

zz

zz

zz

zz

zz zz zz

It occurs in HIV patients with CD4+ T cell counts < 200/µl. 80% arises from B lymphocytes and the rest from T cells. There are three types: 1. Immunoblastic lymphoma 60% 2. Burkitt’s lymphoma 20% 3. Primary CNS lymphoma 20% Extranodal sites commonly affected are CNS, bone marrow, GIT, and liver. CNS lymphoma presents with headache, seizures, cranial nerve palsies. MRI/CT reveals 3 to 5 cm ring enhancing lesions. Tissue biopsy confirms the diagnosis. Combination chemotherapy is advocated and the average survival is 1 year.

Intraepithelial Dysplasia The common manifestations are cervical and perianal carcinoma.

GIT Disorders in HIV HIV—by itself can cause enteropathy leading to diarrhoea, malabsorption, and weight loss. Other causes of diarrhoea are Cryptosporidium, Micro­ sporidium, CMV, MAI, Giardia, and Entamoeba hystolytica infections, Strongyloides stercoralis infestation, and Kaposi’s sarcoma. Oesophagus Candidiasis, CMV oesophagitis, primary lymphoma and Kaposi’s sarcoma. Stomach: Achlorhydria is common. Lymphoma and Kaposi’s sarcoma can occur. Rectum: HSV ulcers, condyloma, Kaposi’s sarcoma and carcinoma are common. Hepatobiliary Disorders in HIV zz zz zz

Viral hepatitis A, B, C, and CMV, MAI infections. Kaposi’s sarcoma and lymphoma. Candida, cryptosporidia, microsporidia cause acalculous sclerosing cholangitis.

Pulmonary Disorders in HIV zz

zz

zz

zz

Pneumocystis pneumonia, tuberculosis, and MAI, CMV, HSV, Streptococcus pneumoniae, H. influenzae, and Staphylococcus aureus infections. Non-specific interstitial pneumonitis and lymphocytic interstitial pneumonia. Fungal infections: Candida, Aspergillus, and Histo­plasmosis. Kaposi’s sarcoma and lymphoma.

Subgroup E: Other Conditions Lymphoid interstitial pneumonia and throm­bocyto­paenia, etc. can occur.

Organ Specific Syndromes Oral Lesions in HIV (Fig. 3.49) The oral lesions are candidiasis, angular stomatitis, hairy leucoplakia, gingivitis, CMV/herpes simplex/zoster-viral stomatitis, warts, aphthous ulcers and Kaposi’s sarcoma. Skin Disorders in HIV They are seborrhoeic dermatitis, folliculitis-impetigo, cellulitis, fungal infections, molluscum contagiosum, herpes simplex, herpes zoster, Kaposi’s sarcoma and drug eruptions.

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Fig. 3.49  Hairy leucoplakia

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Manual of Practical Medicine CNS Disorders in HIV zz

zz

zz

HIV causes meningitis, encephalitis, AIDS dementia complex (ADC), myelopathy, neuropathy and myopathy. CNS lesions can be as a result of secondary infections and neoplasms. Secondary infections such as tuberculosis, toxoplasmo­ sis, cryptococcosis, CMV, HSV, and syphilis causing meningitis, brain abscess and neurosyphilis.

Investigations zz

zz

Psychiatric Disorders in HIV zz

They are mood disorders, behaviour disorders, cognitive disorders, anxiety and depression.

Haematological Disorders in HIV zz

zz

zz

Idiopathic thrombocytopaenic purpura (ITP), lymphopenia, anaemia. Anaemia is either due to direct bone marrow suppres­ sion or due to bone marrow infiltration with MAI/TB/ lymphoma or due to drug induced myelosuppression. Neutropaenia, thrombocytopaenia—either due to HIV or drug therapy.

Lymphadenopathy zz

zz

zz

zz

It is due to HIV/mycobacterial infections/fungal infections or Kaposi’s sarcoma and lymphoma.

Renal Disorders in HIV zz

zz

HIV induces nephropathy—focal segmental glome­ rulo­sclerosis—proteinuria, oedema and hypertension. Drug-induced nephropathy—amphotericin B, pentamidine, foscarnet, tenofovir, etc.

zz

zz

Heart Disease in HIV zz zz

HIV can cause dilated cardiomyopathy. Toxoplasmosis, cryptococcosis, Kaposi’s sarcoma, lymphoma and mycobacterial infections can cause myocarditis and pericarditis.

Metabolic and Endocrine Disorders in HIV zz

zz

zz

Ch-3B.indd 138

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) causes hyponatraemia. Adrenal insufficiency: Mycobacterial infections, CMV, cryptococcal infections, histoplasmosis, Kaposi’s sarcoma, and ketoconazole toxicity can affect adrenals. Low sodium and high potassium levels in serum are diagnostic. Hypogonadism: Impotence due to HIV infection or ganciclovir toxicity.

zz

zz

zz zz zz

zz zz zz

ELISA—Enzyme-linked immunosorbent assay is useful to demonstrate antibodies to HIV (ELISA kit for HIV1 and HIV2). An isolated positive ELISA result should not be reported to the patient until this result is confirmed by a Western blot. Confirmation of HIV is by Western blot test. Following infection, it takes 6 to 12 weeks for the antibodies to appear and so, serial testing may be required. In Western blot test antibodies to multiple antigens of HIV (gag, pol, and envelop proteins) can be detected as discrete bands. Positive Western blot contains bands for at least two of the gene products—p24, gp41, and gp120/160. Indeterminate Western blot may be a pattern indicating mounting antibodies in evolution and the test must be repeated after 1 month. Direct cultivation of HIV from plasma or peripheral blood mononuclear cells. Culture has to be monitored for 28 days. Polymerase chain reaction: There are two types— DNA PCR and RNA PCR. PCR test is useful in patients with indeterminate Western blot test. HIV rapid antibody test: It is a screening test. It produces results in 10 to 20 minutes. It can be performed by personnel with limited training. Positive test must be confirmed with standard HIV test (ELISA and Western blot). Complete blood count: Anaemia, neutropaenia, and thrombocytopaenia are common with advanced HIV infection. Absolute CD4 lymphocyte count: Useful to assess the progress of the disease. The risk for secondary infection and neoplasms are greater if the count is low. CD4 lymphocyte percentage: Percentage may be more reliable than the CD4 count. Risk opportunistic infection or malignancy is high with percentage < 14% in the HIV patients in the absence of treatment. HIV viral load tests: Used to measure the amount of actively replicating HIV virus. Correlate with disease progression and response to antiretroviral drugs. Tuberculin skin test. Rapid plasma regain (RPR) test. Toxoplasma and CMV immunoglobin (Ig) G and hepatitis A, B, and C serologies. Chlamydia/gonococcal urine/cervical probe. Cervical Papanicolaou smear. HIV resistance testing.

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Monitoring zz

zz

zz

Plasma HIV RNA load is used for monitoring of therapy. The goal is to reduce the viral load levels below the detection limits. After starting ART the viral load should be checked every 4 weeks. When the ultrasensitive HIV RNA becomes undetectable and the patient is on a stable regimen, monitoring can be done every three months. CD4 + T cell counts should be checked periodically to assess the immune status of the patient and to define the start of prophylactic therapy. HIV resistance testing is done using two different types of assays—genotypic and phenotypic. Results of resistance testing can be used to guide ART.

Treatment Immunizations Pneumococcal vaccine: Antibody response is good when the CD4 count is > 200 cells/µl. Revaccination after 5 years should be considered. zz HAV and HBV vaccination: If respective antibodies are negative. Currently there is no vaccine for HCV. zz Influenza vaccination has been recommended. zz Tetanus/diphtheria vaccine. zz Human papilloma virus vaccine for HIV infected women age 26 years or less. zz

Prophylaxis: Opportunistic Infections HIV infected individuals with CD4 < 200 cells/mcl— Pneumocystis jiroveci prophylaxis is essential. —— Trimethoprim-sulfamethoxazole—one double strength tablet three times a week to one tablet daily or —— Dapsone—100 mg thrice weekly or 50 mg daily or —— Atovaquone—1500 mg daily with a meal or —— Aerosolized pentamidine—300 mg monthly. zz HIV infected individuals with CD4 < 75 cells/mcl— Myco­b ac­t erium avium complex prophylaxis is required. —— Clarithromycin 500 mg PO twice daily or —— Azithromycin 1200 mg PO once a week. zz HIV infected individuals with CD4 count < 50 cells/ mcl—consider CMV prophylaxis. —— Oral gancyclovir 1000 mg tid with food. The drug causes neutropaenia. CMV IgG negative patients are not at risk for development of CMV disease and so, it is advised to test for CMV IgG antibody prior to gancyclovir therapy. zz Prophylaxis against M. tuberculosis—INH 300 mg daily with pyridoxine 50 mg daily for 1 year to all HIV infected patients with positive tuberculin test (induration > 5 mm). zz

Ch-3B.indd 139

Prophylaxis against toxoplasmosis—TMP-SMX one double strength daily or a combination of pyrimetha­ mine 25 mg PO once a week + leucovorin 25 mg PO/ week + dapsone 50 mg PO daily. zz Prophylaxis against cryptococcosis, candidiasis, and other fungal diseases—Fluconazole 200 mg PO daily for cryptococcal disease. Oral and vaginal candidiasis can be prevented by fluconazole 200 mg PO once a week. Antiretroviral therapy Indications zz Patients with CD4 count of < 200 cells /microlitre or in the symptomatic patient regardless of the CD4 count or viral load. zz Patients when the HIV RNA is > 100,000 copies/ml. zz In the asymptomatic patients, if the CD4 count is > 350 cells/microlitre there is no strong evidence of clinical benefit of early initiation of ART. Initiate ART when the CD4 count is between 200 and 350 cells/ microlitre even though there is some controversy. Antiretroviral drugs are grouped into six categories: 1. Nucleoside reverse transcriptase inhibitors (NRTIs): They constrain HIV replication by incorporating into the elongating strand of DNA, causing chain termination. zz

Drug

Dose

Common side effects Special monitoring Zidovudine 300 mg PO bid Anaemia, No special (AZT) (Retrovir) neutropaenia, monitoring nausea, malaise, headache, insomnia, myopathy Didanosine (ddI) 400 mg PO Peripheral Neurological neuropathy, examination, Daily - WT > pancreatitis, dry K+, amylase, 60 kg mouth, hepatitis TGL Zalcitabine 0.375–0.75 mg Peripheral Neurological (ddC) PO tid neuropathy, examination aphthous ulcers, hepatitis Stavudine (d4T) 40 mg bid Peripheral Neurological neuropathy, examination, PO—WT > pancreatitis, hepatitis amylase 60 kg Lamivudine 150 bid PO Rash, peripheral Neurological (3TC)(3TC) neuropathy examination (Epivir) Emtricitabine 200 mg PO Skin discolouration No special (Emtriva) (FTC) Once daily of palms and soles monitoring (mild) Abacavir 300 mg PO bid Rash and fever—if No special (Ziagen) (ABC) occurs, rechallenge monitoring may be fatal

2. Nucleotide reverse transcriptase inhibitors Tenofovir (TDF)

300 mg PO od

Gastrointestinal distress

Monitor kidney function

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Manual of Practical Medicine 3. Protease inhibitors (PIs): They block the action of the viral protease required for protein processing late in the virus cycle. They are used in combination regimens. Indinavir (IDV)

800 mg PO tid

Saquinavir (SQV)

Renal calculi

1000 mg PO bid usually with RTV 100 mg bid Ritonavir (RTV) 600 mg PO bid or 100 mg bid to boost other PIs Nelfinavir (NFV) 750 mg PO tid

Cholesterol, TGL, bilirubin Gastrointestinal Cholesterol distress and triglycerides (TGL) Gastrointestinal Cholesterol, distress, peripheral TGL paraesthesias Diarrhoea Cholesterol, TGL Gastrointestinal Cholesterol, distress, rash TGL

Fosamprenavir 700 mg PO bid with RTV 100 mg bid Lopinavir/ 400/100 mg Gastrointestinal Ritonavir PO bid distress— diarrhoea Atazanavir (ATZ) 400 mg PO od Hyperbilirubinemia Tipranavir/ 500/200 mg Gastrointerstinal Ritonavir PO bid distress, rash Darunavir/ 600/100 mg Gastrointestinal Ritonavir PO bid distress, rash

Delavirdine (DLV) Efavirenz (EFV)

Etravirine

Bilirubin Cholesterol, TGL Cholesterol, TGL

200 mg PO od 2 weeks and then 200 mg bid 400 mg tid PO

Rash

No monitoring

Rash

No monitoring

600 mg od

Neurologic No monitoring disturbances Rash, nausea No monitoring

200 mg od PO

5. Entry inhibitors: They target different stages of the HIV entry process into the cells. Enfuvirtide (T-20) Maraviroc (CCR5 Antagonists) (CC-Chemokine receptor -5)

90 mg SC bid 150–300 mg od PO

Injection site pain and allergic reaction Cough, fever, rash

No monitoring

400 mg PO bid

Diarrhoea, nausea, headache

zz

zz

zz

zz

No monitoring

Lipodystrophy syndrome —— Alteration in body fat distribution —— Accumulation of visceral fat in the abdomen, neck (Buffalo hump), and pelvic area —— Depletion of subcutaneous fat over the face and periphery Hyperlipidaemia —— Elevated TGL mainly with protease inhibitors —— It can be controlled with statins and fenofibrates Hyperglycemia —— Due to peripheral insulin resistance —— Can cause impaired glucose tolerance Lactic acidosis —— It is due to mitochondrial toxicity —— Hepatomegaly with steatosis Bone metabolism —— Osteopenia and osteoporosis —— Osteonecrosis of the hip.

Treatment Failure zz

zz

zz

zz

zz

Management of HIV infection includes ART, proph­ ylaxis and treatment of opportunistic infections and neoplasms.

Ch-3B.indd 140

zz

No monitoring

6. Integrase inhibitors: They slow HIV replication by blocking the HIV integrase enzyme needed for the virus to multiply. Raltegravir

Complications of ART

Cholesterol, TGL

4. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): They inhibit HIV by binding noncom­ petitively to the reverse transcriptase. They inhibit reverse transcriptase at a site different from that of the nucleoside and nucleotide agents. Nevirapine (NVP)

Only combinations of three or more drugs have been able to decrease HIV viral load by 2 to 3 logs and allow long term suppression of HIV RNA to below the threshold of detection. Potent ART generally consists of a combination of two NRTIs plus one or two PIs or a NNRTI. Current evi­ dence support the use of tenofovir and emtricitabine as the “nucleoside/nucleotide back-bone” combined with efavirenz. It has the advantage of once daily dosage. This combination is more effective and better than zidovudine and lamivudine.

Less than a log (10 fold) reduction of the viral load 6 weeks after therapy Failure to reach an undetectable viral load after 6 months of treatment Detection of the virus after initial complete suppression of viral load Persistent decline of CD4 cell count or clinical deterioration HIV resistance testing is useful in cases of confirmed treatment failure, to select and institute at least two new drugs that have no cross resistance in the ART regimen.

Assessment of Clinical Benefits Following Therapy zz zz zz zz

Increase in CD4 + T cell counts Decrease in viral load Decline in P24 antigen levels Improved sense of well being.

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Anti-HIV Drugs Prophylaxis Prophylaxis with AZT + Lamivudine + Indinavir for four weeks is needed for needlestick injury or on exposure to HIV infected blood—usually due to trauma during surgery.

and female gametocytes—ingestion of RBC by the mosquitoes—fusion of gametozoites in the mosquito gut to form ookinete—develops into an oocyst—maturation into sporozoites—migration into the salivary gland— infected mosquito—human.

Prevention

Immune Response

zz

zz zz zz zz zz zz zz zz zz

Safe sex practices—use of condoms. Avoid penetrative intercourse. Screen and treat sex workers Control of STD and treatment of partners Antenatal screening Avoid pregnancy—if HIV seropositive Avoid breastfeeding in HIV infected mother Screening of blood and blood products Avoid sharing needles/blades Health education Vaccine.

PROTOZOAL INFECTIONS Malaria Malaria is a mosquito-borne tropical disease caused by five species of the genus Plasmodium (P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi). It is transmitted by the bite of infected female anopheline mosquitoes. Malaria may be transmitted from mother to infant (transplacental spread—congenital malaria), and by blood transfusion. It affects mainly the hepatocytes and RBCs and manifests clinically as intermittent fever, and splenomegaly. In India 90 to 95% of patients with malaria have P. vivax infections and the remaining 5 to 10% are due to P. falciparum.

Life Cycle (Fig. 3.50) Infected female anopheline mosquitoes inject sporozoites during feeding—transported to liver by bloodstream (In P. vivax and P. ovale, some sporozoites develop into hypnozoites and remain dormant for 8 to 10 years and then replication and relapse occurs)—undergo asexual maturation in hepatocytes—primary schizonts and then merozoites—hepatocyte rupture—release of merozoites into the circulation—invading RBCs (erythrocytic phase of life cycle)—each merozoites mature into trophozoite and erythrocytic schizont—on maturation RBC rup­ tures to release 6 to 32 daughter merozoites—each merozoite invade one RBC and the cycle continues—a small percentage of merozoites differentiate into male

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In endemic regions, many individuals have a genetic resistance to malarial infection. Both humoral and cellmediated immune response may develop over weeks following infection. This causes amelioration of fever and marked decrease in parasite quantum, but does not eradicate infection. The immune response is complex.

Clinical Features (Fig. 3.51) Constitutional symptoms: Malaise, fatigue, headache, followed by paroxysms of fever zz Cold phase: It lasts for 20 to 40 minutes. Abrupt onset of chills—uncontrollable shivering (rigors) and it is due to cutaneous vasoconstriction. zz Hot phase: The temperature shoots upto 40°C asso­ ciated with headache, flushing and tachycardia. It lasts for 4 to 8 hours. zz Wet phase: The temperature falls down with profuse sweating in the absence of treatment. zz Periodicity of fever: The paroxysms correspond with RBC lysis. Vivax and falciparum causes tertian fever (3rd day fever), P. malariae causes quartan fever (4th day). zz Recurrence of fever: It occurs in vivax infections due to release of merozoites from hepatic hypnozoites for a period of 8 to 10 years and does not occur in P. falciparum infection. zz Chronic malaria: Partial immunity in cases of persist­ent hepatic P. vivax infection may permit asymptomatic low grade parasitaemia and the immune stimulation can cause progressive splenomegaly. Enlarged spleen may rupture spontaneously or following trauma. zz Tropical splenomegaly syndrome: In endemic regions massive splenomegaly is common in the absence of parasitaemia. They have elevated serum IgM levels, antimalarial antibodies, and hepatic sinusoidal lymphocytic infiltration. This excessive immunological response can occur in repeated infections by all species of plasmodium. The symptoms and signs are due to mass effect or hypersplenism. Prolonged course of proguanil therapy results in regression of splenomegaly.

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Fig. 3.50  Life cycle—malarial parasite

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Infectious Diseases

Fig. 3.51  Features of P. falciparum infection Features

P. vivax and P. ovale

P. falci­ parum

P. malariae

Incubation period

1–3 weeks

1–3 weeks

2–4 weeks

Type of fever

Tertian

Quotidian

Quartan

Exo-erythrocytic cycle

Yes

No

No

Relapses

Common (upto 1–2 years)

Recrude­ scence

Recrude­scence (for many years)

Plasmodium falciparum (Figs 3.52A and B) zz

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Severe malaria: About 1% of patients with P. falciparum infection develop severe (pernicious) malaria involving many organs. It is because this species uniquely infects erythrocyte of all ages and mediates the sequestration of infected RBCs in small blood vessels, thereby

evading clearance of infected RBCs by spleen. It can cause dysfunction of any organ system. zz Cerebral malaria: Altered conscious level, repeated seizures and coma. It is more common in children and pregnant women. The mortality rate is high—25%. It is also common in splenectomised individuals and non-immune traveller. Hyperpyrexia is common. There is no neck rigidity. Frequent hypoglycaemia, haemoglobinuria and jaundice (due to haemolysis) are common. In children, decerebrate and decorticate rigidity, opisthotonus, papilloedema and raised intracranial pressure with or without transtentorial herniation may be present. Smear for MP is teeming with parasites— >10% of RBCs are infected. Cerebral oedema is rare in adults.

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Manual of Practical Medicine zz

zz zz

zz

Metabolic disorders: Frequent hypoglycaemia, and acidosis. Fundus: Retinal haemorrhages. Others: Secondary bacterial infections including pneumonia, and salmonella infection with bacteremia. Hyperparasitaemia: > 5% of RBCs are parasitised and it occurs in non-immune patients.

Plasmodium ovale zz zz

zz

It causes benign tertian malaria and it is rare in India. It tends to cease after a few paroxysms even without therapy. Hepatic hypnozoites may persist for years.

Plasmodium malariae Fig. 3.52A  Plasmodium falciparum—“banana-shaped” gametocyte

zz zz

It causes benign quartan fever (72 hours periodicity). Renal damage is more common due to progressive glomerulonephritis caused by deposition of immune complexes and it does not respond to antimalarial drugs or corticosteroids.

Malaria in Pregnancy zz zz

zz

zz

zz

P. vivax and P. falciparum infections can occur. Foetal loss and intrauterine growth retardation are common. Doxycycline, tetracycline, halofantrine, and pri­ maquine are contraindicated. Mefloquine and artemesinin are safe in second and third trimesters. Chloroquine and quinine are safe during pregnancy.

Investigations zz

Fig. 3.52B  Plasmodium falciparum—RBCs containing a ring-shaped trophozoite

zz

zz

zz

zz

zz

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Cardiovascular: Severe hypotension, cold, clammy extremities, and shock. Respiratory: The clinical manifestations are acute respiratory distress syndrome, noncardiogenic pulmo­ nary oedema, hypoxaemia, and respiratory failure. Haematological: Severe anaemia, disseminated intravascular coagulation resulting in bleeding from gums, nose, GIT (Thrombocytopaenia, prolonged PT, PTT), Haemoglobinuria in the absence of G6PD deficiency. Renal: Acute kidney injury due to acute tubular necrosis or severe haemolysis and renal failure—reduced urine output < 400 ml/day and elevated serum creatinine. Hepatic: Haemolysis, hepatic dysfunction and jaundice.

zz

zz

zz

Microscopic examination of thick and thin smears— thick smears provide efficient evaluation of large volumes of blood. Thin smears are simpler for inexperienced personnel and better for discrimination of parasite species. Fluorescence microscopy: Fluorescent dyes are taken up by the nucleic acids in parasite nucleus. This method needs less experience than conventional microscopy. It can detect > 50 parasites/mcl of blood. It is difficult to identify the species. Immediate examination is essential to avoid fading of dye. Polymerase chain reaction (PCR): Most specific and sensitive method, but costly. It can detect as low as 5 parasites/mcl of blood. Results are possible after 24 hours. Immunochromatographic dipstick methods: They are simpler to perform and offer sensitivity and specificity near that of high quality blood smear.

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Infectious Diseases Treatment zz

zz

zz

zz

zz





zz

zz

Ch-3B.indd 145

PLDH detection tests (OptiMAL test): This test uses two monoclonal antibodies directed against parasite LDH. Presence of single band indicates negative test; double band denotes other than falciparum species infection and triple band indicates P. falciparum infection. Complete haemogram, blood sugar, urea, creatinine, LFT, pH and plasma bicarbonate. Rapid diagnostic card test: PF HRP 2 test (Plasmodium falciparum histidine rich protein 2) Noninvasive transdermal detection of malaria: Malarial parasite turns the iron containing haeme component into an insoluble pigment, haemozoin. In this technique, a laser pulse heats the tiny particles of haemozoin to form a ‘vapour nanobubble’ in a malaria infected cell (Infrared light is strongly absorbed by haemozoin but not haemoglobin) and these bubbles collapse with a characteristic sound which is picked up by the ultrasound sensor. This technique does not differentiate the species (Falciparum and vivax) and haemozoin may persist in the blood even after recovery and that might give a false positive result. Acute uncomplicated malaria due to P. vivax, malariae, and ovale infections: Oral chloroquine 4 tablets stratum (600 mg) followed by 2 tablets 6 hours later (300 mg) and 2 tablets on the 2nd and 3rd day mornings (total 10 tablets). Radical cure is essential since chloroquine is ineffective against hepatic forms. Oral primaquine 7.5 mg bid for 14 days is required to prevent relapses in vivax and ovale infections. Primaquine is contraindicated in pregnancy and G6PD deficient patients. The new drug bulaquine is under trial instead of primaquine in G6PD deficient patients. Chloroquine sensitive P. falciparum. Same dose as mentioned above. A single dose of 45 mg of primaquine is given to kill the gametocytes. Chloroquine resistant P. falciparum: Pyrimethamine (25 mg/tablet) + sulphadoxine (500 mg/tablet)— single dose of 3 tablets in adults; or Quinine sulphate 600 mg tid PO for 7 days with tetracycline 250 mg qid or doxycycline 100 mg bid or clindamycin 600 mg bid



zz



zz



for 7 days; or Mefloquine 15 to 25 mg/kg (maximum 1500 mg) PO single dose; or Artesunate 200 mg PO on day 1 followed by 100 mg od for 4 more days or artemisinin 10 mg/kg bid on day 1 followed by 10 mg/kg od for days 2 to 5 can be given. SYNRIAM Arterolane maleate 150 mg + pioeraquine 750 mg OD for 3 days It is used for Acute uncomplicated falciparum malaria. Severe falciparum malaria including cerebral malaria: IV quinine 10 mg/kg as an infusion over 4 to 8 hours thrice daily for 7 days. In quinine resistant cases artemisinin (qinghaosu—Chinese herb) derivatives are used—artesunate 2 mg/kg IM on day 1 and 80 mg (2 mg/kg) IM on days 2 to 5. It clears parasitemia faster than any other antimalarial drugs; or Artemether 160 mg IM on day 1 followed by 80 mg IM on days 2 to 5; or Quinidine gluconate 15 mg/kg IV over 4 hours followed by 7.5 mg/kg IV over 4 hours tid.

Chemoprophylaxis It is advised to non-immune visitors to endemic areas and to pregnant mothers. Start 1 week before exposure and continued for 4 weeks after returning from the endemic area. Drugs used in Chemoprophylaxis Drug

Dose

1. Chloroquine—P. vivax and chloroquine sensitive P. falciparum 2. Chloroquine resistant P. falciparum

300 mg base once weekly— start one week before exposure

– Mefloquine

250 mg base once weekly— start one week before exposure

– Doxycycline

100 mg daily—start 2 days before exposure

– Chloroquine/proguanil

300/200 mg daily—start 1 week/2 days before exposure

– Atovaquone/proguanil

250/100 mg daily

Malaria Vaccine Malaria vaccine has remained an elusive goal. No effective vaccine is available.

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Manual of Practical Medicine Drugs Chloroquine (4-Aminoquinoline) Quinine (Quinoline methanol)

Antimalarial effect Trophozoites of all species

Primaquine (8-Aminoquinoline) Mefloquine (Quinoline methanol)

Exo-erythrocytic forms of P. vivax and ovale; Gametocytes of P. falciparum Blood trophozoites, gametocytes of P. vivax /malariae/ovale

Quinidine (Quinoline methanol) Artemisinin derivatives Artesunate Artemether Arteether Halofantrine (Phenanthrene methanol) Pyrimethamine + sulphadoxine Lumefantrine (Amyl alcohol) Atovaquone

Severe infections of P. falciparum

Blood trophozoites; gametocytes of P. vivax/ovale/malariae

Adverse effects Nausea, vomiting, extrapyramidal reaction, psychosis, neuropathy, myopathy, retinopathy Tinnitus, vertigo, high tone hearing loss, prolonged QT, ventricular tachycardia, Hypoglycaemia, haemolysis, Abdominal cramps, haemoly­sis in G6PD deficiency, Methaemo­globinaemia, teratogenic Nausea, vomiting, dysphoria, vertigo, postural hypoten­sion, convulsions, encephalopathy

Remarks Avoid IM injection in children Monitor QT interval in ECG Safe in pregnancy Contraindicated in pregnancy and G6PD deficient individuals Slow onset of action, unsafe in first trimester of pregnancy

Erythrocyte forms and gametocytes of P. falciparum Fastest clearance of parasites

Neurological problems Drug fever, dark urine

Contraindicated in first trimester of pregnancy Not used in prophylaxis

Effective against all 4 species of plasmodia Blood stages

Cardiac arrhythmias, abdominal pain, diarrhoea, cough, rash Megaloblastic anaemia, pancyto­paenia, Steven-Johnson’s syndrome

Not to be given after meals or with mefloquine

P. falciparum in combination with artemether Chloroquine resistant falciparum

Only in combination with proguanil

Amoebiasis The protozoan parasite, Entamoeba complex contains two morphologically identical species: Entamoeba dispar, which is avirulent, and Entamoeba histolytica, which may remain as avirulent commensal or lead to serious disease. It may cause diarrhoea/dysentery or extra intestinal disease, most commonly liver abscess. Amoebiasis is present worldwide, but most prevalent in subtropical and tropical areas under conditions of crowding, poor sanitation, and poor nutrition. Humans are the only established Entamoeba histolytica host. Transmission occurs through ingestion of cysts from faecally contaminated food/water, facilitated either by person-to-person spread or by flies or other arthropods as mechanical vectors. It is often called a 10% disease. Ten per cent of the world population is affected. Ten per cent among the infected suffer from active amoebic disease. Ten per cent of entamoeba species is pathogenic—E. histolytica. The mortality due to severe disease is 10%.

Life Cycle (Fig. 3.53) The life cycle of E. histolytica consists of two stages—cysts and trophozoites. 1. Cysts measure 10 to 15 µm in diameter and contain 4 nuclei. Excystation of ingested cyst (contaminated food/water) occur in the lumen of small intestine— nuclear division followed by cytoplasmic division. Each cyst gives rise to 8 trophozoites. 2. Trophozoites measure 10 to 50 µm in diameter and contain a single nucleus with a central karyosome. They reside in caecum and large intestine. They (majority) remain either as commensols or (10%) cause colitis or invade the system. Re-encystation of the trophozoites

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Fig. 3.53  Life cycle of amoebiasis

occurs in the colon and excretion of cysts in the faeces. Pathology: The trophozoites can invade the colonic epithelium causing amoebic colitis. Amoebic ulcers are flask-shaped and are usually located in ileocaecal region due to stasis of stool there (caecum and ascending colon) and next common site is sigmoido-rectal region. In severe cases entire colon is affected with multiple ulcerations, size varying from pinhead to 2.5 cm in diameter. Occasionally granulomatous tissue forms a mass called—amoeboma in the above regions. E. histolytica trophozoites can invade all tissues of the body—intestinal mucosa, liver, pleura, lungs, brain and skin.

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Infectious Diseases Clinical Features Intestinal amoebiasis The incubation period is 2 to 4 weeks. zz Ninety per cent of the infected persons are carriers without symptoms. zz Mild abdominal pain and diarrhoea with periods of remission and recurrence may last for weeks. zz Fever is uncommon. Microscopic haematochezia is common. Tenderness on palpation of abdomen and right hypochondrium—tender hepatomegaly. zz In severe form it presents with fever, vomiting, abdominal pain, hepatic enlargement, with frequent dysentery (10–20 stools/day) due to extensive colitis. zz Fulminant colitis can progress to necrotising colitis, toxic megacolon, severe haemorrhage and intestinal perforation. zz Perianal ulceration and post-dysenteric colitis simulating irritable bowel syndrome can occur. zz Chronic form presents with chronic diarrhoea, weight loss, amoebic appendicitis and granulomatous lesions resulting in amoebomas. zz

Extra-intestinal Amoebiasis zz

zz zz

zz

zz

zz

zz

Most common manifestations are non-suppurative amoebic hepatitis and liver abscess. Right lobe of the liver is involved—posterosuperior surface. Alcohol abuse and so, mostly men are commonly affected with amoebic liver abscess. Fever and diffuse abdominal pain over right upper quadrant—hypochondrium. Intercostal tenderness over the right lower part of the chest is the hall-mark of liver abscess. Abscess can rupture into the peritoneal, pleural or peri­ cardial space (left lobe abscess)—empyema, perito­nitis, pericarditis—life-threatening cardiac tamponade. Amoebic infections may involve any system—lungs, brain and genitourinary systems.

Investigations zz

zz

zz zz

zz zz

Ch-3B.indd 147

Stool examination for haematophagous EH trophozoites (RBCs in trophozoites) is diagnostic (Fig. 3.54). Different species of entamoeba cysts look alike and differentiation is not possible. EH cyst contains 4 nuclei whereas E. coli cyst contains 8 nuclei (iodine smear). Serological tests like ELISA, IHA (indirect haemag­ glutination), and IFA (indirect fluorescence antibody) tests are positive in 90% of cases. Species-specific PCR is very useful, but expensive. Trophozoites from chocolate coloured aspirate— especially last few drops from the abscess wall. X-ray chest reveals raised dome of right diaphragm. USG, CT and MRI scans detect the abscess.

Fig. 3.54 Entamoeba histolytica: Long arrow—trophozoite of Entamoeba histolytica. Short arrow—nucleus of the trophozoite. Arrowhead—one of the six ingested red blood cells

Treatment zz

zz

zz

Luminal amoebicides —— Diloxanide furoate—500 mg PO tid for 10 days. —— Diiodohydroxyquin—650 mg PO tid for 21 days. —— Paromomycin—10 mg/kg PO tid for 7 days. Tissue amoebicides —— For all tissues „„ Metronidazole—400 mg PO tid for 10 days (or IV drip) „„ Tinidazole—2 gm PO daily for three days + one luminal agent. „„ Emetine or dehydroemetine—1 mg/kg SC/ IM for 10 days. —— For liver only „„ Chloroquine—300 mg base first 2 days and then 150 mg base for 19 days. —— Intestinal wall only „„ Tetracycline—250 mg qid PO for 10 days. 3. Indications for aspiration/surgical procedure —— Large abscess > 10 cm size. —— Impending rupture of liver abscess. —— Left lobe liver abscess (fear of rupture into pericardial space and cardiac tamponade) —— Rupture into pleural/peritoneal or pericardial space.

Giardiasis (Fig. 3.55) Giardiasis is caused by the flagellate protozoan Giardia lamblia (Lamblia intestinalis). Infected persons may be asymptomatic or have diarrhoea with varying degree of malabsorption. Transmission occurs through contaminated water, and contaminated uncooked food

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Manual of Practical Medicine Investigations zz zz

zz

Identification of trophozoites or cysts in the stool. String test or endoscopy for sampling of duodenal contents or biopsy for cysts/trophozoites—not recom­mended for routine use. Antigen assays may be simpler and cheaper.

Treatment zz zz zz zz zz

Fig. 3.55  Giardia lamblia—pear-shaped trophozoite

containing cysts. Spread can be as a result of homosexual contact or oral sex.

Life Cycle Contaminated food or water—cysts on reaching the small intestine hard cysts excysts—release of active tropho­ zoites—multiplication by binary fission—they adhere to the epithelium of proximal small bowel—encystment occurs in the intestines in altered conditions—excretion of cysts in faeces.

Pathology Large number of trophozoites gets attached to the proximal small bowel causing mechanical interference in absorption (no invasion or destruction).

zz

Cryptosporidiosis zz

zz

zz zz

zz

zz

zz

Clinical Features zz zz

zz

zz

zz

zz

zz

Ch-3B.indd 148

Majority of patients are aymptomatic. The incubation period is 1 to 3 weeks but may be longer. Acute diarrhoeal syndrome—profuse watery diarrhoea leading to dehydration. Chronic diarrhoea with symptoms of abdominal cramps, bloating, flatulence, nausea, malaise, anorexia—fever and vomiting are uncommon. Stools are greasy, frothy, foul smelling without blood, pus, or mucus. Intermittent diarrhoea may persist for weeks to months. Chronic disease can result in malabsorption— protein losing enteropathy, vitamin deficiency and weight loss.

Metronidazole 400 mg PO tid for 7 days; or Tinidazole 2 gm PO once; or Nitazoxanide 500 mg PO bid for 3 days; or Albendazole 400 mg PO od for 5 days; or Paromomycin 500 mg PO tid for 7 days—safe during pregnancy. In refractory cases, prolonged therapy with metronidazole 750 mg tid for 21 day.

zz

It is a protozoal infection caused by Cryptosporidium parvum. Faeco-oral transmission and transmission by contami­ nated water are common modes. The incubation period is 1 to 11 days. Presenting symptoms are anorexia, nausea, abdominal cramps, fever and diarrhoea. It causes severe diarrhoea in immunocompromised hosts, in AIDS patients and in patients with congenital immunoglobulin deficiency. Diagnosis is by demonstration of oocysts in the stool, ELISA and immunofluorescent tests for detection of IgG and IgM antibody. Treatment: Paromomycin, a non-absorbed amino­ glycoside 500 mg PO qid for 14 days; or nitazoxanide 500 mg—1 gm PO bid for 3 days in immunocompetent patients and for 2 to 8 weeks in advanced AIDS patients. Other agents used are azithromycin, spiramycin, bovine hyperimmune colostrum and octreotide. However, the treatment of HIV infected patients with nitazoxanide is not very effective. Improve the immune status by antiretroviral therapy and that can lead to amelioration of cryptosporidiosis.

Trichomoniasis (Fig. 3.56) zz

zz

zz

Trichomonas exist only in trophozite form and there is no cystic phase. Trichomonas vaginalis causes vaginitis in women and non-gonococcal urethritis and prostatitis in men (the most common STD). There is inflammation of vaginal wall and cervix with erosions and punctuate haemorrhages.

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Infectious Diseases zz

zz

zz

zz

Fig. 3.56  Trichomonas vaginalis—trophozoites zz

zz

zz

zz

zz

Infected females present with creamy, yellow, frothy, vaginal discharge with burning and itching—lasting for a few days. Most males remain asymptomatic. TV is diagnosed by demonstration of flagellated motile parasites in vaginal, urethral, and prostatic smears or urinary sediments under microscope. Tests for bacterial vaginosis—pH > 4.5, fishy odour after addition of potassium hydroxide—are often positive with trichomoniasis. Rapid antigen and nucleic acid amplification tests are highly specific. Treatment: Metronidazole 400 mg PO tid for 1 week or metronidazole or tinidazole 2 gm single dose. Treat both partners.

Balantidiasis zz

zz zz

zz

zz

zz

It is caused by Balantidium coli—a large ciliated protozoan. Transmission is by faecally contaminated water. It inhabits in the large bowel and may cause diarrhoea or dysentery. The disease is severe in immunocompromised indivi­ duals—massive ulceration with perforation of large bowel can occur. It is diagnosed by demonstration of trophozoites or cysts in the stool. Treatment: Tetracycline 500 mg qid or metronidazole 400 mg PO tid for 10 days.

zz

Leishmaniasis Leishmaniasis is a zoonosis transmitted by bites of sandflies. It is caused by about 20 species of leishmania. The sand flies feed on infected host—canine and rodents and they ingest parasitised cells along with blood meal. Infected female sandflies bite during the night and feed on animals; humans are incidental hosts.

Life Cycle (Fig. 3.57) The parasite occurs in two forms, flagellar promasti­ gotes—10 to 20 µm in size found in vectors and a flagellar amastigotes—2 to 4 µm in size found in vertebrate hosts including humans. Promastigotes are released by the infected female sand flies while feeding—RE cells (macrophages) take up promastigotes—by loosing flagellum they transform into amastigotes—multiplication by binary fission—cell ruptures and other RE cells are invaded—sand flies pick up amastigotes while feeding on infected hosts—transformation into the flagellar form— multiplication in the gut of the vector and infects a new host while feeding.

Visceral Leishmaniasis (Kala-azar) zz zz zz zz

Isosporiasis zz zz

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The incubation period for Isosporiasis belli is one week. It usually causes self-limited watery diarrhoea lasting for 2 to 3 weeks.

Clinical features include fever, anorexia, nausea, vomiting, diarrhoea, with abdominal pain and flatulence. In immunocompromised patients haemorrhagic colitis results in severe, chronic diarrhoea—malnutrition, and dehydration. Diagnosis is by demonstration of oocysts in stool specimen and duodenal aspirate by acid-fast staining. Duodenal biopsy is also useful. Treatment: Cotrimoxazole (trimethoprim 160 mg + sulphamethoxazole 800 mg) PO qid for 10 days followed by bid schedule for three weeks; or pyrimethamine 75 mg PO in four divided doses with folinic acid 25 mg/ day for 3 to 6 weeks; or furazolidone 400 mg PO daily for 10 days. Relapse in AIDS patients – Maintenance therapy is given with TMP-SMX (160/800 mg) 3 times/week.

zz

zz

It is caused by Leishmania donovani complex. Ninety per cent of these cases occur in India. The incubation period ranges from weeks to months. Symptoms—fever, chills, sweats, anorexia, weight loss, and diarrhoea. Signs—greater enlargement of spleen which is firm and non-tender. Mild hepatomegaly with generalized lymphadeno­pathy.

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Fig. 3.57  Life cycle of Leishmania donovani

zz

zz

zz

zz

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Hyperpigmentation of the skin leading to the name kala-azar—‘Black fever’. Other signs include pancytopaenia, anaemia, leuko­ paenia, thrombocytopaenia leading to petechiae, retinal bleed, gingival bleeding. GIT bleeding, jaundice, and hypoalbuminaemia resulting in oedema, and ascites. As the disease progresses severe wasting and malnutrition occur. Post-kala azar dermal leishmaniasis—hypopigmented macules and nodules simulating leprosy may appear after recovery.

Cutaneous Leishmaniasis zz

zz

zz

Cutaneous swellings appear 2 to 3 months after sandfly bites and can be single or multiple. A papule develops followed by skin ulceration with well demarcated and raised indurated margins. Satellite lesions may be present. The lesions are painless unless secondarily infected. Regional lymphadenopathy is common. Healing with scar formation is spontaneous and it takes a few months to a few years.

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Infectious Diseases zz

Diffuse cutaneous leishmaniasis is characterised by non-ulcerative nodules involving the whole body including face.

Mucosal Leishmaniasis zz

zz

zz

zz

In L. braziliensis infection, months to years after resolution of cutaneous lesions, mucosal lesions appear in the nose or mouth (espundia). Perivascular infiltration and later endarteritis cause destruction of surrounding tissue. Nasal congestion is followed by ulceration and then progresses to involve mouth, lips, palate, pharynx and larynx. Extensive destruction can occur with secondary bacterial infection.

Investigations zz

zz

zz zz

zz

zz

Slit-skin smears or scraping from ulcer may demonstrate parasites. Fine-needle aspiration of the spleen or bone marrow aspiration for culture and tissue evaluation confirms the diagnosis. PCR can also identify the infection. Inoculation of laboratory animals can be used for diagnosis, but it is time consuming. Species are identified by molecular, isoenzyme, and monoclonal antibody methods. Leishmanin skin test is usually positive.

Treatment Visceral leishmaniasis Liposomal amphotericin B—3 mg/kg/day IV on days 1 to 5, 14, and 21. Side effects include GIT symptoms, fever, chills, dyspnoea, hypotension, hepatic and renal toxicity. Conventional amphoterecin B deoxycholate is less expensive, effective but more toxic—slow IV infusion 1 mg/kg/day for 20 days 0.5 to 1 mg/kg every second day for eight weeks. zz Pentavalent antimonials sodium stibogluconate or meglumine antimonite—20 mg/kg/day IV or IM—once daily for 20 days. Toxicity includes GIT symptoms, cardiac arrhythmias, fever, headache, arthralgias, myalgias, pancreatitis and rash. zz Pentamidine isethionate—alternative therapy given daily or alternate days—2 to 4 mg/kg IM or IV 15 doses. Toxicity similar to pentavalent antimonials. zz Miltefosine—first and the best oral drug for the treatment of leishmaniasis in India where resistance to antimonials is increasing—2.5 mg/kg in two divided doses for 28 days—mild GI tract/nephro/ hepatotoxicity can occur. zz

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Paromomycin—an aminoglycoside is equally effec­ tive for the treatment of visceral leishmaniasis— 11 mg/kg/day IM for 21days. It is less expensive than ampho-tericin and miltefosine. Side effects include ototoxicity and reversible elevation of liver enzymes. Cutaneous leishmaniasis: Pentavalent antimonials for 20 days—allopurinol and azole antifungals can also be used—topical therapy using intralesional antimony, paromomycin ointment, cryotherapy, local heat and surgical removal. Diffuse cutaneous leishmaniasis respond poorly to therapy. Mucocutaneous leishmaniasis: Treatment is similar to visceral leishmaniasis. Prevention and control of leishmaniasis: Insecticide spray, insecticide impregnated mosquito-nets or curtains to keep out sandflies and culling of infected/ stray dogs and early detection and treatment of human disease.

zz

Trypanosomiasis African Trypanosomiasis (Sleeping Sickness) (Fig. 3.58) African trypanosomiasis is caused by Trypanosoma brucei rhodesiense and T. brucei gambiense and the organisms are transmitted by bites of tsetse flies (genus Glossina). zz Acute sleeping sickness (East African trypanosomiasis) caused by Trypanosoma brucei rhodesiense—it has an acute, virulent and faster course causing death in a matter of weeks or months. zz Chronic sleeping sickness (West African trypanoso­ miasis) caused by T. brucei gambiense—asymptomatic for several years and manifests in advanced stage. At the site of inoculation painful trypanosomal chan­ cre appears with regional adenopathy. The common symptoms are fever, headache, and joint pains. There are two stages: 1. Haemolymphatic stage—lymphadenopathy (especially posterior triangle cervical nodes— Winterbottom’s sign), splenomegaly, rash, pruritus, muscular pain, anaemia, thrombo­cytopaenia, and carditis. 2. Meningoencephalitic stage—CNS dysfunction resulting in day-time somnolence and nighttime insomnia with behaviour changes, incoordi­ nation, ataxia, chorea, confusion, delirium, convulsions and coma. Neurological damage can be irreversible. zz

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Fig. 3.58  Life cycle of Trypanosoma brucei

Investigations Demonstration of parasite in blood, bone­­marrow and lymph node aspirate, chancre aspi­rate and centrifuged CSF sediment. Serological tests like card agglutination test for trypanosomes—CATT. Molecular studies—PCR is useful to identify species.

zz

zz

Management Improve the general health of the patient by treating concomitant viral, bacterial infections and nutritional deficiencies before giving anti-trypanosomal drugs. Choice of drug therapy depends on the stage of the disease and species of the involved parasites.

American Trypanosomiasis (Chagas’ Disease) (Fig. 3.59) zz

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It is caused by T. cruzi and spread by blood sucking reduviids (kissing bugs)—triatomine bugs. The disease

zz

zz

is transmitted to humans by contamination of bite wound with infected faeces of reduviids. They get infected by biting infected humans or animals. The disease can also be transmitted by blood transfusion, organ transplantation, breast milk, and consumption of uncooked contaminated food. Acute stage: A local skin nodule appears at the site of inoculation with erythema and local lymph­ adenopathy—chagoma. When the conjunctiva gets inoculated—unilateral painless periorbital oedema, conjunctivitis, and periauricular lymphadenitis (Romana’s sign) occur. Other symptoms include lymphadenopathy, hepato-splenomegaly, fever, fatigue, myocarditis and meningoencephalitis. The acute phase resolves in 2 months. Asymptomatic stage: The patients remain symptom free for many years. Chronic stage: Chronic stage develops after 10 to 20 years with multi-organ invasion. Megaoesophagus— dysphagia, aspiration; megacolon—abdominal

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Infectious Diseases Type of Disease

Stage 1 (Drug – Dose – adverse effects)

Stage 2

West African Trypanosomiasis (T. brucei gambiense)

1st line—Pentamidine—4 mg/kg/day IM for 7 days (reversible renal failure and hypotension, pancreatitis arrhythmias, hypoglycaemia) 2nd line—Eflornithine—400 mg/kg/day in 4 divided doses IV infusion in 250 ml saline over 2 hours for 14 days (Anaemia, thrombocytopaenia, convulsions, hearing loss, diarrhoea, vomiting) or Melarsoprol—3.6 mg/kg/day IV for 3 days—3 such courses at intervals of 10 days (Encephalopathy, thrombophlebitis, exfoliative dermatitis)

Eflornithine or melarsoprol

East African Trypanosomiasis (T. brucei rhodesiense)

1st line—Suramin—20 mg/kg—maximum of 1 gm—IV infusion 10% aqueous solution—5 doses at weekly intervals (Anaphylaxis, arthralgias, pruritus, renal complications, exfoliative dermatitis) 2nd line—Melarsoprol

1st line—Melarsoprol 2nd line—Melarsoprol combined with Nifurtimox*

*Nifurtimox—10 to 15 mg/kg—PO—in 4 divided doses for 3 months—Adverse effects include anorexia, nausea, vomiting, weight loss, twitching, polyneuritis, and seizures.

Fig. 3.59  Life cycle of Trypanosoma cruzi

zz

Ch-3B.indd 153

distension, constipation; dilated cardiomyopathy, conduction blocks, arrhythmias, heart failure and thromboembolism; and dementia can also manifest. Investigations: Trypomastigotes isolated or grown in blood, CSF, lymphnode aspirate in acute stage and in chronic disease—serology Chagas’ IgG by ELISA.

zz

Treatment: Nifurtimox 10 mg/kg/day in 4 divided doses after meals for 3 months or benznidazole 5 mg/ kg/day in 3 divided doses for 2 months. The treatment is effective only in acute sage and the treatment is symptomatic in chronic stage. Other drugs tried are— amphotericin, allopurinol, fluconazole, itraconazole, and recombinant interferon-γ.

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Toxoplasmosis (Fig. 3.60) T. gondii is an obligate intracellular protozoan. The definitive hosts are cats. Humans are infected after ingestion of cysts in raw or undercooked meat, ingestion of oocysts in food or water contaminated by cats, transplacental transmission of trophozoites, or direct inoculation of trophozoites by blood transfusion or organ transplantation. zz Primary infection in immunocompetent person: After ingestion, infection spreads through GIT lymphatics. In acute infections most patients are asymptomatic. Patients may present with mild febrile illness— fever, malaise, cervical or diffuse lymphadenopathy, hepatosplenomegaly and atypical lymphocytosis. Rare severe manifestations are pneumonitis, encephalitis, hepatitis, myocarditis, polymyositis, and retinochoroiditis. Most patients recover. zz Congenital infection: Foetal infection follows maternal infection in 30 to 50% of cases. While the risk of zz

zz

zz

zz

foetal infection increases (Risk varies by trimester: 1st 15%; 2nd 30%; 3rd 60%) the severity of foetal disease decreases over the course of pregnancy. Early infection leads to spontaneous abortion, still births or severe neonatal disease. Clinical manifestations vary—seizures, retinochoroiditis, mental retardation, deafness, hydrocephalus, lymphadenopathy, hepato­ splenomegaly, pneumonitis, myocarditis, anaemia, jaundice, rash, microcephaly and intracranial calcifications. Retinochoroiditis: It manifests weeks or years after congenital infection. Unilateral disease is common. Disease presents with uveitis, pain, photophobia, and visual changes without systemic symptoms. Visual defect persists. Fundus examination reveals yellowishwhite cotton-wool patches and later punched out and pigmented black lesions. Severe disease can lead to cataract, micro-ophthalmia, strabismus, and nystagmus. Rarely, progression may result in glaucoma and blindness. Infection in immunocompromised patient: Immuno­ compromised patients are those with AIDS, haemato­ logical malignancies, organ transplant recipients and those on immunosuppressive therapy. The most common manifestation is encephalitis with multiple necrotizing brain lesions. Reactivation of existing lesion can also occur. They present with altered sensorium, seizures, focal neurological deficits, headache, and fever. They may present with brainstem, basal ganglia and cerebellar dysfunction. Less commonly generalized toxoplasmosis can involve many organ systems—pneumonitis, myocarditis. Diagnosis: Organisms can be seen in tissue or body fluids. Strong suspicion is required for prompt diagnosis. Tissue culture and mouse inoculation are helpful to isolate the organism. Histological diagnosis is made by fluorescent antibody. PCR is useful. IgG antibodies denote prior infection. Four-fold rise of IgG titers in paired sera 3 weeks apart indicates acute infection. IgM, IgE, and IgA antibodies denote new infection. CT/MRI brain is useful.

Management

Fig. 3.60  Life cycle of toxoplasmosis

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Drugs do not eradicate toxoplasmosis infection and they act only against tachyzoites. Standard therapy is the combination of Pyrimethamine 200 mg loading dose followed by 1 mg/kg PO once daily + sulphadiazine 1 gm qid PO along with folinic acid 10 to 20 mg once daily to prevent bone marrow suppression. Sulphadiazine can be replaced by clindamycin 600 mg qid.

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Infectious Diseases Other drugs used are: TMP-SMX 5 mg/kg/day zz Atovaquone 1500 mg bid zz Clarithromycin 500 mg bid zz Azithromycin 900 to 1200 mg/day zz Dapsone 100 mg od zz For congenital infection, oral pyrimethamine 1 mg/ kg and sulphadiazine 100 mg/kg is given for one year. zz In pregnancy to prevent transmission to the foetus, spiramycin 1 gm tid throughout pregnancy is advocated. Immunotherapy with IFN-γ or IL-12 can be added to the above therapy. zz

Investigations zz

zz

zz

zz

zz

Pneumocystis jiroveci zz

zz

Pneumocystis carinii refers only to pneumocystis that infects rodents, while Pneumocystis jiroveci refers to distinct species that infect humans. The incubation period varies from 4 to 8 weeks. The mode of spread is by person to person air-borne transmission.

Pathogenesis Intact cellular and humoral immunity is essential to protect against pneumocystis infection. The risk of infection increases when the CD4 count falls below 200/µl. Pneumocystis pneumonia (PCP) is the commonest manifestation. Alveolar macrophages are the main phagocytes mediating the uptake and degradation of organisms in the lungs. Variety of inflammatory mediators such as TNFa, interleukin-8, and macrophage inflammatory protein-2 are recruited to fight against the invading organism.

zz

Sputum examination for pneumocystis under microscopy or hypertonic saline induced sputum or bronchoscopy with bronchoalveolar lavage (BAL) are useful. Immunofluorescence with monoclonal antibodies is sensitive but expensive. DNA amplification by the polymerase chain reaction (PCR) is most sensitive. X-ray chest—bilateral diffuse perihilar interstitial infiltration or it may be normal. If chest radiography is normal, perform high-resolution computed tomography (HRCT) which may reveal extensive ground-glass attenuation or cystic lesions. DLCO—diffusion capacity of carbon monoxide is < 75% of the predicted; and PCP is unlikely if DLCO is normal.

Treatment Although pneumocystis is a fungus, it does not respond to anti-fungal drugs. zz 1st choice: Trimethoprim-sulfamethoxazole (TMPSMX) is the drug of choice. It acts by inhibiting folic acid synthesis. TMP—15 to 20 mg/kg and SMX—75 to 100 mg/kg PO in divided doses for 2 to 3 weeks. zz 2nd choice: TMP + dapsone 100 mg qd PO or Primaquine 30 mg daily + clindamycin 600 mg tid. zz 3rd choice: Atovaquone 750 mg bid PO. In severe cases IV regimens can be used. 1st choice: TMP-SMX. 2 zz 2nd choice: Trimetrexate 45 mg/m qd IV or leucovorin 20 mg/kg q 6 hours IV and dapsone 100 mg qd PO or Prima­quine + clindamycin IV. zz 3rd choice: Pentamidine 4 mg/kg daily IV. zz

Risk Factors Predisposing to Pneumocystis Pneumonia zz zz zz zz zz

HIV infection with CD4 count below 2. Patients on immunosuppressive therapy. Organ transplant patients. Children with primary immunodeficiency diseases. Premature malnourished infants.

Clinical Features zz

zz

zz

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Fever, sudden onset of respiratory insufficiency resulting in dyspnoea and non-productive cough (classic triad) are the main clinical features of pneumocystis pneumonia (PCP) along with LDH level >460 U/L and PaO2 < 75 mm Hg. The common signs are tachypnoea, tachycardia and cyanosis with minimal respiratory signs. Extrapulmonary manifestations are lymphadeno­ pathy, hepatosplenomegaly, bone marrow and eye involvement (choroiditis).

Prophylaxis Primary prophylaxis is indicated for HIV infected patients with CD4+ cell count < 200/µL or with oropharyngeal candidiasis. Secondary prophylaxis is required for both HIV infected and non-HIV infected patients who have recovered from pneumocystis. The following drugs are used. zz Trimethoprim+sulphamethoxazole—one double strength tablet daily or 3 times/week. zz Alternate choice—Dapsone 100 mg daily or zz Dapsone 50 mg daily + pyrimethamine 50 mg weekly + leucovorin 25 mg weekly or zz Atovaquone—1500 mg daily or zz Pentamidine 300 mg monthly.

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HELMINTHIC INFESTATIONS Helminths vary in size and they have complex life-cycles. They induce an eosinophil response. They are able to reproduce within the human host. Helminths infect man when ingested, or by direct penetration of the skin, or through the bites of insects. Stool examination helps in arriving at a diagnosis.

Classification of Helminths that Infest Humans Nematodes or Roundworms zz

zz

zz

Intestinal human nematodes: Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Ascaris lumbricoides, Enterobius vermicularis, Trichuris trichiura. Tissue-dwelling human nematodes: Wuchereria bancrofti, Brugia malayi, Loa loa, Onchocerca volvulus, Dracunculus medinencis, Mansonella perstans, Dirofilaria immitis. Zoonotic nematodes: Trichinella spiralis.

Trematodes or Flukes zz

zz zz

zz

Blood flukes: Schistosoma haematobium, S. mansoni, S. japonicum, S. mekongi, S. intercalatum. Lung flukes: Paragonimus spp. Hepatobiliary flukes: Clonorchis sinensis, Fasciola hepatica, Opisthorchis felineus. Intestinal flukes: Fasciolopsis buski.

sucking blood (0.2 ml/day/ancylostoma) and interstitial fluid. The adult hookworms living in duodenum and jejunum lay thousands of eggs per day (N. americanus 5000–10,000 and A. duodenale 10,000–25,000/day/worm). The excreted eggs in faeces hatch into rhabditiform larvae and develop over one week period into infectious filariform larvae. They penetrate the human skin and enter the lungs by way of bloodstream. From the alveoli they ascend up the airway before being swallowed. On reaching the small bowel they develop into adult worm (Longevity N. americanus 3–5 and A. duodenale 6–8 years) and the lifecycle is repeated. The transmission is exclusively by percutaneous route in case of N. americanus, whereas in case of A. duodenale it is usually by percutaneous route but at times it can be through ingestion of contaminated food; the larvae penetrate the buccal mucosa and develop in gut mucosa. Infection may also be transplacental.

Clinical Features zz zz

zz

zz

zz

zz

Cestodes or Tapeworms zz

zz

Intestinal tapeworms: Taenia saginata, Taenia solium, Diphyllobothrium latum, Hymenolepsis nana. Tissue-dwelling cysts or worms: Taenia solium, Echinococcus granulosus.

Ankylostomiasis (Hookworm) Most infected individuals are asymptomatic. Hookworm disease is due to sucking of blood by the hookworm, prolonged duration of infection, heavy worm burden and inadequate intake of iron resulting in iron-deficiency anaemia and at times hypoproteinaemia.

Life Cycle (Fig. 3.61) Adult hookworms are 1 cm long. They use their buccal teeth (Ancylostoma duodenale) or cutting edges (Necator americanus) to attach to the small bowel mucosa for

Ch-3B.indd 156

zz

Most patients are asymptomatic. Maculopapular dermatitis at the site of penetration (ground itch) and at times along the path of subcutaneous migration. Transient pneumonitis due to larvae migrating through the lungs. Epigastric pain with postprandial accentuation/ inflammatory diarrhoea with eosinophilia. Iron deficiency anaemia (Hypochromic microcytic), eosinophilia, and hypoalbuminaemia are common manifestations of hookworm disease. Anaemia with high-output cardiac failure may result. In severe infection physical and mental development may be retarded in children.

Investigations (Fig. 3.62) zz zz zz

Fresh stool examination for eggs and old stool for larvae. Complete haemogram (anaemia and eosinophilia) Serum proteins—hypoproteinaemia.

Management zz zz zz zz

Albendazole 400 mg once or Mebendazole 100 mg bid for three days or Pyrantel pamoate 11 mg/kg for three days Treat anaemia, hypoproteinaemia and heart failure if present.

Ascariasis Ascariasis lumbricoides is the largest intestinal nematode (reaching upto 40 cm). Clinical disease is due to larval

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Fig. 3.61  Life cycle of hookworm

migration in the lungs and the bulk effect of the adult worms in the intestine.

Life Cycle (Fig. 3.63)

Fig. 3.62  Ancylostoma (hookworms)—egg

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Adult worms live in the lumen of the small intestine. Mature female worm lay 250,000 eggs/day. Excreted eggs in the faeces are extremely resistant to environmental stresses. After several weeks they mature into infective form and they remain infective for many years. On swallowing the infected eggs, larvae are hatched in the intestine which invade the intestinal mucosa and migrate to the lungs by way of circulation. The larvae ascend the bronchial tree to be swallowed. In the small intestine they develop into adult worms in 2 to 3 months. Adult worms live for 1 to 2 years and the life cycle is repeated.

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Fig. 3.63  Life cycle of Ascaris lumbricoides

Clinical Features zz

zz

zz

zz

zz

zz

Ch-3B.indd 158

Larval migration in the lungs (10 days after ingestion of eggs) cause transient, intermittent eosinophilic pneumonitis (round infiltrates a few mm—cms in size) with irritating non-productive cough and substernal burning discomfort. Adult worms in the intestine usually cause no symptoms. Heavy infections can cause abdominal pain, smallbowel obstruction, perforation, intussusceptions or volvulus (Fig. 3.64). A large worm can enter and occlude biliary tree— biliary colic, cholecystitis, cholangitis, pancreatitis, or rarely intrahepatic abscesses. Single worm may cause symptoms due to migration into aberrant sites. Migration of worms into oesophagus and expulsion by vomiting.

Investigations (Fig. 3.65) zz zz

zz

zz

Examination of stool for eggs. Passage of round worms in stool, vomitus, expulsion through the nose. Plain X-ray abdomen—masses of worms in gas-filled loops of bowel in intestinal obstruction. Contrast studies of GIT may reveal the worms. Ultrasound abdomen and ERCP may reveal the hepato-biliary worm infestation.

Management zz zz zz zz

zz

Albendazole 400 mg once or Mebendazole 100 mg bid for three days or Ivermectin 150 to 200 µg/kg once or Pyrental pamoate 11 mg/kg to a maximum of 1 gm once. This is safe in pregnancy and other drugs are contraindicated. Surgical intervention is needed for obstruction of bowel or biliary tract.

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Fig. 3.64  CT—ascariasis in terminal ileum

Fig. 3.66  Strongyloides: Filariform larvae

Fig. 3.65  Ascaris lumbricoides—egg. Typical “scalloped” edge

Strongyloidiasis (Fig. 3.66) Strongyloides stercoralis is a very small nematode— 2 mm × 0.4 mm. It is distinguished by its ability to replicate in the human host (unusual among helminthes). This capacity permits ongoing cycles of autoinfection as infective larvae are internally produced. Thus the infection can persist for decades without further exposure of the host to exogenous infective larvae. In immunocompromised hosts, large numbers of larvae can disseminate widely and can be fatal.

Life Cycle (Fig. 3.67) The 2 mm long adult female worms living in the mucosa of the upper part of the small intestine reproduce by parthenogenesis; adult males do not exist. They lay eggs

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Fig. 3.67  Life cycle of Strongyloides stercoralis

(5000–10,000 eggs/day/worm) which hatch in the bowel and only larvae are passed in the faeces. Rhabditiform larvae passed in the stool can transform into infective filariform larvae by moulting in the moist soil. The cycle is completed when the infective larvae penetrate the skin and carried to the lungs in the venous circulation. They ascend

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Manual of Practical Medicine up the airway to be swallowed. On reaching the upper small bowel they mature. In internal autoinfection, larvae mature to infective stage in the lumen of the gut and then invade the intestinal or colonic mucosa and then pass via the lymphatics—portal veins—lungs and back to the gut.

Clinical Features zz

zz

zz

zz

zz

Migrating larvae can cause serpigenous eruption, larva currens (‘running larva’). This erythematous lesion advances as rapidly as 10 cm/hour along the course of larval migration. Recurrent urticaria involving buttocks and wrists is common. Abdominal pain similar to peptic ulcer syndrome, nausea, vomiting, GI bleeding, mild chronic colitis and weight loss can occur. In immunosuppressed patients dissemination of large numbers of larvae into CNS, peritoneum, liver, kidneys in addition to GIT and lungs. Gram negative sepsis, pneumonia, meningoence­ phalitis may complicate the clinical course.

Clinical Features zz

zz

zz

Investigation (Figs 3.69A and B) Since the eggs are not released in the faeces, either a perianal swab moistened with saline or examination of cellophane tape which has been applied in the perianal region in the morning hours will detect the eggs on microscopy.

Management zz

Investigations zz

zz

zz

Repeated examination of stool and sputum for motile larvae. Jejunal aspiration and string test may be required to demonstrate the larvae. Serology (ELISA) is helpful.

Perianal itching is the common symptom. Itching is worse at night because of the nocturnal migration of the female worms. Itching results in excoriation and secondary bacterial infection. In females it can cause vulvovaginitis and pelvic inflammatory disorders. Heavy infections can result in eosinophilia, abdominal pain and at times weight loss.

zz

Tablet mebendazole 100 mg once or albendazole 400 mg once or pyrantel pamoate 11 mg/kg (maximum 1 gm) once or piperazine 4 gm once and repeat the treatment after 2 weeks. Treatment of household members is advocated to eliminate reinfection.

Management zz

zz zz

Ivermectin 200 µg/kg as a single dose or two doses on successive days; or Albendazole 15 mg/kg twice daily for 3 days. For systemic strongyloidosis ivermectin 200 µg/kg on day 1, 2, 15, and 16.

Enterobius vermicularis (Threadworm or Pinworm) This helminth is common throughout the world. Children are mainly affected.

Life Cycle (Fig. 3.68) Adult worms are 1 cm long and dwell in the caecum. Gravid female worms migrate in the night to lay eggs in the perianal region (2000–10,000/day/worm). The eggs become infective within hours and transmitted by handto-mouth route (perianal itching). Larvae hatch from the ingested eggs and mature into adult in one month and they live for 2 months. Pinworm infections are common in family members because of person-to-person spread.

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Fig. 3.68  Life cycle of Enterobius vermicularis

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A

B Figs 3.69A and B  (A) Enterobius vermicularis—egg; (B) Diagrammatic

Trichuris trichiura (Whipworm) Whipworm infection is common all over the world. They live in the caecum, ileum, appendix, colon and anal canal. Most infections with trichuris are asymptomatic.

Life Cycle (Fig. 3.70) 3000 to 7000 eggs are laid by the adult female worm. They are passed in the faeces and mature in the soil. After ingestion, the infective eggs hatch in the duodenum releasing larvae which mature before migrating to the large bowel. The entire life cycle takes three months and adult worms may live for five years.

Clinical Features zz zz

zz zz

Most infected individuals are asymptomatic. Heavy infections may cause abdominal pain, anorexia, bloody/mucoid diarrhoea. Massive infections can result in rectal prolapse. Heavy infections may cause malnutrition and growth retardation.

Investigations (Fig. 3.71) zz zz

Stool examination for trichuris eggs Proctoscopy may reveal 3 to 5 cm long adult worms.

Management Any one drug can be used—Mebendazole 500 mg once or albendazole 400 mg od 3 days or Ivermectin 200 mcg/ kg daily for 3 days.

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Tissue-dwelling Human Nematodes (Figs 3.72A to C) Filarial worms are tissue-dwelling nematodes. They dwell in the subcutaneous tissues and the lymphatics. Eight filarial species infect humans and of these, four species are responsible for most serious filarial infections—Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus, and Loa loa.

Life Cycle The larvae are inoculated by biting mosquitoes or flies. The larvae develop into adult worms (2–50 cm long) which, after mating produce millions of microfilariae (150– 300 µm long) that migrate in blood or skin. The vector takes up the microfilariae while feeding on humans. Ingested microfilariae develop into infective larvae in the vector and is ready for inoculation in humans.

Pathogenesis Infection occurs only with repeated, prolonged exposure to infective larvae. The disease is due to immune response Organism

Periodicity Vector

Adult worm site Microfilariae site

W. bancrofti Nocturnal Culex, Aedes, Lymphatic Anopheles tissue

Blood

Brugia malayi

Nocturnal Anopheles, Mansonia

Blood

Loa loa

Diurnal

Onchocerca None volvulus

Chrysops (deer flies)

Lymphatic tissue

Subcutaneous Blood tissue

Simulium Subcutaneous Skin and eye (black flies) tissue

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Fig. 3.70  Life cycle of Trichuris trichiura

A Fig. 3.71  Trichuris trichiura—egg with two “plugs” on each end

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B C Figs 3.72A to C  (A) Tip nuclei free; (B) Tip single nuclei; (C) Tip multiple nuclei

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Infectious Diseases to adult worms (developing, mature, and dying) and microfilariae. Adult worms live for 10 to 15 years and microfilariae live for 2 to 3 years. The disease is more acute and intense in newly infected individuals than in natives living in endemic area.

Clinical Features (Figs 3.74A and B) zz

zz

Lymphatic Filariasis It is caused by W. bancrofti, B. malayi or B. timori. The threadlike adult worms live in the lymphatic channels and lymph nodes for more than 15 years.

Pathology (Fig. 3.73) The adult worms cause inflammatory damage to the lymphatics. It causes lymphatic dilatation and thickening of the vessel wall along with infiltration of plasma cells, eosinophils, and macrophages. It leads to damage of lymph valves with dilatation, tortuosity of lymphatics and lymphoedema. The inflammatory response ultimately causes granulomatous and proliferative changes that precede total lymphatic obstruction. The lymphatic vessels remain patent as long as the adult worms live and after the death of the worms there is enhanced inflammatory response leading to excess granulation, fibrosis and total lymphatic obstruction.



zz

zz

zz

Most patients in endemic area remain asymptomatic inspite of microfilaremia, or they may present with hydrocele. Acute adenolymphangitis (ADL): They present with lymphangitis and lymphadenitis leading to high fever. The lymphangitis is retrograde, extending peripherally from the lymph nodes (in contrast to bacterial lymphangitis, which spreads centrally). The lymphatic channel is indurated and inflamed. There is enlargement of regional lymph nodes. This process can involve both upper and lower limbs. Involvement of renal lymphatics leads to microscopic haematuria, proteinuria, and chyluria. Chyluria is intermittent and more common in the morning. Genital lymphatics are involved almost exclusively with W. bancrofti infection. It causes funiculitis, epididymitis with scrotal pain and tenderness leading to hydrocele. Lymphoedema can affect female genitalia and breasts. Dermatolymphangioadenitis (DLA): They present with fever, chills, headache, myalgias and oedema­ tous inflammation of the skin. They may manifest with vesicles, ulcerations and hyperpigmentation. DLA is often diagnosed as cellulitis. The lymphatic damage can progress—transient lympho­edema, recurrent lymphangitis, lymphatic obstruction, brawny oedema follows early pitting oedema, thickening of subcutaneous tissue with hyperplastic changes, ultimately leading to elephantiasis of scrotum and lower limbs.

Investigations (Fig. 3.75) zz

zz

zz

zz

zz

zz

Fig. 3.73  The life cycle of lymphatic filariasis

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Demonstration of microfilaria in blood (mid-night blood samples), hydrocele fluid or in other body fluids either in the direct smear or after concentration techniques. ELISA: Assays for circulating antigens and a rapid format immunochromatographic card test. Both assays are sensitive and specific. These tests are available only for W. bancrofti and not for B. malayi. PCR—polymerase chain reaction based on assays for DNA are useful for both W. bancrofti and B. malayi. High frequency ultrasound Doppler examination of scrotum and female breast for identification of motile adult worm (Filaria dance sign). Eosinophilia, elevated serum concentration of IgE and antifilarial antibody supports the diagnosis of lymphatic filariasis. Radionuclide lymphoscintigraphic imaging is useful to demonstrate the lymphatic abnormalities and helpful in assessing lymphoedema.

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Manual of Practical Medicine Management zz

zz

zz

Fig. 3.74A  Filariasis—hydrocele zz

zz

zz

Diethylcarbamazine (DEC) kills microfilariae and adult worms. The dose is 6 mg/kg PO in three divided doses for 12 days. The adverse effects seen with DEC therapy—fever, headache, nausea, vomiting, prostration—are due to the host response to dying microfilariae. The adverse effects can be tackled with antihistamines and corticosteroids. A single dose of either ivermectin—200 µg/kg or albendazole 400 mg in combination with DEC 300 mg for 7 days eliminates microfilariae for one year. Doxycycline is useful in eliminating the endo­ symbiotic bacterium—Wolbachia, Eight weeks course of doxycycline 200 mg/day leads to interrup­ tion of embyo-genesis and hence the production of micro­­filariae. Chronic lymphatic disease: Meticulous skin care and prevention of secondary bacterial and fungal infections with suitable antimicrobials. For lymphoedematous limbs—tight bandaging, massage, bed rest with elevation of the affected limb. Plastic surgery for elephantiasis—removal of excess tissue gives great relief. Recurrences are expected unless new lymphatic drainage is established. Surgical management is advised for hydrocele and chyluria.

Prevention

Fig. 3.74B  Filariasis—elephantiasis

Annual treatment of endemic population with single dose of DEC 6 mg/kg either alone or combination with albendazole/ ivermectin and mosquito control programmes.

Tropical Pulmonary Eosinophilia zz

zz

zz

zz

Fig. 3.75  Wuchereria bancrofti: Filarial worm in blood

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This syndrome develops in some individuals infected with lymphatic filarial species. It affects both males and females (4:1) usually in the third decade of life. The main clinical features are paroxysmal cough and nocturnal wheezing, weight loss, low grade fever, adenopathy, and pronounced eosinophilia—>3000 eosinophils/µL. Chest X-rays and CT scans may be normal or show miliary mottling involving middle and lower lung fields. PFT may reveal restrictive/ obstructive abnormalities. Total serum IgE levels—10,000 to 100,000 ng/ml and antifilarial antibody titers are markedly elevated. Pathogenesis: The microfilariae and parasite antigens are rapidly cleared from the bloodstream by the lungs. This elicits allergic and inflammatory reactions. Trapping of MF in reticuloendothelial system can cause

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zz

hepato-splenomegaly and lymphadenopathy. If not treated, it leads to interstitial fibrosis and progressive pulmonary damage. DEC 6 mg/kg PO in three divided doses for 14 days. Symptoms usually resolve in a weeks time. Relapses require re-treatment.

Clinical Features zz

zz

Loiasis Infection is caused by filarial species Loa loa. The adult worm 3 to 7 cm × 4 mm and lives in subcutaneous tissue of humans and release the larval MF into the bloodstream in the day time. The vector is Chrysops, a forest-dwelling, Day-biting fly. The host response is mild—short lived inflammatory swelling “Calabar swelling” is produced around the adult worm. Adult worms migrate through the subcutaneous tissues, including the subconjunctiva (Eye worm). Adult worms can live upto 17 years.

Clinical Features zz

zz

zz

They may remain asymptomatic or transient subcuta­ neous swellings—Calabar swellings appear, which are nonerythematous, and upto 20 cm in diameter. They usually resolve in 4 days or may persist for many weeks. Nephropathy, encephalopathy and cardiomyopathy are rare but can occur. Encephalitis occurs in patients with high levels of microfilaremia or follows treatment with DEC.

zz

zz



zz

Investigations zz

Investigations zz

zz zz

Blood smear for MF or identification of adult worm in subcutaneous tissue or subconjunctiva. PCR based assays for the detection of L. loa DNA. Elevated levels of neutrophils, eosinophils and IgE, and antifilarial antibodies.

zz

zz

zz

Management zz zz

DEC 10 mg/kg/day PO for 21 days. Heavy infections can be treated with apheresis to remove the MF and 40 to 60 mg of prednisone/day followed by DEC 0.5 mg/kg/day. If antifilarial treatment has no side effects, gradually taper the dose of steroid and increase the dose of DEC to10 mg/kg/day.

Onchocerciasis (River Blindness) Onchocerciasis is caused by Onchocerca volulus. The infection is conveyed by flies of the genus Simulium. An infected fly inoculates larvae on biting and the worms mature in 2 to 4 months. The adult worms live for 17 years in subcutaneous and connective tissues.

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Severe pruritus, skin excoriations, thickening and depigmentation of the skin are common manifestations. Onchocercomata: Numerous firm, nontender, movable subcutaneous nodules of about 1 to 3 cm, which contain adult worms may be present. These nodules are more common in the lower body in Africa but on the head and upper body in Latin America. There is inguinal and femoral lymphadenopathy— “Hanging groin” lymph nodes hanging within a sling of atrophic skin. Eye involvement: Microfilariae migrating through the eyes elicit various host responses—Punctate keratitis, corneal opacities, progressing to sclerosing keratitis and blindness. Iridocyclitis, glaucoma, choroiditis, and optic atrophy may lead on to blindness. Systemic manifestations: Heavily infected individuals may develop cachexia with loss of adipose tissue and muscle mass.

zz

Detection of adult worm in an excised nodule or microfilariae in a skin snip. Skin snips are obtained with a corneal-sclera punch, which collects a blood free skin biopsy (just below the epidermis). The biopsy tissue is incubated in tissue culture medium or in saline on a glass slide. After incubation for four hours or overnight, emerging microfilaria from the skin can be seen under low-power microscopy. Slit-lamp examination of the eyes—visualising MF in the cornea or anterior chamber. Ultrasound examination of the skin nodule to identify adult worms. Mazzotti test: On administering 50 mg dose of DEC, there is an exacerbation of skin rash and pruritus within 3 hours, which is highly suggestive of diagnosis. As with other parasitic infections, there is eosinophilia and elevated levels of IgE.

Management zz

zz

zz

Ivermectin single dose 150 µg/kg PO either annually or semiannually or every 3 months. Surgical excision is recommended for nodules on the head because of the proximity of MF producing adult worms to the eyes. Doxycycline is given for six weeks. It renders the female adult worms sterile for long periods. Doxycycline acts by eliminating Wolbachia, endosymbiont of the filarial parasite.

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Dracunculiasis (Guinea Worm Infection) Life Cycle (Fig. 3.76) Humans are infected by ingesting water containing cyclops, a crustacean that is the intermediate host. Cyclops inhabits in wells and ponds and contains infective larval stage of the worm. The infective larvae on release penetrate the stomach or intestinal wall, mate and mature. The adult male dies. The female worm migrates to subcutaneous tissues, usually of the legs, over about a year. A subcutaneous ulcer then forms. Upon contact with water, the parasite discharges large number of larvae, which are ingested by cyclops. Adult worm is 30 cm to one meter in length. Worm death and disintegration in tissue may provoke severe inflammatory reaction.

Clinical Features zz

zz

zz

zz

zz

zz

Patients remain asymptomatic until the time of worm extrusion. Painful papule develops, with erythema, pruritus, and burning, usually on the lower leg. Multiple lesions may be present. Short lived systemic reaction may occur, which include fever, urticaria, nausea, vomiting, diarrhoea, and dyspnoea. Vesicle formation, which later ulcerates with a visible worm. The worm is then extruded or absorbed followed by ulcer healing. Secondary infection of the ulcer with cellulitis and abscess formation and rarely tetanus can occur.

Diagnosis zz

zz

Identification of the typical skin ulcer with protruding worm. Identification of larvae on smears or seen after immersion in cold water and there is associated eosinophilia.

Management zz

zz zz

zz

zz zz

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Protruding worm should be extracted gently by winding it out on a stick over several days. The worm must never be broken. Surgical excision of the worm, when possible. Treat the secondary infection with suitable antimicrobials. Metronidazole 400 mg tid for 10 days may be helpful along with mebendazole for limiting inflammation and they facilidate worm removal. Tetanus prophylaxis is advocated. Prevention is by eradication of water fleas from drinking water either by filtration or chemical treatment of water supplies.

Fig. 3.76  Life cycle of dracunculosis

Zoonotic Nematodes Trichinosis (Trichinellosis): Trichinella spiralis parasitises rats and pigs. Cutaneous larva migrans is due to larval migration of dog hookworm. Both can be transmitted to humans.

Trichinosis (Trichinellosis) (Fig. 3.77) Trichinella spiralis inhabits in rats and pigs. Humans get infected by eating partially cooked infected pork. Ingested larvae invade intestinal submucosa and develop into adult worms. They release larvae and that results in secondary invasion of striated muscle.

Clinical Features zz zz

zz

zz

In light infections the patients are asymptomatic. Heavy infection causes abdominal pain, nausea, vomiting and diarrhoea. This occurs within a week after cosuming the infected meat. Larval migration occurs in the 2nd and 3rd week which evoke various symptoms depending on the organ involvement—fever, oedema of the face, eyelids and conjunctivae, invasion of diaphragm causes pain, cough, dyspnoea, pain and tenderness of the affected muscles, myocarditis, and encephalitis. There is associated eosinophilia.

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Fig. 3.77  Life cycle of Trichinella spiralis

Investigations zz

zz

zz

Elevated serum muscle enzymes—creatine kinase, lactate dehydrogenase, aspartate aminotransferase. Serological tests may become positive in 3 weeks— ELISA, immunofluorescence, indirect haemag­glutinin, precipitin and bentonite flocculation assays. Rising antibody titers are highly suggestive of the diagnosis. Muscle biopsy of a tender swollen muscle to identify Trichinella larvae.

Management zz

zz

zz

Albendazole 20 mg/kg PO daily for 7 days. Mebendazole can also be used. Supportive therapy with analgesics, antipyretics and corticosteroids, when and where needed. Prevention is by proper cooking and irradiation of the meat.

Cutaneous Larva Migrans (CLM)(Fig. 3.78) Cutaneous larva migrans is caused by larvae of the dog and cat hookworms, Ancylostoma caninum and Ancylostoma braziliense. Other animal hookworms, Gnathostomiasis and strongyloidiasis may also cause this syndrome. The disease is due to the cutaneous migration of the larvae and

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is most common in children. The non-human parasites can cause only cutaneous disease since they cannot complete their life cycle.

Clinical Features zz

zz

zz

zz

zz

Erythematous papules with intense pruritus develop usually on the exposed area feet or hands but elbows, breasts, buttocks may be affected. The serpiginous track moves at the rate of 2 to 3 cm/ day (In strongyloides it is fast and transient). Several tracks may be present. The above process may continue for many weeks, with lesions become vesicualated, encrusted or secondarily infected. There are no systemic symptoms or associated eosinophilia. Charateristic skin lesions clinch the diagnosis and biopsy is not indicated.

Management zz

zz

zz

Mild cases do not require treatment (the larvae die and are absorbed). Thiabendazole 10% suspension can be applied topically TID for 5 days. Albendazole 400 mg OD/BID for 5 days or ivermectin 200 µg/kg PO single dose.

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Fig. 3.78  Cutaneous larva migrans—serpiginous lesions

Trematodes (Flatworms/Flukes) Trematode infections of humans may be classified according to tissues invaded by adult flukes: blood, biliary tree, intestines and lungs. They are leaf shaped, 1 cm to several cm in size. Except for schistosomes, all human parasitic trematodes are hermaphrodites.

Life Cycle (Fig. 3.79) Their life cycle involves a definitive host (mammalian/ human), in whom adult worms initiate sexual reproduction, and an intermediate host (snails) in which asexual multiplication of larvae occurs. Some species of trematodes require more than one intermediate hosts. Human infection is either by direct penetration of the intact skin or by ingestion. After maturation within humans, adult flukes initiate sexual reproduction and egg production. Eggs are passed in the excreta or sputum. Under favourable environment, the eggs hatch and release free living miracidia that seek the intermediate host (snails). After asexual reproduction, infected snails release cercariae. They infect the humans.

Fig. 3.79  Life cycle of Schistosoma species

Schistosomiasis (Blood Flukes)(Fig. 3.80) There are five species of the genus Schistosoma that cause disease in humans. They are the intestinal species—S. mansoni, S. japonicum, S. mekongi, S. intercalatum and the urinary species S. haematobium. Infections may cause consider­ able morbidity in the intestines, liver, and urinary tract. Humans are infected with schistosomes after contact with fresh water containing cercariae released by infected snails. Cercariae penetrate the skin/mucous membranes and migrate to the portal circulation where they mature. Adult worms mate and migrate to mesenteric or bladder venules where females deposit their eggs.

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Fig. 3.80  Schistosoma: Cercaria of Schistosoma with the typical forked tail

Some of the eggs reach the bowel or bladder and are passed in the faeces or urine. Others are retained in bowel or bladder wall or transported in the circulation to other tissues especially liver. The eggs cause inflammation, granuloma formation and then fibrosis.

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Infectious Diseases Clinical Features Cercarial dermatitis: It presents as localised erythema with pruritic maculo­papular rash which develop at the site of penetration. Acute schistosomiasis (Katayama syndrome) Febrile illness may develop 4 to 8 weeks after exposure—fever, headache, malaise, myalgias, cough, urticaria, diarrhoea. zz Other signs include hepatosplenomegaly, lymph­ adenopathy, and pulmonary infiltrates. zz Severe cases manifest with CNS abnormalities (seizures, blindness, hemiplegia, paraplegia due to deposition of eggs or worms in the brain or spinal cord) and may end fatally. zz Most cases resolve in 4 to 8 weeks. zz

Chronic schistosomiasis: Patients with light infections are asymptomatic. 50% have intestinal or urinary symptoms. 10% have organ damage. Anaemia and growth retardation are common in infected children. zz Intestinal schistosomiasis: It manifests with abdominal pain, diarrhoea, hepatomegaly, progressing to anorexia, weight loss and features of portal hypertension. Late manifestations include haematemesis from oesophageal varices, hepatic failure and pulmonary hypertension. zz Urinary schistosomiasis: It manifests with haematuria and dysuria. Fibrotic changes in the urinary tract can lead to hydroureter, hydronephrosis, bacterial urinary infections and ultimately kidney disease and bladder cancer. It can involve seminal vesicles, vulva, and cervix.

Investigations (Figs 3.81A and B) zz

zz

zz

zz zz

zz

zz

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Microscopic examination of stool or urine for charac­teristic eggs by filtration or concentration method can improve yields. Quantitative test that yields > 400 eggs per gram of faeces or 10 ml of urine are indicative of heavy infections with increased incidence of complications. Serologic tests ELISA is specific for all species. Serologic tests may become positive before eggs are seen in stool or urine. Species-specific immunoblots can increase sensitivity. Imaging of the liver and liver function tests. Ultrasound is used for assessing the urinary tract— bladder wall thickening, calcification, hydronephrosis can be detected. Cystoscopy—sandy patches with bleeding mucosa and later distorted and contracted bladder. Sigmoidoscopy may show inflamed bleeding mucosa and rectal biopsy.

Management Praziquantel is the drug of choice. The dose is 40 mg/kg od/bid single day therapy for S. mansoni, S. haema­tobium and S. intercalatum. The dose for S. japonicum, and S. mekongi is 60 mg/kg bid single day therapy. The adverse effects are abdominal pain, nausea, vomiting, diarrhoea, headache, urticaria and fever and it is due to direct effect of the drug or dying worms. The cure rate is generally > 80%. Corticosteroids can be used to decrease the adverse effects. zz Other drugs used are—oxamniquine, metrifonate, and artemether. zz Examine for eggs every three months for one year. If eggs are present, retreatment is required. zz Surgery—ureteric stricture, distorted bladder, gran­ uloma of brain, spinal cord, and rectal papillomas. zz

A

B Figs 3.81A and B (A) Schistosoma hematobium—egg short terminal spine; (B) Schistosoma mansoni—egg with large lateral spine

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Hepatobiliary Flukes Fasciola hepatica, clonorchis sinensis and opisthorchis felineus cause abdominal pain, hepatomegaly and relapsing cholangitis. They have similar life cycles.

Other mammalian hosts Mode of spread

Fasciola hepatica Clonorchis sinensis Sheep, cattle Dogs, cats, pigs

Ova in faeces on Ova in faeces, to wet pasture water 1st intermediate Snails Snails host 2nd intermediate Encysts on Fresh water fish host vegetation Distribution Worldwide Far East—China Pathology

Symptoms

Diagnosis

Treatment

Prevention

Opisthorchis felineus Dogs, cats, pigs, foxes Ova in faeces, water Snails Fresh water fish

Far East— Thailand Cholangitis, Cholangitis—E. Cholangitis, toxaemia, coli abscesses abscesses, eosinophilia Biliary carcinoma Biliary carcinoma Fever, tender liver, Recurrent Recurrent subcutaneous jaundice, or jaundice flukes asymptomatic Ova in stool or Ova in stool Ova in stool serology or duodenal and duodenal aspirate aspirate Triclabendazole Praziquantel 25 Praziquantel 25 10 mg/kg single mg/kg tid for mg/kg tid single dose—repeat if two days day therapy required Avoid Cook fish Cook fish contaminated watercress

Intestinal Flukes Two species cause human infection. They are the large Fasciolopsis buski (2 × 7 cm in size) and the smaller Heterophyes heterophyes. Human infection is initiated by ingestion of metacercariae attached to the aquatic plants (F. buski) or by consuming infected fish (H. heterophyes). Flukes mature in human intestines and eggs are passed in the stools. Heavy infection may cause abdominal pain, diarrhoea, and malabsorption. Diagnosis is confirmed by detection of ova in the stool. The treatment is praziquantel 25 mg/kg tid for single day.

Lung Flukes The lung fluke Paragonimus westermani—7 to 12 mm in length are found encapsulated in the lungs and rarely

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in the CNS or abdominal cavity. Human infection is by ingesting infective metacercariae encysted in the muscles of crayfish or crabs. On reaching the duodenum they excyst and penetrate the gut wall—peritoneal cavity, diaphragm, pleural space—and reach the lung. They mature in the lung. Eggs are passed in the sputum or stools. The life cycle is completed in the snails and fresh water crustacea. Inflammatory changes occur in the lungs with eosino­ phil infiltration leading to necrosis, cyst formation (1–2 cm in diameter) and that may contain one or two worms. The surrounding lung tissues may show the following changes—pneumonia, bronchitis, bron­ chiectasis, cavity formation, pleural effusion and fibrosis. Cerebral involve­ment presents as either space occupying lesions or epilepsy. Diagnosis is by detection of ova in the sputum or stools or by serology. Praziquantel is the drug of choice 25 mg/kg tid for two days.

Cestodes (Tapeworms) Cestodes are ribbon-shaped tapeworms. The adult worms reside in the GI tract and the larvae can be found in any organ. There are two major clinical groups in cestodes causing human infection: zz In one group in which humans are definitive hosts with the adult worms living in the gastrointestinal tract (Taenia saginata, Diphyllobothrium, Hymenolepis, and Dipylidium caninum). zz In another group humans are intermediate hosts with larval stage of parasites present in the tissues (Echinococcosis, Sparganosis, and coenurosis). zz For Taenia solium humans may be either the definitive or the intermediate hosts. The ribbon-shaped tapeworm attaches to the intestinal mucosa by means of sucking cups or hooks located in the scolex. Behind the scolex there is a short narrow neck from which proglottids (segments) form. When they mature, it is displaced further back from the neck by the formation of new, less mature segments. The mature proglottids are hermaphroditic and produce eggs that are passed in the stool.

Taenia saginata (Fig. 3.82) Humans get infected when raw or undercooked beef is eaten. Humans are the only definitive hosts for the adult stage of T. saginata.

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Life Cycle It inhabits in the upper jejunum and has a scolex with four prominent suckers. It can reach 8 m in length and has 1000 to 2000 proglottids. Eggs are deposited on vegetations. They are alive for months or years until they are ingested by cattle or other herbivores. The embryo released after ingestion invades the intestinal wall and is carried to striated muscle. There, they get transformed into cysticercus. In humans it takes 2 months for the mature adult worm to develop from cysticercus.

Clinical Features zz

zz

Mild abdominal discomfort, change in appetite pattern, nausea, weakness and weight loss can occur. Patients are aware of the infection by noting passage of motile proglottids in the stool and they have perianal discomfort when proglottids are passed.

Fig. 3.82  Taenia saginata—adult tapeworm— arrow pointing tiny scolex

Investigations (Fig. 3.83) zz zz

zz

zz zz

Detection of eggs or proglottids in the stool. Cellophane-tape swab taken from the perianal region is useful when the eggs or proglottids are not seen in the stool. Since the eggs are identical, to differentiate between T. saginata and T. solium—mature proglottids or scolex must be examined. Serologic tests are not useful. Eosinophilia and elevated levels of IgE can be detected.

Management zz

zz

zz

zz

A single dose of praziquantel 10 mg/kg is highly effective. The alternative therapy is single dose of 2 gm chewable niclosamide or nitazoxanide. Prevention is by adequate cooking of meat (56°C for 5 minutes). Refrigeration or salting for long periods or freezing at 10°C for 10 days kills cysticerci in the beef. General prevention is by proper inspection of beef and proper disposal of human faeces.

Fig. 3.83  Taenia saginata and Echinococcus granulosus eggs— similar to Taenia solium egg but do not have hooklets

Taenia solium and Cysticercosis (Fig. 3.84) Human infection of the pork tapeworm T. solium can exist in two distinct forms—adult tapeworms in the intestine or larval forms in the tissues (Cysticercosis). Humans are the only definitive hosts for T. solium and the pigs (usual) or other animals are intermediate hosts.

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Fig. 3.84 Taenia solium—Scolex and several proglottids. Long arrow—one of the four suckers on the scolex, short arrow point to the circle of hooklets

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Life Cycle (Fig. 3.85) The adult tapeworm (Often only one), 3 m in length, has 1000 proglottids, each of which produce upto 50,000 eggs. 3 to 5 proglottids are passed in the stool and the eggs are infective to both humans and animals. The eggs may survive for several months. After ingestion by the pigs, the larvae are released from the eggs and they penetrate the intestinal wall and are carried to the tissues especially to the striated muscles. The encysted larval stage develops within 2 to 3 months. These cysticerci can survive for many months to years. Humans get infected by consuming undercooked infected pork or ingesting eggs derived from their own faeces (Autoinfection).

Clinical Features zz

zz

zz

zz

zz

Intestinal infections with T. solium may remain asymptomatic. Faecal passage of proglottids may be noted by the patients. Subcutaneous cysticercosis presents with multiple painless palpable skin lesions. Cysticercosis of muscles is visualised by radiography as multiple calcified lesions. Extraocular muscle involvement may present with ptosis. Neurocysticercosis can cause intracerebral, sub­ a rachnoid, and spinal cord lesions and intraventricular cysts. Lesions may be single or multiple. Lesions may persist for years without symptoms. Symptoms are due to local inflammation (meningitis/encephalitis—headache, vomiting, papilloedema and visual loss) or ventricular obstruction (hydrocephalus). Presenting symptoms include seizures, focal neurological deficits, altered cognition, and psychiatric disorders (Fig. 3.86).

Diagnostic criteria for human cysticercosis: —— Absolute criteria (Histological demonstration of cysticerci from tissue biopsy/Funduscopic visualisation of parasite in the eye/Neuroimaging demonstrating cystic lesion containing characteri­stic scolex) —— Major criteria (Neuroimaging suggestive of cysticercosis/Demonstration of antibodies—ELISA or immunoblot assay/Resolution of cystic lesions after therapy with albendazole or praziquantel) —— Minor criteria (lesions compatible with neuro­ cysticercosis by imaging/Clinical features suggestive of neurocysticercosis/demonstration of antibodies ELISA/Evidence of cysticercosis outside CNS—cigar shaped tissue calcifications) —— Epidemiological criteria (residence in endemic area/travel to endemic area/contact with infected individual). Diagnosis is confirmed by either one absolute criteria or a combination of two major criteria, one minor criteria, and epidemiologic criteria. A probable diagnosis is supported by—one major criteria plus two minor criteria or one from each of major, minor and epidemiologic criteria or three minor criteria plus one epidemiological criteria.

zz

Management zz

zz

zz

Investigations (Fig. 3.87) zz zz

zz

zz

zz

zz

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Detection of eggs or proglottids in the stool. Demonstration of parasite in tissue biopsy (histologic observation). Funduscopic visualization of parasite in the eye— anterior chamber, vitreous, or subretinal spaces. Neuroimaging studies (CT for calcified lesions and MRI for cystic lesions) demonstrating cystic lesions containing characteristic scolex. Detection of specific antibodies to cysticerci—ELISA or immunoblot assay. Antigen detection assays by using monoclonal antibodies to detect parasite antigen either in the blood or CSF.

zz

zz

zz

A single dose of praziquantel 10 mg/kg is effective for intestinal T. solium infection or niclosamide 2 gm is also effective. For seizures in neurocysticercosis, antiepileptic therapy should be given for a period of 1 to 2 years. For brain parenchymal cysticerci, albendazole 15 mg/kg/day for 28 days or praziquantel 50 to 60 mg/kg/day in three divided doses for 30 days is effective. Both the drugs may exacerbate inflammatory response around the dying parasites, thereby exacerbating seizures and incidence of hydrocephalus. High dose glucocorticoids are useful to curtail the adverse effects. Emergent reduction of intracranial pressure in cases of obstructive hydrocephalus is either by endoscopic surgical removal of cysticercus or by performing ventriculoperitoneal shunt. Inflammatory response induced arachnoiditis and vasculitis should be treated with high dose glucocorticoids. Prednisolone 10 mg tid for 14 days is effective, especially if given earlier than that of antiparasitic drugs. In some difficult cases surgical removal of cysticercus can be done.

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Fig. 3.85  Life cycle of Taenia solium

Fig. 3.86  Neurocysticercosis—ring enhancing lesion at left parieto-occipital lobe

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Fig. 3.87  Taenia solium egg oncosphere embryo with four hooklets

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Echinococcosis Dogs are the definitive hosts of the tiny tapeworm Echinococcus granulosus (5 mm long) and they live in the jejunum of the dogs for 5 to 20 months. E. granulosus has only three proglottids—one immature, one mature, and one gravid. The gravid segment release eggs. The larval stage occurs in the intermediate hosts—sheep, cattle, camels, humans, goats and horses.

Larvae develop into fluid filled unilocular hydatid cysts. Hydatid cysts have an external membrane and an inner germinal layer. Daughter cysts develop from the inner aspect of the germinal layer. When a dog ingests infected meat containing cysts, the life cycle is completed.

Clinical Features zz

zz

Life Cycle (Fig. 3.88) The definitive hosts are canines that pass eggs in their faeces. Humans get infected after ingestion of eggs. Embryos escape from the eggs, penetrate the intestinal mucosa, enter the portal circulation and are carried to various organs (brain, bones, kidneys, spleen, skeletal muscles, breasts, adrenal, bladder, and heart), but the larvae develop, most commonly in liver and lungs.

zz

zz

Infections are commonly asymptomatic or they may present with symptoms caused by an enlarging or superinfected mass. Hepatic involvement usually presents with hepato­ megaly, obstructive jaundice, recurrent cholangitis, PUO, portal hypertension, and cirrhosis. Lung involvement presents with lung cysts, dyspnoea, chest pain, haemoptysis, bronchial obstruction with segmental collapse, abscesses, and cyst leakage with anaphylaxis. It may cause pressure symptoms depending on the organ system involved.

Fig. 3.88  Life cycle of Echinococcus granulosus

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Infectious Diseases Investigations zz

zz

zz zz

Imaging studies are important in detecting and evaluating echinococcal cysts. Pulmonary cyst of E. granulosus is easily diagnosed in plain films. Ultrasound, CT, and MRI reveal well-defined cysts with thick or thin walls. Pathognomonic sign is demonstration of daughter cysts within the larger cyst. This finding, like eggshell or mural calcification on CT is indicative of E. granulosus infection (Fig. 3.89). Examination of aspirated fluid for protoscolices or hooklets confirms the diagnosis of E. granulosus infection (not recommended usually because of likelyhood of leakage and anaphylaxis). Serodiagnostic assays (ELISA) are useful and specific. Detection of antibody to specific echinococcal antigens by immunoblotting is specific.

Management zz

zz

zz

PAIR is recommended instead of surgery (Puncture, percutaneous aspiration, infusion of scolicidal agents, and respiration). PAIR is contraindicated for superficially located cysts (because of the risk of rupture), cysts with multiple internal septal divisions, and for cysts communicating with biliary tree. Scolicidal agents infused are 0.5% silver nitrate or 2.7% sodium chloride or 95% ethanol or cetrimide. Albendazole 15 mg/kg/day in two divided doses for 30 days. Repeat the course after 15 days interval. Surgery is the treatment of choice for cysts communi­ cating with biliary tree or for areas where PAIR is not possible.

Hymenolepiasis nana H. nana is the only cestode of humans that does not require an intermediate host.

Life Cycle The adult worm 2 cm long inhabits in the proximal ileum. Small proglottids are passed in the stool and they release the eggs, each of which contains an oncosphere with six hooklets. The eggs are immediately infective and unable to survive for more than 10 days. The eggs when ingested, the oncosphere is freed and penetrate the intestinal villi and becomes a cysticercoids larva. Larvae migrate back into the intestinal mucosa and mature into adult worm within 10 days. Eggs may also hatch before passing in the stool. Autoinfection is common that perpetuates the infection.

Clinical Features zz zz

Many infected individuals are asymptomatic. Heavy infection may cause abdominal discomfort, anorexia and diarrhoea.

Investigations zz

Stool examination for eggs.

Management zz

zz

Praziquantel 25 mg/kg once is effective or an alternative drug nitazoxanide 500 mg bid for 3 days. Prevention is by good personal hygiene and improved sanitation.

Diphyllobothrium latum They are found in the lakes and rivers. The adult worm— the longest tapeworm up to 25 m, attaches to the ileal mucosa by its suckers, which are located on its elongated scolex.

Life Cycle (Fig. 3.90)

Fig. 3.89  Hydatid cyst involving liver and lung

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The adult worm has 3000 to 4000 proglottids, which release one million eggs daily in the faeces. The eggs on reaching water hatch and release free swimming embryos. They are eaten by freshwater crustaceans—cyclops. Procercoid stage develops in cyclops. Infected cyclops are swallowed by fish and the larvae migrate into the flesh of fish. Human acquires the infection by consuming raw or smoked fish. In 4 weeks time the tapeworm matures into adult form in human intestine.

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FUNGAL INFECTIONS

Fig. 3.90  Life cycle of Diphyllobothrium latum

Clinical Features zz zz

zz

zz

Most infected individuals are asymptomatic. They may develop abdominal pain, nausea, vomiting, diarrhoea, weakness, and weight loss. Occasionally they may develop acute abdominal pain either due to intestinal obstruction or due to cholangitis/cholecystitis due to migrating proglottids. Because the tapeworm absorbs large quantum of vita­ min B12 and prevents absorption of vitamin B12, vitamin B12 deficiency can develop. This is more common in elderly and results in megaloblastic anaemia. Vitamin B12 deficiency can lead to neurologic complications.

Investigations Examine the stool for the characteristic eggs. The eggs possess a single shell with an operculum at one end and a knob at the other. Eosinophilia may be present.

Management zz zz

zz

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Praziquantel 10 mg/kg single dose is highly effective. Parenteral vitamin B 12 should be given if B 12 deficiency is present. Prevention is by cooking fish (54°C for 5 minutes) or freezing it at 18°C for 24 hours or placing the fish in high salt concentration for long periods.

Fungal infections have been classified into specific categories based on anatomic location, epidemiology and the modality of growth. Anatomically it can be superficial-mucocutaneous or subcutaneous or deep organ infection. Epidemiologically it can be endemic or opportunistic. Mucocutaneous infections can cause serious morbidity, but they are rarely fatal. Deep organ infections can cause severe illness and are often fatal. The endemic mycoses (coccidioidomycosis) the organisms are not part of normal human microbial flora and are acquired from environmental sources. Endemic mycoses cause severe illness in immunocompromised patients. In opportunistic infections, the organisms that normally exist as commensals transform into invasive pathogens, when the patient’s immunity is compromised (Candida, Aspergillus). Depending on the mode of growth it can be classified as yeast, mould and dimorphic fungus. Yeasts are seen as rounded single cells or as budding organisms (Candida, Cryptococcus). Moulds grow as filamentous forms called hyphae (Aspergillus fumigatus, Fusarium, Dermatophyte fungi, Mucorales). Dimorphic form is the term used to describe the fungi that grow as yeasts or large spherical structures in tissue but as filamentous form at room temperature in the environment (Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides brasiliensis, Blastomyces dermatitidis, Sporothrix schenckii, Penicillium marneffei, Malassezia).

Candidiasis (Fig. 3.91) Candida albicans can be cultured from the mouth, vagina, and faeces of most people. They are part of the common normal flora and they cause opportunistic infection.

Mucocutaneous Candidiasis It may involve almost any cutaneous or mucous surface of the body. It is more common in diabetics, during pregnancy and in obese persons who sweat freely. Systemic antimicrobials, corticosteroids, and oral contra­ ceptive agents, prolonged neutropaenia, recent abdominal surgery, chronic kidney disease, catheter associated infections and immunodeficiency state induced by cytotoxic drugs, radiation or due to illness can all predispose to candidial infection. Oral candidiasis is more common in those who wear dentures, those who are debilitated with poor oral hygiene and is also the first sign of HIV infection.

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Fig. 3.91  Candida with chlamydoconidia

Fig. 3.92  Oral candidiasis

Clinical Features (Figs 3.92 and 3.93) zz

zz

zz

zz zz

zz

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zz

Intense itching and burning around the vulva, anus and body folds. Superficial denuded beefy-red areas with or without satellite vesicopustules occur in the depth of the body folds such as in the groin, intergluteal cleft, beneath the breasts, at the angles of the mouth, and umbilical region. Whitish curd-like concretions may be present on the oral and vaginal mucous membranes. Paronychia may occur. Oesophageal involvement is most common and it presents with substernal odynophagia, nausea and GERD. Diagnosis is by endoscopy, biopsy and culture. Disseminated candidiasis: The organisms on entering the bloodstream either from the GI tract or from the skin through the site of an indwelling intravascular catheter, it may spread to various deep organs— brain, chorioretina, heart, kidneys, liver, spleen, adrenals, pancreas, bones, skeletal muscles, joints and heart valves (native and prosthetic), meninges and may also spread haematogenously to the skin causing macronodular lesions. Candidal endocarditis is due to direct inoculation of candida at the time of heart surgery or catheter induced. Splenomegaly and petechiae are common. The diagnosis by culturing candida from emboli or vegetation. Candidal funguria is catheter induced or therapy induced after major surgery or organ transplant.

Investigations zz

zz

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Direct microscopy of skin scales or curd-like lesions after staining with potassium hydroxide reveals cluster of budding cells and pseudohyphae. Tissue biopsy and culture or urine, sputum or blood culture confirms the diagnosis.

Fig. 3.93  Oesophageal candidiasis

Management zz

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Mucocutaneous candidiasis: Affected parts should be kept clean and dry and exposed to air as much as possible. Nails and paronychia: Apply clotrimazole 1% solution twice daily or thymol 4% in ethanol once daily. Skin: Nystatin ointment or clortrimazole cream 1% twice daily application is effective. Gentian violet 0.5% is economical and effective, but the cosmetic issue because of discolouration is to be considered. Vulvar and anal candidiasis: Single dose of flucona­ zole 150 mg PO is effective. Intravaginal clotrimazole, miconazole, terconazole or nystatin may also be used. For recurrent/refractory cases and non-albicans candidal species, itraconazole 200 mg bid for 2 to 4 weeks may be used.

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Manual of Practical Medicine zz

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Balanitis: Topical nystatin ointment is effective. Soaking with dilute aluminum acetate for 15 minutes twice daily relieve burning/itching. Consider bacterial infection in cases of purulent discharge and use antibiotics. Mastitis: Candidal infection of the breast ducts can cause breast pain and nipple dermatitis and it can be treated with oral fluconazole 200 mg daily along with antifungal cream application. Oral candidiasis: Any of the following drugs can be used—Fluconazole 100 mg/day for 1 to 2 weeks or ketoconazole 200 to 400 mg with breakfast for 1 to 2 weeks. Mouth application clotrimazole troches or nystatin vaginal troches 3 to 5 times daily is useful. In refractory cases itraconazole 200 mg/day can be used. Nystatin powder 100,000/gm can be applied to dentures tid for several weeks. Oesophageal candidiasis: Fluconazole 100 mg or itraconazole 200 mg PO for 10 to 14 days if the patient can swallow. If the patient cannot swallow or is seriously ill, use IV antifungal drugs—Voriconazole 200 mg bid or amphotericin B 0.3 mg/kg/day or anidulafungin 100 mg on day 1 and then 50 mg/day or micafungin 150 mg/day. Candidal funguria: Oral fluconazole 200 mg/day for 1 to 2 weeks is very effective. Newer generation azoles are not very effective. Disseminated invasive candidiasis: Fluconazole loading dose of 800 mg (12 mg/kg) followed by 400 mg (6 mg/kg) or caspofungin loading dose 70 mg on day 1, followed by 50 mg/day or micafungin 100 mg/ day or anidulafungin loading dose of 200 mg on day 1, followed by 100 mg daily—any one of the above drugs can be given IV for upto the period of 2 weeks after the last positive culture and resolution of symptoms and signs of infection. Once the patient is stable, oral fluconazole 200 to 800 mg od or bid can be started. Candida endophthalmitis: Partial vitrectomy combined with IV and intravitreal antifungal therapy may be useful. Candidal endocarditis: Amphotericin B 0.5 to 1 mg/kg/day IV along with aggressive surgical intervention or newer generation azoles or any one of echinocandins can be administered. In high risk patients undergoing induction chemo­ therapy, bone marrow transplantation or organ transplantation, prophylactic therapy with antifungal agents can prevent invasive fungal infections.

Mississippi river). They exist in two forms—microconidial and macroconidial forms. Though named as H. capsula­tum, the organism is unencapsulated. Infection is by inhalation. It simulates tuberculosis both clinically, radiologically and to some extent pathologically as evidenced by caseous necrosis.

Clinical Features zz

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Most cases are asymptomatic. Past infections are recognised by incidental pulmonary and splenic calcifications. Symptomatic infection may present with influenza-like illness lasting for 1 to 4 days. Moderately severe infections present as atypical pneumonia lasting for 5 to 15 days. Acute histoplasmosis: It is a severe form of disease presenting with high fever, prostration, a few pulmonary symptoms with diffuse pneumonia lasting for several weeks to 6 months. Progressive disseminated histoplasmosis (PDH): It is commonly seen in immunocompromised and HIV patients. They present with fever, cough, dyspnoea, loss of weight, prostration, oropharyngeal ulcers, hepatosplenomegaly, GIT involvement simulating inflammatory bowel disorder, adrenal involvement with adrenal insufficiency, miliary lesions in chest radiograph and the mortality is high if not treated. Chronic progressive pulmonary histoplasmosis: It is common in older patients. Apical cavities, infiltrates and nodules are seen in chest X-ray. Chronic progressive disseminated histoplasmosis: Presentation is similar to acute disseminated histoplasmosis and is common in middle aged and elderly. It is chronic and ends fatally if not treated. Complications of pulmonary histoplasmosis: They present with enlarged mediastinal lymph nodes— granulomatous mediastinitis and compromised great vessels.

Histoplasmosis (Fig. 3.94) Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus (2–4 µm in size) isolated from soil contaminated with bird or bat droppings in endemic areas (common along river valleys—Ohio River and the

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Fig. 3.94  Histoplasma: Mycelial form—tuberculate macroconidia

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Infectious Diseases Investigations zz

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Biopsy of the affected organ with culture confirms the diagnosis. In pulmonary disease sputum culture is rarely positive except in chronic disease. Antigen testing of bronchoalveolar lavage fluid may be helpful. The combination of urine and serum antigen assay has an 80% sensitivity in acute pulmonary histoplasmosis. Blood and bone marrow culture are useful in immunocompromised patients. Alkaline phosphatase, LDH, ferritin, and AST are elevated. Bone marrow involvement may reveal anaemia of chronic disease and pancytopaenia. Patients with disseminated disease may have a falsepositive Aspergillus galactomannan assay. Chest radiograph and CT are useful.

immunocompetent persons develop disseminated disease with increased mortality. In HIV infected patients it is the common opportunistic infection in endemic regions and the disease manifestations range from focal pulmonary infiltrate to miliary form with multiple organ involvement and meningitis.

Clinical Features zz

zz

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Management Type of Histoplasmosis Mild cases Moderate to severe–acute pulmonary with diffuse infiltrates and / or hypoxaemia Chronic cavitary pulmonary Progressive disseminated

CNS involvement

Histoplasmosis in AIDS

Recommended Treatment Recover without therapy. If not, itraconazole 200 mg bid 1–3 months Lipid amphotericin B 3–5 mg/kg/day IV ± glucocorticoids for 1–2 weeks, then itraconazole 200 mg bid PO for 12 weeks Itraconazole 200 mg bid or qid for 12 months Lipid amphotericin B 3–5 mg/kg/day IV for 1–2 weeks, then itraconazole 200 mg bid PO for 12 months Lipid amphotericin B 3–5 mg/kg/day IV for 4–6 weeks, then itraconazole 200 mg bid/tid PO for 12 months Life-long itraconazole suppressive therapy

Lipid complexed preparations of amphotericin B: Amphotericin B lipid complex, liposomal amphotericin B, and amphotericin B colloidal dispersion – out of which liposomal amphotericin B is best tolerated. They have fewer infusion-related reactions and less nephrotoxic. Amphotericin therapy is associated with potassium and magnesium wasting and requires supplementation. Monitor serum creatinine and electrolytes thrice a week. LFT should be monitored regularly while treating with azoles – itraconazole. In CNS lesions continue itraconazole till CSF or CT abnormalities clear.

After an incubation period of 10 to 30 days, the disease manifests as influenza-like illness with malaise, fever, headache, backache and cough. Erythema nodosum appears in acute infection. Arthralgia with periarticular swelling often affects knees and ankles. Pulmonary lesions vary from simple pneumona to miliary lesion, bronchiectasis, cavitary lesions and abscess formation. Disseminated disease occurs in about 0.5% and involves many organs including mediastinal lymph node involvement, pleural, pericardial and myocardial involvement. Meningitis is common. In HIV infected patients, the disease is disseminated with multiorgan involvement including bone, joints, and meninges.

Investigations zz

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Serologic testing is useful for both diagnosis and prognosis. The immunodiffusion tube precipitin test detects IgM antibodies and is diagnostic. Persistent rising IgG complement fixation titer (≥ 1:16) is suggestive of disseminated disease. Detection of complement fixing antibodies in spinal fluid are diagnostic of coccidioidal meningitis. Biopsy specimens, blood, CSF, urine and sputum culture may reveal spherules filled with endospores. Imaging—chest radiograph and CT chest are useful.

Coccidioidomycosis (Fig. 3.95) Infection results from the inhalation of arthroconidia of Coccidioides immitis or C. posadasii; both the organisms are molds that grow in soil in certain endemic regions— Mexico, Central and South America. Less than 1% of

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Fig. 3.95  Coccidiomycosis

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Manual of Practical Medicine Management zz

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Fluconazole 200 to 400 mg once daily PO or itraconazole 200 mg bid PO is given for diseases of chest, bones, and soft tissues for six months. For progressive pulmonary or extrapulmonary disease, amphotericin B IV is used (0.6 mg/kg/day). For mild cases oral azoles may be used. For meningitis high dose fluconazole 400 to 800 mg/day PO along with intrathecal administration of amphotericin B by increasing doses upto 1 to 1.5 mg/ day is used. Voriconazole or posaconazole may be alternatives for intrathecal amphotericin B. Thoracic surgery is indicated for giant infected, ruptured cavities. Surgical drainage is necessary for abscesses in bones and soft tissues. Amphotericin B 1 mg/kg/day IV is advised following surgery.

Pneumocystosis (Pneumocystis jiroveci Pneumonia) (Fig. 3.96) Pneumocystis jiroveci is distributed worldwide. It causes acute interstitial plasma cell pneumonia. Asymptomatic infection is common in young age as evidenced by positive serology. Overt infection occurs with high frequency among two groups: (1) premature or debilitated or marasmic infants, and (2) individuals with altered cellular immunity—cancer patients on chemotherapy or radiotherapy, organ transplant patients or severely malnou­ rished individuals or patients with AIDS. Pneumocystis pneumonia occurs in upto 80% of AIDS patients and is a major cause of death.

Clinical Features Pulmonary disease onset is abrupt, with fever, tachypnoea, shortness of breath and nonproductive cough. Pulmonary physical findings are minimal and disproportionate to degree of illness and the radiological findings. Clinically bibasilar crackles may be the only sign. They may present with spontaneous pneumothorax. Without treatment the mortality is high.

Investigations zz

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Management zz

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Fig. 3.96  Cystic forms of Pneumocystis jiroveci (Methenamine silver stain)

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Chest radiograph: The findings may range from normal X-ray to diffuse interstitial infiltration, patchy consolidation, cystic changes, nodules, and cavitation. Pleural effusions are uncommon. High resolution chest CT scan is useful. Arterial blood gas study may be normal or it may reveal hypoxaemia with hypocapnia. Elevated (1–3)-β-D-glucan levels along with isolated elevation of serum LDH have reasonably good sensitivity and specificity for the diagnosis of Pneumo­cystis jiroveci pneumonia. Demonstration of organisms in clinical specimens either by Giemsa stain or methenamine stain is diagnostic. The organism cannot be cultured. The use of monoclonal antibody with immuno­ fluorescece is helpful for the diagnosis. The specimens can be obtained by sputum induction, bronchoalveolar lavage, transbronchial lung biopsy or open lung biopsy and needle lung biopsy.

Trimethoprim 15 to 20 mg/kg and sulfamethoxazole 100 mg/kg given PO or IV in three divided doses for 14 to 21 days. The adverse effects are fever, rashes, neutro­ p aenia, thrombocytopaenia, hepatitis, nephritis, hyperkalaemia and hyperbilirubinaemia. Clindamycin 600 mg tid along with primaquine 7.5 mg bid is the best second line therapy. Pentamidine Isethionate IV/IM single dose 3 mg/ kg/day for 21 days. 50% of patients develop adverse effects—hypoglycaemia, hyperglycaemia, hyponat­ raemia, ventricular arrhythmias, pancreatitis, throm­b o­c ytopaenia and delayed nephrotoxicity with azotaemia. Atovaquone 750 mg tid for 21 days is another alternative. Other alternative is dapsone 100 mg/day along with trimetoprim 15 mg/kg/day in three divided doses. Prednisone is given for moderate to severe pneumonia when PaO2 is less than 70 mm Hg or oxygen saturation is less than 90%. Dosage schedule is 40 mg bid for 5 days, 40 mg od for 5 days and then 20 mg od for the entire period of therapy.

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Cryptococcosis (Fig. 3.97) It is mainly caused by an encapsulated budding yeast Cryptococcus neoformans. It is found in soil on dried pigeon dung. Infection is acquired by inhalation. It is the most common cause of fungal meningitis.

Clinical Features zz

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Pulmonary disease ranges from simple nodule to wide-spread infiltration with respiratory failure. Disseminated form may involve any organ. Meningeal signs—headache, nausea, vomiting, confusion, altered mental status and cranial nerve palsies are seen. Nuchal rigidity and above meningeal signs occur only in 50% of cases and they are uncommon in HIV infected patients. Clinical worsening associated with improved immunological status has been noted in HIV infected and transplant patients with cryptococcosis and this peculiar entity is named as “Immune reconstitution inflammatory syndrome” (IRIS).

Investigations zz

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Pulmonary involvement is confirmed by culture of sputum or pleural fluid. Meningeal involvement is by CSF analysis— increased pressure, increased pleocytosis, increased protein, decreased glucose and Gram stain usually reveals budding, encapsulated fungal cells. Culture of CSF and blood confirms the diagnosis. Visualisation of capsule of fungal cell in CSF mixed with India ink is a useful rapid diagnostic technique. Cryptococcal capsular antigen in CSF and positive culture confirms the diagnosis. Ninety-five per cent of HIV infected and solid organ transplant patients have a positive capsular polysaccharide serum antigen. Antigen can also be detected in blood, lungs and urine. MRI than CT brain is sensitive for detecting cryptococcomas.

Management zz

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Amphotericin B 1 mg/kg/day IV is given for 15 days followed by fluconazole 400 mg/day PO for 8 weeks. Flucytosine 100 mg/kg/day in four divided doses PO, when added improved survival. Frequent repeated lumbar puncture and ventricular shunting should be performed to relieve high CSF pressure. Lipid amphotericin B have equivalent efficacy with reduced incidence of nephrotoxicity. Therapy is continued till the CSF culture is negative and CSF antigen titers are below 1:8.

Fig. 3.97  Cryptococcus in KOH

Aspergillosis (Figs 3.98A to C) Aspergillus fumigatus is the usual cause of aspergillosis. The other species that cause disease are A. flavus and A. niger. The most prevalent species in the world is A. fumigatus; but in India and Pakistan the commoner organism is A. flavus. The lungs, brain and sinuses are commonly affected. Infection of sinuses is by inhalation.

Clinical Features zz

zz

Allergic bronchopulmonary aspergillosis: It occurs in patients with pre-existing bronchial asthma and cystic fibrosis who develop worsening bronchos­ pasm and fleeting pulmonary infiltrates. They have eosinophilia, high levels of IgE, and IgG aspergillus precipitins in the blood. Invasive aspergillosis: It is common in immuno­ competent or mildly immunocompromised adults. They manifest in different clinical forms: —— Sinusitis: Suspect aspergillus infection in cases of chronic sinusitis and the diagnosis is confirmed by histopathological examination. —— Aspergillomas (Fig. 3.99): It occurs in the preexisting cavity of the lung. Lung lesions become secondarily colonized with aspergillus species and results in significant haemoptysis. Chest radiograph reveals the lesion. —— Chronic necrotizing aspergillosis: It is relatively rare and seen in immunocompromised patients. It has a protracted course and fibrosis and cavity formation are common. —— Life-threatening invasive aspergillosis: It occurs in profoundly immunodeficient patients such as patients who have undergone haematopoe­ itic stem cell transplant, in those with prolonged

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Manual of Practical Medicine neutropaenia, and patients with chronic granulo­matous disorders. Pulmonary disease starts as patchy infiltration and later leads to severe necrotising pneumonia. Haematogenous dis­semi­­nation may occur at any time leading to involvement of CNS, skin and other organs.

Investigations

Fig. 3.98A  Aspergillus flavus A. Spherical vesicles, B. Metulae, C. Phialides

Fig. 3.98B  Aspergillus fumigatus

Blood cultures have very low yield. Detection of galactomannan by enzyme-linked immunosorbent assay (ELISA) or β-D-glucan, or both confirms early diagnosis of invasive aspergillosis. A definitive diagnosis requires demons­tration of aspergillus in tissue or culture from a sterile site. CT scan of the chest may reveal “halo sign” suggestive of invasive aspergillosis.

Fig. 3.98C  Aspergillus niger

Fig. 3.99  Aspergillus fungal ball in a pre-existing lung cavity

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Infectious Diseases Management zz

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Clinical Features

Allergic bronchopulmonary aspergillosis: Prednisone 1 mg/kg/day PO and then eapered slowly over several months. Itraconazole 200 mg/day PO for 3 to 4 months. Voriconazole can be given in place of itraconazole. Sinusitis: Protracted courses of antifungals– itraconazole 200 mg bid PO for 2 to 3 months. Aspergilloma: Surgical resection is the best option. Chronic necrotising aspergillosis: Long term course of itraconazole therapy is advocated. Life-threatening invasive aspergillosis: Voriconazole 6 mg/kg bid IV on day 1, and then 4 mg/kg/day thereafter improves survival and it is better than amphotericin B. Voriconazole 4 mg/kg bid/day PO following IV therapy. Alternatively, lipid preparations of amphotericin B 3 to 5 mg/kg/day IV. The other alternative is caspofungin—70 mg IV on day 1, then 50 mg/day thereafter. The other drugs used are micafungin 100 to 150 mg IV/day and posaconazole 200 mg PO qid. Prevention: Prophylactic therapy for those on pro­ found immunosuppression is by giving any one of the azole—fluconazole, itraconazole, voriconazole and posaconazole.

Mucormycosis (Zygomycosis/ Phycomycosis) (Fig. 3.100) The term is applied to opportunistic infections caused by members of the genera Rhizopus, Mucor, Absidia, and Cunninghamella. Predisposing conditions include haematologic malignancy, stem cell transplantation, solid organ transplantation, diabetic ketoacidosis, chronic kidney disease, desferoxamine therapy, and treatment with corticstroids or cytotoxic drugs.

The clinical manifestations depend on the site of infection. zz Rhinocerebral mucormycosis: It starts as sinusitis with intense headache, bloody nasal discharge, changes in mental status, black eschar of the palate (Hallmark of rhinocerebral mucormycosis), which indicates angioinvasion and tissue necrosis. Involvement of the orbit leading to proptosis, ptosis, invasion of retinal artery causing blindness, progression of infection into the brain, and cavernous sinus thrombosis (ominous sign). CT/MRI reveals sinus opacification and destruction of contiguous bone with brain involvement. zz Pulmonary mucormycosis: Severe progressive tissue destructive pneumonia with high fever is the common sign. Cavitation of involved lung and haematogenous spread to other organs including brain. zz Gastrointestinal mucormycosis: It is more common in patients with protein-calorie malnutrition and usually present as perforated viscus. zz Cutaneous mucormycosis: Infection follows traumatic injuries. Area of tissue necrosis enlarges rapidly involving all layers of skin and underlying structures.

Investigations zz

zz

There are no pathognomonic haematologic changes. The main abnormality is the underlying predisposing disorder, e.g. diabetic ketoacidosis. There are elevated white blood cell counts and acute-phase reactant levels. Blood cultures are usually negative. Biopsy with histologic examination is required for diagnosis.

Management zz

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Fig. 3.100  Mucor—sporangia

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High dosage amphotericin B 1 to 1.5 mg/kg/day IV or a lipid preparation of amphotericin B should be started early and continued for prolonged period. After controlling acute infection posaconazole can be given. Other azoles are ineffective. Control of diabetes and other underlying conditions are essential. Surgical removal of necrotic, non-perfused tissue is essential. The mortality rate is very high and it ranges from 30 to 50% in localised disease and much more for disseminated disease.

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Penicillium marneffei Infections It is a dimorphic fungus that causes systemic infection in both healthy and immunocompromised individuals. Clinical manifestations include fever, generalised umbilicated popular rash, lymphadenopathy, cough, and diarrhoea. Diagnosis is made by identification of the organism on smears or histopathologic specimens or by culture. The culture reveals characteristic red pigment produced by the fungus. Fungus can be isolated from the skin, blood, bone marrow, respiratory tract and lymph nodes. Mild to moderate disease can be treated with itraconazole 200 mg bid PO for 8 weeks. Amphotericin B 0.5 mg/kg/day IV is the drug of choice for severe cases. Indefinite course of itraconazole 200 mg od PO is indicated for relapse.

Mycetoma (Maduromycosis and Actinomycetoma) It is a chronic local, slowly progressive destructive lesion usually involving the foot. It starts in the subcutaneous tissue following trauma and spreads to contiguous structures—fascia and bone. It is caused by Actinomadura

species and Nocardia. Mycetoma due to fungi is called eumycetoma. The other one caused by actinomycetes is called as actinomycetoma.

Clinical Features Clinically, eumycetoma and actinomycetoma are similar. It begins as small, painless plaques or nodules on the foot or leg and less frequently on the arms, torso and scalp. Multiple subcutaneous abscesses are seen with draining sinus tracts, fibrosis with woody induration and it extends to fascia and bone.

Investigations zz

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Diagnosis is based on visualisation of grains in pus, sinus exudates and tissue biopsy. Both fungi and actinomycetes can be cultured. Gram stain of tissue reveals fine branching hyphae with actinomycotic mycetoma and larger hyphae with fungal mycetoma. The causative organism can be identified by the colour of the characteristic grains within the infected tissue. Radiograph of the affected region may reveal destructive changes in the underlying bone.

Antifungal Agents for Systemic Mycoses Drug

Dose

Amphotericin B

0.3–1.5 mg/kg/day IV

Indications

Aspergillosis, mucosal and invasive candidiasis Mucosal and invasive candidiasis and prophylaxis for stem cell transplant Cryptococcosis, candidiasis, chromomycosis

Terbinafine

Dermatophytes, sporotrichosis

Fluconazole Itraconazole

Ketoconazole

Posaconazole Voriconazole

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Adverse effects

Fever, azotemia, hypokalemia, Hypomagnesemia Renal tubular acidosis, anaemia Amphotericin B—lipid 5 mg/kg/day IV Fever, rigor, hypotension, azotemia, anaemia, complex tachypnoea Liposomal amphotericin B 3–6 mg/kg/day IV As above Anidulafungin 100 mg loading dose Diarrhoea, elevated hepatic enzymes, histamine followed by 50 mg/day IV mediated reactions Caspofungin acetate 70 mg loading dose followed Transient neutropaenia, elevation of hepatic by 50 mg od IV enzymes Micafungin sodium 150 mg od IV and 50 mg for Rash, rigor, headache, phlebitis prophylaxis Flucytosine 100–150 mg/kg/day in 4 Leukopaenia, diarrhoea, rash, hepatitis, nausea, divided doses vomiting (5-FC) 250 mg /day PO single dose Abdominal pain, nausea, taste disturbance, rash, diarrhoea, hepatic enzyme elevation for 4–12 weeks 100–800 mg/day od/bid IV/PO Nausea, rash, alopecia, headache, hepatic enzyme elevations

All major fungal infections except Scedosporium As above As above Mucosal and invasive candidiasis

Mucosal candidiasis, cryptococcosis Histoplasmosis coccidioidomycosis 100–400 mg/day od/bid PO Nausea, oedema, hypokalemia, hypertension Mucosal candidiasis, aspergillosis Histoplasmosis Coccidioidomycosis 200–800 mg/day od/bid PO Anorexia, nausea, rash, headache, suppression of Non-meningeal histoplasmosis, testosterone and cortisol Coccidioidomycosis Hepatic enzyme elevation and hepatic failure Mucosal candidiasis blastomycosis 400–800 mg/day od/bid PO Nausea, vomiting, abdominal pain, diarrhoea, headache Broad-spectrum including zygomycosis 200–400 mg/day od/bid PO or Transient visual disturbances, rash, Hepatic enzyme Broad-spectrum except zygomycosis 12 mg/kg IV 2 days—then elevations and sporotrichosis 6 mg/kg IV

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Infectious Diseases Management zz

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Actinomycetoma responds well to sulfonamides and sulfones. TMP-SMZ 160/800 mg bid PO or dapsone 100 mg bid PO has been effective. Injection streptomycin 0.75 to 1.0 gm IM may be given during the first month of therapy. The treatment has to be continued for several months. For maduromycosis (fungal infection), prolonged itraconazole therapy is advised. In both the cases, surgical debridement assists healing. Amputation is necessary for advanced cases.

Adult Immunisation zz



IMMUNISATION AGAINST INFECTIOUS DISEASES Immunisation is one of the most important tools used to prevent morbidity and mortality from infectious diseases. Active immunization by administering vaccine induces durable antibody response. Passive immunization by giving antibodies (Immune globulin from pooled serum) results in immediate, temporary protection which is less durable.



Milestones in Vaccine Evolution Edward Jenner, as a youth noticed that people who caught the relatively harmless disease ‘cowpox’ did not contract small pox. In 1796, he inoculated a young boy with matter taken from dairy-maid’s fresh cowpox lesions. The boy caught cowpox and when subsequently inoculated with small pox, did not contract the deadlier small pox. It is the starting point for vaccine development. 1895 – Commercial diphtheria serum 1963 – Measles (live virus) 1967 – Mumps 1968 – Measles (live attenuate) 1971 – MMR—measles, mumps, rubella—live virus vaccine 1977 – Pneumococcal (14-valent polysaccharide) 1978 – MMR (new rubella strain RA 27/3) 1981 – Hepatitis B (plasma derived) 1983 – Pneumococcal (23- valent polysaccharide) 1986 – Hepatitis B (recombinant) 1989 – Haemophilus 1995 – Varicella virus 1996 – Hepatitis A 1996 – Haemophilus influenzae Type b 1996 – Haemophilus influenzae Type b/Hepatitis B 2005 – MMR + Varicella 2006 – Rotavirus 2006 – Herpes zoster 2006 – HPV—human papilloma virus

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TT/Td/Tdap (Tdap—Tetanus toxoid, Diphtheria toxoid, acellular pertussis) Indications: —— All adults—not immunised earlier—0.5 ml IM deltoid—3 doses—0, 1, and 6 to 12 months. —— Contacts with infected children—diphtheria/ pertussis—single dose 2 weeks before contact. —— Last Td dose > 2 years ago —— Health care personnel. —— Pertussis outbreak—single dose if ≥ 2 years elapsed from the last Td. —— Pregnancy—last Td < 10 years—booster in postpartum. —— Last Td > 10 years—booster in 2nd or 3rd trimester. —— Not immunised—3 doses in 2nd or 3rd trimester. —— Post-exposure prophylaxis Contraindications: —— History of anaphylaxis —— Encephalopathy or any unstable neurological condition —— Moderate to acute severe illness —— GBS/Arthus reaction within 6 weeks after previous dose of TT—defer at least for 10 years. Booster dose is to be taken once in every 10 years. Hepatitis A Indications: —— Universal immunisation is not recommended. —— Adults with high risk—illicit drug users, haemo­ philiacs, food handlers, men sex with men, postexposure prophylaxis —— Chronic liver disease not immune to hepatitis A —— Patients infected with other hepatitis viruses —— Received or awaiting liver transplant.

Immunisation Schedule for Children Age At birth 6 Weeks 10 Weeks 14 Weeks 9 Months 12 Months 16–18 Months 2 Years 5–6 Years 10 years 16 years Vitamin A

Vaccine BCG, OPV 0 (for institutional deliveries) DTw P1, OPV1, Hep B1, Hib1(*BCG if not given at birth) Rotavirus1, PCV1 DTw P2, OPV2, Hep B2, Hib2, Rotavirus 2, PCV2 DTw P3, OPV3, Hep B3, Hib3, Rotavirus 3, PCV3 Measles Hepatitis A1 DTwP Booster 1, OPV4, MMR, Hib Booster1, Hepatitis A2, Varicella 1, PCV Booster Typhoid 1 DTwP Booster 2, OPV5, MMR 2, Typhoid 2, Varicella 2 TT TT Supplementation at 9, 18, 24, 30 and 36 months

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Manual of Practical Medicine Precaution: Pregnancy Dosage schedule: Single-antigen vaccine—two doses— 0, and at 6 to 12 months. zz Hepatitis B (Recombinant vaccine) Indications: —— All unvaccinated adults at risk of HBV infection —— IV drug abuse, household/ occupational exposure to HBV —— Disorders requiring multiple blood transfusions —— Chronic illness—HIV seropositive, chronic lung and kidney disease, STD —— Partners of HBsAG positive, men sex with men, promiscuous partners. Post-exposure prophylaxis: Single IM dose of HBIG 0.06 ml/kg as soon as possible followed by full course of vaccination. Dosage schedule: —— Engerix B 20 µg/ml IM deltoid—0, 1, 2, and 12 months. —— Chronic kidney disease and other immuno­ compromised patients 40 µg/2 ml (double the standard dose) is given at 0, 1, 2, and 6 months. —— Booster dose not recommended except in immuno­compromised who have lost detectable antibodies—maintain anti HBs level >10 mIU/ml. —— Vaccination contraindicated in yeast hypersensitivity. zz Human papillomavirus Indications: —— Routinely at 11 to 12 years with the catch-up vaccination at ages 13 through 26 years. Ideally vaccine should be administered before potential exposure to HPV through sexual activity (including men sex with men). —— HPV4 vaccine prevents four types 6, 11, 16, and 18. HPV2 prevents two types—16 and 18. —— HPV4 vaccine administered at 9 to 26 years prevents genital warts. Dosage schedule: 0.5 ml IM at 0, 1, and 6 months. Contraindication: —— Pregnancy —— Yeast hypersensitivity. zz Japanese B encephalitis —— Primary Hamster Kidney (PHK) cell cultured live attenuated vaccine for paediatric age group. —— Single dose of 0.5 ml SC followed by a booster dose at 1 year. —— Mass vaccination for children 1 to 15 years in endemic districts. —— Integration of JE vaccine in routine immunization schedule along with DPT booster dose at 1 to 2 years.

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Pneumococcal polysaccharide vaccination (PPSV): There are two types—pneumococcal capsular types 23 (PCV 23) and conjugate pneumococcal vaccine (Heptavalent). Indications: —— Elective splenectomy—two weeks before surgery. —— Chronic lung disease including bronchial asthma. —— Chronic cardiovascular disease. —— Chronic liver disease including cirrhosis liver. —— Chronic alcoholism —— Diabetes mellitus —— Functional or anatomic asplenia —— Sickle cell disease —— Chronic kidney disease including nephrotic syndrome —— Cerebrospinal fluid leaks —— Cochlear implants —— Chronic smokers —— Health care workers. Dosage schedule: —— 0.5 ml IM/SC—one or two doses —— For splenectomy individuals one time revaccination after 5 years. —— Adults 19 to 64 years—revaccinate after 5 years. —— > 65 years—all should receive single dose. zz Influenza vaccine (TIV)—trivalent inactivated Indications: —— All individuals 6 months of age and older including pregnant —— Chronic medical illness —— Immunocompromised individuals —— Single dose 0.5 ml IM deltoid—annually. Contraindications: —— H/O GBS following vaccine —— Moderate to severe illness with fever —— Hypersensitivity to eggs (TIV and LAIV) —— Allergy to formaldehyde, gentamycin or sodium deoxycholate. Live Attenuated Influenza Vaccine (LAIV) —— Healthy non-pregnant individuals—2 to 49 years —— Intranasal administration. Contraindications: —— Age < 2 and > 50 years —— Pregnancy —— Chronic medical disease —— Severe immunosuppression or close contact with them. zz Meningococcal vaccine—polysaccharide/conjugate Bivalent (A and C)—MPSV 2 Quadrivalent (A, C, Y, W-135)—MPSV 4 Meningococcal conjugate vaccine (MCV 4) zz

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Infectious Diseases

zz

zz

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Indications: —— Outbreak—single dose bivalent vaccine —— Health care/laboratory workers and close contacts of cases —— Travellers, pilgrims, people attending fairs and festivals to countries where meningococcal infection is epidemic or hyperendemic—single dose of bivalent vaccine 10 to 14 days before scheduled visit. —— Interepidemic period—military recruits, jail inmates, people living in dormitories, and immunocompromised individuals —— Persistent complement component deficiencies —— Anatomic or functional asplenia. Dosage schedule —— 0.5 ml SC deltoid single dose. —— Two doses 0, 2 months for functional/anatomic asplenia. —— MCV 4 is preferred for adults aged ≤ 55 years. —— MPSV 4 is preferred for adults aged ≤ 56 years. —— Contraindicated in patients who are allergic to dry natural rubber. Typhoid vaccine —— Live oral Ty21a vaccine (Liquid suspension in enteric coated capsule) „„ Indications: Entire community at risk during an outbreak „„ Dosage: Three doses on alternate days and booster dose once in three years. „„ Contraindicated in pregnancy, age < 6 years and immunocompromised individuals. —— V capsular polysaccharide vaccine: i „„ Indicated to travellers to endemic area, laboratory workers and house hold contacts of S. typhi carriers. „„ Not recommended for adults in typhoid enemic are and children aged < 2 years. „„ Dose: Single 0.5 ml SC/IM and booster dose once in three years. Rabies vaccine —— PVRV: Purified vero cell rabies vaccine. —— PCECV: Purified chick embryo cell vaccine —— PDEV: Purified duck embryo vaccine. —— HDCV: Human diploid cell culture vaccine. Indications: —— Post-exposure prophylaxis: Bites by dogs. Bites by rats and rodents may be considered. —— Pre-exposure prophylaxis: High risk individuals like veterinarians, health care and laboratory personnel.



zz



zz







zz





Dosage schedule: —— Post-exposure prophylaxis: IM deltoid 1 ml—days 0, 3, 7, 14, 28 and 90 (optional). —— Pre-exposure prophylaxis: IM deltoid 1 ml—days 0, 7, and 21 or 0.1 ml intradermal on days 0, 7, and 21 (Only HDCV can be used for intradermal prophylaxis). —— Re-exposure: IM or ID booster dose on days 0, and 3. —— Rabies vaccine and immunoglobulin are safe in pregnancy, HIV and immunocompromised states. —— Use only modern tissue culture vaccine for preexposure prophylaxis. Herpes zoster (Shingles) vaccine Indications: —— Adults aged > 60 years regardless of previous zoster episode. —— Chronic medical illness. Contraindications: —— Pregnancy —— Age < 60 years —— Known severe immunodeficiency —— H/O immediate hypersensitivity to gelatin or neomycin. Dosage schedule: Live attenuated varicella zoster virus (Oka strain)—0.65 ml SC deltoid—single dose. Anthrax vaccine Indications: Those 18 to 65 years of age exposed to anthrax infection—laboratory workers, military personnel, and people handling animal/animal products. Contraindications: —— Allergic reactions —— H/O GBS —— Severe illness. Dosage schedule: —— 5 doses IM—0 and 4 weeks and 6, 12, 18 months. —— Post-exposure prophylaxis—3 doses SC—0, 2, and 4 weeks. —— Annual booster doses recommended. Plague vaccine Indications: —— All laboratory and field workers working with Yersinia pestis. —— Persons engaged in field operation in areas with enzootic plague. Adverse effects: Local reaction and hypersensitivity. Killed whole cell plague vaccine: —— IM 3 doses—0 (1 ml), 1 month (0.2 ml) and 6 months (0.2 ml) —— Accelarated dose—0.5 ml 3 doses 1 week apart.

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Manual of Practical Medicine Booster—3 doses at 6 monthly intervals. Subunit vaccine—based on F1 and V antigen— reduces incidence and severity of disease resulting from bite of infected fleas. zz Yellow fever vaccine Indications: —— 9 months to 59 years of age travelling to or living in endemic areas. —— Laboratory personnel exposed to yellow fever or vaccine virus. Dosage schedule: Live attenuated virus—single shot 0.5 ml SC and booster dose every 10 years. Contraindications: —— Allergy to any component of the vaccine including egg, gelatin and chick proteins. —— < 6 months of age —— ——

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Pregnant and nursing mothers. Immunocompromised individuals. “International Certificate of Vaccination or Prophylaxis” is valid 10 days after vaccination and holds good for 10 years. zz Haemophilus influenzae type b (Hib) vaccine Hib: Polysaccharide vaccine. Hib: Polysaccharide-protein conjugate vaccine. —— Hib vaccine generally is not recommended for persons aged > 5 years. Efficacy data is not available for older children and adults. —— Recommended for persons having sickle cell disease, leukaemia, HIV, and splenectomy indivi­ duals if they have not received Hib previously. —— Administer one dose of Hib vaccine to the above high risk individual. —— ——

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4

Cardiovascular System

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SYMPTOMS AND SIGNS Dyspnoea Dyspnoea is defined as an abnormally uncomfortable awareness of breathing.

New York Heart Association Grading for dyspnoea, palpitation, fatigue and angina in patients with cardiovascular disease. zz Class I: No symptoms with ordinary physical activity. zz Class II: Symptoms with ordinary activity, slight limita­ tion of physical activity zz Class III: Symptoms with less than ordinary activity. Marked limitation of activity zz Class IV: Symptoms with any physical activity or even at rest.

—— ——

Pulmonary embolism Laryngeal or tracheal obstruction

Inhalation of toxic gases and fumes. Haematological: Severe anaemia. zz Miscellaneous: Anxiety, hysterical hyperventilation. zz

Orthopnoea Dyspnoea that develops in recumbent position and is relieved by sitting up or elevation of the head with pillows. Orthopnoea occurs within 1 to 2 minutes after assuming recumbency and recovery on sitting up is also immediate. Mechanism

Causes

During the day, gravitational effects on the control of fluid balance may favour a loss of intravascular fluid into the inter­ stitial space. When the patient is in a horizontal position, the oedema fluid may return to the vascular system, augmenting the venous return. The failing left ventricle is not able to cope with extra volume of blood delivered to it, resulting in increase in pulmonary venous and capillary pressure leading to pul­monary interstitial oedema and decreased airway compliance. This factor, along with the elevated diaphragm in the lying posture decrease the vital capacity of the lung. The patient is unable to breathe easily, when lying down and must elevate his or her head on pillows to breathe comfortably.

Cardiac

Causes

Note: Patients with major heart disease may have no, or only minor symptoms, while patients with only minor heart disease may have major symptoms. Normal individuals also develop dyspnoea on severe exertion but the recovery time is short, whereas in patients with heart disease the recovery time is prolonged.

zz zz zz zz zz zz

Left heart failure Congenital heart diseases (Shunts and valvular lesions) Acquired valvular heart diseases Coronary heart disease Hypertensive heart disease Cardiomyopathies.

Dyspnoea is the major symptom of left heart failure. Respiratory zz Bronchial asthma zz Chronic obstructive lung disease—chronic bronchi­tis, emphysema zz Chronic restrictive lung disease —— Parenchymal „„ Pneumoconiosis „„ Interstitial lung disease —— Extra parenchymal „„ Myasthenia gravis „„ Guillain-Barré syndrome „„ Ankylosing spondylitis „„ Kyphoscoliosis „„ Obesity —— Pneumonias —— Pulmonary neoplasm

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zz zz

Acute left heart failure Extreme degree of congestive cardiac failure (CCF).

Paroxysmal Nocturnal Dyspnoea Attacks of dyspnoea which occur at night and awaken the patient from sleep. Paroxysmal nocturnal dyspnoea occurs 2 to 5 hours after the onset of sleep and takes 10 to 30 minutes for recovery after assuming the upright posture. Mechanism Mechanism of PND is similar to that of orthopnoea. However, a fall in PaO2 and a decreased sympathetic support to left ventricular function during sleep also contribute to the development of PND. Causes Ischaemic heart disease zz Aortic valve disease zz Hypertension zz Cardiomyopathy zz Atrial fibrillation zz Rarely in mitral disease or atrial tumours. zz PND is the earliest symptom of left heart failure.

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Trepopnoea Dyspnoea occurs only in the left or right lateral decu­bitus position, most often in patients with heart disease.

zz

Platypnoea

zz

Platypnoea is dyspnoea which occurs only in the upright position.

zz

Causes zz zz zz

Anginal Equivalent

A discomfort in the chest and adjacent area due to myocardial ischaemia. It is due to a discrepancy between myocardial oxygen demand and supply.

Canadian Heart Association Grading of Angina zz

zz

zz

Grade I: Angina on severe exertion Grade II: Angina on walking uphill or climbing more than one flight of ordinary stairs Grade III: Angina on walking on level ground or climbing one flight of ordinary stairs Grade IV: Angina at rest. Differentiation between Cardiac Asthma and Chronic Pulmonary Disease

Features Age

Left sided failure (cardiac asthma) Old age

Chronic pulmonary disease Young and middle age

History Onset

Heart disease Acute

Lung disease Gradual

Symptoms

Dyspnoea precedes cough and expectoration

Cough with expectoration precedes dyspnoea Pulsus paradoxus Normal or hyper-resonant note Wheeze over both lung fields

Pulse Percussion

Pulsus alternans Dull note due to pulmonary oedema or hydrothorax Auscultation S3 over cardiac apex; crackles over both lung bases

Characteristics of Anginal Pain zz zz

zz

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Levine Test Relief of anginal pain by carotid sinus massage.

Left atrial thrombus Left atrial tumours—myxomas Pulmonary arteriovenous fistula.

Angina Pectoris

zz

directions, as mentioned above, but more commonly radiates to the left shoulder and ulnar aspect of the left arm. Duration: 5 to 15 minutes Aggravating factors: Exertion, emotion, after a heavy meal, or exposure to cold Relieving factors: Rest, nitrates.

Site: Substernal Nature: Pressing, squeezing, strangling, cons­trict­ing, ‘a band across the chest’, ‘a weight in the centre of the chest’. The patient cannot pinpoint the site of pain. Radiation: To both the shoulders, epigastrium, back, neck, jaw, teeth. Anginal pain can radiate in all

Anginal equivalents are symptoms of myocardial ischaemia other than angina such as dyspnoea, faintness, fatigue and eructations. They are precipitated by exertion and relieved by rest and nitrates.

Prinzmetal Angina Prinzmetal angina is a type of angina pectoris, which typically occurs during rest and may recur in a nightly cyclic pattern. ST-segment elevation or depression on the electro­cardiogram and coronary artery spasm have been documented during an attack.

Nocturnal Angina Angina occurs during sleep at night due to coronary ostial stenosis, as seen in cardiovascular syphilis.

Unstable Angina The following three patient groups may be said to have unstable angina pectoris: 1. Patients with new onset (4 g per dl or > 30% of total Hb, and PaO2 1.5 gm per dl) „„ Hereditary „„ Acquired-drugs (nitrates, nitrites, sulphonamides). —— Sulfhemoglobinaemia (> 0.5 gm per dl). —— Carboxyhemoglobinaemia (smokers).

The diagnosis of methemoglobinaemia can be sus­ pected, if on exposing the patient’s blood to air, it remains brown whereas in cyanosis due to decreased arterial oxygen saturation, it turns bright red. In Case of Peripheral Cyanosis zz zz zz zz zz

Reduced cardiac output Cold exposure Redistribution of blood flow from extremities Arterial obstruction Venous obstruction.

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Manual of Practical Medicine In Case of Differential Cyanosis (see Fig. 4.99) zz

zz

zz

Cyanosis is seen only in the lower limbs: Patent ductus arteriosus with pulmonary hypertension, with right to left shunt. Cyanosis is seen only in the upper limbs: Patent ductus arteriosus with pulmonary hypertension, with right to left shunt and transposition of great vessels. Rarely, in addition to the lower limbs, the left upper limb may also be cyanosed when the patent ductus opens proximal to the origin of left subclavian artery.

Pulse Rate Pulse rate should be counted for one full minute by palpating the radial artery (Fig. 4.1). zz Normal pulse rate is 60 to 100 per minute zz Sinus bradycardia—pulse rate < 60 per minute zz Sinus tachycardia—pulse rate >100 per minute. Causes of Sinus Bradycardia zz

Intermittent cyanosis is seen in Ebstein’s anomaly. Differentiating Features between Central and Peripheral Cyanosis Features Mechanism

Central cyanosis Right to left shunts or lung disorders Whole body

Site Associations

Clubbing Polycythaemia Extremities Warm On warming the extremities No change Slight improvement O2 inhalation Arterial blood gas-PaO2 Low < 85%

zz

Peripheral cyanosis Peripheral stasis Nail bed, nose tip, earlobe, extremities –– Cold Disappears No change Normal 85–100%

Causes of Sinus Tachycardia zz

Arterial Pulse A pulse wave is a waveform that is felt by the finger, produced by cardiac systole, which traverses the arterial tree in a peripheral direction at a rate much faster than that of the blood column. Artery Carotid Brachial Femoral Radial

Time at which pulse wave arrives after cardiac systole 30 milliseconds 60 milliseconds 75 milliseconds 80 milliseconds

Arterial pulse is assessed in the following way: Rate zz Rhythm zz Volume zz Character zz Whether felt in all peripheral vessels zz Radio femoral delay. —— Radial pulse is felt to assess rate and rhythm. —— Carotid pulse is felt to assess volume and character. —— Brachial pulse is felt to record blood pressure. zz Condition of the vessel wall. zz Pulse can be recorded in the following way: —— Normal + —— Reduced ± —— Absent – —— Aneurysmal ++

Physiological —— Athletes —— Sleep Pathological —— Severe hypoxia —— Hypothermia —— Sick sinus syndrome —— Myxoedema —— Obstructive jaundice —— Acute inferior wall infarction —— Raised intraocular pressure —— Raised intracranial tension —— Heart blocks —— Drugs (beta blockers, verapamil, diltiazem, digoxin).

zz

Physiological —— Infants —— Children —— Emotion —— Exertion. Pathological —— Tachyarrhythmias: Supra-ventricular, ventricular. —— High output states: Anaemia, pyrexia, beriberi, thyro­toxi­cosis, pheochromocytoma, arteriovenous fistula. —— Acute anterior wall myocardial infarction. —— Cardiac failure, cardiogenic shock.

zz

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Fig. 4.1  Palpating the radial artery by compressing over the styloid process of radial bone

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Cardiovascular System —— ——

Hypovolemia, hypotension. Drugs (atropine, nifedipine, beta agonists— salbutamol, thyroxine, catecholamines, nicotine, caffeine).

zz

zz

When pulse pressure is greater than 60 mm Hg, it is a large volume pulse. Pulse volume depends on stroke volume and arterial compliance.

Pulse Deficit (Apex-Pulse Deficit)

Pulse Character

It is the difference between the heart rate and the pulse rate, when counted simultaneously for one full minute.

Pulse character is best assessed in the carotid arteries (Figs 4.2 and 4.3).

Causes

Hypokinetic Pulse (Fig. 4.4)

zz zz

Atrial fibrillation Ventricular premature beats.

Small weak pulse (small volume and narrow pulse pressure).

Rhythm

Causes

Rhythm is assessed by palpating the radial artery. In certain conditions rhythm may be irregular.

zz

Regularly Irregular Rhythm

zz

Seen in: Atrial tachyarrhythmias (PAT and atrial flutter) with fixed AV block zz Ventricular bigemini, trigemini.

Anacrotic Pulse (Parvus et Tardus) (Fig. 4.5)

zz

Differentiating Features between VPC and AF Features

Ventricular pre-mature beats (VPCs)

Atrial fibrillation (AF)

Pulse deficit

Less than 10 per minutes

More than 10 per minutes

‘a’ wave in JVP

Present

Absent

On exertion

Decreases or disappears

Persists or increases

Rhythm

Short pause (between normal beat and VPC) followed by a long pause (following VPC)

Pauses are variable and chaotic

Irregularly Irregular Rhythm Seen in: Atrial or ventricular ectopics zz Atrial fibrillation zz Atrial tachyarrhythmias (PAT and atrial flutter) with varying AV blocks. zz

Pulse Volume Pulse volume is best assessed by palpating the carotid artery. However, the pulse pressure (the difference between systolic and diastolic BP), gives an accurate measure of pulse volume. zz When pulse pressure is between 30 and 60 mm Hg, pulse volume is normal. zz When pulse pressure is less than 30 mm Hg, it is a small volume pulse.

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zz zz

Cardiac failure Shock Mitral stenosis Aortic stenosis.

A low amplitude pulse (parvus) with a slow rising and late peak (tardus). It is seen in severe valvular aortic stenosis. Hyperkinetic Pulse (Fig. 4.6) A high amplitude pulse with a rapid rise (large volume and wide pulse pressure). Causes zz zz zz

High output states—anaemia, pyrexia, beriberi Mitral regurgitation Ventricular septal defect.

Collapsing Pulse (Water-Hammer Pulse, Corrigans Pulse) (Figs 4.7 and 4.8) It is a large volume pulse with a rapid upstroke (systolic pressure is high) and a rapid downstroke (diastolic pressure is low). The rapid upstroke is because of an increased stroke volume. The rapid downstroke is because of diastolic run-off into the left ventricle, and decreased peripheral resistance and rapid run-off to the peri­phery. Decreased peripheral resistance is due to large stroke volume stretching carotid and aortic sinus leading to reflex decrease in peripheral resistance. Causes zz zz

Patent ductus arteriosus Aortic regurgitation —— Arteriovenous (AV) fistula —— Rupture of sinus of Valsalva —— Thready pulse is seen in shock —— Jerky pulse is seen in hypertrophic obstructive cardiomyopathy (HOCM).

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A

B

C

D

E

F

Figs 4.2A to E:  Examination of peripheral pulses. (A) Palpating the left carotid artery with right thumb; (B) Palpating the right carotid artery with left thumb; (C) Palpating the brachial pulse just medial to biceps tendon; (D) Palpating the brachial pulse against the lower end to humerus; (E) Locating the posterior tibial pulse behind the medial malleolus; (F) Palpating the dorsalis pedis pulse lateral to external hallucis longus

Pulsus Bisferiens (Fig. 4.9) Pulsus bisferiens is a single pulse wave with two peaks in systole. This is best felt in brachial and femoral artery. It is due to ejection of rapid jet of blood through the aortic valve. During the peak of flow, Bernouli’s effect on the walls

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of ascending aorta causes a sudden decrease in lateral pressure on the inner aspect of the wall. Causes zz zz

Aortic stenosis and aortic regurgitation Severe aortic regurgitation

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Fig. 4.6  Hyperkinetic pulse

Fig. 4.7  Collapsing pulse

Fig. 4.3  Normal carotid pulse

Fig. 4.4  Hypokinetic pulse Fig. 4.8  Raise the arm to feel for the collapsing pulse zz zz

Hypertrophic obstructive cardiomyopathy Dissection of aorta (unilateral bisferiens).

Pulsus Dicroticus (Fig. 4.10) It is a single pulse wave with one peak in systole and one peak in diastole due to a very low stroke volume with decreased peripheral resistance. Causes zz

Fig. 4.5  Pulsus parvus et Tardus

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zz

Left ventricular failure Typhoid fever

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zz zz zz

Fig. 4.9  Bisferiens pulse

Fig. 4.11  Pulsus alternans

Fig. 4.10  Dicrotic pulse

Fig. 4.12  Pulsus paradoxus

Dehydration Dilated cardiomyopathy Cardiac tamponade.

Pulsus Alternans (Fig. 4.11) Alternating small and large volume pulse in regular rhythm. It is best appreciated by palpating radial or femoral pulses, rather than the carotids. Causes zz zz zz

It is a sign of severe left ventricular dysfunction It may occur following paroxysmal tachycardia It may occur for several beats, following a pre-mature beat, in an otherwise normal heart.

Coupled ventricular pre-mature beats may also mimic pulsus alternans, but however the rhythm is irregular. Pulsus alternans may be associated with S3 and electrical alternans—alternate small and large ECG complexes (in 10% of cases).

Pulsus Paradoxus (Fig. 4.12) It is an exaggerated reduction in the strength of arterial pulse during normal inspiration or an exag­g erated inspiratory fall in systolic pressure of more than 10 mm Hg during quiet breathing. Causes zz zz zz zz

Cardiac tamponade Constrictive pericarditis Airway obstruction—acute severe asthma Superior vena cava obstruction.

Reverse pulsus paradoxus is an inspiratory rise in arterial pressure. Causes zz zz zz

Hypertrophic obstructive cardiomyopathy Intermittent positive pressure ventilation Atrioventricular dissociation.

Pulsus Bigeminus

Radio-femoral Delay (Fig. 4.13)

A pulse wave with a normal beat followed by a pre-mature beat and a compensatory pause, occurring in rapid succession, resulting in alternation of the strength of the pulse. In pulsus alternans, compensatory pause is absent, whereas in pulsus bigeminus, compensatory pause is present. Pulsus bigeminus is a sign of digitalis toxicity.

Delay of the femoral compared with the right radial pulse is found in coarctation of the aorta.

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Blood Pressure The lateral force exerted by the blood column per unit area of the vascular wall that is expressed in mm of Hg.

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Cardiovascular System This phenomenon of a silent gap is found in certain patients with hypertension. It overestimates the diastolic pressure and underestimates the systolic pressure thereby necessitating the palpatory method of BP recording to always precede the auscultatory method. Auscultatory gap occurs when there is venous distension or reduced velocity of arterial flow in the arm. Various Cuff Sizes for BP Measurement

Fig. 4.13  Method of examination for radio-femoral delay

Korotkoff Sounds Korotkoff sounds should be examined preferably with bell of the stethoscope. There are five phases of korotkoff sounds, i.e. the sounds produced by the flow of blood as the constricting BP cuff is gradually released. zz Phase I: First appearance of clear, tapping sound. It represents the systolic blood pressure zz Phase II: Tapping sounds are replaced by soft murmurs zz Phase III: Murmurs become louder zz Phase IV: Muffling of sounds zz Phase V: Disappearance of sounds. Diastolic pressure closely corresponds to phase V. However, in aortic regurgitation, the disappearance point is extremely low, sometimes 0 mm Hg and so phase IV is taken as diastolic BP in adults as well as children. When Korotkoff sounds are not heard while record­ing blood pressure, ask the patient to raise the cuffed upper limb and ask him to open and close the fist of that hand repeatedly and then record the BP. The length of the bladder is approximately twice that of the width. The average length of the rubber bag is 25 cm. The air bag within the cuff should extend for at least 2/3rd of the arm length and circumference. The midportion of the rubber bag within the cuff should lie over the brachial artery. After inflation, the cuff should be deflated at a rate of 2–3 mm Hg per second. Auscultatory Gap Occasionally, after the initial appearance of the Korotkoff sounds, indicating the systolic pressure, the sounds disappear for some time, to re-appear again and finally disappear at the diastolic pressure.

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Age in years

Width of the bladder of the cuff

< 1 year

2.5 cm

1–5 years

5 cm

6–10 years

10 cm

Normal adult

12.5 cm

Obese adult

14 cm

Thigh

20–25 cm

Blood Pressure in the Basal Condition In order to determine BP in basal condition, the patient should have rested in a quiet room for 15 minutes. He should not have consumed coffee or tea for the preceding one hour or smoked for the preceding 15 minutes. He should not be on adrenergic stimulants and there should be no bladder distension. It is desirable to record the BP in both the arms as the differences in systolic pressure exceeding 10 mm Hg between the two arms when measured simul­taneously or in rapid sequence suggest obstructive lesions of aorta, innominate or subclavian arteries. In vertebrobasilar insufficiency, a difference in pressure between the arms may signify that a sub­clavian steal is responsible for cerebrovascular symp­toms. Normally systolic pressure in the legs is up to 20 mm Hg higher than in the arms, but diastolic BP is the same. When systolic pressure in the popliteal artery exceeds that in brachial artery by > 20 mm Hg (Hill’s sign), AR is usually present. Measuring lower limb BP is useful in detecting coarctation of aorta or obstructive disease of the aorta or its immediate branches.

Postural or Orthostatic Hypotension Blood pressure must be recorded in lying, sitting and standing positions especially when postural hypotension is suspected. When there is a fall in systolic pressure of >20 mm Hg after standing for 3 minutes, from the lying pos­ture, the patient is said to have postural hypotension.

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Manual of Practical Medicine Causes

Isolated Systolic Hypertension

Hypovolaemia (blood or fluid loss) Autonomic neuropathy (diabetes mellitus, old age) Drugs (ganglion blocking agents, centrally acting anti-hypertensives) Myocardial pump failure Secondary hypertension* (pheochromocytoma).

This is said to be present when systolic blood pressure is >140 mm Hg and diastolic blood pressure is < 90 mm Hg. It is commonly seen in old age (above 65 years).

In atrial fibrillation, an average of three BP recordings in the same limb must be taken.

A significant recent increase in blood pressure over previous hypertensive levels, associated with evidence of vascular damage on fundoscopic examination, but without papilloedema.

zz zz zz

zz zz

Normal Blood Pressure zz zz

Systolic: 100–140 mm Hg. Diastolic: 60–90 mm Hg.

Pulse pressure is the difference between systolic and diastolic blood pressure. Normal pulse pressure is 30–60 mm Hg. Mean arterial pressure is the product of cardiac output and total peripheral resistance. It is the tissue perfusion pressure. Mean arterial pressure = Diastolic blood pressure + 1/3 of pulse pressure. Normal mean arterial pressure is approximately 100 mm Hg. To confirm the presence of hypertension, multiple BP recordings should be taken with a mercurial mano­metre on several occasions. Home monitoring and ambulatory monitoring are preferable as they elimi­nate anxiety. When the diastolic pressure is below 90 mm Hg, a systolic pressure zz below 140 mm Hg indicates normal blood pressure. zz between 140 and 149 mm Hg indicates borderline iso­ lated systolic hypertension zz 140 mm Hg or higher indicates isolated systolic hyper­tension. When there is an elevation of systolic pressure of >30 mm Hg and a diastolic pressure of >20 mm Hg from the basal original level, it indicates presence of hyper­tension. Common Causes of Hypertension zz zz

Essential or primary hypertension (94%) Secondary hypertension (6%) —— Renal (4%) —— Endocrine (1%) —— Miscellaneous (1%).

*When there is a rise in diastolic BP in the standing posture, it is more in favour of essential hypertension.

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Accelerated Hypertension

Malignant Hypertension A triad of blood pressure of >200/140 mm Hg, grade IV retinopathy (papilloedema) and renal dysfunction.

Hypertensive Urgency This is a situation in which the BP is markedly ele­vated, but without any evidence of end organ damage. In this condition, the control of the elevated BP can be done gradually.

Hypertensive Emergency This is a situation in which the BP is markedly ele­vated, but with evidence of some end organ damage. In this condition, the control of the elevated BP has to be done immediately in order to prevent further end organ damage.

White Coat Hypertension A transient increase in blood pressure in normal individuals, when BP is recorded in a physician’s consulting room, or in a hospital.

Pseudohypertension A false increase in blood pressure recording due to stiff and noncompliant vessels (Osler’s sign), occurring in old age. In these individuals, actual intra-arterial BP is lower than the BP measured by a sphygmomano­meter.

Transient Hypertension This may be seen in: Acute cerebrovascular accidents zz Acute myocardial infarction zz Acute glomerulonephritis zz Pregnancy zz Acute intermittent porphyria. zz

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Cardiovascular System It is systemic hypertension seen for a transient phase of time when the patient is under stress or when he is having a disorder with a transient hypertensive phase, as may occur in the above-mentioned con­ditions.

Measurement of BP may be useful in detecting: 1. Pulsus paradoxus 2. Pulsus alternans.

Episodic or Paroxysmal Hypertension

Inflate the BP cuff to suprasystolic level and deflate slowly at a rate of 2 mm Hg per heartbeat. The peak systolic pressure during expiration is noted. The cuff is then deflated even more slowly, and the pressure is again noted when Korotkoff sound becomes audible throughout the respiratory cycle. Normally, the differ­ence between the two pressures should not exceed 10 mm Hg during quiet respiration. If it is more than 10 mm Hg, pulsus paradoxus is said to be present.

This is seen in pheochromocytoma. However, a patient with pheochromocytoma may be normotensive, hypo­ tensive or hypertensive.

Labile Hypertension Patients who sometimes, but not always have arterial pressure within the hypertensive range, are classified as having labile hypertension.

Paradoxical Hypertension In this form of hypertension, patients paradoxically show an increase in BP, even when on anti-hyper­tensive drugs. Examples 1. Patients with DM and HTN, on β blockers, on developing hypoglycaemia show a paradoxical rise over previously well-controlled BP. This is because the excess adrenaline released secondary to hypo­ glycaemia, acts unopposed on the α1 receptors and thereby raises the BP. 2. With high doses of clonidine, the peripheral α1 receptors are stimulated, apart from its central action, thereby raising the BP. 3. In patients with bilateral renal artery stenosis, adminis­ tration of ACE inhibitors, results in a para­doxical rise in BP. 4. Administration of β blockers in patients with pheo­chro­ mocytoma leads to uninhibited α receptor stimulation by epinephrine leading to paradoxical rise in BP.

Resistant Hypertension Blood pressure remains above goal in spite of the concurrent use of three antihypertensive agents of different classes at optimal dose and ideally, one of the three agents should be a diuretic. Resistant hypertension also includes patients whose blood pressure is controlled with the use of more than three drugs.

Hypertensive States These are situations in which there is a marked increase in both systolic and diastolic BP, occurring in normal individuals, as during sexual intercourse or on diving into cold water.

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Pulsus Paradoxus

Paradox: Heart sounds are still heard over the pre­cordium at a time when no pulse is palpable at the radial artery. Pulsus Alternans Inflate the BP cuff to suprasystolic level and deflate slowly. Pulsus alternans is present if there is an alter­ation in the intensity of Korotkoff sound.

EXAMINATION OF NECK VEINS Examination of the neck veins has a two-fold purpose. 1. To assess approximately the mean right atrial pressure. 2. To study the waveforms.

Jugular Venous Pressure Jugular venous pressure (JVP) is expressed as the vertical height from the sternal angle to the zone of transition of distended and collapsed internal jugular veins. When measured with the patient reclining at 45° is normally about 4 to 5 cm. The right internal jugular vein is selected because it is larger, straighter and has no valves. It is situated between two heads of sternomastoid.

Patient Position in Examination of JVP Since right atrial pressure is often very low, optimal positioning of the patient to visualise the column of venous blood above the level of the clavicle is critical. The examiner must position the patient’s upper thorax so that the column of blood in the internal jugular vein is visible in the neck. In general, in positioning the patient, the lower the pressure in the venous system, the more supine the patient’s position should be; the higher the pressure, the more upright the patient’s position should be (Fig. 4.14).

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Fig. 4.15  Pressure in heart chambers (in mm Hg)

Fig. 4.14  Measurement of jugular venous pressure

JVP as Indicator of Mean Right Atrial Pressure The overall height of the pulsating column is an indicator of mean right atrial pressure, which can be estimated based on a simple anatomic fact, that in most indivi­duals, the centre of the right atrium is approximately 5 cm from the sternal angle of Louis. This relation is maintained in every position between supine and upright posture. Thus, the vertical height of the column of blood in the neck can be estimated from the sternal angle, to which 5 cm is added to obtain an estimate of mean right atrial pressure in centi­meters of blood. This amount can be converted to millimetres of mercury by multiplying by 0.736. Normal values are less than 8 cm of blood or less than 6 mm Hg. This estimation may be erroneous in patients with deformed chest walls or malpositioning of the heart (Fig. 4.15).

Causes of Elevated JVP zz

zz

zz

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Unilateral non-pulsatile —— Innominate vein —— Thrombosis Bilateral non-pulsatile —— SVC obstruction —— Massive right sided —— Pleural effusion Bilateral pulsatile —— Cardiac „„ Cardiac failure „„ Tricuspid stenosis „„ Tricuspid regurgitation „„ Constrictive pericarditis „„ Cardiac tamponade

——

——

——

Pulmonary „„ COPD/cor pulmonale Abdominal „„ Ascites „„ Pregnancy Iatrogenic „„ Excess IV fluids

Most common cause of raised JVP is CCF.

Causes of Fall in JVP zz zz zz

Hypovolaemia Shock Addison’s disease.

Jugular Venous Pulse Jugular venous pulse (JVP) is the reflection of phasic pressure changes in the right atrium and consists of three positive waves (a, c, v) and two negative troughs (x, y) (Fig. 4.16). Differentiating Features between Carotid Artery Pulse and JVP Carotid artery pulse Seen internal to the sternomastoid Better palpable Predominant outward movement One peak per heart beat No variation with posture or respiration Not obliterable

Jugular venous pulse Seen in the triangle formed by the two heads of the sternomastoid and the clavicle Better visible Predominant inward movement Two peaks per heart beat Variation with posture, respiration, abdominal compression Obliterable

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Fig. 4.16  Jugular venous pulse

Abnormalities of JVP ‘a’ wave

Absent Atrial fibrillation Present Prominent ‘a’ waves a. Pulmonary stenosis b. Pulmonary hypertension c. Tricuspid atresia or stenosis. Waves in JVP ‘a’ wave (atrial wave) ‘c’ wave (closure wave) ‘x’ wave ‘x’ wave ‘v’ wave ‘y’ wave

Cardiac event Right atrial contraction Carotid artery impact Tricuspid valve ascends Right atrial relaxation Tricuspid valve descends Venous filling into atrium Tricuspid valve opens

‘a’ wave precedes Sl ‘x’ wave precedes S2 ‘c’ wave succeeds S1 ‘y’ wave succeeds S2 Cannon waves (Giant ‘a’ waves seen in arrhyth­mias) Regular Junctional rhythm Irregular Multiple ectopics Complete heart block Independent ‘a’ waves Complete heart block ‘v’ wave Prominent Tricuspid regurgitation ‘x’ descent Prominent Constrictive pericarditis ‘y’ descent Slow Tricuspid stenosis Fast Tricuspid regurgitation Absent Cardiac tamponade.

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Kussmaul’s sign is an inspiratory increase in JVP. Friedreich’s sign is the rapid fall (steep ‘y’ descent) and rise of JVP seen in constrictive pericarditis and tricuspid regurgitation.

False Rise in JVP zz zz

zz

Increased blood volume as in polycythaemia vera Increased sympathetic stimulation due to pain, acute infarct, or nervousness Inability to tolerate the resistance to downward move­ ment of diaphragm, when pressure on abdomen raises the diaphragm as in patients with severe COPD or in any other condition that cause loss of vital capacity.

Causes of Kussmaul’s Sign zz zz zz zz

Constrictive pericarditis Restrictive cardiomyopathy Right ventricle infarct Right ventricle failure.

Abdominal Jugular Reflux Firm compression is given in the periumbilical area for 30 seconds. In normal individuals the JVP rises tran­siently by less than 3 cm and falls down even when pressure is continued, whereas in patients with right or left heart failure, the JVP remains elevated. Abdominal jugular reflux is positive in right or left heart failure and/or tricuspid regurgitation. In the absence of

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Manual of Practical Medicine these conditions, a positive abdominal jugular reflux suggests an elevated pulmonary artery wedge or central venous pressure. It is negative in Budd-Chiari syndrome.

GENERAL EXAMINATION External Features of Cardiac Disease In congenital heart disease look for: Cyanosis zz Clubbing zz Polycythaemia zz Hypertelorism zz Low set ears zz High arched palate zz Webbed neck zz Syndactyly, polydactyly, arachnodactyly � (Polydactyly: Trisomy 13 to 1 and 18. Bradydactyly: Down’s, Turner’s, Ellis-de Crevald syndromes) zz Cubitus valgus, Absent radius zz Pectus excavatum, carinatum zz Kyphoscoliosis, Shield chest zz Abdominal hernia, Cryptorchidism zz Upper segment/lower segment inequality zz Dwarfism zz Gigantism. zz

In acquired heart disease look for: Markers of rheumatic fever —— Joint swelling (Migrating polyarthritis involving major joints, leaving no residual deformities) —— Erythema marginatum —— Subcutaneous nodules. zz Markers of infective endocarditis —— Anaemia, jaundice —— Clubbing, splinter haemorrhages —— Osler’s nodes —— Janeway lesions —— Arthritis. —— Embolic complications of IE: „„ Osler’s node—painful „„ Janeway lesion—painless „„ Splinter haemorrhage zz Markers of coronary heart disease —— Arcus senilis —— Xanthelasma, xanthomas —— Earlobe creases—diagonal —— Nicotine stains on fingers and teeth —— Obesity —— Arcus senilis—Starts superiorly and no iris is visible between limbus and arcus —— Corneal arcus—Starts inferiorly and iris is visible between limbus and arcus.

Eyes in Cardiology zz

zz

zz

zz

zz

Eye in cardiology: Hypertelorism may be a sign of congenital heart disease. Eye lid: —— Xanthelasma: Hyperlipidemia —— Raccoon eye sign: Primary amyloidosis Cornea: —— Flat cornea: Marfan syndrome —— Arcus juvenilis/senilis: Hyperlipidemia Sclera: —— Blue sclera: Ehlers-Danlos syndrome —— Scleral pigmentation: Alkaptonuria—associated with aortic stenosis. Pupil: —— Iridodonesis: Marfan syndrome —— Landolfi’s sign: Aortic regurgitation —— Argyll Robertson pupil: Tertiary syphilis—aortic regurgitation —— Coloboma of iris: CHARGE association (C-colo­ boma of eye, H-heart anomaly, A-choanal atresia, R-retardation of growth, G-genital hypoplasia, E-ear anomaly)

zz

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Fig. 4.17  Malignant hypertension—grade IV retinopathy Keith-Wagner-Barker Grading of Hypertensive Retinopathy Degree

AV Ratio (ratio of arterial Haemor- Exudates Papilloto venous diameter) rhages edema

Normal

3 : 4

0

0

0

Grade I (focal 1 : 2 spasm)

0

0

0

Grade II (AV nipping)

1 : 3

0

0

0

Grade III

1 : 4

+

+

0

Grade IV

Fine, fibrous cords

+

+

+

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Cardiovascular System Carotid artery dissection: Ipsilateral Horner’s syndrome Lens: —— Congenital cataract: Congenital rubella syndrome —— Dislocation: Upward and outward (Marfan syn­ drome), Downward and inward (Homocystinuria) Vitreous: Vitreal deposits: Pathognomonic of ATTR amyloidosis Retina: —— Pale fundus: Severe anaemia —— Roth spots: Infective endocarditis (also seen in leukaemia, anaemia, DM, hypertension) —— Cork-screw tortuous retinal artery: Coarctation of aorta —— Retinopathy: HTN, DM, arteriosclerosis —— Lipaemia retinalis: Hypertriglyceridemia —— Becker’s sign: Aortic regurgitation —— Retinal artery occlusion: Emboli, arteritis —— Papilloedema: Malignant hypertension, corpul­ monale (Hypercarbia). ——

zz

zz

zz

zz

zz

zz

zz

zz

zz

Inspection Precordium is the anterior aspect of chest overlying the heart. Precordial bulge indicates the presence of right ventricular hypertrophy presenting since early child­hood.

zz

Visible Pulsations zz

zz

zz

zz

zz

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Carotid artery pulsation —— Hyperdynamic states —— Aortic regurgitation —— Coarctation of aorta —— Systemic hypertension Aortic pulsation —— Dilatation of ascending aorta —— Aortic aneurysm —— Aortic regurgitation Pulmonary artery pulsation —— Pulmonary artery dilatation —— High output states —— Pulmonary hypertension —— Pulmonary hypercirculation (ASD) Suprasternal pulsation —— Aortic regurgitation —— Aortic arch aneurysm —— Thyrotoxicosis —— Coarctation of aorta Supraclavicular pulsation —— Aortic regurgitation —— Subclavian artery aneurysm

Sternoclavicular pulsation —— Aortic regurgitation —— Aortic dissection —— Aortic aneurysm —— Right sided aortic arch (TOF) Left parasternal pulsation —— Right ventricular hypertrophy —— Mitral regurgitation Apical pulsation —— May be due to left ventricular or right ventricular enlargement Ectopic pulsation —— Ischaemic heart disease —— Left ventricular dysfunction or aneurysm —— Cardiomyopathies Inter and infra scapular pulsations —— Coarctation of aorta (Suzman’s sign) Epigastric pulsation —— Aortic aneurysm (expansile pulsation) —— Tumour or nodes over the aorta (transmitted pulsation) —— Aortic regurgitation —— Right ventricular hypertrophy —— Hepatic pulsation (left lobe of liver) Hepatic pulsation —— Tricuspid stenosis —— Tricuspid regurgitation —— Aortic regurgitation

Chest Wall Defects zz

zz

zz

Sternum —— Pectus excavatum, —— Pectus carinatum Costal cartilages —— Costochondritis Spine —— Kyphosis, scoliosis —— Ankylosing spondylitis —— Straight back syndrome.

Palpation General rule (Fig. 4.18): The fingertips are used to feel pulsa­tions, the base of fingers for thrills and hand base for heaves. Ideal position is supine or upper trunk elevated to 30°.

Apical Impulse Apical impulse is the lower most and outer most point of definite cardiac impulse with a maximum perpen­dicular thrust to the palpating finger.

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Fig. 4.18  Application of hand in cardiac palpation

Fig. 4.19  Palpating the apical impulse with hand

Normal apical impulse is produced by left ventricle and the left ventricular portion of the interventricular septum. Normal site of the apical impulse is about zz 1 cm medial to midclavicular line or 10 cm lateral to midsternal line at the left 5th intercostal space in adults. zz Normal displacement is 1 cm laterally in left lateral decubitus position. zz Normal apical impulse is confined to one intercostal space and has an area of 2.5 cm2. zz Normal duration of thrust of apical impulse is less than 1/3 of systole. Golden Rules Before commenting on the position and character of apical impulse, look for the presence of chest wall or spinal deformities, and the tracheal position. When the apical impulse is not localisable on the left side, palpate the right hemithorax for its presence (dextrocardia or pseudo-dextrocardia) (Figs 4.19 to 4.21).

Fig. 4.20  Locating the apical impulse with the finger

Abnormalities of Apical Impulse zz

zz

zz

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Absent apical impulse —— Behind the rib or sternum —— Dextrocardia Tapping apical impulse —— Palpable S1 (closing snap), e.g. Mitral stenosis Hypodynamic apical impulse (felt with decreased thrust) —— Obesity —— Acute myocardial infarction —— Pleural effusion  —— Pericardial effusion —— Constrictive pericarditis —— Chronic obstructive pul­monary disease (COPD)

Fig. 4.21  Character of apical impulse is best studied in left lateral position

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Cardiovascular System Differentiating Features between Heaving and Hyperdynamic Apical Impulse Features Time Amplitude Duration Location Causes

Heaving Increased Increased >2/3 of systole Occupies one intercostal space LV pressure over-load, e.g. AS, HTN, Coarctation of aorta

Hyperdynamic Normal Increased >1/3 to 150 m sec

Site

Mid or entire precordial

Apical

Pitch

High

Low

Character

Snapping

Thudding

Associations

Loud S1 Mid diastolic murmur MS or TS

Normal or soft S1 Pansystolic murmur MR or TR

Variation on standing

A2-OS interval increases

No change

Abbreviations: MS, Mitral stenosis; TS, Tricuspid stenosis; MR, Mitral regurgitation; TR, Tricuspid regurgitation

Fourth Heart Sound (S4) zz zz

Third Heart Sound (S3) S3 is also known as protodiastolic sound or ventricular gallop. S3 is produced by initial passive filling of the ventricles. Causes of physiological S3 zz Children zz Young adults (50 years), when it is known as 50/50 murmur, i.e. 50% of adults above 50 years of age may have a systolic murmur.

Functional Murmurs These are murmurs caused by dilatation of heart chambers or vessels or increased flow. Systolic Murmurs Ejection systolic murmur (ESM): ESM may be heard over aortic area in: zz Severe AR zz Dilatation of aorta. ESM may be heard over pulmonary area in: zz Severe PR zz ASD zz VSD zz PDA zz Dilatation of pulmonary artery. ESM may also be heard in certain skeletal deformities like pectus excavatum or straight back syndrome. Pansystolic murmur (PSM): In dilatation of left ventri­cle or right ventricle, functional PSM of mitral or tricuspid regurgi­tation may be heard respectively. Diastolic Murmurs Mid-diastolic flow murmurs: Mid-diastolic flow mur­murs may be heard over the mitral or tricuspid areas, the causes of which have already been discussed.

Changing Murmurs These are murmurs which change in character or intensity from moment to moment, e.g.

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Austin flint murmur: It is a low pitched rumbling middiastolic or pre-systolic murmur best heard at the apex in cases of severe aortic regurgitation. Rytand’s murmur: It is a short late diastolic or pre-systolic murmur heard at the apex in cases of complete heart block. Gibson murmur: It is a continuous machinery murmur of patent ductus arteriosus. Graham Steel murmur: It is a high pitched early diastolic murmur best heard at the left sternal edge 2nd intercostals space with patient in full expiration in cases of pulmonary regurgitation. Dock’s murmur: It is an early diastolic murmur heard in left anterior descending artery stenosis. Mill wheel murmur: It is a loud machinery like churning or splashing sound heard over the precordium due to blood mixing with air in the right ventricle and is a late sign of air embolism (>200 mL). Cole–Cecil murmur: It is an early diastolic murmur of aortic insufficiency well heard in the left axilla. Gallavardin phenomenon: The harsh noisy component of ESM is best heard at the right sterna border which radiates to the neck due to high velocity jet in the ascending aorta. The musical high frequency component of ESM is best herd at the cardiac apex, but does not radiate to axilla.

Dynamic Auscultation Dynamic auscultation refers to the changes in circulatory haemodynamics by physiological and pharmacological manoeuvres and about the effect of these manoeuvres on the heart sounds and murmurs. Respiration Murmurs that arise on the right side of the heart becomes louder during inspiration as this increases venous return and therefore blood flow to the right side of the heart. Left sided murmurs are either unchanged or becomes softer. Expiration has the opposite effect (Left sided murmurs are louder during expiration).

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Manual of Practical Medicine Deep Expiration The patient leans forward during expiration to bring the base of the heart close to the chest wall and in this posture aortic regurgitant murmur and the scraping sound of a pericardial friction rub are better heard. Valsalva Manoeuvre In this manoeuvre, patient is advised to close the nose with the fingers and breathe out forcibly with mouth closed against closed glottis. This manoeuvre has four phases. Phase 1: At the beginning, there is rise in intrathoracic pressure and transient increase in left ventricular output. Phase 2: During straining phase, systemic venous return falls resulting in reduced filling of right and left ventricle. As a result the stroke volume and the BP falls, but the heart rate increases. Most of the cardiac murmurs become softer. However, the systolic murmur of hypertrophic cardio­ myopathy becomes louder and the systolic click and the murmur of mitral valve prolapse syndrome (MVPS) begin earlier. Phase 3: During the release phase, first the right sided and then the left sided cardiac murmurs become louder briefly before returning to normal. Phase 4: Overshoot of systemic arterial pressure and reflex bradycardia. Standing to Squatting When the patient suddenly squats from the standing position, venous return and systemic arterial resistance increase simultaneously causing a rise in stroke volume and arterial pressure. Most of the murmurs become louder. However, left ventricular size is increased which reduces the obstruction to outflow and thus the intensity of systolic murmur of hypertrophic cardiomyopathy is reduced, while the midsystolic click and murmur of MVPS are delayed.

Dynamic Auscultation Manoeuvre Valsalva–phase II Hand grip or Squatting Standing Exercise Amyl nitrate Isoproterenol

HCM ↑ ↓

MVPS ↑ or ↓ ↓

AS ↓ ↑

MR ↓ or ↔ ↑

↑ ↑ ↑↑ ↑↑

↑ ↑ ↑ ↑

↓ ↑ or ↔ ↑ ↑

↓ or ↔ ↓ ↓ ↓

Abbreviations: HCM, Hypertrophic cardiomyopathy; MVPS, Mitral valve prolapse syndrome; AS, Aortic stenosis; MR, Mitral regurgitation

ELECTROCARDIOGRAM zz zz

Normal P-wave duration is 0.08 sec to 0.10 sec Maximum amplitude is 2.5 mm (Figs 4.37 and 4.38).

Electrical Axis Electrical axis must be taken into account for the correct interpretation of the ECG. It is determined from the frontal plane leads—I, II, III, aVR, aVL and aVF. It is quantified by using the hexaxial reference system (Fig. 4.39). The normal QRS axis shows a wide range of normality from –30° to +90°. If a cardiac vector courses parallel to a particular lead, it will make the greatest impression on that lead and the ECG record will be maximum positive. The same vector records a small and equiphasic complex in the lead which is perpendicular to the previous one. Therefore, to determine the axis locate the frontal plane lead which shows small equiphasic QRS deflexion (least net QRS deflexion), and its perpendicular lead forms the electrical axis of the heart which shows maximum positive QRS deflexion.

Squatting to Standing When the patient stands up quickly after squatting the opposite changes occur. Isometric Exercise Sustained hand grip for 20 to 30 seconds increases systemic arterial resistance, blood pressure and heart size. The systolic murmur of aortic stenosis may become softer because of the reduction in the pressure gradient across the valve, but often remains unchanged. Most other murmurs become louder except systolic murmur of HCM, which is softer and the MVPS murmur is delayed because of the increased ventricular volume.

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Fig. 4.37  Principal ECG segments and time intervals

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A

B Figs 4.38A and B:  (A) Normal ‘P’ wave; (B) Changes in P-wave morphology

zz

zz zz

QRS complex predominantly positive in lead III and negative in lead I—Right axis Left axis deviation is more negative than–30° Right axis deviation is more positive than +90°

Left Atrial Enlargement (Fig. 4.40B) P mitrale—P-wave is broad and bifid occupying > 0.11 sec in Lead II or biphasic P-wave in V1.

Right Atrial Enlargement (Fig. 4.40A) Tall P-waves of amplitude > 2.5 mm in Lead II (Ppulmonale). P pulmonale: Tall peaked ‘P’ wave of right atrial enlarge­ ment with right ‘P’ wave axis deviation of acquired disease is called P pulmonale. Fig. 4.39  Hexaxial reference system in ECG

P congenitale: Tall peaked ‘P’ wave of right atrial enlargement with left ‘P’ wave axis deviation of congenital heart disease is called P congenitale.

It is useful to memorise the paired leads which are perpendicular to each other (Lead I to aVF, lead II to aVL, lead III to aVR). Similar method can be adopted for determining the ‘P’ wave and ‘T’ wave axis.

P tricuspidale: Notched ‘P’ wave of biatrial enlargement and the first component is taller than the second as occurs in tricuspid valve disease and mitral valve disease with pulmonary hypertension.

Simple Methods (Not Accurate)

Left Ventricular Hypertrophy (Fig. 4.41)

zz

zz

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Lead I and II show predominantly positive QRS complex—Normal axis QRS complex predominantly positive in lead I and negative in lead III—Left axis

zz

Sum of the S-wave in lead Vl and R-wave in lead V6 should not exceed 35 mm normally. If it does, it constitutes presumptive evidence of LVH (Sokolow -Lyon index)

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A

B Figs 4.40A and B  Atrial enlargement: (A) Right atrial enlargment; (B) Left atrial enlargement

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Fig. 4.41  Left ventricular hypertrophy zz zz

zz zz

zz zz zz

S-wave in V1 is 20 mm or more in depth. R-wave in LI is 20 mm or more in height, or in V6 > 25 mm. R-wave in V6 equals or exceeds the R-wave in V5. Total QRS voltage in all 12 leads is less than 175 mm in normal. Values greater than 175 mm constitute a good criterion of LVH (Fig. 4.42). R-wave in aVL > 13 mm. Any R + any S > 45 mm. Cornell voltage criteria – For men, Sv3 + RaVL > 28 mm and for women, > 20 mm.

Fig. 4.42  QRS complexes in ventricular enlargement

In LVH due to systolic overload, there is attenua­tion or disappearance of small initial q-wave in left oriented leads (LI, aVL, V5, V6). There may be ST depression and T-wave inversion. Romhilt and Estes Point Score System for LVH due to Systolic Overload Increased QRS magnitude 3 points ST-T abnormalities 3 points A “P” wave of left atrial enlargement 3 points Left axis deviation 2 points Increased left ventricular activation time 1 point

zz

A score of 5 or more indicates LVH.

zz

In LVH due to diastolic overload, there are deep narrow q-waves in left oriented leads. There may be tall and symmetrical T-waves in left precordial leads.

Right Ventricular Hypertrophy (Fig. 4.43) zz zz

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Right axis deviation Dominant R-waves in right oriented leads. This is often expressed as R : S ratio. If this ratio exceeds 1, RVH is diagnosed

Fig. 4.43  Right ventricular hypertrophy

zz zz

R-wave is > 5 mm in amplitude in V1 Dominance of S-wave in left precordial leads Sum of R-wave in Vl and S-wave in V6 is more than 10 Terminal S-waves in all standard leads—SI, SII, SIII syndrome.

Tall R-wave in V1 RVH zz RBBB zz WPW (Type A) zz Dextrocardia zz Posterior wall MI zz HOCM. zz

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Biventricular Hypertrophy (Fig. 4.44) zz zz zz zz

zz

ECG evidence of LVH + Right axis deviation ECG evidence of LVH + clockwise electrical rotation ECG evidence of LVH + R : S ratio > 1 in V1 Large equiphasic QRS in midprecordial leads (KatzWachtel phenomenon) LAE + R : S ratio in V5 and V6 ≤1 or S-wave in V5 and V6 ≥7 mm or right axis deviation.

Significance zz zz

RBBB may be physiological It may also occur with: —— Coronary artery disease —— ASD —— Atypical Ebstein’s anomaly —— Cardiomyopathy —— Massive pulmonary embolism.

Right Bundle Branch Block (Fig. 4.45)

Left Bundle Branch Block (Fig. 4.46)

Complete RBBB

Complete LBBB

zz zz zz zz

Wide S-wave in LI, V5 and V6 In V1, tall, wide notched R deflection QRS duration ≥ 0.12 sec in V1, V2 Secondary S-T, T changes.

zz

zz zz zz

Incomplete RBBB zz zz

Diminution of S in V2 (earliest sign of RBBB) QRS duration 0. 12 sec; may be as long as 0.20 sec. RsR complex or a wide, unnotched complex in aVL LI, V5, V6 show RR or M-shaped complexes Secondary S-T, T changes opposite in direction to terminal QRS deflection.

Incomplete LBBB zz

zz

Initial ‘q’ in V5 and V6 disappears and it results in single tall R-wave Small initial ‘r’-wave of rS complex in V1 disappears and it results in a QS complex.

Significance LBBB indicates organic heart disease. It is commonly seen in hypertensive heart disease (HHD).

Fig. 4.44  Biventricular enlargement

Fig. 4.45  Right bundle branch block

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Fig. 4.46  Left bundle branch block

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Hemiblocks (Fascicular Blocks) Left Anterior Hemiblock (LAHB) Causes zz zz zz zz zz

Coronary artery disease Cardiomyopathy Longstanding systemic hypertension Longstanding carotid cavernous fistula May be due to MI (divisional peri-infarction block).

ECG Features (Fig. 4.47) zz zz

zz

zz zz

zz

Left axis deviation rS complex in lead II; No terminal r or R-wave as in inferior wall MI Lead I and aVL may reflect a prominent initial q-wave followed by a tall ensuing R-wave Lead aVR may reflect a late, slurred terminal r-wave Lead V5 and V6 show no initial q-waves which are nor­ mally seen. There is attenuation of R-waves and promi­ nence of S-waves in these leads T-waves are in opposite direction to the main QRS deflection.

Fig. 4.47  Left anterior fascicular block

LAHB when occurs in association with RBBB, it usually indicates a poor prognosis and may lead to complete AV block. When it occurs with LBBB, prog­nosis is worse.

Left Posterior Hemiblock (LPHB) Occurrence of LPHB is very rare.

Fig. 4.48  Left posterior fascicular block

ECG Features (Fig. 4.48) zz zz

zz

zz

Right axis deviation Prominent small initial q-waves in lead II, III and aVF; and a small initial r-wave in standard lead I The distal limb of the tall R-wave in lead III is notched or slurred Low to inverted T-waves in leads II, III and aVF and upright T-waves in lead I.

LPHB with sinus tachycardia may denote pulmonary embolism.

Bi-fascicular Block (Fig. 4.49) It is the combination of RBBB and left bundle hemi­block (mani­fest as an axis deviation, e.g. LAD in left anterior hemiblock).

Tri-fascicular Block (Fig. 4.50) It is the combination of bi-fascicular block and first degree heart block.

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Fig. 4.49  Bi-fascicular block (RBBB + LPHB)

Causes of ST Segment Elevation zz zz zz

Coronary vasospasm (Prinzmetal’s angina) Organic stenosis of coronary arteries (MI) Left ventricular aneurysm

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ECG in Coronary Artery Disease (Fig. 4.51) Myocardial Necrosis This is by the appearance of pathological Q-waves (depth of the Q-wave is more than 25% of the height of succeeding R-wave and its width is more than 0.04 sec.) This may also manifest as QS complexes.

Myocardial Injury This is characterised by S-T segment elevation on the ECG. An elevation of >1 mm is significant.

Myocardial Ischaemia Fig. 4.50  Tri-fascicular block (first degree heart block + LBBB)

This is characterised by inverted, symmetrical, pointed and sometimes deep T-waves.

Localisation of MI zz

zz

Pericarditis (elevated concave upwards S-T seg­ment associated with tall, peaked T-waves and no reciprocal changes in the opposite leads) Early repolarisation.

Left Ventricular Infarct zz

zz

Causes of S-T Segment Depression zz

zz zz zz zz zz zz zz zz zz zz zz zz

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In coronary insufficiency —— Horizontal S-T segment (earliest sign) —— Upward sloping S-T segment depression (It may be a physiological change also. A hypo­thetical parabola joining the distal limb of the P-wave, the P-R segment, the S-T segment and the proxi­mal limb of the T-wave will be smooth and unbro­ken in physiological junctional S-T seg­ment depres­ sion, whereas the para­bola is broken in abnormal junctional S-T segment depression) —— Plane S-T segment depression —— Downward sloping S-T segment depression (This reflects a severe form of impaired coro­nary blood flow). Hypokalaemia Hypothermia Tachycardia Hyperventilation Anxiety Post-prandial, cold drinks Mitral valve prolapse Cerebrovascular accident Smoking Pheochromocytoma Digoxin therapy RBBB and LBBB.

zz zz zz zz

Extensive anterior wall MI (Fig. 4.52)—LI, aVL and precordial leads Anteroseptal wall MI—V1 to V4 Anterolateral wall MI—LI, aVL, V4, V5, V6 Apical wall MI—V5, V6 Inferior wall MI (Fig. 4.53)—LII, LIII and aVF Inferolateral wall MI—LII, LIII, aVF, V5 and V6.

Right Ventricular Infarct (Fig. 4.54) zz

zz

This is suspected in the setting of acute inferior wall infarction. There is an elevated S-T segment (of 1 mm) in extreme right oriented leads V1 and V4R (to V6R). There is failure of reciprocal S-T segment depres­sion in the right precordial leads in cases of inferior wall MI.

True Posterior Wall Infarct (Fig. 4.55) Right precordial leads V1 to V3, especially lead V2, reflect the inverse change or mirror image of a classic anterior wall MI, i.e.

Fig. 4.51  ECG changes in coronary artery disease

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Cardiovascular System zz

zz

zz

Mirror image of QS complex is reflected by a tall and slightly widened R-wave. Mirror image of the coved and elevated S-T seg­ment is reflected by a depressed, concave upward S-T segment. Usually, this change is not seen. Mirror image of inverted, symmetrical T-wave is reflected by an upright, widened and usually tall T-wave. Diagnosis of true posterior wall MI should not be entertained without this change.

Subendocardial Infarct Fig. 4.52  Extensive anterior wall MI

Electrocardiograph presents with ST depression and deeply inverted T-waves in the mid-precordial and lateral precordial leads as well as in LI and LII. These changes persist for several days (mirror image of epicardial infarction). Myocardial Ischemia with LBBB

Fig. 4.53  Hyperacute inferior wall MI

Fig. 4.54  Right ventricular MI

Fig. 4.55  Posterior wall MI

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It is very difficult to detect the presence of MI in the presence of associated LBBB (Fig. 4.56). The various ECG signs that are proposed for diag­nosis of acute MI in the presence of LBBB are: zz S-T segment elevation ≥1 mm and concordant with QRS complex zz S-T segment depression ≥1 mm in leads V1V2 (or) V3 zz S-T segment elevation ≥5 mm and discordant with QRS complex. Points 1, 2, and 3 are called as Sgarbossa’s criteria. zz Presence of Q-waves in two contiguous precordial leads or in two limb leads zz Left axis deviation > –30° zz R-wave regression from V1–V4 zz QS pattern from V1–V4 zz Terminal S-wave in V5 or V6 zz Positive T-waves in V5 or V6 zz Notching ≥ 0.05 second in the ascending limb of S-wave in V3 or V4 (Cabrera’s sign) zz Notching ≥ 0.05 second in the ascending limb of R-wave in Ll, aVL, V5 (or) V6 (Chapman’s sign).

Fig. 4.56  Non-Q-wave MI (non-ST elevation MI)

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Manual of Practical Medicine Infarct pattern is not masked in LII, LIII, aVF and premature beats. MI with RBBB The presence of RBBB does not interfere with the diagnosis of associated MI.

Acute Pericarditis (Fig. 4.57) ECG shows Sinus tachycardia zz An elevated, concave upwards S-T segment zz Upright, tall, peaked T-waves (earliest change) zz No reciprocal changes in the opposite leads. zz

Electrical alternans is an ECG manifestation in which there is alternation in the amplitude of QRS complexes and/or the T-waves. It often accompanies fast rates. When found with slow rates, it indicates left ventri­cular failure. This is occasionally seen in pericardial effusion. When pulsus alternans is also present in addition to electrical alternans, it is said to be complete. When electrical alternans is in isolation, it is said to be incomplete.

ECG in Electrolyte Imbalance Hyperkalaemia (Figs 4.59A and B) zz

Pericardial Effusion (Fig. 4.58) ECG shows Low to inverted T-waves in most leads zz Low voltage complexes (Voltage of QRS is 120 msec).

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Manual of Practical Medicine Paroxysmal Supraventricular Tachycardia Electrophysiological studies have demonstrated that reentry is responsible for the majority of SVT. Anatomical site has been localised to the sinus node, atrium, AV node or a macroentry circuit involving AV node and AV bypass tract. The mechanism of PSVT can be traced on the basis of RP interval, the time interval between the peak of an R-wave and the subsequent P-wave during tachycardia (Fig. 4.68). Short R-P Tachycardia

Fig. 4.67  Classification of arrhythmias (based on origin)

Analysis of ECG zz zz

zz zz zz

Frequency, morphology and regularity of ‘P’ waves Look for sinus ‘P’ wave/Ectopic P’2 deflection/Flutter wave/Fibrillation wave Relationship between atrial and ventricular activity QRS morphology during sinus rhythm/tachy- arrhythmia Response to carotid sinus massage/vagal manoeuvres.

Rule of Hundreds for Tachycardias The rule refers to atrial rate. Atrial tachycardia: 200 ± 50 zz Atrial flutter: 300 ± 50 zz Atrial fibrillation: 400 ± 50 zz

Ventricular tachycardia has the same range as atrial tachycardia: 200 ± 50, but usually has a rate on the slower side.

They have an R-P interval that is less than 50% of the RR interval. These include: zz Typical AV nodal re-entrant tachycardia (AVNRT): It occurs in patients who have functional dissociation of the AV node into ‘slow’ and ‘fast’ pathways. Conduction proceeds antegradely down the slow pathway and retrograde conduction up the fast pathway resulting in atrial and ventricular excitation concurrently. P-waves are hidden within the QRS complexes and can be distinguished only by the comparison of QRS morphologies in tachycardia and in sinus rhythm. zz Orthodromic AV re-entrant tachycardia (O-AVRT): It is an accessory pathway mediated re-entrant rhythm. (Anterograde conduction to the ventricle through the AV node and retrograde conduction to the atrium through the accessory pathway). P-waves are seen shortly after QRS complexes (Fig. 4.69). zz Sinus tachycardia or ectopic atrial tachycardia with first degree AV block zz Junctional tachycardia: It is a narrow-complex tachycardia arising from the AV junction. The impulse is conducted to the atrium and ventricle simultaneously and the P-wave is not easily discernible. It is seen in acute MI, mitral/aortic valve surgery or digitalis toxicity.

Narrow Complex Tachycardia (SVT) P-wave

QRS-complex

Rate

Contour

Rhythm

Rate

Sinus tachycardia

100–180

Normal/Peaked

Regular

100–180 Regular

Rhythm

Normal

Atrial flutter

250–350

Saw-toothed

Regular

75–175

Normal

Atrial fibrillation

400–600

Regular except drugs/ disease

Contour

Absent ‘P’ with ‘f’ waves Irregular

100–160 Irregularly irregular

Normal

Atrial tachycardia with block 150–250

Abnormal ‘P’ waves

75–200

Normal

AVNRT

150–250

Retrograde ‘P’/merged Regular except onset/termination 150–250 Regular except onset/end

Normal

AVRT

150–250

Retrograde ‘P’/merged Regular except onset/termination 150–250 Regular except onset/end

Normal

Non-paroxysmal AV junctional tachycardia

60–100

Normal

Normal

Regular or may be irregular

Regular

70–130

Regular except drugs/ disease

Regular

Abbreviations: AVNRT, Atrioventricular nodal reentrant tachycardia; AVRT, Atrioventricular reentrant tachycardia; AV, Atrioventricular

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zz

retrograde conduction P-wave is well seen after the QRS complex (Fig. 4.70). O-AVRT mediated by an accessory bypass tract with slow or decremental conduction properties.

WPW Syndrome

Fig. 4.68  RP interval

Pre-excitation is as a result of anterograde activation of the ventricle via an accessory pathway as well as the AV node, resulting in a short PR interval with a delta wave slurring the upstroke of the QRS complex (Fig. 4.71). The presence of accessory pathway predis­poses the indivi­duals for SVT (narrow complex orthodromic AVRT). zz Antidromic AVRT: (5% of patients with WPW) The conduction to the ventricle proceeds down the accessory pathway and the retrograde conduction through the His-Purkinje system and the AV node to the atria. zz Atrial fibrillation: Atrial fibrillation in patients with WPW syndrome may facilitate rapid ventricular response since the accessory pathway has no decremental properties and ultimately VF. Multifocal Atrial Tachycardia (Fig. 4.72) Multifocal atrial tachycardia is revealed by 3 or more varying ‘P’ wave morphologies with irregular QRS complexes. This tachycardia is commonly seen in COPD patients especially when on theophylline therapy.

Fig. 4.70  Paroxysmal atrial tachycardia with 2:1 AV block

Fig. 4.69  Mechanisms in PSVT Abbreviations: AVNRT, Atrioventricular nodal reentry tachycardia; AVRT, Atrioventricular

Long R-P Tachycardia They have an RP interval that is greater than 50% of the RR interval. zz Sinus tachycardia or ectopic atrial tachycardia with normal PR intervals. zz ‘Atypical’ AVNRT: Anterograde conduction proceeds over the fast AV nodal pathway and the retrograde conduction over the slow AV nodal pathway in patients with dual AV nodal physiology. Because of the slow

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Fig. 4.71  Wolff-Parkinson-White syndrome

Fig. 4.72  Multifocal atrial tachycardia

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Manual of Practical Medicine Atrial Tachycardia with Complete Heart Block This is often a manifestation of digoxin toxicity unless proved otherwise.

Coronary artery disease Myocarditis and cardiomyopathy Cardiac surgery Hypothyroidism Hyperthyroidism Pheochromocytoma Pericarditis.

zz zz zz zz

Atrial Flutter (Fig. 4.73) It is as a result of single re-entrant circuit around functional or structural (scar due to prior cardiac surgery) conduction barriers within the atria. Flutter waves are negative in inferior leads (II, III and aVF) and positive in V1 with ‘sawtooth’ appearance. Atrial rate is usually 300 beats/ minute with 2:1 or varying conduction to the ventricle. Atrial Fibrillation (Fig. 4.74) It is the most common sustained tachyarrhythmia seen in many patients. Common Causes zz zz zz zz

10% of elderly > 75 years Lone AF - < 65 years (normotensive with normal heart) Valvular heart disease Hypertensive heart disease

zz zz zz

Atrial rate is 400 to 600/minute with an irregularly irregular rapid ventricular response (> 100 beats/ minute). The ECG is characterised by irregular baseline with no discernible P-waves. The AF waves may be either fine (AF of recent onset) or coarse (AF of long standing duration) The RR interval is irregularly irregular. The RR interval may be deceptively regular and slow in patients with complete heart block, either due to conduction system disease or digoxin toxicity. Symptoms of AF (Due to rapid ventricular rate): Acute pulmonary oedema Syncope Angina Palpitations Thromboembolic (cerebral, peripheral, renal, coronary).

zz zz zz zz zz

Fig. 4.73  Atrial flutter

Prolonged episodes of rapid ventricular rate may cause a tachycardia mediated cardiomyopathy.

Stroke Risk Non-valvular Atrial Fibrillation CHA2 DS2-VASc Scoring System Parameter

Score

C

Congestive heart failure

1

H

Hypertension history

1

A2

Age ≥75 years

2

D

Diabetes mellitus

1

S2

Previous stroke or TIA

2

V

Vascular disease

1

A

Age 65–74 years

1

Sc

Sex category female

1

Maximum total score

9

Annual Stroke Risk – Recommended Therapy zz zz

Fig. 4.74  Atrial fibrillation

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zz

0 Point – 0% (No prophylaxis required) 1 Point – 1.3% (Aspirin/oral anticoagulant) 2 + Points – 2.2% (Oral anticoagulant)

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Cardiovascular System Management of narrow complex tachycardia (SVT) Initial therapy of acute episodes of narrow complex tachycardia includes hospitalisation, administration of oxygen, establish IV line, vagal manoeuvres such as Valsalva manoeuvre, carotid massage with caution (avoid in the presence of carotid bruit, acute ischaemia and digoxin toxicity) and if it fails, administer IV bolus either one of the short acting drugs that slow or block AV nodal conduction. zz Adenosine (Drug of choice) 6 mg IV and repeat if necessary every 2 minutes using 12 mg or zz Metoprolol 5 mg IV every 5 minutes zz Verapamil 5 mg IV (over 3 minutes) and repeat after 15 to 30 minutes zz Diltiazem 0.25 mg/kg over 3 minutes and repeat the bolus after 30 minutes zz Esmolol 40 mg IV over one minute followed by IV infusion 4 mg/minute and titrated upto 12 mg/ minute zz Digoxin maximum IV dose 0.5 mg over 3 minutes and repeat if needed once zz Amiodarone IV infusion 300 mg over one hour zz Over-drive pacing. Use the above drugs in the absence of following adverse signs: zz Hypotension—BP < 90 mm Hg zz Acute severe chest pain zz Heart failure zz Altered conscious level zz Heart rate > 200 bpm In the presence of above adverse signs—give sedation and synchronised cardioversion. Synchronised cardioversion 100 J – 200 J – 300 J (If refractory or to maintain sinus rhythm use) zz Amiodarone 150 mg IV over 10 minutes and then 300 mg over one hour. zz

Chronic therapy of SVT: (Use either one of the drugs) Diltiazem sustained release 120 to 360 mg PO qd zz Verapamil sustained release 120 to 480 mg PO qd zz Metoprolol 25 to 100 mg PO bid zz Atenolol 25 to 100 mg PO qd zz Digoxin 0.25 to 0.5 mg PO qd. zz

Radiofrequency Ablation It offers definitive cure for different type of SVTs: zz AVNRT/AVRT zz Accessory pathway mediated tachycardias zz Focal atrial tachycardia zz Atrial flutter.

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Complications of radiofrequency ablation (less than 1%) zz zz zz zz zz zz

Groin haematomas Bleeding Cardiac perforation Cardiac tamponade Complete heart block Stroke.

With the advent of successful radiofrequency ablation, antiarrhythmic agents are rarely indicated for the management of SVT. Specific management Sinus tachycardia: The cause has to be identified and treated accordingly. Atrial tachycardia: It is rare and usually due to digoxin toxicity. Stop digoxin and maintain potassium level at 4 to 5 mmol/L. Digoxin-specific Fab antibody fragments should be used. Multifocal tachycardia: It is most commonly seen in COPD. After correcting hypoxia and hypercapnia, if the heart rate remains > 110 b/minute verapamil should be used. Junctional tachycardia: If vagal manoeuvres fail adenosine can be used. If it recurs beta-blocker and amiodarone should be used. Radiofrequency ablation is most ideal in the management. Atrial fibrillation: Management protocol consists drugs to reduce rate, rhythm correction and to prevent thromboembolism by using anticoagluants. Acute AF ( 30 msec or R to S > 60 msec or notched S wave In lead V6 ~ QR or QS RBBB: In lead V1-V2 ~Monophasic R or QR or RS In lead V6 ~ R/S < 1 zz zz

Basic Classification of Ventricular Tachycardia zz

zz

zz

Non-sustained ventricular tachycardia—lasting for 30 seconds or less Sustained ventricular tachycardia—longer than 30 seconds or requiring DC shock due to haemodynamic instability Appearance can be either monomorphic or polymorphic.

Sustained Monomorphic VT

Fig. 4.78  Ventricular bigeminy

Three or more successive ventricular pre-mature complexes are termed ventricular tachycardia. It is called sustained when it lasts longer than 30 seconds at a rate of 100 to 250 beats/minute with only one type QRS morphology throughout the arrhythmia.

Polymorphic VT It is characterised by changing QRS morphology from beat to beat and is frequently due to coronary artery disease. Torsade de pointes (TdP) is a polymorphic VT that is prece­ ded by a prolonged QT interval in sinus rhythm (Fig. 4.80). Ventricular Flutter (Fig. 4.81) Fig. 4.79  Extrasystoles in pairs

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Heart rate—150–300. This is characterised in the ECG by a very rapid and regular ectopic ventricular discharge.

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Fig. 4.80  Ventricular tachycardia

The QRS and T deflections are very wide and bizarre, resulting in a sine-like waveform. Note: Ventricular flutter differs from ventricular fibrillation in the uniformity, constancy, regularity and relatively large amplitude of the deflections. The deflections of ventricular fibrillation are small and completely chaotic and irregular.

Fig. 4.81  Ventricular flutter

Torsades de pointes (Fig. 4.82): Ventricular flutter may present with multiform QRS complexes, a manifestation which has been termed ‘torsades de pointes’. In this presentation, the QRS complexes tend to be bizarre and multiform, and have sharply pointed apices or nadirs. This form of ventricular flutter is likely to complicate advanced and third degree AV block, and is frequently associated with syncopal attacks. The syncopal attacks may result in marked prolongation of the QTc interval and there may be ‘giant T-wave inversion’. This may be an expression of: zz Severe coronary artery disease zz Hypokalaemia zz Hypomagnesaemia zz Quinidine therapy.

Fig. 4.82  Torsades de pointes

Fig. 4.83  Ventricular fibrillation

Management of Broad Complex Tachycardia Haemodynamically stable VT: Correct hypokalaemia and hypomagnesaemia zz Amiodarone 150 mg IV over 20 minutes and then 300 mg over 1 hour or zz Lignocaine 50 mg IV over 2 minutes and repeated every 5 minutes to a maximum of 200 mg. zz

Ventricular Fibrillation (Fig. 4.83) This is characterised in the ECG by the presence of completely irregular, chaotic, and deformed deflec­tions of varying height, width and shape.

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Cardiovascular System If the above drugs fail or the patient haemodynamically unstable: zz DC cardioversion – 200 J – 200 J – 360 J Resistant VT/VF: Amiodarone 300 mg IV followed by an infusion 1 mg/ minute for 6 hours and then 0.5 mg/minute for another 6 hours or zz Lidocaine 100 mg IV—repeat once more—followed by infusion 2 to 4 mg/minute or Procainamide 30 mg/ minute IV—maximum dose 15 mg/kg or zz Bretylium 5 mg/kg and repeat boluses as needed to a maximum of 35 mg/kg or sotalol—use with caution in the presence of congestive heart failure. zz

TdP associated with long QT syndrome: Immediate DC cardioversion zz Magnesium sulfate IV bolus 1 to 2 grams (maximum 4 to 6 gm). zz

Prevention of Recurrent VT: Radiofrequency catheter ablation of VT for haemo­ dynamically stable forms of VT without structural heart disease. zz Surgical isolation of arrhythmogenic area zz Implantation of tiny automatic defibrillators. zz

Heart Block First degree heart block (Fig. 4.85) is characterised by a con­ stantly prolonged PR interval (> 0.20 sec). Second Degree Heart Block zz

zz

Mobitz type I (Fig. 4.86): The PR interval increases with each cycle until there is a P-wave which is not followed by a QRS complex (Wenckebach’s phenomenon). Mobitz type II (Fig. 4.87): The P-R interval is constant. Some P-waves are not followed by a QRS complex and the degree of block can be quantified as 2:1, 3:1, etc.

Complete or third degree heart block (Fig. 4.88) is charac­ terised by the P-waves and the QRS complexes occurring completely independent of each other. Administration of 1 to 2 mg of atropine IV does not increase the heart rate in sick sinus syndrome and complete heart block, whereas the heart rate increases in sinus bradycardia and first or second degree heart blocks.

Indications for implantable cardioverter-defibrillators (ICDs): zz Spontaneous VT with structural heart disease zz Irreversible causes for VT/VF zz Recurrent VT/VF zz Failure of anti-arrhythmic agents to control VT zz Patients with high risk for sudden cardiac death (SCD).

Brugada Syndrome (Fig. 4.84) zz zz

zz

zz zz

zz zz zz

Common in males and Asian countries Most common cause of sudden cardiac death in young age The lesion is commonly seen near right ventricular outflow tract It is due to sodium channel defect Three types of ECG variants are seen – RBBB with unusual morphology of raised ST segments in V1-3 Coronary arteries are normal Highly prone for cardiac arrhythmias Indication for implantable cardiac defibrillator (ICD).

Fig. 4.84  Brugada syndrome

Bradyarrhythmias Sick Sinus Syndrome (TachyBrady Syndrome) This is due to sinus node dysfunction and ECG shows sinus bradycardia, sometimes associated with AV nodal block or SVT alternating with bradycardia or asystole.

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Fig. 4.85  First degree AV block

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Fig. 4.86  Second degree heart block (Mobitz type I- Wenckebach type)

Fig. 4.87  Second degree heart block (Mobitz type II)

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CONGENITAL HEART DISEASES Fig. 4.88  Complete heart block

Indications for Permanent Pacemakers zz zz

zz

zz zz zz zz

Symptomatic sinus bradycardia or AV block Advanced AV block with: —— Asystole >3 seconds —— Escape rates 3 seconds.

Classification of Congenital Heart Diseases Gross Anomalies zz zz zz

Lesions Without Shunts Left Heart Malformations zz

zz

Exercise (Stress) ECG By performing an ECG during progressively increas­ing exercise (on a treadmill), it is possible to detect stress induced arrhythmia or evidence of ischaemia. zz Horizontal or downsloping ST segment depression of >1 mm suggests ischaemia. zz Failure to achieve an increase in BP or occurrence of a fall in BP during exertion is an evidence for ventricular decompensation and is indicative of ex­ t ensive ischaemia. zz Inability to achieve the predicted heart rate renders the test inconclusive (predicted heart rate is 220 – age of the patient).

zz

zz zz

Contraindicated in: Unstable angina zz Decompensated heart failure zz Severe hypertension or outflow tract obstruction, e.g. AS. Holter Monitoring or Ambulatory ECG For detecting transient episodes of arrhythmia or isch­ aemia which seldom occur fortuitiously during the short time taken for routine 12 lead ECG monitoring.

zz

zz zz zz

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Acyanotic Ebstein’s anomaly Pulmonic stenosis —— Supravalvular —— Valvular —— Infundibular —— Subinfundibular. Congenital pulmonary valve regurgitation Idiopathic dilatation of the pulmonary trunk Pulmonary artery branch stenosis.

Shunt Lesions—Left to Right (Acyanotic) Atrial Level Shunt zz

Stress ECHO A stress ECHO can be done following administration of adenosine, dobutamine or dipyridamole to detect evidence of ischaemia.

Congenital obstruction to left sided inflow —— Pulmonary vein stenosis —— Cor triatriatum —— Mitral stenosis. Mitral regurgitation —— Mitral valve prolapse —— Double orifice mitral valve —— Congenital perforation —— Cleft posterior leaflet —— Parachute mitral valve —— Chordae anomalies. Aortic stenosis —— Supravalvular —— Valvular —— Subvalvular Aortic valve regurgitation Coarctation of aorta.

Right Heart Malformations zz

Following MI, it is used in assessing the risk. zz

Ectopia cordis Cardiac malpositions Congenital complete heart block.

zz

zz

Atrial septal defect (ASD) —— Ostium primum —— Ostium secundum —— Sinus venosus ASD with acquired mitral stenosis (Lutembacher’s syndrome) Partial anomalous pulmonary venous con­nection.

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Ventricular Level Shunt zz

zz zz

Ventricular septal defect (VSD) —— Perimembranous or paramembranous defect —— Muscular defect VSD with aortic regurgitation VSD with left ventricular to right atrial shunt (Gerbode defect).

Aortic Root to Right Heart Shunt zz zz zz

Ruptured sinus of Valsalva aneurysm Coronary arteriovenous fistula Anomalous origin of left coronary artery from the pulmonary artery (ALCAPA).

Aorto-pulmonary Level Shunt zz zz

Aorto-pulmonary window Patent ductus arteriosus (PDA).

Multiple Level Shunts zz zz

VSD with ASD VSD with PDA.

Shunt Lesions—Right to Left (Cyanotic) With Increased Pulmonary Blood Flow zz zz zz zz

Complete transposition of the great arteries Double outlet right ventricle Truncus arteriosus Total anomalous pulmonary venous connection.

With Normal or Decreased Pulmonary Blood Flow zz zz zz zz zz

Tetralogy of Fallot Tricuspid atresia Ebstein’s anomaly with right to left atrial shunt Pulmonary atresia with intact ventricular septum Pulmonary arteriovenous fistula.

Cyanotic congenital heart disease with prominent LV apex— tricuspid atresia. The incidence of coarctation of aorta, transposition of the great arteries, and aortic stenosis is greater in males. The incidence of patent ductus arteriosus and atrial septal defect is greater in females. The incidence of other congenital heart diseases is almost equal in both males and females. Figure 4.89 shows various external markers of congenital heart diseases.

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Incidence of Congenital Heart Diseases Congenital heart disease   1.  Ventricular septal defect   2.  Patent ductus arteriosus  3. Aortic stenosis  4. Pulmonary stenosis   5.  Tetralogy of Fallot   6.  Atrial septal defect   7.  Mitral valve prolapse   8.  Coarctation of aorta   9.  Transposition of the great arteries 10.  Truncus arteriosus 11. Total anomalous pulmonary venous connection 12.  Tricuspid atresia 13. Miscellaneous

Percentage 30% 10% 10% 10% 10% 7% 7% 5% 5% 1% 1% 1% 3%

Cardiac Malposition (Figs 4.90 to 4.92) An abnormal anatomic position of the entire heart or its chambers constitutes a cardiac malposition. zz Normally, cardiac apex is to the left side of chest —levocardia. zz When cardiac apex is to the right side of chest —dextrocardia. zz When cardiac apex is situated over the centre of chest —mesocardia. In describing a cardiac abnormality, three segments must be individually considered, i.e. The position of the atria, position of the ventricles and their connections to the atria and the position of the great vessels and their con­nections to the ventricles. 1. In general, the position of the atria can be identified by the body situs (configuration of the visceral organs). —— The liver and right atrium are located on the same side of the body. —— The left atrium is on the same side as that of stomach and spleen. —— The normal arrangement of abdominal viscera and atria is termed situs solitus. —— When the abdominal viscera (along with the atria) is completely reversed, it is termed situs inversus. Situs ambiguous is associated with asplenia or polys­ plenia, when the cardiac position cannot be determined. 2. After determination of the visceroatrial situs, one must define the position of the ventricles and their connections to the atria. The ventricles are morpho­ logically different and can usually be distinguished on the basis of angiography or echocardiography. The atrioventricular valves always remain with their res­ pective ventricles.

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Fig. 4.89  External markers of congenital heart disease

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A

B A

C

B

D

Figs 4.90A to D  Cardiac malpositions (Anatomical). (A) Normal position situs solitus; (B) Situs inversus with dextrocardia; (C) Situs solitus with dextrocardia; (D)Situs inversus with levocardia Abbreviations: LA, Left atrium; LV, Left ventricle; RA, Right atrium; RV, Right ventricle

C Figs 4.92A to C  Cardiac malpositions—radiological. (A) Dextrocardia; (B) Situs inversus totalis; (C) Situs ambiguous

right ventricle, are situated on the patient’s right side. The right ventricle lies to the right of left ventricle). An l-loop is normal in situs inversus (the liver and the right atrium, connected to the right ventricle are situated on the patient’s left side. The right ventricle lies to the left of left ventricle). 3. The anatomy of the great arteries is defined in terms of: —— Their positional relationships —— Their ventricular attachments. The positional relationships of the great vessels are described as d (dextro) when the ascending aorta lies to the right of the pulmonary artery. It is described as l (levo) when the aorta lies to the left of the pulmonary artery.

Fig. 4.91  Situs solitus





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In normal development, the primitive, straight cardiac tube bends to the right, forming the so-called d-loop (d for dextro or right). This places the mor­phologic right ventricle to the right of the morphologic left ventricle. Conversely, if the cardiac tube bends to the left, an l-loop (l for levo or left) is formed and the morphologic right ventricle lies to the left of the left ventricle. Using this classification, a d-loop is normal in situs solitus (the liver and the right atrium, connected to the

Examples: 1. Normal heart would be described as solitus/d-loop/ d-normal 2. Situs inversus and dextrocardia is described as inversus/l-loop/l-normal.

Dextrocardia Dextrocardia with Situs Inversus (Situs Inversus Totalis) Dextrocardia, with situs inversus is the relatively common condition that is usually an incidental finding on chest X-ray or physical examination and is gener­ally benign. About 90% of patients with this condition have hearts that are otherwise normal. The ECG shows negative P-wave in standard lead I.

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Cardiovascular System If the left and right arm leads are reversed and the precordial leads are positioned across the right side of the chest, the ECG appears normal. Isolated Dextrocardia Patients with isolated dextrocardia without situs inversus almost invariably have additional cardiac malformations, the most common being zz Corrected transposition of the great vessels zz Pulmonic stenosis zz Ventricular septal defect zz Atrial septal defect.

zz

zz

zz

zz

zz

Cardiac Abnormalities with Various Genetic Disorders Genetic diseases of the heart may be classified into one of three categories 1. Chromosomal disorders 2. Single-gene disorders (autosomal dominant or recessive; or X-linked) 3. Multifactorial disorders. Patients with chromosomal or single-gene defects com­ prise 5 to 10% of subjects with congenital heart disease and generally have abnormalities in multiple organ systems. Patients with multifactorial inheritance pattern have discrete cardiac abnormality (VSD, ASD, PDA) without abnormalities in other organs.

zz

zz

zz

Chromosomal Disorders zz

zz

Down syndrome (Trisomy-21) —— Endocardial cushion defect —— VSD —— Tetralogy of Fallot —— ASD (ostium primum) —— PDA —— Transposition of great vessels —— Coarctation of aorta. Turner’s syndrome (45 XO) —— Coarctation of aorta —— Bicuspid aortic valve —— Aortic stenosis.

Single-gene Disorders zz

zz

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Noonan’s syndrome (autosomal dominant dis­order) —— Dysplasia of pulmonary valve, with result­ant stenosis —— ASD —— HOCM. Williams syndrome (autosomal dominant dis­order) —— Supravalvular aortic stenosis —— Peripheral pulmonary artery stenosis.

zz

Leopard syndrome (autosomal dominant dis­order) —— Complete heart block —— Pulmonic valve stenosis. Holt-Oram syndrome (autosomal dominant dis­order) —— ASD (ostium secundum) —— VSD. Supravalvular aortic stenosis (autosomal domi­nant disorder) Kartagener’s syndrome (autosomal recessive disorder) —— Dextrocardia with situs inversus —— Transposition of great vessels. Hereditary disorders of connective tissue (Marfan’s syndrome, Ehlers-Danlos, homocys­ti­nuria) —— Mitral or tricuspid valve prolapse —— Premature coronary artery disease —— Aortic regurgitation —— Mitral regurgitation. Cardiomyopathy —— HOCM —— Familial dilated cardiomyopathy. 22q11 deletion syndrome (DiGeorge or velocardiofacial or Takao syndrome) —— Conotruncal defects—interrupted aortic arch/ Tetralogy of Fallot/Truncus arteriosus —— Double-outlet right ventricle Scimitar syndrome —— Total or partial anomalous pulmonary venous connection (Chest X-ray PA view reveals a shadow that resembles Turkish sword –scimitar) —— Hypoplasia of right pulmonary artery and right lung with additional arterial supply from abdominal aorta. Shone complex syndrome —— Left ventricular injflow/outflow obstruction at multiple levels—MS, AS, coarctation of aorta, LV hypoplasia —— NOTCH1 mutations are associated with aortic stenosis.

Maternal Disease causing CHD zz

zz

zz

zz

Infections: Any febrile illness in the first trimester of pregnancy—two fold increase in the risk of CHD Maternal rubella: PDA, pulmonary valve anomaly, VSD, TOF, (with cataract, retinopathy, deafness, mental retardation, maternal SLE/Sjogren syndrome), congenital complete heart block Intake of drugs: Lithium-Ebstein anomaly; AlcoholVSD (foetal alcohol syndrome); Thalidomide, vitamin A, antiepileptics can cause CHD Maternal diabetes: TGA, AV septal defects, VSD, hypoplastic left heart syndrome, cardiomyopathy, PDA

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Manual of Practical Medicine zz

zz

Phenylketonuria (PKU): 6 fold increase in the risk of CHD—VSD, TOF, PDA, single ventricle Exposure to organic solvents: Pesticides, ionizing radiation may increase the risk of CHD

zz

Atrial Septal Defect Atrial septal defect (ASD) is the most common congenital heart disease presenting with symptoms in adults. There are four types of ASD; of which first three are most common (Fig. 4.93): ASD is more common in females. 1. Ostium secundum (90%) 2. Ostium primum (5%) 3. Sinus venosus (5%) 4. Coronary sinus type—very rare

Ostium secundum type of ASD can be sporadic or transmitted as autosomal dominant condition. PFO (Persistent foramen ovale)—there is only anatomical patency. In ostium secundum ASD there is both anatomical and functional patency.

zz

Holt-Oram syndrome (Ostium secundum ASD): Triphalangeal (fingerised) thumb, sometimes abrachia or phocomelia, autosomal dominant inheritance. Trisomy 13 (Patau syndrome): Polydactyly, flexion deformity of fingers, simian crease, microcephaly, holoprosencephaly, cleft lip and palate and low set malformed ears (ASD, VSD, PDA) Trisomy 18 (Edward syndrome): Prominent occiput, low set malformed ears and micro­gnathia together with clenched fists and rocker bottom feet (ASD, VSD, PDA)

A

zz

zz

zz

zz zz

zz

Syndromes with ASD

zz

Sinus venosus type of ASD occurs high in the septum near the SVC entrance. It is sometimes associated with partial anomalous pulmonary venous connection. zz AF is common in ASD. zz Infective endocarditis is uncommon in ASD, except in ostium primum type, due to associated MR or TR.

Clinical Features

Ostium primum type of ASD is commonly associated with either Down’s syndrome or with endocardial cushion defects (MR, TR).

zz

Others: Ellis van Creveld (polydactyly, nail dysplasia, chondrodystrophic dwarfism), thrombocytopeniaabsent radius (TAR), trisomy 21 and rubella. ASD can be associated with: —— Mitral valve prolapse —— Acquired mitral stenosis (Lutembacher’s syndrome).

B

One-third of patients with ASD have a systolic thrill. If thrill is prominent, associated PS should be thought of. Wide, fixed split of S2 is the characteristic auscul­ tatory finding of ASD S2 split is narrowed with development of pulmonary hypertension Split is variable with development of atrial fibrillation Flow ejection systolic murmur (ESM) across pulmonary valve Flow mid-diastolic murmur (MDM) across tricuspid valve.

Differential Diagnosis zz

zz

zz

Partial anomalous pulmonary venous connection can simulate ASD (Acyanotic). Total anomalous pulmonary venous connection with a large interatrial communication without pulmo­ nary hypertension or pulmonary venous obstruc­­tion can also simulate ASD (Cyanotic). Mitral stenosis with pulmonary hypertension.

C

Figs 4.93A to C  Types of atrial septal defect. (A) Ostium primum; (B) Ostium secundum; (C) Sinus venosus Abbreviations: PA, Pulmonary artery; PV, Pulmonary value; SVC, Superior vena cava; LA, Left atrium; RA, Right atrium; IVC, Inferior vina cava; RV, Right ventricular; LV, Left ventricle; RVH, Right ventriclar hypertrophy

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Cardiovascular System ECG zz

zz zz

Ostium secundum: Right-axis deviation with RV dominance and incomplete RBBB Ostium primum: LAD with incomplete RBBB Sinus venosus: Inverted P-wave in inferior leads. Junctional rhythm may be present. Rarely ostium primum defects may be associated with complete heart block.

Chest X-ray Dilated right atrium, right ventricle and pulmonary arteries, with a less prominent aortic knuckle gives a characteristic ‘Jug handle appearance’ (Fig. 4.94). Dilatation of SVC is in favour of sinus venosus type of ASD. The lung fields are plethoric. Fig. 4.94  Jug handle appearance

Treatment Surgical closure (ideal age 3–6 years). Indication for surgery—significant shunt with pulmonary to sys­temic flow > 1.5 : 1. A new non-invasive surgical procedure is closure of the defect using an umbrella (Fig. 4.95). However, ASDs can close spontaneously up to 2 years of age. Prosthetic closure of ASD using pericardial graft can be done.

Ventricular Septal Defect Ventricular septal defect (VSD) is the most common congenital heart disease.

Classification (Figs 4.96A and B) Perimembranous or paramembranous type (most common 80%). It has variable extension into outlet, inlet or trabecular septum. It is also called infracristal, subaortic or conoventricular type. zz Muscular type—It can be of three types: —— Inlet (8%) —— Trabecular (central, apical or marginal) (5–20%) (Swiss cheese type—multiple sieve like) —— Outlet (5–7%): It is also called as supracristal, sub­ pulmonic, conoseptal, subarterial or infundibular. zz

Syndromes with VSD zz zz

zz

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Trisomy’s 8,13,18 and 21 Cri-du-chat syndrome (cat cry, microcephaly, mental retardation, anti-mongoloid slant) Cornelia de Lange syndrome (micromelia, mental and growth retardation)

Fig. 4.95  Device closure of ASD

Klippel-Feil syndrome Velacardio facial syndrome (cleft palate, prominent nose, slender hands, learning disability) zz Foetal alcohol syndrome (microcephaly, growth and mental retardation, thin upper lip, short palpebral fissure) zz Apert syndrome (craniosynostosis, mid-facial hypoplasia, syndactyly) zz Conradi-Hunermann syndrome (asymmetrical limb short­n ess, large skin pores, early punctate minerali­sation). zz VATER association (vertebral anomaly, anal atresia, tracheoesophageal fistula, renal and radial anomalies). Ventricular septal defects may vary in size, shape and number. Spontaneous closure of the defect may occur in 50% of those having a defect less than 0.5 cm in diameter (in muscular septal defect only) up to 6 years of age. zz zz

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A

B Figs 4.96A and B  (A) Ventricular septal defect; (B) Types of VSD

Abbreviations: SVC, Superior vena cava; AO, Aorta; PA, Pulmonary artery; LA, Left atrium; PV, Pulmonary valve; RA, Right atrium; LV, Left ventricle; RV, Right ventricle

Mechanism of Closure of Defect zz zz

zz

Septal muscle grows around defect. Prolapsed aortic or tricuspid valve gets adherent to defect along with over growth of fibrous tissue. Infective endocarditis occurrence or development of ventricular septal aneurysm may close the defect.

Anatomical location of subaortic VSD predisposes for aortic valve prolapse and development of AR. VSD may produce symptoms much earlier in life.

Clinical Features zz

zz

zz

Grade IV pansystolic murmur over 3rd or 4th intercostal space in the left parasternal region with signs of bi-ventricular enlargement. A mid-diastolic flow murmur may be heard across the mitral valve. Occurrence of infective endocarditis is very common.

Fig. 4.97  X-ray showing pulmonary plethora

Maladie-de-Roger Syndrome It is a small sized muscular VSD with a prominent thrill and a loud pansystolic murmur, without any haemo­dynamic changes. ECG is normal. Spontaneous closure of defect may occur. Electrocardiography May show evidence of bi-ventricular enlargement with or without RBBB and occasionally with complete heart block. Chest X-ray/USG Left ventricular enlargement with pulmonary plethora (Fig. 4.97). VSD with patent forament ovale (Fig. 4.98).

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Fig. 4.98  Ventricular septal defect with patent foramen ovale

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Cardiovascular System

Syndromes with PDA

Treatment zz zz zz

Surgical closure is the treatment of choice Ideal age for surgery < 2 years of age Indication for surgery is when pulmonary to systemic blood flow is > 1.5 : 1.

zz

zz zz

Patent Ductus Arteriosus (Fig. 4.99)

zz

Patent ductus arteriosus connects the descending aorta (distal to left sub-clavian artery origin) and the left pulmonary artery (just after the bifurcation of the main pulmonary artery). Functional closure (physiological) occurs within 24 to 48 hours of birth, and the anatomical closure is complete in 2 to 3 weeks after birth. Physiological closure, due to muscular contraction, is influenced by abrupt rise in PaO2 and reduction in the local prostaglandin-E synthesis. Infants born at high altitudes and premature infants have a higher incidence of PDA. Its incidence is also high when the mother is affected by rubella in the first trimester of pregnancy. Compared to ASD and VSD, about 85 to 90% of PDAs occur as isolated defects without associated anomalies.

zz

zz

zz

Maternal rubella syndrome (cataract, deafness, micro­cephaly). Trisomy 18. Foetal hydantoin syndrome (hypertelorism, growth and mental retardation, short phalanges, bowed upper lip). Incontinentia pigmenti (patchy alopecia, irregular pigmen­ted skin lesions, hypodontia). Crouzon syndrome (ptosis with shallow orbit, cranio­ synostosis, maxillary hypoplasia). Rubinstein-Taybi syndrome (broad thumbs and toes, maxillary hypoplasia, slanted palpebral fissure). Conradi-Hunermann syndrome.

Clinical Features Grade IV continuous murmur heard best over the left second intercostal space at mid-clavicular line. Differential Diagnosis of Continuous Murmurs Location

Underlying disease entity

Left upper sternal border and below left clavicle

Patent ductus arteriosus

Second to fourth intercostal spaces

Aortopulmonary septal defect

Along the lower left sternal border

Rupture of sinus of Valsalva aneurysm

Over lower or mid-sternal border or entire precordium

Coronary arteriovenous fistulae

May be audible anywhere over the chest

Pulmonary arteriovenous fistulae

Electrocardiography Left atrial enlargement is commonly seen. Left ventricular enlargement may be seen (volume over­load). Right ventricular enlargement may be seen (pressure overload). Chest X-ray

Fig. 4.99  Patent ductus arteriosus Abbreviations: SVC, Superior vena cava; AO, Aorta; PA, Pulmonary artery; LA, Left atrium; PV, Pulmonary value; RA, Right atrium; RV, Right ventricular; LV, Left ventricle; IVC, Inferior vena cava

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The lung fields are plethoric (Fig. 4.99). The angle between the main pulmonary artery and aortic knuckle can be obliterated by presence of a patent ductus. zz Calcification at the site of ductus indicates a fibrosed or a calcified ductus. zz PDA can close spontaneously after early infancy. zz Ductal endarteritis is common either near the ductal orifice in the pulmonary artery or in the pulmonary end of the ductus. zz Aneurysms or rupture (secondary to development of aneurysm or calcification) of the PDA can occur. Congestive cardiac failure is the commonest cause of death.

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A

B

C

Figs 4.100A to C  Patent ductus arteriosus—X-ray. (A) X-ray showing pulmonary plethora; (B) PDA-coil occlusion; (C) Angiogram showing coil occlusion of PDA

Treatment Medical: Administration of indomethacin within the first 2–7 days of life. Note: Indomethacin favours ductal closure by reduc­ing prostaglandin levels especially PG-E. Surgical: Ligation and excision of patent ductus. Ideal age for surgery is below 2 years. Transcatheter closure of patent ductus using a variety of approaches using coils, buttons, plugs and umbrellas can be done (Fig. 4.100). Conditions where PDA is essential for survival Pulmonary atresia zz Hypoplastic left heart syndrome zz Preductal coarctation of aorta zz Complete the great vessel (TGV) without septal defects. zz

Eisenmenger Syndrome (Fig. 4.101) It is the condition in which left to right shunt gets reversed (right to left) with the development of severe pulmonary hypertension, resulting in central cyanosis, clubbing, and secondary polycythaemia. Its incidence is equal in both males and females. Since this syndrome is uncommon below 2 years of age, surgical closure of left to right shunt lesions is advocated below 2 years of age. Haemoptysis is uncommon, but when it occurs, prognosis is bad, as it is caused by rupture of thin-walled, fragile pulmonary arteries or their small aneurysms. Conditions that cause systemic vasodilatation (exer­­­ cise, fever, hot bath, hot weather) may exag­ger­ate the shunt from right to left resulting in systemic desaturation and poor tolerance.

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Fig. 4.101  VSD with Eisenmenger’s syndrome

Clinical Features zz

zz

zz zz

Generalised cyanosis occurs in presence of VSD and ASD Differential cyanosis involving the lower limbs occurs in the presence of PDA (Fig. 4.102) P2 is loud and palpable There is a prominent parasternal heave.

Eisenmenger syndrome occurs earlier in life in VSD, a little later in PDA, and very late in adult life in ASD. • In ASD with reversal • In VSD with reversal (Eisenmenger complex) • In PDA with reversal

Narrowly fixed split of S2 Single S2 and decreased intensity of murmur Closely split S2 which varies normally with respiration.

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Cardiovascular System

A

B

C

Figs 4.102A to C  Patent ductus arteriosus—Differential cyanosis: (A) Left to right shunt; (B) Right to left shunt; (C) Right to left shunt—ductal

Surgery is not contraindicated in the early phase of Eisenmenger’s syndrome, developing as the result of volume overload without evidence of increased pulmonary vascular resistance (normal pulmonary wedge pressure). Death is caused by Congestive heart failure zz Pulmonary infection zz Pulmonary thrombosis (pulmonary infarction) zz Brain abscess zz Infective endocarditis zz Severe haemoptysis zz Ventricular arrhythmias. Pregnancy must be avoided or terminated with devel­ opment of Eisenmenger’s syndrome. The only curative treatment of Eisenmenger’s syn­drome is heart-lung transplantation. zz

Differential Diagnosis 1. Primary pulmonary hypertension 2. Recurrent pulmonary embolism 3. Idiopathic dilatation of pulmonary artery.

Tetralogy of Fallot (Fig. 4.103) Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in patients who survive infancy. It is composed of four distinct anatomic abnormalities: Large non-restrictive VSD zz Right ventricular outflow tract obstruction* (infun­di­ bular pulmonary stenosis) zz Overriding of the aorta zz Right ventricular hypertrophy. zz

*Rarely valvular PS or a combination of infundibular and valvular PS may be present.

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Fig. 4.103  Tetralogy of Fallot Abbreviations: VSD, Ventricular septal defect

Embryology Tetralogy of Fallot occurs as the result of anterocephalad malalignment of the infundibular septum, resulting in a ventricular septal defect, right ventricular outflow tract obstruction (subpulmonic obstruction) and over­riding of the aorta.

Cyanotic Fallot When the resistance to pulmonary outflow is greater than the systemic resistance, right to left shunting of blood across the VSD occurs, resulting in central cyanosis.

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Acyanotic Fallot When the resistance to the pulmonary outflow is lower than the systemic resistance, then a predominant left to right shunt occurs across the VSD and cyanosis is absent. Initially, in TOF, cyanosis is episodic, occurring during feeding, crying, fever, exercise, etc. when systemic vaso­ dilatation occurs causing an increased right to left shunting across the VSD. A baby born cyanotic is unlikely to have TOF. Cyanosis becomes more prominent after about 5–6 months of life due to the following reasons: zz HbF is the predominant Hb present in the first few years of life. It binds less avidly to O2 and releases it easily at times of need. Hence, when an infant with TOF, in the first 5 to 6 months of life develops cyanotic spells, O2 is easily released from HbF and hence cyanosis is minimal.   After 5–6 months of age, HbF is replaced by HbA2. HbA2 binds O2 more avidly and releases it less readily at times of need and so the child becomes cyanotic. zz With the growth of the child, the O demand for growth 2 increases and cyanosis becomes more prominent. TOF may be associated with other cardiac anomalies like: Patent foramen ovale zz Atrial septal defect zz Aortic regurgitation zz Right sided aortic arch (It is the most common anomaly, seen in 25–30% of cases, its likelihood increasing with increasing severity of RVOT obs­truc­ tion and particularly in pulmonary atresia) zz Patent ductus arteriosus zz Anomalous origin of the coronary arteries zz Absence of left pulmonary artery. zz

2. Down syndrome (hypotonia, mental retardation, mongo­loid facies, hyperextensible joints) 3. Di-George syndrome (Thymic hypoplasia, para­thyroid hypoplasia, ear anomalies) 4. CHARGE association (coloboma, heart defects, atresia choanae, growth retardation, genital and ear abnormalities) 5. Velocardiofacial.

Clinical Features zz zz

zz

zz

A silent precordium is often characteristic On auscultation, a loud, single S2 (representing aortic valve closure) and an ESM is best heard over the 3rd and 4th left intercostal spaces The intensity and duration of the murmur is inver­ sely proportional to the severity of RVOT obstruc­tion Because of a large ventricular septal defect, VSD murmur is inconspicuous.

Electrocardiography ECG shows right axis deviation. A large monophasic R-wave is present in V1, with abrupt transition to a rS complex in V2, V3 and Rs complexes in V5, V6. Chest X-ray This shows a normal sized heart with a characteristic appearance termed as ‘Coeur en Sabot’ or ‘boot shaped heart’ (tilted apex). There is pulmonary oligaemia. Bootshaped heart (Fig. 4.104) is due to the prominence of RV and concavity in the region is due to underdeveloped RVOT and main pulmonary artery.

Pentology of Fallot Presence of ASD along with TOF is called pentology of Fallot.

Trilogy of Fallot Right ventricular outflow tract obstruction with RV hypertrophy and right to left shunt across interatrial septum in the absence of VSD is called trilogy of Fallot (PS, RVH, and ASD).

TOF Associated Syndromes 1. Thrombocytopenia–absent radius (TAR)

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Fig. 4.104  Boot-shaped heart

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Cardiovascular System Complications zz

zz

zz

zz

zz

Treatment

Marked secondary polycythaemia may result in intra­vascular thrombosis leading to cerebrovas­cular accidents and paradoxical emboli. Cerebral abscess (common causative organism being Streptococcus) (Fig. 4.105). Incidence of pulmonary tuberculosis and tubercu­ loma is high. Infective endocarditis (common causative organism being Streptococcus). Congestive cardiac failure is a rare complication and if present, may be secon­dary to: —— Infective endocarditis —— Pregnancy —— Anaemia —— Systemic hypertension —— Aortic regurgitation —— Acquired calcific stenosis of the bicuspid aortic valve —— Pulmonary atresia with large systemic arterial collaterals—RV failure —— Accessory tricuspid leaflet occluding the VSD— RV failure.

Medical Treatment of cyanotic spells by: zz Squatting or knee chest position zz Nasal O 2 zz Morphine zz β-blockers (propranolol): —— Morphine and β-blockers (propranolol) help to relieve infundibular spasm. —— Propranolol initially at the dose of 0.01 mg/ kg IV followed by oral dose of 3–5 mg/kg/day is advocated. Morphine sulphate is given at the dose of 0.1 mg/kg IV. zz Correct metabolic acidosis with sodium bicarbo­ nate—1 mEq/kg IV. Surgical Total correction is advocated and is the definitive treatment. If pulmonary arteries are excessively small, then early definitive correction of TOF is not possible and a palliative procedure (Blalock-Taussig shunt) is done till the time when the pulmonary arteries have enlarged sufficiently.

Fig. 4.105  Tetralogy of Fallot—Cerebral abscess

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Manual of Practical Medicine Blalock-Taussig procedure: In left sided aortic arch—left subclavian to left pulmonary artery. In right sided aortic arch—right subclavian to right pulmonary artery. This procedure results in absent radial pulse on the side of anastomosis and a continuous murmur at the site of anastomosis. Waterston procedure: Ascending aorta to right pul­ monary artery. Pott’s procedure: Descending aorta to left pulmonary artery.

Pulmonary Stenosis Pulmonary stenosis (PS) may occur as an isolated defect or may accompany other anomalies, notably ventricular septal defect. It may occur at various levels (Fig. 4.106). zz Supravalvular zz Valvular zz Infundibular zz Subinfundibular. Congenital stenosis of the valve presents as a domeshaped diaphragm, consisting of fused cusps, with small central aperture, and bulging into the pulmo­nary artery. In infundibular stenosis, the infundibular imped­ ance may consist of localised fibrous stricture or dif­fuse obstructive infundibular hypertrophy. Supravalvular pulmonary stenosis occurs at the level of the pulmonary trunk, pulmonary arteries, or its peripheral

branches. This is often a manifestation of the congenital rubella syndrome. Concentric hypertrophy of the right ventricle occurs. Reduced right ventricular compliance may raise right atrial pressure, enough to force open the foramen ovale, with resultant right-to-left shunt. Marked pulmonary stenosis causes dyspnoea and fatigue, and central cyanosis may develop (secondary to right-to-left shunt across foramen ovale).

PS Associated Syndromes zz zz

zz

zz zz

zz

zz

Maternal rubella Noonan syndrome (webbed neck, pectus excavatum, cryptorchidism) Williams syndrome (Elfin facies, mental retardation, loquacious personality, coarse voice) Foetal hydantoin syndrome Cutis laxa (generalised disruption of elastic fibres, diminished skin resilience, hernias) Alagille syndrome (biliary hypoplasia, vertebral anoma­lies, prominent forehead, deep set ears) LEOPARD syndrome (broad facies, basal cell naevi, rib anomalies and deafness).

Clinical Features zz zz zz zz zz

zz

zz

A raised JVP, with prominent ‘a’-wave Lower left parasternal heave Systolic thrill felt over pulmonary area S2 is widely split (mild PS) P2 is soft and delayed, in valvular PS (in other types, P2 is normal) Pulmonary ejection click may be heard, in valvular PS (other types not heard) Harsh, loud ejection systolic murmur heard over the pulmonary area, increasing in intensity with inspi­ration.

Electrocardiography ECG shows right ventricular hypertrophy. RBBB may be seen. Chest X-Ray Right atrial and right ventricular enlargement. Pro­mi­nance of the main pulmonary artery (post-stenotic dilatation).

Complications Fig. 4.106  Pulmonary stenosis Abbreviations: SVC, Superior vena cava; AO, Aorta; PA, Pulmonary artery; LA, Left atrium; PV, Pulmonary vein; RA, Right atrium; RV, Right ventricular; LV, Left ventricle

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zz zz zz

Right ventricular failure Infective endocarditis Sudden death.

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Cardiovascular System Assessment of Severity of Pulmonary Stenosis Features

Mild

Moderate

Severe

 1. Symptoms

Absent

Absent or minimal

Dyspnoea and fatigue

 2. Central cyanosis

Absent

Absent

Present

 3. Pulse

Normal volume

Normal volume

Small volume

  4.  Jugular venous pressure

Normal

‘a’-wave prominent

Giant ‘a’-wave seen

 5. Parasternal heave

Grade I

Grade II

Grade III

  6. Systolic thrill over pulmonary area

No thrill

Thrill may or may not be palpable

Thrill palpable

 7. P2

Heard

Faint and delayed

Absent

  8.  Pulmonary ejection click

Prominent

Less prominent and occurs earlier (close to S1)

Very faint or absent

  9. Duration and contour of ejection systolic murmur

Short duration of murmur with intensity peaking in early systole

Medium duration murmur with intensity peaking in mid-systole

Long duration of murmur with intensity peaking in late systole

10. Area of pulmonary valve orifice (normal area is 3–4 cm2)

> 1 cm2

0.8–1 cm2

< 0.8 cm2

11. Right ventricular systolic pressure (normal pressure is 25 mm Hg)

30–50 mm Hg

50–80 mm Hg

> 80 mm Hg

12. Treatment

Medical

Medical or surgical

Surgical

Treatment Patients with mild stenosis do well with medical manage­­­ ment, consisting of antibiotic coverage of bacteremic events, and with periodic examination. Patients with severe stenosis warrant corrective surgery. Pulmonary balloon valvuloplasty is prefer­red. Other corrective surgeries are: zz Pulmonary valvotomy zz Pulmonary valve repair zz Pulmonary valve replacement.

Differentiating Severity of Pulmonary Stenosis in Isolated Pulmonary Stenosis and Tetralogy of Fallot In isolated pulmonary stenosis, the intensity of the murmur (ESM) across the stenosed pulmonary valve is directly proportional to the severity of stenosis. Hence, the more severe the stenosis, the louder the murmur and later is the peaking of its intensity. In TOF, the intensity of the murmur (ESM), across the infundibular stenosis, is inversely proportional to the severity of stenosis. This occurs because as the infundibular stenosis becomes more severe, the blood is directed to the overriding aorta, thereby reducing the pulmonary blood flow and therefore also the inten­si­­ty of the murmur.

Congenital Aortic Stenosis It is one of the most common congenital defects in both children and adults.

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Types zz zz zz

Supravalvular Valvular Subvalvular.

Both valvular and subvalvular aortic stenosis may be associated with: zz PDA zz VSD zz Coarctation of the aorta.

Supravalvular Aortic Stenosis (Williams Syndrome) Features Supravalvular aortic stenosis (localised constriction immediately above the sinuses of Valsalva or a diffuse narrowing of the ascending aorta) zz Elfin facies (prominent forehead, widely spaced eyes, blunt upturned nose, underdeveloped mandi­b le, dental hypoplasia and malocclusion, large mouth and patulous lips) zz Mental retardation zz Hypercalcaemia (due to vitamin D excess or intol­erance). zz

Valvular Aortic Stenosis This usually consists of a dome-shaped diaphragm with an eccentric aperture and fused commissures. Post-stenotic dilatation of the ascending aorta is common.

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Subvalvular Aortic Stenosis This consists of a fibrous or fibromuscular shelf encircling the outflow tract beneath the valve.

Congenital AS Associated Syndromes Williams syndrome and fetal hydantoin syndrome.

Clinical Features Congenital valvular stenosis causes physical findings similar to those of acquired valvular stenosis. The congenital valve remains flexible in contrast to the thick, calcified stenotic valve of acquired aortic stenosis. Hence, aortic ejection sounds and normal aortic closure sounds (A2) are usually heard in con­genital valvular stenosis. The harsh aortic ejection systolic murmur is heard. Congenital subvalvular aortic stenosis causes clini­ cal findings similar to those of valvular stenosis. Aortic regurgitation is more common and ejection sounds are not heard. The ejection systolic murmur is sometimes maxi­mal along the mid or lower left sternal edge. Congenital supravalvular aortic stenosis causes a harsh aortic ejection systolic murmur that occasion­ally is maximal in the first right interspace. Ejection sounds are not heard. Aortic regurgitation may be present. Systolic blood pressure is usually higher in the right arm than in the left arm, by approximately 30 mm Hg. ECG ECG shows left ventricular hypertrophy; occasion­ally con­genital valvular stenosis is associated with partial or complete atrioventricular block.

In case of valvular aortic stenosis, corrective surgery may be performed only after the patient becomes symptomatic (develops angina, syncope or left ventricular failure) or when the patient develops left ventricular dysfunction, as evidenced by echo, whichever may be earlier. Surgery is in the form of valve replacement and this procedure is delayed as complications developing with a prosthetic valve (infec­­tive endocarditis) is more than with the native valve.

Coarctation of the Aorta (Figs 4.107 and 4.108) In adults, coarctation of the aorta (COA) typically consists of a discrete, diaphragm-like ridge that extends into the aortic lumen in the region of the ligamentum arteriosum. Post-ductal coarctation: Narrowing of the thoracic aorta immediately distal to the origin of the ductus and left subclavian artery. Pre-ductal coarctation: Diffuse coarctation of the ascend­ ing aorta and transverse aortic arch, often in association with a hypoplastic left ventricle, aortic valve or mitral valve. In this condition, upper half of the body is perfused via the systemic circulation, whereas flow to the lower half of the body comes from the pulmonary artery through a patent ductus arteriosus. This results in “differential cyanosis”, where the lower extremities are cyanotic. Pseudocoarctation: Anatomically, there is buckling or kinking of the aorta in the vicinity of ligamentum

Chest X-ray Chest X-ray shows left ventricular enlargement. Poststenotic dila­tation of the ascending aorta may be seen in valvular stenosis.

Treatment Treatment is surgical repair of the stenotic lesion obstructing the left ventricular outflow tract. In case of infravalvular stenosis, the defect must be corrected immediately after its detection, as it may lead to progressive obstruction, valvular deformity and development of AR if uncorrected. AR may also develop as a result of infective endocarditis. In supravalvular aortic stenosis (AS), surgery is recommended when aortic arch hypoplasia is less and when the obstruction is discrete and significant (gradient > 50 mm Hg).

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Fig. 4.107  Coarctation of the aorta Abbreviations: SVC, Superior vena cava; AO, Aorta; PA, Pulmonary artery; LA, Left atrium; PV, Pulmonary vein; RA, Right atrium; RV, Right ventricular; LV, Left ventricle

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C A B Figs 4.108A to C  Coarctation of the aorta. (A and B) Post-ductal; (C) Post-ductal [Anomalous origin of right subclavian]

arteriosum but there is no gradient or development of systemic hypertension or collaterals.

Associated Cardiac Abnormalities zz zz zz

Patent ductus arteriosus Bicuspid aortic valve Ventricular septal defect —— About 85% of patients with CoA have bicuspid aortic valve. —— About 15% of patients with bicuspid aortic valve have CoA.

Coarctation of Aorta Syndromes Turner syndrome, foetal hydantoin syndrome, and Crouzon syndrome.

Clinical Features • Systolic arterial pressure is higher in the arms than in the legs, but the diastolic pressures are usually similar. • In comparison to the radial or brachial pulses, the femoral pulses are weak and delayed. • Systolic thrill may be palpable in the suprasternal notch and left ventricular enlargement may be present. • A systolic ejection click often is audible (from a bicuspid aortic valve). • A characteristic rough ejection systolic murmur may be audible along the left sternal border and in the back. • A continuous murmur may be heard over the inter­ scapular or infrascapular areas, indicating blood flow through collateral channels. • Coarctation of the abdominal aorta may be asso­ ciated with renal artery stenosis. Electrocardiography Evidence of left ventricular hypertrophy is seen. Chest X-ray Left ventricular enlargement is seen.

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Fig. 4.109  Inverted ‘E’ sign

Notching of the ribs, due to increased collateral flow through the intercostal arteries, develops along the inferior and posterior aspect of 3rd to 8th ribs, bi­laterally. “Reversed E sign” (due to pre- and post-stenotic aortic dilatation and dilatation of the subclavian artery)(Fig. 4.109). Fundus—Cork-screw appearance of retinal arteries.

Complications • Bacterial endocarditis (at the site of the coarctation, bicuspid aortic valve or associated collateral chan­ nels) (Fig. 4.110). • Aortic dissection and rupture of the proximal ascend­ ing aorta may occur, sometimes during preg­nancy. • Leak or rupture of a berry aneurysm (these patients have increased incidence of berry aneu­rysms of the circle of Willis).

Treatment Medical treatment consists of control of hypertension. Surgical treatment consists of resection of the coarc­tation and reanasto­mosis or by aortoplasty. Elective surgery should be preferably performed at 4–5 years of age, since earlier surgical therapy is likely to result in restenosis of the aortic lumen and later repair may be associated with persistent hypertension.

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Pulmonary valve stenosis Truncus arteriosus.

Clinical Features

Fig. 4.110  MR angiography showing coarcted segment and collaterals Abbreviations: IMA, Inferior mesenteric artery

Anomalous Pulmonary Venous Connection The term anomalous pulmonary venous connection is used when any [in partial anomalous connection (PAPVC)] or all [in total anomalous connection (TAPVC)] of the pulmonary veins drain into a site other than the left atrium.

Total Anomalous Pulmonary Venous Connection In patients with TAPVC, the pulmonary veins may connect to a systemic vein within the thorax (supra­diaphragmatic) or portal vein in abdomen (subdia­phragmatic) (Fig. 4.111). Associated Cardiac Malformations zz zz zz

Common atrium Single ventricle PDA

• Almost all patients are cyanotic. • Some patients may have a continuous murmur along the left sternal border due to flow through the anomalous pulmonary venous channels. • Pulmonic component of S2 is accentuated with deve­lopment of PHT and the murmur becomes less marked or is even absent. • Patients with TAPVC, with large left to right shunt, with­out pulmonary hypertension or pulmonary venous obstruction, show clinical findings resem­ bling that of an uncomplicated ostium secundum ASD (except for the presence of cyanosis). Chest X-ray Snow man or figure of eight appearance (Figs 4.112 and 4.113).

Partial Anomalous Pulmonary Venous Connection This implies that one or more (but not all) of the pulmo­ nary veins are connected to the right atrium or its venous tributaries. zz The right lung is involved 10 times more frequently than the left. zz An ASD generally accompanies PAPVC in 80–90% of the cases and is usually of the sinus venosus type. zz It may be accompanied by hypoplasia of the right lung or dextroposition of the heart. zz The physical findings in patient with PAPVC are similar to those of an ASD. Treatment of TAPVC and PAPVC is total surgical correction.

Fig. 4.111  Types of total anamolous pulmonary venous connection (TAPVC) Abbreviations: SVC, Superior vena cava; PA, Pulmonary artery; RA, Right atrium; IVC, Inferior vena cava; RV, Right ventricle; LV, Left ventricle; LA, Left atrium

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Fig. 4.112  Total anomalous pulmonary venous drainage

Fig. 4.114  Ebstein’s anomaly Fig. 4.113  Snow man appearance

Abbreviations: RA, Right atrium; LA, Left atrium; LV, left ventricle; RV, Right ventricle; ASD, Atrial septal defect

Ebstein’s Anomaly

Associated Cardiac Abnormalities

Ebstein’s anomaly is a congenital malformation involv­ ing the tricuspid valve, the right atrium and the right ventricle. The inferior and septal leaflets of the tricuspid valve are commonly rudimentary and dys­plastic, dis­ plac­ed apically and often adherent to the right ventri­cle, whereas the anterior leaflet is usually large, redun­dant and normally placed. Functionally, the tricuspid valve is regurgitant. The displacement of the valve apparatus causes a portion of the right ventricle (in between the atrio­ ventricular ring and the origin of the valve) to be “atrialised”. The right atrium is dilated, since it consists of a normal right atrium plus the atrialised portion of the right ventricle (Fig. 4.112).

zz

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ASD or patent foramen ovale (seen in 50–75% of patients with resultant right-to-left shunt). zz PS zz Pulmonary atresia zz VSD zz Mitral valve prolapse. Left-sided Ebstein’s anomaly is common in corrected transposition of the great vessels (the anatomic right ventricle is left-sided and systemic as is the abnormal tricuspid valve).

Clinical Features Many patients are asymptomatic until the third or fourth decade. They typically develop cyanosis, usual­ly with exertion (intermittent cyanosis).

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Manual of Practical Medicine In the presence of central cyanosis, the absence of a right ventricular impulse strongly suggests Ebstein’s anomaly or pulmonary atresia. • The S1 is typically loud and widely split (malformed tricuspid valve closes relatively late). • The S2 is widely split (due to presence of RBBB and delayed pulmonic valve closure). • Multiple systolic clicks from the vibrations of the saillike tricuspid anterior leaflet are often heard. The rightsided S3 or S4 may be heard. • A murmur of tricuspid regurgitation is heard and is often accompanied by a scratchy diastolic murmur of tricuspid stenosis.

Diagnosis The diagnosis of Ebstein’s anomaly is most readily made by recording the intracardiac pressure and elec­tro­gram simulta­neously with an electrode catheter. When this catheter is pulled from the right ventricle to the right atrium, right ventricular electrical potentials continue to be recorded after the pressure contour has changed from right ventricular to right atrial in form. Chest X-ray A globular heart (enlarged right atrium) with the narrow pedicle is seen, mimicking pericardial effusion (Fig. 4.115). Electrocardiography Himalayan ‘P’ waves (giant, peaked ‘P’ waves), pro­longed PR interval, incomplete or complete RBBB, wide QRS complex or type B-WPW syndrome (short PR interval and wide QRS) may be seen.

Fig. 4.115  Globular heart

Treatment Surgical correction.

Complete Transposition of the Great Vessels (D-transposition) D-transposition of the great arteries is the most com­mon cause of cyanotic congenital heart disease in the neonate, after TOF. It is a potentially lethal condition. In complete transposition of the great vessels, the aorta arises from the morphologic right ventricle and lies anterior to the pulmonary artery, which originates from the morpho­logic left ventricle (Fig. 4.116).

Associated Cardiac Abnormalities Virtually all patients have an interatrial communi­ cation (a patent foramen ovale or an ASD) zz PDA (in two-thirds of patients) zz VSD (in one-third of patients). Infants with D-transposition of the great vessels are usually males, have increased birth weight and are more likely to have a diabetic mother. zz

Clinical Features • Normal S1 and single loud S2 because of anteriorly placed aorta which masks P2. • Associated murmurs of VSD, PDA or pulmonic steno­sis. Electrocardiography Shows evidence of right ventricular hypertrophy.

Fig. 4.116  Transposition of great vessels Abbreviations: SVC, Superior vena cava; AO, Aorta; PA, Pulmonary artery; LA, Left atrium; PV, Pulmonary vein; RA, Right atrium; RV, Right ventricle; LV, Left ventricle; IVC, Inferior vena cava

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Associated Cardiac Abnormalities zz zz zz zz zz

VSD Single ventricle Left sided Ebstein’s anomaly Pulmonic or subpulmonic stenosis Abnormal AV conduction system (seen in all patients).

Clinical Features • S1 may be reduced in intensity. • S2 is generally single and loud because of anteriorly placed aorta, which masks P2. ECG Fig. 4.117  Egg-shaped heart

Chest X-ray Shows “egg-on-a-stalk” appearance (egg-shaped heart with narrow vascular pedicle) (Fig. 4.117). The presence of pulmonary plethora in an infant with cyanosis strongly suggests a diagnosis of D-trans­position of the great vessels.

Treatment In the early neonatal period: • Prostaglandin E1 infusion to dilate the ductus arte­riosus • Emergency enlargement of the interatrial commu­ni­ cation by balloon atrial septostomy • Anti-failure measures: — Definitive treatment is surgical (“arterial switch” opera­tion) — “Arterial switch” operation—Jatene procedure. For older infants—“atrial switch” operation— mustard or senning procedure.

Congenitally Corrected Transposi­tion of the Great Vessels In the patient with congenitally corrected transposi­tion of the great vessels, there is both atrioventricular discordance (the atria are connected to the opposite ventricles) and ventriculo­arterial discordance (the ventri­cles are connected to the opposite great vessels). It is also known as L-transposition of the great vessels, because the defect is formed when the primi­ tive cardiac tube rotates to the left (levo- or l-ventri­ cular loop) during embryogenesis, instead of its normal rightward rotation.

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Disturbances of AV conduction, including PR interval prolongation, second degree AV block and even complete heart block may be seen. Corrected transposition should be suspected in any young person with AV block.

Treatment • • • •

Associated anomalies should be corrected Treatment of cardiac failure Prevention of infective endocarditis In the presence of symptomatic AV block, pace­maker insertion is indicated.

Truncus Arteriosus Truncus arteriosus is an uncommon congenital ano­maly in which a single common vessel forms the outflow tract for both ventricles and subsequently gives rise to the systemic, pulmonary and coronary arterial circulation. It results from failure of the aorticopulmonary septum to form during embryogenesis. It is always associated with a large supracristal VSD.

Three Types Type I Short pulmonary artery arises from the truncus and then branches into the right and left pulmonary arteries (most common). Type II Right and left pulmonary arteries may emerge directly from the posterior wall of the truncus. Type III Right and left pulmonary arteries may emerge directly from the lateral wall of the truncus. Truncus arteriosus may be associated with: Increased pulmonary blood flow and minimal cyanosis. zz Decreased pulmonary blood flow and marked cyanosis. zz

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Manual of Practical Medicine Near normal pulmonary blood flow and moderate cyanosis. Di-George syndrome is associated with truncus arteriosus.

zz

Clinical Features • S1 is normal followed by a systolic ejection click (from dilated solitary trunk). • S2 is loud and lacks splitting (the truncus valve is usually tricuspid and in 1/3rd, it is quadricuspid. Rarely, it is bicuspid). • Ejection systolic murmurs are commonly heard. ECG Shows left ventricular volume overload and right ven­tri­ cular pressure overload. Chest X-ray The combination of pulmonary plethora and presence of cyanosis is an important clue to the clinical recog­nition of truncus arteriosus. There is gross cardiomegaly (bi-ventricular en­large­­ ment) and small or absent main pulmonary arterial segment.

Treatment Surgical correction before 3–6 months of age.

Tricuspid Atresia (Fig. 4.118) In this condition, the tricuspid valve is absent, the floor of the right atrium is intact and the systemic venous blood

flows from the right atrium, through an inter­atrial septum, to the left atrium. There is nearly always, also, presence of a ventricular septal defect. This malformation features two atria, a normal or enlarged left ventricle and a diminutive right ventricle.

Types 1. Tricuspid atresia with normally related great arteries —— With pulmonary stenosis (common) —— Without pulmonary stenosis. 2. Tricuspid atresia with transposed great arteries —— With pulmonary stenosis —— Without pulmonary stenosis.

Clinical Features • Central cyanosis (since birth). • JVP shows prominent ‘a’-wave. • Prominent apical impulse and quiet left parasternal area. • First and second heart sounds may be single. • Systolic murmur often present. Electrocardiography Left axis deviation (since this axis is rare in other cyanotic conditions of childhood, it constitutes a valu­able clue to the diagnosis of tricuspid atresia). Chest X-ray Heart shows the ‘tilted’ appearance (concavity of the left upper cardiac border due to decreased prominence of the main pulmonary artery and prominent convex­ity of the lower left border due to left ventricular enlargement). Pulmonary oligaemia is seen.

Treatment Surgical correction.

Congenital Complete Heart Block Congenital complete heart block is characterised by severe bradycardia caused by atrioventricular block that appears at the time of birth or in early childhood. Anatomically the following defects may be seen: Lack of communication between the atrial conduc­tion system and AV node zz Complete absence of the AV node zz Degeneration and fibrosis of the AV node zz Interruption of the connection between the AV node and bundle of His zz Disruption of the His bundle. zz

Fig. 4.118  Tricuspid atresia Abbreviations: SVC, Superior vena cava; PV, Pulmonary vein; PA, Pulmonary artery; RA, Right atrium; LA, Left atrium; LV, Left ventricle; RV, Right ventricle

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Cardiovascular System Differentiation between Congenital and Acquired Complete Heart Block Congenital complete heart block

Acquired complete heart block

1. Appears at the time of birth or in early childhood

Seen in adults

2. Anatomic discontinuity may be at several levels of conduction system

Discontinuity is at the level of AV node

3. Secondary to infection in utero or a maternal connective tissue disease

Secondary to ischaemic heart disease or degeneration

4. May be associated with other cardiac abnormalities

Usually not associated with other cardiac abnormalities

5.  Relatively asymptomatic for years Become symptomatic early 6.  Heart rate 40–60 per minute

Heart rate less than 40 per minute

7. Heart rate can increase with exertion or stress (as junctional escape rhythm is under autonomic control)

Heart rate does not increase with exertion or stress (as junctional escape rhythm is not under autonomic control)

8.  Stokes-Adams attacks are rare

Stokes-Adams attacks are common

Aetiology Congenital complete heart block, on occasion, is asso­ ciated with: a. An infection in utero b. Maternal inflammatory disorder, such as connective tissue disease (discoid lupus, SLE or rheumatoid arthritis).

Associated Cardiac Abnormalities 1. Corrected transposition of the great vessels 2. ASD 3. VSD. Most of the patients are relatively asymptomatic for years, since the junctional escape rhythm is under autonomic control and therefore the heart rate can increase with exertion or stress.

Severe bradycardia, causing symptoms, necessitates the insertion of a permanent pacemaker.

Idiopathic Dilatation of the Pulmonary Artery Idiopathic dilatation of the pulmonary artery is a relatively uncommon congenital defect characterised by a congenital dilatation of the main pulmonary trunk. This may be associated with pulmonic regurgitation or progressive dilatation and aneurysm formation. It is usually asymptomatic and its clinical import­ance lies in its recognition and distinction from other conditions, such as ASD, PS and severe PHT.

Clinical Features • Precordium frequently shows a visible and palpable systolic impulse in the second left intercostal space, particularly when breath is held in expiration. • No evidence of right ventricular impulse. The presence of a right ventricular impulse is in­com­ patible with a diagnosis of idiopathic dilatation of the pulmonary artery, since this condition causes neither pressure nor volume overload of the right ventricle. • S1 is normal followed by a pulmonic ejection click. • A short systolic ejection murmur and a decrescendo diastolic murmur of pulmonic regurgitation may be present. • The pulmonic component of the S2 is frequently accentuated. • In some patients S2 may be widely split, suggesting a diagnosis of ASD (due to delayed elastic recoil of the dilated pulmonary trunk). ECG

Complications

Usually normal.

• • • •

Chest X-ray

Bradycardia Stokes-Adams attacks (syncope) Congestive cardiac failure Sudden death.

Factors Identifying High Risk Patients zz zz zz zz zz

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Treatment

Persistently low resting heart rate Associated cardiac abnormalities Prolonged QT interval Wide QRS complex Ventricular arrhythmias.

Shows dilatation of the main pulmonary artery.

Treatment No specific therapy is indicated.

Congenital Abnormalities of the Coronary Arteries These are seen in 1–1.5% of patients and may be of the following types:

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Coronary arteriovenous fistulae Origin of a coronary artery from the pulmonary artery Aberrant origin of one or both coronary arteries from the aorta.

ECG Shows ischaemic injury with poor R-wave progression over the anterior precordium. Definitive diagnosis is made with selective arteriography of the coronary artery.

Coronary Arteriovenous Fistula

Treatment

It is a communication between a coronary artery and a cardiac chamber. The fistula most commonly arises from the right coronary artery or its branches and usually drains into the right ventricle, right atrium or coronary sinus. It results in a left-to-right shunt that is usually small, so that coronary blood flow is rarely compro­mised. Patients are generally asymptomatic. A continuous murmur (mimicking a PDA) is heard at the lower or midsternal border or entire precord­ium.

By surgical correction.

Complications zz zz zz zz

Infective endocarditis Pulmonary hypertension (if shunt is large) Rupture or thrombosis of fistula Myocardial ischaemia.

Acute, recurrent, inflammatory disease, mainly of children (aged 5–15 years), typically occurring 1 to 5 weeks after group A streptococcal infection.

Pathophysiology zz

zz

Cross reactivity of host anti-streptococcal antibodies to cardiac antigens Microbe-initiated autoimmune reactivity.

Jones Criteria for Diagnosis of Rheumatic Fever Major Criteria

Diagnosis

Carditis

Diagnosis is by coronary arteriography.

Pancarditis, seen in 50–60% of patients, develops within the first 2 weeks of rheumatic fever. Peri­carditis is evidenced by presence of a pericardial rub, myocarditis by tachycardia, soft S1, presence of S3 and CCF and endocarditis by the presence of Carey-Coombs’ murmur (mitral diastolic murmur).

Treatment Surgical closure of fistula.

Anomalous Origin of a Coronary Artery from the Pulmonary Artery This may involve either the main right or left coronary arteries or their branches. Left main coronary artery is commonly involved. Coronary arteries involved in order of descending frequency are: • The left main coronary artery • The right coronary artery • The anterior descending coronary artery • The circumflex coronary artery. Symptoms may be of: Myocardial ischaemia zz CCF zz Mitral regurgitation (ischaemic injury to papillary muscle). zz

Sudden death may occur.

Clinical Features zz

zz

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Rheumatic Fever

A loud continuous murmur along the sternal border or at the base. A mitral regurgitation murmur and an S3 may be heard.

Arthritis (60–75%) Flitting and fleeting type of polyarthritis involving large joints with no residual deformity is seen in 60–75% of patients and occurs early in rheumatic fever. Jaccod’s arthritis: Ulnar deviation of 4th and 5th finger with flexion at metacarpophalangeal joints is the only residual deformity seen in rheumatic polyarthritis. Subcutaneous Nodules Non-tender nodules are seen over bony prominences like elbows, shin, occiput, spine in 3–5% of patients and occur 3–6 weeks after onset of rheumatic fever. Patients who have subcutaneous nodules almost always have carditis. Erythema Marginatum (< 5% and Evanescent) Macular lesions with an erythematous rim and central clearing in a bathing suit distribution are seen in 0.2 sec).

WHO Criteria Jones major and part of the minor criteria except prior history of rheumatic fever/rheumatic heart disease and C-reactive protein.

Essential Criteria Evidence for recent streptococcal infection as evidenced by: zz Increase in ASO titre —— > 333 Todd units (in children) —— > 250 Todd units (in adults). zz Positive throat culture for streptococcal infection. zz Recent history of scarlet fever. Two major (or) one major and two minor criteria, in the presence of essential criteria, is required to diag­nose acute rheumatic fever. A positive rheumatic fever history is usually elicited in only 50% of patient with rheumatic heart disease. Probable Rheumatic Fever zz

zz

zz

Polyarthritis/polyarthralgia/monoarthritis with 3 or more minor manifestations together with the evidence of recent group A streptococcal infection suggests probable rheumatic fever. Later, some of these cases turn out to be rheumatic fever. Regular follow-up and secondary prophylaxis is required.

Differential Diagnosis zz zz

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Post-streptococccal reactive arthritis (PSRA) Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).

Valve Involvement in Rheumatic Heart Disease Mitral valve alone 50% Aortic valve alone 15–20% Mitral and aortic valves together 35–40% Mitral, aortic and tricuspid valves 2–3% Pulmonary valve is virtually never involved. In RHD, mitral valve is most commonly involved followed by involvement of the aortic valve as the pressure gradient across the mitral valve is the great­est, followed by that across the aortic valve. So, the mitral valve is more susceptible to develop patho­logical changes than the aortic valve.

Treatment zz

zz

zz

Tab aspirin 75 to 100 mg/kg/day in 4 to 5 divided doses, till the activity of the disease subsides (ESR becomes normal). Steroids in dose of 1 to 2 mg/kg/day if symptoms of RF and/or carditis persist despite adequate aspirin therapy. Continuous prophylaxis against recurrent RF with inj. benzathine penicillin 1.2 million units IM every 3 to 4 weeks. In patients allergic to penicillin, tab. sulfadiazine 1 gm daily or tab. erythromycin 250 mg twice daily may be given. Prophylaxis must con­ tinue, up to the age of 25 years or 5 years after the last attack, whichever is longer.

Prevention of Rheumatic Fever Primary prevention: Benzathine penicillin—Once only < 27 kg 6,00,000 Units > 27 kg 12,00,000 Units Penicillin–V Children—250 mg tid for 10 days Adolescents/adults—500 mg tid for 10 days For penicillin allergic patients: Erythromycin 40 mg/kg/day-tid/qid for 10 days. Secondary prevention: Benzathine penicillin—12,00,000 Units IM—every 3/4 weeks Penicillin–V—250 mg bid daily Sulphadiazine—< 27 kg – 0.5 gm; > 27 kg – 1 gm once daily Duration of treatment: Rheumatic fever with no carditis—5 years or until the age of 18 years (whichever is longer). Rheumatic fever with carditis without valvular lesion—10 years or until the age of 25 years (whichever is longer). Rheumatic fever with carditis with valvular lesions—life long.

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VALVULAR HEART DISEASE Mitral Stenosis (MS) (Fig. 4.119)

Symptoms

Causes zz zz zz zz zz zz zz zz zz zz

4. Abnormalities associated with LVOTO zz Abnormal attachment of subvalvular apparatus to the septum.

Rheumatic heart disease Hunter’s syndrome Hurler’s syndrome Drugs—methysergide Carcinoid syndrome Amyloidosis Mitral annular calcification Rheumatoid arthritis Systemic lupus erythematosis Infective endocarditis with large vegetations.

Types of Congenital Mitral Stenosis 1. Supravalvular zz Fibrous ring zz Shone’s syndrome 2. Valvular zz Fusion of commissure and papillary muscle zz Double orifice zz Excessive valve tissue zz Annular hypoplasia [usually associated with hypoplastic left heart syndrome (HLHS)] 3. Subvalvular zz Single papillary muscle (parachute valve) zz Abnormally large or numerous papillary muscle (Hammock valve) zz Absent papillary muscle

Dyspnoea, palpitation, fatigue, haemoptysis, recurrent bronchitis.

Signs • • • • • • • • •

Mitral facies (malar flush) Malar flush: Cyanotic cheek with slight telangiectasia. (Other causes—PS, ASD, Carcinoid) Small volume pulse Left parasternal heave Tapping apical impulse (palpable S1) Palpable P2 Diastolic thrill over mitral area Loud S1, opening snap (indicate pliability of valve) A low pitched, rough, rumbling, mid-diastolic mur­mur with pre-systolic accentuation, best heard over the apex, with the bell of the stethoscope in the left lateral position, in expiration • MS murmur is accentuated by mild exercise • Murmur disappears in severe MS due to decreased cardiac output • With the development of pulmonary hypertension, an ESM may be heard over the pulmonary area and a PSM which increases on inspiration, may be heard along the left sternal border (functional TR).

Asymptomatic MS Physical signs of MS are often found before symptoms develop and their recognition is of particular impor­tance in pregnancy.

Severity According to valve area and symptoms. Normal Mitral Valve Area is 4–6 cm2 Valve area

Symptoms

> 2.5 cm2

None

1.5–2.5

cm2

(Mild MS)

1–1.5 cm2 (Moderate MS) 15 mm Hg Duration of the diastolic murmur is directly propor­tional to the severity.

Juvenile Mitral Stenosis (JMS) zz zz zz zz zz zz zz zz zz zz zz zz

Common in Afro-Asian countries Age of onset < 20 years Females are commonly affected It is of rheumatic origin Severe MS is common (Pin point mitral valve) Early onset of severe symptoms Highly prone for pulmonary hypertension Recurrent pulmonary oedema Less prone for atrial fibrillation and valve calcification More prone for restenosis Immediate surgery in symptomatic cases It has poor prognosis.

Complications Hemoptysis a. Pulmonary apoplexy due to rupture of thin-walled, dilated bronchopulmonary veins usually as a conse­­­ quence of a sudden rise in left atrial pressure. b. Blood stained sputum associated with episodes of PND due to pulmonary congestion. c. Pink, frothy sputum of pulmonary oedema. d. Blood stained sputum as a result of recurrent bronchi­tis and bronchiectasis e. Pulmonary infarction, a late complication of MS associated with heart failure f. Anticoagulants g. Lobar and bronchopneumonia h. Pulmonary haemosiderosis. Atrial fibrillation (AF) a. Two thirds of patients with MS have AF b. AF is more common in MS than in MR c. With AF, pulse becomes irregularly irregular d. There are no ‘a’-waves in JVP and intensity of S1 is variable. e. AF may precipitate CCF and thromboembolic epi­ sodes. Emboli may reach cerebral, peripheral, renal and coronary vessels. Thromboembolic episodes are more common in elderly and severe MS with low cardiac output.

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Pulmonary oedema This occurs when there is a sudden surge in flow across a markedly narrowed mitral valve, when the LA pres­ sure is more than 25 mm Hg (in the early phase of MS). Pulmonary oedema is less common in long-standing MS because of thickening of alveolar capillary membrane. Infective endocarditis This occurs less commonly in patients with isolated MS than in patients with associated MR. With isolated MS, it occurs more frequently in mild MS with pliable valves and less frequen­tly in severe MS with rigid, calcified and thickened valves. Chest pain Anginal pain may be due to coincidental coronary athero­ sclerosis or secondary to coronary embolisation. Angina like pain occurs in severe pulmonary hyper­tension due to hypoxia, hypotension and reduced car­diac output. Pressure symptoms a. Compression of left recurrent laryngeal nerve by enlarged left atrium, tracheobronchial lymph nodes and dilated pulmonary artery results in hoarseness of voice (Ortner’s syndrome). b. Pressure on left main bronchus may result in bronchiec­tasis. c. Rarely erosion of spine may occur causing para­plegia. Pulmonary haemosiderosis and ossification It may occur in long-standing pulmonary hyper­tension.

Conditions Simulating MS 1. Left atrial myxoma 2. Cortriatriatum 3. Ball valve thrombus of left atrium 4. Diastolic flow murmurs across normal mitral valve as in VSD, PDA, severe MR, etc. 5. Carey-Coombs murmur of mitral valvulitis. 6. TS (also masks the features of MS) 7. Austin-Flint’s murmur. Atrial Myxoma It may present with fever, anaemia, weight loss, clubbing, systemic emboli, increased IgG and IL-6. ECG • ‘P’ mitrale (left atrial enlargement) and RVH. • Features of atrial fibrillation (absent ‘P’-waves and varying RR intervals). Chest X-ray • Left atrial enlargement (double shadow behind the heart in right heart border—shadow within shadow).

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Manual of Practical Medicine • Splayed carina. • Straightening of the left heart border (Figs 4.120 and 4.121,) (due to prominent pulmonary artery and LA appendage). • Later, mitral valve calcification (Figs 4.122 and 4.123). • Kerley B lines (Dense, short, horizontal lines most com­ monly seen in the costophrenic angles when pulmonary venous pressure is between 20 and 30 mm Hg).

• Kerley A lines (Straight, dense lines up to 4 cm in length and running towards the hilum when pulmo­nary venous pressure is more than 30 mm Hg). • Rarely, findings of pulmonary haemosiderosis and parenchymal ossification. • Barium swallow in RAO view may demonstrate sickling of barium filled oesophagus due to comp­ression by enlarged LA.

Fig. 4.120: Double density sign (inner border left atrium and outer border right atrium with prosthetic mitral valve replacement)

Fig. 4.121  X-ray showing straightened left heart border

Fig. 4.122  Mitral stenosis—candle flame jet

Fig. 4.123  Right atrial myxoma with mild mitral and tricuspid regurgitation

Abbreviations: RV, Right ventricle; RA, Right atrium; LA, Left atrium; LV, Left ventricle

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Abbreviations: RA, Right atrium; LV, Left ventricle; LA, Left atrium

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Cardiovascular System Echocardiogram

Closed Mitral Valvotomy/Commissurotomy

Thickened immobile cusps; reduced rate of diastolic filling; reduced valve area.

Preferred in patients with pliable valve and when there is no associated MR. This is done with the aid of TUBBS transventricular dilator or transatrial finger fracture.

Abascal or Wilkins Echocardiography Score Score Leaflet mobility

Valve thickness

Subvalvular thickening

Valvular calcification

Open Mitral Valvotomy/Commissurotomy Open mitral valvotomy is done for patients with pure MS who have not been operated upon previously. In addition to opening the valve commissures, any subvalvular fusion of papillary muscles and chordae tendinae are loosened and calcium deposits are also removed. Thrombi, if present, are removed from LA and its appendage and the latter is often amputated to remove a potential source of postoperative emboli. Following this procedure, patient can survive for 5 to 15 years. This is preferred to valve replacement in young patients with MS.

1

Highly mobile with little restriction

Normal thickness (4–5 mm)

Minimal chordal thickening

A single area of calcification

2

Decreased mobility midportion and base

Midleaflet/ marginal thickening

Chordal thickening 1/3 of chordal length

Confined to leaflet margins

3

Forward movement of leaflet in diastole

Total leaflet thickening (5–8 mm)

Chordal thickening 2/3 of chordal length

Up to midleaflet

4

No / minimal Severe forward thickening movement (>8 mm)

Complete chordal Most of the thickening valve leaflets extending to papillary muscle

Note: If the score is 8 or less than 8 (8/16), surgery is advised.

Cardiac Catheterisation Pressure gradient between LA (or pulmonary wedge) and LV; useful in assessing co-existent MR and coro­nary disease. Coronary angiogram is indicated in all males > 45 years and females > 55 years or young persons with evidence of IHD before mitral valve surgery to rule out CAD.

Percutaneous Balloon Valvuloplasty It is useful in pregnant women with MS and also for older patients with severe valvular deformity and other extracardiac disease who are poor operative candidates (Fig. 4.124). This procedure is similar to that of closed mitral valvo­ tomy except that the hospital stay is minimised and there is no scar. Criteria for Valvuloplasty zz zz zz zz

Management

zz

Significant symptoms Isolated MS No (or trivial) MR Mobile, noncalcified valve/subvalve apparatus LA free of thrombus.

Medical 1. Antifailure measures 2. Anticoagulation in atrial fibrillation and treatment of AF Use digoxin, verapamil, or beta-blockers in AF to reduce the ventricular rate. 3. Rheumatic fever prophylaxis 4. Infective endocarditis prophylaxis. Surgical Four modalities of surgery are available: 1. Closed mitral valvotomy/commissurotomy (without car­diopulmonary bypass). 2. Open mitral valvotomy/commissurotomy (with the aid of cardiopulmonary bypass). 3. Percutaneous balloon valvuloplasty. 4. Mitral valve replacement.

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Fig. 4.124  Balloon mitral valvuloplasty

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Manual of Practical Medicine Complications of Valvuloplasty zz zz zz zz

Embolic events Cardiac perforation (0–4%) Development of MR Iatrogenic, residual ASD which later closes or decrea­ ses in size.

Valve Replacement When there is associated MR or when the valve is rigid and calcified, valve replacement is indicated. Valve replacement is done using: Mechanical Prosthesis zz zz

Caged ball valve (Starr-Edwards prosthesis) Tilting-disc valve (St Jude, Bjork-Shiley valves).

Bioprosthesis zz zz zz

Porcine bioprosthesis Pericardial xenograft prosthesis Homografts: Autograft with pulmonary valve in cases of aortic valve IE or allografts from cadaveric valves.

Among the mechanical prosthesis, tilting-disc valve is preferred to caged ball valve because: a. It occupies less space and hence useful in patients with a small left ventricle b. Incidence of haemolysis is less common c. Incidence of strut fractures is less common. Life long anticoagulation is indicated in patients receiv­ ing mechanical prosthesis. The advantage of bioprosthetic valve is the low inci­ dence of thromboembolic phenomenon. Biopros­thetic valves are not usually used in young patients 45 mm or LVEF < 60% denotes severe LV dys­function Surgery is indicated when there is progressive deterio­ ration in LV function despite antifailure measures.

Diastolic MR In acute aortic regurgitation, the pressure in the left ventricle may rise rapidly during diastole to high levels resulting in regurgitation of blood into the left atrium.

Severity The following indicate severity of MR: a. Presence of systolic thrill over apex b. Large LV indicates severe MR c. Presence of S3 d. Flow MDM across non-stenotic mitral valve indi­cates severe MR.

Complications zz zz

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AF may result in thromboembolism Infective endocarditis (more common than in MS).

Fig. 4.126  Mitral regurgitation (Echocardiogram) Abbreviations: LA, Left atrium; RA, Right atrium; RV, Right ventricle; LV, Left ventricle

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Manual of Practical Medicine • Plastic reparative procedure of mitral valve (in young patients). • Valve replacement in older patients.

Surgery for Acute MR • Failure of medical therapy to stabilise the patient in acute MR • Stable MR in infective endocarditis surgery is delayed till the completion of antibiotic therapy (If unstable immediate surgery under antibiotic coverage). —— Recent onset of AF —— Pulmonary hypertension > 50 mm Hg —— LV end systolic dimension > 40 mm —— LVEF < 60% Emergency surgery is indicated in case of papillary muscle rupture.

Mitral Valve Prolapse Syndrome (MVPS) (Fig. 4.127) MVPS is also known as systolic click—murmur syndrome, Barlow syndrome, floppy valve syndrome. Also known as billowing mitral leaflet syndrome. There is excessive or redundant mitral leaflet tissue, with myxomatous degeneration and increased concen­ trations of acid mucopolysaccharide. Posterior leaflet is commonly involved. Involve­ment of anterior leaflet alone is very rare.

Conditions Causing or Associated with MVP • • • • • • • • • • • • • •

Idiopathic/unknown (in majority) Genetically determined collagen tissue disorder Marfan’s syndrome Acute rheumatic fever Chronic rheumatic heart disease Following mitral valvulotomy Ischaemic heart disease Cardiomyopathies Ostium secundum ASD Trauma LV aneurysm Connective tissue disorders Ehler-Danlos syndrome Osteogenesis imperfecta. Difference between Acute MR and Chronic MR

Features Symptoms

Acute MR Chronic MR Sudden onset of dyspnoea, Gradual onset of symptoms PND, orthopnoea

Signs: Apex beat Unremarkable Displaced and dynamic First heart Soft Normal/Soft sound Murmur Early/Holosystolic Holosystolic Fourth heart sound is heard mainly in the MR of recent onset ECG Normal except in acute Left atrial enlargement myocardial ischaemia P-mitrale), atrial fibrillation, LVH Radiology Heart size—normal Cardiomegaly (LVH); left and atrial enlargement; on fluoroscopy fluoroscopy, calcium on valve leaflets ECHO Cause of acute MR may be Cause of chronic MR may be demonstrated defined (Flail leaflet, ruptured chordae or vegetations)

MVP is more common in females; MVP may present with only a systolic click and murmur with a mild prolapse of the posterior leaflet or with severe MR. MVP is the most common cause of isolated severe MR.

Symptoms zz zz

Palpitations (due to tachyarrhythmias) Chest pain.

Signs

Fig. 4.127  Mitral valve prolapse Abbreviations: SVC, Superior vena cava; AO, Aorta; PA, Pulmonary artery; LA, Left atrium; PV, Pulmonary vein; RV, Right ventricle; IVC, Inferior vena cava

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A mid or late systolic click (about 0.14 sec after S1) due to sudden tensing of slack, elongated chordae tendi­neae or by prolapsing mitral valve which reaches its maximum excursion. Clicks may be multiple due to scalloping of the redundant mitral valve.

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Cardiovascular System A high pitched late systolic crescendo-decrescendo murmur (whooping or honking) heard best at the apex. Click and murmur occur earlier with standing (decrea­ sed LV volume); squatting and isometric exer­cise (increased LV end diastolic volume) delay the click and murmur and may even make them disappear.

Complications zz

zz

Transient cerebral ischaemic attacks (due to emboli from mitral valve) Infective endocarditis when MVP is associated with MR.

ECG Bi-phasic or inverted ‘T’-waves in leads II, III and aVF and occasional supraventricular or ventricular extra­systole.

Surgical When MR becomes severe, either reconstruction or valve replacement may be done. Most common cause of combined mitral stenosis and mitral regurgitation is rheumatic heart disease.

Aortic Stenosis (AS) (Fig. 4.129) Common Causes Congenital aortic stenosis (supravalvular AS, valvular AS, subvalvular AS) zz Rheumatic aortic stenosis zz Degenerative (senile) calcific aortic stenosis zz Atherosclerotic aortic stenosis (common after 65 years). Patients with rheumatic aortic stenosis almost always have concomitant mitral valve involvement. zz

Echocardiogram

Symptoms

Useful in identifying the abnormal position and pro­ lapse of the mitral valve leaflets. Mitral valve prolapse is diagnosed when systolic displacement of mitral leaflets > 2 mm into the left atrium with coaptation superior to the plane of mitral annulus (Fig. 4.128).

Angina, dyspnoea, syncope, dizziness, sudden death (may be as a result of intolerance to complete heart block or atrial tachyarrhythmia). Pure aortic valve disease may remain asympto­matic for 10 to 15 years.

Management

Signs

Medical • Reassurance • Prevention of infective endocarditis, when there is MR • Beta blockers for chest pain and tachyarrhythmias • Antiarrhythmic agents for VPC’s and tachyarrhyth­mias • Aspirin for TIA • Anticoagulation therapy—Warfarin.

• • • •

Fig. 4.128  Mitral valve prolapse—flail posterior mitral leaflet pointing towards left atrium Abbreviations: LV, Left ventricle; LA, Left atrium; AO, Aorta; RV, Right ventricle

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Slow rising, small volume pulse Heaving apex beat S4 may be heard Ejection click (indicates valvular AS and excludes supra and subvalvular AS; disappears on calci­fication of aortic valve)

Fig. 4.129  Aortic stenosis Abbreviations: RA, Right atrium; PV, Pulmonary vein; SVC, Superior vena cava

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Fig. 4.130  Mechanical valves

• Carotid thrill (shudder) is felt • A rough, ejection systolic murmur loudest in the aortic area radiating to the carotids and the apex • AS murmur—low pitched, rough, rasping in character.

Complications zz zz zz

Severity 1. According to S2 Mild stenosis A2 followed by P2 Moderate stenosis A2 is delayed giving rise to single S2 Severe stenosis Reverse splitting of S2 (P2-A2). 2. According to valve area 2 2 —— Normal aortic valve area is 3 cm to 4 cm 2 2 —— In severe aortic stenosis, valve area is 45 years with severe AS.

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Cardiovascular System

Prognosis Patients developing angina have a life expectancy of about 4 years. Patients developing syncope have a life expectancy of about 3 years. Patients developing LVF have a life expec­ tancy of about 2 years.

Management Medical Treatment of cardiac failure Rheumatic fever prophylaxis Infective endocarditis prophylaxis. Use diuretics with caution to avoid volume depletion in the management of cardiac failure. Similarly digitalis and vasodilators—ACE inhibitors should be avoided in moderate or severe aortic stenosis. Nitroglycerine is useful for the relief of angina. Statins are useful in the manage­ment of degenerative calcific aortic stenosis. Surgical • Patients are prone for Stokes-Adams attacks and sudden death and so valve replacement is normally needed. • Valve replacement when systolic gradient across the valve is > 40 mm Hg and when there is progres­sive LV dys­function. • If patient is unfit for surgery, percutaneous, trans­ luminal aortic valvuloplasty can be tried. It is also useful in children and young adults with congenital AS, and also as a bridge to surgery in patients with severe LV dysfunction. • Simple commissural incision under direct vision is done in children and adolescents with non-calcific con­genital AS; it is indicated in symptomatic patients and also for asymptomatic patients with pressure gradient above 50 mm Hg, i.e. aortic valve orifice is < 0.75 cm2.

zz zz zz zz zz zz zz zz zz zz

Rheumatoid arthritis Ankylosing spondylitis Marfan’s syndrome Ehlers-Danlos syndrome Takayasu’s arteritis Aortic dissection Systemic hypertension Osteogenesis imperfecta Idiopathic dilatation of aorta Annuloaortic ectasia.

Fig. 4.131  Aortic regurgitation Abbreviations: SVC, Superior vena cava; AO, Aorta; PA, Pulmonary artery; LA, Left atrium; PV, Pulmonary vein; LV, Left ventricle; RV, Right ventricle; RA, Right atrium; IVC, Inferior vena cava

Aortic Regurgitation (AR) (Fig. 4.131) • Pure AR is more common in males. • Mitral valve disorder with AR is more common in females.

Causes Aortic Valve Involvement Rheumatic heart disease zz Infective endocarditis zz Congenital bicuspid aortic valve (Fig. 4.132) zz Congenital fenestration of AV zz AV prolapse associated with VSD zz Secondary AR in membranous sub-aortic stenosis. zz

Aortic Wall Involvement Syphilis

zz

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Fig. 4.132  Congenital bicuspid aortic valve

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Symptoms Dyspnoea, palpitation, angina (in severe AR).

• AR murmur in aortic area—Aortic root dilatation • AR murmur in 2nd aortic area—Valvular lesion • AR murmur is increased by hand grip.

Signs of Wide Pulse Pressure

Severity

zz

zz

zz zz

zz zz

zz zz zz

zz zz

zz



zz

zz zz

Light house sign (alternate flushing and blanch­ing of forehead). Landolfi’s sign (Change in pupillary size in accor­dance with cardiac cycle and not related to light). Retinal artery pulsations (Becker’s sign). de Musset’s sign (head bobbing with each heart beat). It is due to ballistic effect of severe AR. Muller’s sign—Systolic pulsations of uvula. Quincke’s sign (capillary pulsations) can be detect­ed by pressing a glass slide on patients lip or nail bed. Dancing carotids (Corrigan’s sign). Locomotor brachii. Collapsing or water-hammer pulse (↑ systolic pressure and ↓ diastolic pressure); usually pulse pressure is more than the diastolic pressure. Bisferiens pulse. Pistol shot femorals (Traube’s sign) arteries Pistol shot sound over the femoral vein is heard in severe TR. Duroziez’s sign—systolic murmur heard over fem­oral artery when it is compressed proximally and a diastolic murmur when it is compressed distally using the ‘bell’ of the stethoscope. Duroziez’s murmur—diastolic murmur heard with the diaphragm of the stethoscope when distal pres­­sure is applied. Hill’s sign—popliteal cuff systolic pressure exceeds brachial cuff pressure by > 20 mm Hg. Mild AR 20–40 mm Hg Moderate AR 40–60 mm Hg Severe AR >60 mm Hg. Rosenbach’s sign—pulsations of liver. Gerhardt’s sign—pulsations over enlarged spleen.

The presence of the following indicate severe AR: Duration of murmur (> 2/3 of diastole) is directly proportional to the severity. In moderate to severe AR, murmur becomes holodiastolic and may have a rough quality zz Bisferiens pulse zz Hill’s sign > 60 mm Hg. zz Apical impulse (down and out) zz Austin-Flint murmur zz Marked peripheral signs. They are absent in depressed myocardial function. zz

In the presence of heart failure, due to peripheral vasoconstriction, there may be a rise in arterial diastolic pressure. This may cause an erroneous judgement as to the severity of AR. Proper assessment can be done, only after correcting the failure. ECG LV enlargement (volume overload)—‘q’-waves in V5, V6. Chest X-ray • Gross cardiomegaly (Cor Bovinum) • In syphilitic AR, there may be calcification of ascend­ ing aorta • In bicuspid aortic valve or rheumatic AR, there may be calcification of the aortic valve. Echocardiogram Dilated LV, hyperdynamic ventricle, fluttering ante­rior mitral leaflet; Doppler detects reflux (Fig. 4.133).

Other Signs • Apical impulse is displaced downwards and out­wards and hyperdynamic in nature. • Soft S1 (only in acute AR) • S3 may be heard A high frequency decresendo early diastolic mur­ mur immediately after A2, best heard in left 3rd or 4th spaces with the diaphragm of the stethoscope with the patient leaning forwards, in expiration. • Flow ESM across aortic valve heard at heart base, conducted to carotids. • Flow MDM across mitral valve (Austin-Flint mur­mur). In MS, there is loud S1 and there is opening snap.

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Fig. 4.133  Colour Doppler flow imaging aortic regurgitation Abbreviations: AO, Aorta; LA, Left atrium; LV, Left ventricle

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Cardiovascular System Cardiac Catheterisation Dilated LV, aortic regurgitation Dilated aortic root.

Management Medical Antifailure measures zz Rheumatic fever prophylaxis zz Infective endocarditis prophylaxis. Vasodilators like ACE inhibitors are very useful in the management of AR. zz

zz zz

Austin-Flint Murmur Due to absence of LV enlargement, in acute AR, an early increase in LV pressure more than that of LA pressure causes a pre-mature closure of mitral valve resulting in absent pre-systolic murmur. Causes of Combined AS and AR zz zz

Acute AR 1. Diuretics 2. IV nitroprusside 3. Surgery β-blockers and intra-aortic balloon counterpulsation are contraindicated. Chronic AR Other vasodilators like hydralazine, dihydropyridine calcium channel blockers are useful. zz Penicillin prophylaxis is essential in syphilitic aortitis. zz β-blockers are useful in aortic root dilatation with or without AR. zz The goal is to reduce systolic BP to 140 mm of Hg. zz

Surgical Early left ventricular systolic dysfunction even in the absence of symptoms is an indication for surgery. zz Valve replacement zz Surgical repair in case of perforation of a leaflet by infective endocarditis or in case of a torn leaflet. zz Narrowing of annulus or excising a portion of the aortic root without replacing the valve. Echocardiography must be performed every year and aortic valve replacement is indicated in: 1. All symptomatic patients 2. Asymptomatic patients with a. Abnormal LVEF 50 mm (Left Ventricle End Systolic Diameter) c. Normal EF but LVEDD >65 mm (Left Ventricle End Diastolic Diameter) d. Undergoing other heart surgery. Causes of Acute AR zz zz zz

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Aortic dissection Trauma Infective endocarditis

Collagen vascular disorders Prosthetic valve dysfunction.

zz zz

Congenital-bicuspid aortic valve. Rheumatic heart disease (usually associated with mitral valve involvement) Systemic lupus erythematosus Subvalvular AS when complicated by infective endo­carditis.

Tricuspid Stenosis (TS) This is an uncommon valvular lesion usually asso­ciated with mitral valve disease. TS is more common in females.

Causes zz zz zz

Rheumatic heart disease Congenital TS Carcinoid syndrome.

When to Entertain the Diagnosis of TS • When pulmonary congestion disappears in patients with mitral stenosis • When MS findings are masked • When there is no improvement after MS surgery.

Symptoms Dyspnoea (relatively less for the degree of hepato­megaly, ascites and oedema), fatigue.

Signs • Giant ‘a’-waves in JVP • Prominent presystolic pulsations of the liver (repre­ sents an equivalent of ‘a’-wave) • No palpable P2 or right ventricular enlargement • Occasionally OS of tricuspid valve may be heard • A diastolic murmur over tricuspid area which increas­es during inspiration (Carvallo’s sign) and reduces during expiration or Valsalva manoeuvre • Signs of right heart failure—ascites, oedema, etc. ECG Absence of evidence of RVH in patients with right sided failure.

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Manual of Practical Medicine Differentiating Features between Acute and Chronic AR Features

Acute AR

Chronic AR

Onset

Early, sudden

Late, insidious

Pulse pressure

Near normal

Wide

Systolic pressure

Normal or decreased

Increased

Diastolic pressure

Normal or decreased

Markedly decreased

LV impulse

May be normal and not hyperdynamic

Hyperdynamic

Auscultation a. S1 b. P2 c. S3 d.  AR murmur e.  Aortic systolic murmur f.  Austin-Flint murmur

Soft or absent Normal or increased Common Short, medium pitched Grade 3 or less No pre-systolic murmur

Normal Normal Uncommon Long, high pitched Grade 3 or more Pre-systolic murmur may be heard

Peripheral arterial signs

Absent

Present

ECG

Normal LV

LV enlargement

Chest X-ray

Normal to moderately increased LV; pulmonary venous pattern redistributed to upper lobes

LV markedly increased; aortic root prominent; pulmonary venous pattern normal

Differentiating Features between Rheumatic AR and Syphilitic AR Features

Rheumatic AR

Syphilitic AR

History

Rheumatic fever

Syphilis

Angina

Less common

Common

A2

Normal or soft

Loud, tambour like

Diastolic murmur-site

Third left space (to the left of sternum)

Second right space (to the right of sternum)

Peripheral signs of AR

Not well-marked

Very well-marked

Other valvular lesions

Common

Never present

VDRL

Negative

Positive

X-ray

Calcification of the valve may be seen when there is associated AS; No irregularity of aortic shadow

Calcification confined to ascending aorta; Irregularity of aortic shadow may be seen

Difference between Austin-Flint Murmur and MS Features

MS

Austin-Flint murmur

Opening snap

Present

Absent

Loud S1

Present

Absent

S3

Absent

Present

LVH

Absent

Present

RVH

Present

Absent

Change in murmur with amylnitrite

Intensity of murmur does not decrease

Intensity of murmur decreases

AF

May be present

Usually absent

Chest X-ray In combined MS and TS, there is prominence of right atrium and SVC without much enlargement of pulmo­nary artery.

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Echocardiogram Fused, thickened tricuspid valve; Dilated RA, Doppler features of TS.

Treatment Antifailure measures. In mild TS, surgery is not ordinarily indicated. In moderate to severe TS, definitive surgical treatment is indicated (i.e. mean diastolic pressure gradients exceed­ ing 4 to 5 mm Hg and tricuspid orifice < 1.5 to 2 cm2). TS is mostly accompanied by TR and in such cases, valve replacement may be indicated. The incidence of thromboembolic episode is more common after mechanical valve replacement. In the presence of TS, TR is mostly organic. In the absence of TS, TR is mostly functional.

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Cardiovascular System

Tricuspid Regurgitation (TR)

Chest X-ray

Causes

Marked cardiomegaly (prominent RA and RV).

Primary

Echocardiogram

zz zz zz zz zz

Rheumatic Infective endocarditis (in IV Drug Addicts) Ebstein’s anomaly Carcinoid syndrome Trauma.

Secondary zz

zz zz zz

Right ventricular dilatation (functional TR as seen in MS or MR with PHT, Eisenmenger’s syndrome, PS and primary pulmonary hypertension). Right ventricular infarction. Dilated cardiomyopathy RV apical pacing.

Symptoms and Signs • • • • • • • • • • • • • • • •

Weakness, fatigue Throbbing pulsations in the neck (raised JVP) Cyanosis (right to left shunt through patent foramen ovale) Jaundice Massive oedema Irregularly irregular pulse (due to AF) Jugular venous distension (large, systolic ‘cv’ wave or ‘s’ wave) A venous systolic thrill and murmur in the neck may be present RV type of apical impulse which is hyperdynamic and thrusting S3 originating from RV P2 loud when TR is associated with PHT A high pitched PSM loudest in 4th intercostal space in the parasternal region augmented during inspi­ration (*Carvallo’s sign) Systolic hepatic pulsation Positive hepatojugular reflux Ascites Painful congestive hepatomegaly.

Severity Murmur is short in mild TR and long in severe TR. ECG Non-specific; incomplete RBBB; ‘Q’-waves in Vl and features of AF. *  Auscultatory augmentation of a tricuspid murmur during inspiration is called as Carvallo’s sign.

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RV dilatation; Tricuspid valve may be structurally abnormal.

Management Isolated TR without PHT (as a consequence of trauma or infective endocarditis) is usually well-tolerated. Effective correction of mitral valve disease and antifailure measures result in marked improvement. Rarely, tricuspid annuloplasty or valve replace­ment is done.

Pulmonary Stenosis (PS) Causes Congenital Isolated Associated with VSD (Fallot’s tetralogy) zz Carcinoid syndrome zz Rheumatic heart disease. zz

PS is usually of congenital origin; Rheumatic inflam­mation of the pulmonic valve is very uncommon and is usually associated with involvement of other valves and rarely leads to serious deformity. Congenital PS is dealt in detail under congenital heart disease.

Pulmonary Regurgitation (PR) Causes Pulmonary dilatation Idiopathic Marfan’s syndrome Pulmonary hypertension Primary Secondary a. Eisenmenger’s syndrome b. Mitral stenosis Infective endocarditis IV Drug addicts Trauma

Signs Graham-Steell murmur—a high pitched decrescendo diastolic blowing murmur along left sternal border resembling AR murmur. Trivial PR is a frequent echocardiographic finding in normal individuals (not of clinical significance).

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Clinical Manifestations

Difference between AR and PR Features

AR

PR

Symptoms

Signs of wide pulse pressure

Present

Absent

zz

Apex beat

Hyperdynamic

Normal

Relation of murmur to respiration

None

Increases on inspiration

zz

Ventricular enlargement

LVH

RVH

zz

zz

Fever (low grade in subacute infective endocarditis and high grade in acute infective endocarditis). Malaise Fatigue Anorexia.

Signs (Fig. 4.134)

Infective Endocarditis (IE) It is the colonisation of the heart valves with micro­biologic organisms, leading to the formation of friable, infected vegetations and frequently valve injury.

Types Acute infective endocarditis: Caused by highly viru­lent organisms mainly S. aureus (20–30%), seeding a pre­ viously normal valve. zz Subacute infective endocarditis: Caused by orga­ nisms of moderate or low virulence mainly Strepto­cocci (60– 70%), seeding an abnormal or previously injured valve. zz Endocarditis occurring in IV drug abusers: Caused predominantly by organisms found on the skin (S. aureus, Candida) and affecting the valves on the right side of the heart. zz Prosthetic valve endocarditis: This may be early (symptoms appearing within 60 days of valve inser­ tion), due to intraoperative infection of the valve or insertion of an infected valve or late (symptoms appear­ing after 60 days of valve insertion), due to late bacteraemia or earlier infection with micro-organisms having a long incubation period. Prosthetic aortic valve is more prone for infective endocarditis than the mitral valve. Right sided IE has a more favourable prognosis than the left sided IE. However, when right sided IE vegetation size exceeds 2 cm, the mortality increases. zz

Predisposing Factors to Development of Infective Endocarditis 1. Congenital cardiac anomalies (shunts or stenosis with jet streams) 2. Rheumatic heart disease 3. Mitral valve prolapse 4. Degenerative calcific stenosis 5. Bicuspid aortic valve 6. Prosthetic valves 7. Indwelling catheters.

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zz zz zz zz

zz

zz zz

zz

zz

zz

Clubbing (seen after 6 weeks in 10–20% of patients) Splenomegaly (seen after 6 weeks in 30% of patients) Pallor (anaemia) Heart murmurs (new, esp. regurgitant murmurs, or changing murmurs) Petechiae (seen after 6 weeks over conjunctiva, palate, buccal mucosa and skin above clavicle) Splinter subungual haemorrhages Osler nodes (small tender nodules, 1–10 mm dia­meter, on the finger or toe pads as a result of septic emboli and immune complex deposition) Janeway lesions (1–4 mm non-tender erythematous macules over palms and soles due to septic emboli) Roth’s spots (oval retinal haemorrhages with a pale centre) Arthralgia or arthritis.

Clinical Consequences of Infective Endocarditis (Figs 4.135 and 4.136) zz

zz

zz zz zz

Injury to valves or myocardium (abscess formation or perforation) Embolism (brain, spleen, kidneys and pulmonary embolism) Mycotic aneurysm Cerebral abscess Diffuse or focal glomerulonephritis or nephrotic syndrome.

Lab Diagnosis Laboratory Features zz zz zz zz zz zz zz zz

Anaemia Leukocytosis Microscopic haematuria Elevated ESR Elevated C-reactive protein level Circulating immune complexes Rheumatoid factor Decreased serum complement.

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Cardiovascular System

Fig. 4.134  Infective endocarditis

Blood Culture zz

zz

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At least 3 blood culture samples and maximum of six blood culture samples to be taken. Each sample to be collected from different veni­ puncture sites and after 30 minutes to 1 hour gap (to demonstrate continuous bacteraemia).

zz

zz

zz

At least 10 ml of blood to be obtained for culture and diluted 10 fold in culture medium (l00 ml of culture medium). Culture to be done for both aerobic and anaerobic organisms. Yield of positive culture increased by observing them over 3 weeks and making periodic subcul­tures.

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Manual of Practical Medicine 2D Echo zz

zz

The smallest size of vegetation that can be picked up by echo is 2 mm. Transoesophageal echocardiography is more sensi­ tive in detect­ing vegetations in the aortic valve (90%) and mitral valve (100%) than transthoracic echocardio­graphy.

Duke’s Criteria

Fig. 4.135  Mitral valve vegetation Abbreviation: VEG, Vegetations

Major criteria: 1. Positive blood culture (Typical organisms in two separate cultures or persistently positive blood cultures) 2. Involvement of endocardium (Echo based evidence-vegetations, abscess, peri­ valvular dehiscence or new valvular regurgitation). Minor criteria: 1. Predisposition (Cardiac lesion, IV drug abuse) 2. Fever > 38°C 3. Vascular or immunological signs 4. Positive blood culture—that does not meet major criteria 5. Positive echo—that does not meet major criteria Diagnosis: Diagnosis confirmed by 2 major/1 major + 3 minor/all 5 minor criteria.

Indications for Endocarditis Prophylaxis A

B Figs 4.136A and B  Transoesophageal echo—large mitral valvular abscess

Abbreviations: AML, Anterior mitral leaflet; LA, Left atrium; A, Aorta; PML, Posterior mitral leaflet

zz

Presumptive antibiotics to be started immediately after obtaining culture samples.

Negative Blood Culture in Infective Endocarditis zz

zz zz

zz

zz zz

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Infection with fastidious organisms (H. parainfluen­ zae, Brucella) Anaerobic infection Candida, Aspergillus, Histoplasma, Coxiella burnetii, Chlamydia psittaci endocarditis Inadequate quantity of blood sample for culture or inadequate amount of culture media Prior antibiotic therapy Right sided endocarditis.

1. Dental procedures: Dental procedures widely considered as a predisposing factor to endocarditis occur no more frequently than in matched controls. Good oral hygiene must be maintained. Prophylaxis is required only in manipulation of gingival tissue or periapical region of teeth or perforation of oral mucosa. 2. Respiratory tract procedures Rigid bronchoscopy (not for flexible) 3. GIT—Procedures i. Variceal sclerotherapy ii. Stricture dilatation iii. ERCP, Biliary tract surgery iv. Surgery involving mucosa 4. Genitourinary procedures i. Cystoscopy ii. Urethral dilatation iii. Prostate/Uretheral surgery 5. Cardiac conditions High risk: i. Prosthetic valves

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Cardiovascular System ii. Prior IE iii. Complex congenital cyanotic heart disease iv. PDA/COA v. Created systemic pulmonary shunts vi. Completely repaired congenital heart disease during first six months after repair vii. Incompletely repaired congenital heart defects adjacent to prosthetic material viii. Valvulopathy developing after cardiac trans­plantation. Moderate risk: VSD, Bicuspid aortic valve, Acquired—AS, AR, MR, MVPS (MR/Thickened valves), Congenital cardiac malformations. Prophylaxis not needed: i. Isolated secundum ASD ii. Surgically corrected ASD, VSD, PDA (more than 6 months after repair) iii. MVPS without complications iv. Prior CABG v. Implanted defibrillators/Pacemakers vi. Physiological/Functional murmurs vii. Acute rheumatic fever without valve dysfunction.

Emergency – same day zz

zz

Acute aortic regurgitation with preclosure of mitral valve Sinus of Valsalva abscess ruptured into right heart or into pericardium.

Urgent within 1–2 days zz zz zz zz zz

zz

Valve obstruction by vegetation Unstable prosthesis Acute MR/AR with cardiac failure Septal perforation Perivalvular extension of infection with or without conduction defects Lack/failure of antibiotic therapy.

Earlier Elective Surgery zz

zz zz

zz

Vegetation diameter > 10 mm with aortic/mitral valve dysfunction Progressive paravalvular prosthetic regurgitation Valve dysfunction with persisting infection even after 10 days therapy Fungal endocarditis.

Treatment

Non-infective Endocarditis

• Inj. Benzyl penicillin 20 to 40 lakh units IV 4 hourly for 4 weeks. • Parenteral aminoglycosides (SM, GM, Amikacin) given in appropriate divided doses for the first 2 weeks. • Appropriate antibiotic changes may be made on receiving the results of blood culture.

Non-bacterial thrombotic endocarditis (Marantic endo­­ carditis): Non-bacterial thrombotic vegetations seen in malignancy or wasting disorders which are prone for bacterial seedling.

Prophylaxis in IE zz

zz

zz

zz

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Indications for Surgical Management

Standard oral regimen —— Amoxicillin 2 gm PO 1 hour before procedure Unable to take oral drugs —— Ampicillin 2 gm IV/IM within 1 hour before procedure Penicillin allergy —— Azithromycin/Clarithromycin 500 mg PO 1 hour before procedure —— Cephalexin 2 gm/Clindamycin 600 mg PO 1 hour before procedure Penicillin allergy and inability to consume oral drugs —— Cefazolin/ceftriaxone 1 gm IV/IM 30 minutes before procedure —— Clindamycin 600 mg IV/IM 1 hour before procedure.

Endocarditis associated with SLE (Libman-Sacks endo­ carditis): The vegetations are 3–4 mm in size, composed of degenerating valve tissue; functional dis­ability is minimal; ventricular surface of the mitral valve is commonly involved; aortic valve involvement is rare; entire valve apparatus can be involved.

CARDIAC FAILURE Cardiac failure is the inability of the heart to maintain an adequate output to meet the metabolic demands of the body. Heart fails to maintain sufficient circulation to provide adequate tissue oxygenation in the presence of normal filling pressures. The terms “systolic” and “diastolic” heart failure are replaced by heart failure with reduced ejection fraction {HFrEF – formerly systolic failure) and heart failure with preserved ejection fraction (HFpEF – formerly diastolic failure).

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Aetiology

Pathophysiology

Reduced Ejection Fraction (40–50%) zz

zz

zz zz

Pathologic hypertrophy —— Primary hypertrophic cardiomyopathy —— Secondary to hypertension —— Ageing Restrictive cardiomyopathy —— Infiltrative disorders (Amyloidosis, sarcoidosis) —— Storage disorders Fibrosis Endomyocardial disorders

High-output states zz

zz

Metabolic disorders —— Thyrotoxicosis —— Nutritional (Beriberi) Excessive blood flow requirements —— Systemic arteriovenous shunting —— Chronic anaemia.

*Indicates conditions that can also have preserved ejection fraction

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Left Ventricular Remodeling zz

zz

zz

Alterations in myocyte biology —— Excitation—contraction coupling —— Myosin heavy chain (foetal) expression —— B-adrenergic desensitization —— Hypertrophy —— Myocytolysis —— Cytoskeletal proteins Myocardial changes —— Myocyte loss—necrosis, apoptosis, autophagy —— Matrix degradation and myocardial fibrosis Geometry alterations of LV chamber —— LV dilation with increased LV sphericity —— LV wall thinning and mitral valve incompetence.

Preload Preload is the left ventricular end-diastolic pressure and it depends on left ventricular compliance and venous return.

Afterload Afterload is the left ventricular systolic wall tension that develops during ventricular systole and is determin­ed by aortic valve resistance, the peripheral vascular resistance and the elasticity of major blood vessels.

Classification of Cardiac Failure High Output and Low Output Failure a. High output failure: The normal heart fails to main­ tain a normal or increased output, in the face of grossly elevated requirements, as in anaemia, hyper­ thyroidism, Paget’s disease, A-V malform­ a tion, pregnancy. Features of RVF predominate at first, but later LVF becomes evident. It is difficult to determine if the patient with high output state has developed

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Cardiovascular System b.

cardiac failure. The only clue to the develop­ment of CCF in these patients may be the presence of shortened circulatory time. Low output failure: The heart fails to generate adequate out­put, or can only do so with high filling pressures, as in i. Intrinsic heart muscle disease (Cardiomyo­pathy, IHD, Myocarditis, Chagas’ disease). ii. Chronic excessive afterload (Aortic stenosis, Hyper­tension). iii. Chronic excessive preload (Mitral regurgi­tation). iv. Negative inotropic drugs (Anti-arrhythmic agents). v. Restricted filling (Constrictive pericarditis or tamponade, restrictive cardiomyopathy). vi. Extreme bradycardia (beta-blockers, complete heart block).

Right and Left Sided Heart Failure a. Right sided heart failure: This causes peripheral oedema, abdominal discomfort (congestive hepato­ megaly) raised JVP and hypotension. There is no evidence of pulmonary oedema. b. Left sided heart failure: Most prominent sign is the presence of pulmonary oedema. Other signs are tachy­pnoea, tachycardia, third heart sound, pulsus alternans, cardio­megaly. c. Congestive cardiac failure: Patient has features of both right and left sided heart failure.

b. Backward heart failure: This results from the failure of one or the other ventricle to fill normally and discharge its contents, causing an elevated atrial and venous system pressure behind the fail­ing ventricle.

Systolic and Diastolic Failure (Fig. 4.137) a. Systolic failure occurs when there is inadequate cardiac output (IHD) and is usually associated with cardio­megaly. This is managed by using predomi­ nantly inotropic agents, e.g. Digoxin, Dopa­­­mine and Dobutamine. b. Diastolic failure occurs when there is increased resis­ tance to ventricular inflow and reduced ventri­cular diastolic capacity (constrictive pericarditis, restrictive cardiomyo­pathy, IHD) and is usually associated with cardiomegaly. This is mana­ged by predominantly using vasodilator therapy, e.g. (ACE inhibitor and Calcium channel blocker).

Major Criteria zz zz zz zz zz zz

Paroxysmal nocturnal dyspnoea Neck vein distension Crackles—lung fields Cardiomegaly Acute pulmonary oedema Third heart sound—gallop

Investigations Chest X-ray Prominent upper lobe veins (PCWP = 15 mm Hg). zz Kerley B lines (engorged peripheral lymphatics seen in the lower lobe (PCWP = 20 mm Hg). zz Fluid in the fissures or interlobar effusion, known as ‘phantom tumour’ as it disappears with the treatment of left sided failure. zz Increase in broncho-vascular markings (‘bat’s wing’ or ‘inverted moustache’ signs)—features of pulmonary oedema (PCWP: 25 mm Hg). zz Pleural effusion may be bilateral and symmetri­ cal, but if unilate­ral, is usually right sided. zz Cardiomegaly. zz

Forward and Backward Heart Failure a. Forward heart failure: This results from an in­adequate discharge of blood into the arterial system leading to poor tissue perfusion; Poor renal per­fusion results in excessive proximal tubular Na+ reabsorption through activation of the renin-angiotensin-aldosterone system.

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Fig. 4.137  Types of heart failure

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284

Manual of Practical Medicine Characteristics of Systolic and Diastolic Heart Failure Characteristics

Diastolic heart failure

Systolic heart failure

Age

Elderly

Any age group

Sex

More often female

More often male

LV ejection fraction

Often preserved - > 40%

Decreased - < 40%

Cavity size of LV

Normal or concentric LVH Usually dilated

Chest X-ray

Congestion with or without cardiomegaly

Cardiomegaly with congestion

Gallop rhythm

Fourth heart sound

Third heart sound

Associated disorders •  Obesity •  Hypertension •  Diabetes mellitus •  Previous MI •  COPD •  Long-term dialysis •  Sleep apnoea •  Atrial fibrillation

+++ +++ +++ + ++ ++ ++ +

+ ++ ++ +++ 0 0 ++ +

zz zz

Increased venous pressure (>16 cm H2O) Positive hepato-jugular reflex.

Minor Criteria zz zz zz zz zz zz zz

Extremity oedema Nocturnal cough Dyspnoea on exertion Hepatomegaly Pleural effusion Tachycardia (>120 bpm) Decreased vital capacity by 1/3.

Major/Minor Criteria Five days treatment causing weight loss ≥ 4.5 kg. For diagnosis: 1 Major + 2 Minor.

Causes of Refractory Cardiac Failure 1. Silent myocardial infarction 2. Pulmonary emboli 3. Thyrotoxicosis 4. Left ventricular aneurysm. B-Type Natriuretic Peptide (BNP) This hormone is synthesised by the right and left ventricular myocytes and released in response to stretch, volume overload and elevated filling pressures. The serum level of this hormone is very specific and sensitive to identify or to exclude heart failure. BNP is extremely useful in diagnosis, prognosis and monitor­ing therapy. Serum levels of BNP are elevated in heart failure and as well as

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in asymptomatic LV dysfunction. BNP level 60 mm Hg If oxygenation is inadequate—mechanical ventilation Strict bed rest, pain control and anxiety relief Treatment of precipitating disorders—HTN, MI. IHD, volume overload, arrhythmias Morphine sulphate 5 mg IV (anxiety relief, dilata­tion of pulmonary and systemic veins) Repeat every 15 minutes if needed Frusemide 40-80 mg IV and can be repeated to a maximum dose of 200 mg Nitroglycerin—a powerful venodilator as IV infusion

zz

Physical Rest

Mental Rest Diazepam 2 to 5 mg twice or thrice daily is given for several days. Oxygen It improves oxygen delivery and relieves dyspnoea. Diet Small frequent feeds instead of large meals and opti­mal calories depending on the nutritional status of the patient. zz Sodium restriction: In severe cases, sodium is restric­t­ed to 500 mg/day and subsequently it can be increased to 2 to 3 gm/day with the usage of potent diuretics. zz Water restriction: 1 to 1.5 litres/day is permitted. Strict fluid restriction is critical when serum sod­ium is less than 130 mEq/L to prevent arrhythmias and neurologic abnor­ma­lities. Water intake may be ad libitum in all but the most severe forms of CCF. Dialysis and Ultrafiltration This procedure is indicated in severe HF with renal dysfunction. Therapeutic paracentesis, phlebotomy, rotating tourniquet are other mechanical methods of fluid removal which are useful in the management of refractory failure.

B. Pharmacologic Therapy 1. Diuretics a. High potency loop diuretics (Furosemide, Bume­ tanide, Ethacrynic acid): These drugs are most useful in severe heart failure and also in the presence of impaired renal function. Furosemide causes direct venodilatation and reduces preload. It also prevents reabsorption of Na+

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Manual of Practical Medicine American Heart Association Guidelines—Treatment of Chronic Heart Failure Stage

Nature of cardiac lesion

Treatment

A

No structural heart disease and no symptoms Risk factors for HF – DM, HTN, CAD, Dislipidaemia Familial cardiomyopathy, cardiotoxins

Life style modification, cessation of smoking, diet, exercise and treat the risk factors, treat HTN with ACE inhibitors

B

Structural heart disease with abnormal LV systolic function– MI, valvular disease but no heart failure symptoms

Life style modification, ACE inhibitors and β-blockers

C

Structural heart disease and heart failure symptoms

Add diuretics and digoxin along with therapy as under stage A and B

D

Refractory heart failure symptoms to maximal medical management

Therapy as listed under stage A, B, C, mechanical assist devices, IV inotropic infusion, heart transplantation

and Cl– from thick ascending limb of loop of Henle and also from proximal tubule. In severe failure, IV route is preferable since the GIT mucosal congestion may interfere with absorption of orally administered drug. Dose Furosemide—40 to 200 mg/day zz Bumetanide—0.5 to 2 mg—maximum 10 mg/day zz Ethacrynic acid—25 to 100 mg/day zz Torsemide—5 mg IV/10 mg od or bid. zz

Adverse effects: Hypokalaemia, hypomagnesaemia, hypo­­­ calcaemia, hyperglycaemia, hyperuricaemia, oto­toxici­ty, rash, vasculitis and postural hypotension. Allergic reactions are less with ethacrynic acid than with other loop diuretics and thiazides due to absence of sulfhydryl moiety. b. Medium potency thiazide diuretics: They are useful in mild cardiac failure and in the presence of normal renal function. They act in the distal tubule except metolazone which acts in the proximal and distal tubule. Indapamide is a long acting drug and it has fewer side effects on serum lipids. Dose zz Chlorothiazides—250 to 500 mg/day zz Hydrochlorothiazide—25 to 100 mg/day zz Chlorthalidone—25 to 100 mg/day zz Metolazone—2.5 to 20 mg/day zz Indapamide—5 to 10 mg/day. zz Bendroflumethiazide—5 mg PO daily zz Benzthiazide—25 mg PO bid zz Hydroflumethiazide—50 mg PO daily zz Methyclothiazide—2.5 mg PO daily zz Metolazone—2.5 mg PO daily zz Polythiazide—2.0 mg PO daily zz Quinethazone—50 mg PO daily zz Trichlormethiazide—2.0 mg PO daily Adverse effects: Hypokalaemia, hyponatraemia, hypo­mag­ nesaemia, hyperglycaemia, hypercalcaemia, hyper­uri­ caemia, hyperlipidaemia, alkalosis, pancreatitis, vasculitis, rash.

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c. Low potency potassium sparing diuretics: They are weak diuretics and they act in the distal tubule and collecting duct. They are contraindicated in the presen­ce of renal failure. Concomitant use of ACE inhibitors, NSAIDs, and presence of DM increase the risk of hyperkalaemia. Dose Spironolactone—50 to 200 mg/day zz Triamterene—100 to 200 mg/day zz Amiloride—5 to 10 mg/day. zz

Adverse effects: Hyperkalaemia, acidosis, and in addition, for spironolactone, gynaecomastia and for triamterene, renal stone and ARF when used with indomethacin. Eplerenone: It is a selective aldosterone receptor antagonist without the hormonal side effects of spironolactone. It reduces the mortality in heart failure. Aldosterone blockade with eplerenone 25 mg daily with reasonable renal function (serum creatinine < 2 mg and serum potassium < 5 mEq/L) improves heart failure. 2. Vasodilator Therapy Vasodilators are used to minimise the workload to the heart. Arterial dilators reduce the afterload and the venodilators reduce the preload to the heart. In the presence of volume depletion with hypotension, vaso­dilators should be used with caution. Vasodilators are not beneficial in HF with outflow tract obstruction and predominant diastolic dysfunction (Restrictive or hypertrophic cardiomyopathy or tamponade). a. Oral Vasodilators i. ACE inhibitors: They inhibit the formation of angiotensin II (powerful vasoconstrictor) by blocking angiotensin converting enzyme and this blockade results in reduction of preload and afterload. Dose Captopril—6.5 to 25 mg tid zz Enalapril—2.5 to 20 mg bid zz Lisinopril—2.5 to 10 mg od zz

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Cardiovascular System zz zz zz zz zz zz zz zz zz

Quinapril—10 to 40 mg od Ramipril—1.25 to 5 mg bid Fosinopril—5 to 10 mg od can be used bid Benazepril—5 to 10 mg od can be used bid Moexipril—5 to 7.5 mg od can be used bid Trandolapril—1 to 2 mg od Spirapril—12.5 to 50 mg bid Cilazapril—2.5 to 5 mg bid Perindopril—1 to 16 mg bid

Adverse effects: First dose hypotension, (withhold the diuretics for 24 hours before starting ACE inhibitors), dry cough, altered taste, skin rash, hyperkalaemia. They should not be given when the serum creatinine is more than 3 mg% and in bilateral renal artery stenosis. Agranulocytosis and angioedema are common with captopril because of the presence of sulfhydryl moiety. ACE inhibitor is very useful in post-infarction fail­ure with reduced ejection fraction below 40%. The reduction in workload allows the ventricle to remodel and reduce the incidence of development of severe cardiac failure. In ACE inhibitors intolerant patients angiotensin receptor blockers can be used with equal efficacy. ii. Nitrates: They are predominantly venodilators and are useful in CHD with HF. It relieves venous and pulmonary congestion. Dose Isosorbide dinitrate—5 to 20 mg qid zz Isosorbide mononitrate—10 to 20 mg tid zz Nitroglycerin sustained release—2.5 to 9 mg bid zz Transdermal nitroglycerin patches—5 to 15 mg bid. Headache is the main adverse effect and that might subside with sustained therapy; nitrate tolerance can be prevented by nitrate free interval of at least 10 to 12 hours/ day. zz

Molsidomine: A nitrate to which tolerance does not develop. iii. Hydralazine: It is an arterial dilator and it reduces the afterload. It is useful in the presence of valvular regurgitant lesions with volume overload. By com­bining it with nitrate a balanced preload and afterload reduction can be achieved. Dose: Hydralazine—25 to 100 mg tid. Adverse effects: Reflex tachycardia (use with caution in IHD), headache, flushing, nausea, vomiting, fluid retention and SLE like syndrome. iv. Adrenergic blockers a. Alpha-blockers: They are powerful vasodilators and they reduce the systemic vascular resistance and thereby reduce the afterload. However, the adverse effects like orthostatic

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hypotension and reflex tachy­cardia limit their role in the management of heart failure. b. Beta-blockers: The adverse effects of endogenous catecholamines on the failing heart can be antago­nised by beta-blockers. Beta-blockers with ISA activity like pindolol, xamoterol have been tried. A minimum of two months therapy is required to demonstrate improve­ ment in ejection fraction and exercise tolerance. Caution must be exercised in advocating beta-blockers in HF with low ejection fraction. They are useful in hypertro­phic cardiomyopathy, dynamic outflow tract obstruction and those with diastolic dysfunction. The drugs approved for use in cardiac failure are carvedilol, metoprolol and bisoprolol. v. Calcium channel blockers: Even though they dilate the vascular smooth muscle, their negative inotropic effect limit the usage in HF. Amlodipine and felodipine are preferable than verapamil and diltiazem in the management of heart failure especially in the presence of diastolic dysfunction. They enhance the diastolic relaxation of the ventricle (lusitropic effect). They are absolutely contraindicated in cardiac failure with low ejection fraction (below 40%). b. Parenteral Vasodilators They are useful in severe HF. Central haemodynamic monitoring and optimal titration of dosage are essential. Nitroglycerin: It is a potent venodilator and it relieves systemic and pulmonary venous congestion. This drug is useful in myocardial infarction with HF and also in unstable angina. The dose is 10 to 200 µg/minute. The adverse effects are hypotension and nitrate tolerance. Sodium nitroprusside: It is a potent arterial dilator and it is very useful in severe hypertensive heart failure and in valvular regurgitant lesions with volume overload. Dose: 10 to 300 µg/minute In IHD, it can cause coronary steal. Serum thio­cyanate level should be monitored. Levels above 10  mg/dl is manifested as abdominal pain, nausea, seizure, change in the conscious level and metabolic acidosis especially in the presence of renal failure. Enalaprilat: It can be used in the dose of 1.25 to 5 mg IV six hourly. The indications and adverse effects are similar to oral form of enalapril. Recombinant BNP-Nesiritide: It can be used as a parenteral vasodilator in a dose of 2 µg/kg IV bolus followed by continuous IV infusion of 0.01–0.03 µg/kg/minute. Hypo­ tension is the most common side effect of nesiri­tide. Avoid using it in cardiogenic shock and in patients with systolic blood pressure < 90 mm of Hg. Episodes of hypotension can be treated with volume expansion vasopressor drugs.

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Manual of Practical Medicine Ecadotril: It is an inhibitor of Neutral endopeptidase (NEP) which causes breakdown of BNP.

symptoms like scotomas, flickering halos, altered colour vision.

3. Digitalis

Cardiac toxicities: Bradycardia, multiple VPCs, ventri­ cular bigeminy (hallmark of digitoxicity), PAT, VT, VF and any type of cardiac arrhythmias except sinus tachycardia, bundle branch block and Mobitz type II block.

Digoxin is the most effective drug in the management of heart failure especially in the presence of: a. Supraventricular tachycardia b. Dilated left ventricle (increased TCD, 3rd heart sound) c. Impaired systolic function (low ejection fraction). It causes reversible inhibition of sarcolemmal sodiumpotassium adenosine triphosphatase. This enhances the myocardial contractility (positive inotropic effect). It slows conduction and prolongs refractory period in AV node, and Purkinje fibres (negative chronotropic effect) and thus reduces the ventricular rate. However, it shortens the refractory period and enhances the excitability in the atria, ventricles and accessory conduction pathways (atrial and ventricular tachyarrhythmias as in toxic doses). Conduction velocity and effective refractory period are increased in atrium and ventricle. It improves cardiac output and augments ejection fraction. It has little value in hypertrophic cardiomyopathy, myo­carditis, constric­ tive pericarditis, mitral stenosis in sinus rhythm without right ventricular involvement and chronic cor pulmo­ nale. It has no effect in HF with diastolic dysfunction with preserved systolic function and good ejection fraction. The toxic therapeutic ratio is narrow. Hypokalaemia, hypoxaemia, hypomag­n esaemia and hyper­calcaemia potentiates digitoxicity. Digoxin should be admini­stered with caution in elder­ly patients with hypo­thyroidism and in renal failure. Dose Digitalising dose: Adult—1 to 1.5 mg. Initiate with 0.5 mg and follow it with 0.25 mg qid. This schedule is implemented in patients who have not received digitalis therapy earlier. Maintenance dose: Digoxin—0.25 mg od or bid. Maintain serum level of digoxin between 1 to 2 ng/ml. Drug interactions: Antacids, cholestyramine, kaolinpectin, bran, neomycin, sulfasalazine and PAS can impair the absorption of digoxin. Digoxin levels are increased by oral erythromycin and tetracycline, quinidine, verapamil, flecainide and amiodarone. Adverse effects GIT symptoms: Anorexia, nausea, vomiting, diarrhoea are signs of digitoxicity (if the above symptoms occur only after the initiation of digitalis therapy and not present earlier due to GIT mucosal congestion). Neurological symptoms: Headache, fatigue, malaise, disorien­tation, delirium, confusion, convulsions, visual

Ch-4c.indd 288

Other manifestations: Gynaecomastia, skin rash and sexual dysfunction. Management of digitoxicity: Stop digoxin and correct the electrolyte abnormalities, titrate the dose of diuret­ ics. Correct the bradycardia with IV atropine 0.6 mg or temporary pacing. Treat the atrial or ventricular ar­rhyth­ mias with phenytoin, beta-blockers or lidocaine (never treat with quinidine or verapamil). Cardio­version is usually contraindicated in digitalis induced arrhythmias. However, as a last resort it can be tried in low joules after discontinuing the digitalis, under cover of lidocaine infusion. Digoxin specific Fab antibody fragment: Fab antibody fragments are considered when other modes of therapy fail. Each 40 mg vial (add 4 ml sterile water) is given in the form of infusion in 100 ml of normal saline in 30 minutes (80 drops/mt). It will neutralise 0.6 mg of digoxin. Dose can be calculated as follows: Number of vials =  Serum level (ng/ml) × Weight in kg/100. 4. Sympathomimetic Amines Norepinephrine, epinephrine, isoprenaline, dopamine and dobutamine. These drugs improve cardiac output and improve tissue perfusion at the expense of increased oxygen demand. Dopamine: It increases renal blood flow, GFR and sodium excretion by stimulating specific dopaminergic receptors at doses of 1 to 3 µg/kg/minute. By stimulat­ing beta1 adrenorecep­tors at doses of 3 to 5 µg/kg/minute, it increases the myocardial contractility (ino­tropic effect) and heart rate. At a higher doses of 5 to 10 µg/kg/minute it causes vasoconstriction by stimu­lat­ing alpha-adreno­receptors resulting in elevation of blood pressure. Dopamine should be used primarily to stabilise the hypotensive patient. When large doses of dopamine are required for inotropic effect, nitroprus­side or nitrogly­c erin can be infused simultaneously to counteract the vasoconstrictor action. It is widely used in the manage­ment of acute heart failure. Dobutamine: It is a synthetic catecholamine with marked beta1 and weak beta2 and alpha receptor activity. In contrast to dopamine, dobutamine is not a renal vasodilator. A low dose infusion of dopamine may be added to dobutamine to obtain a balanced renal vasodilator and inotropic effect. The dose is 2.5 to 10 µg/kg/minute.

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Cardiovascular System Mode of Action of Inotropic-Vasopressor Agents Dopamine

Adverse effects: Headache, hypotension, arrhythmias and hypokalemia. Agents that Decrease the Mortality in CHF

Mode of action

Dobutamine

Low dose

High dose

Norepinephrine

β-receptor agonism

+

+

+++

++++

β 1-receptor agonism

++++

+

++

+

β 2-receptor agonism

++

0

0

0

Dopaminergic

0

+++

++

0

zz

Systemic vascularresistance

↓↓

↓

↑↑

↑↑↑↑

Mechanical Circulatory Support

Cardiac output

↓↓↓↓

↑

↑↑

↑

Increases systemic BP

↑

0

↑↑↑

↑↑↑↑

Ventricular filling pressure

↓↓

0

0 -↑↑

0 -↑↑

Chronotropic

0 -↑↑

0

0 -↑↑↑

0 -↑

Myocardial O

↓

0

0 - ↑↑

0-↑

2 Adverse demand effects: Precipitation of myocardial ischaemia, ventricular arrhythmias; dopamine can cause severe peripheral vasoconstriction resulting in digital gan­grene and local tissue necrosis at the site of extrava­sation. Inject at the site of extravasation, 5 mg of phentolamine mixed with saline to prevent tissue necrosis.

5. Phosphodiesterase Inhibitors (Amrinone, Milrinone, Enoximone, Pimobendan) They exert positive inotropic and vasodilator effect through the inhibition of phosphodiesterase III which is a membrane bound enzyme responsible for the breakdown of cyclic AMP. They are indicated for short-term treatment of refractory heart failure. They reduce the pulmonary and systemic vascular resis­tance and have a favourable effect on myocardial oxygen consumption. Long-term administration increases the mortality in chronic failure.

zz zz zz zz zz

ACE inhibitors Angiotensin receptor blockers b-blockers Aldosterone antagonists Isosorbide dinitrate Hydralazine

This may be considered when medical measures fail either in transient myocardial dysfunction or when alternative proce­dures like CABG or cardiac trans­plan­tation are planned. a. Intra-aortic balloon pump b. Ventricular assist devices (Fig. 4.138) c. Enhanced external counterpulsation d. Resynchronisation therapy/biventricular pacing (Fig. 4.139). Cardiac resynchronisation therapy or biventricular pacing in cases of refractory failure with conduction abnormalities like LBBB may be beneficial. Management of cardiogenic pulmonary oedema: 1. Strict bed-rest to reduce cardiac workload. 2. Sitting position to improve pulmonary function by relieving pulmonary congestion. 3. Oxygen by nasal cannula or mask to raise PaO2 more than 60 mm Hg. 4. Morphine sulphate (2 to 5 mg IV) is used to relieve anxiety and it results in pulmonary and systemic venous dilatation.

Dose Amrinone—750 µg/kg bolus followed by 2.5 to 10 µg/kg/ minute. Milrinone—50 µg/kg bolus followed by 0.5 to 0.75 µg/kg/ minute. Adverse effects: Cardiac arrhythmias and thrombo­­­cytopenia. Levosimendan: By increasing the sensitivity of cardiac muscle to calcium, cardiac contractility is increased without a rise in intracellular calcium–positive inotrophic effect. It also causes vasodilatation by opening ATP sensitive K+ channels. Dose: Initial bolus dose 12 µg/kg followed by maintenance dose 0.1 to 0.2 µg/kg/min.

Ch-4c.indd 289

Fig. 4.138  Left ventricular assist device

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Manual of Practical Medicine zz zz

Oxygen toxicity Pulmonary embolism.

2.  Haematogenous Injury to Lungs zz zz zz zz zz zz

Sepsis Pancreatitis Non-thoracic trauma Multiple transfusions IV drugs—heroin Cardiopulmonary bypass.

3.  Lung Injury + Elevated Hydrostatic Pressure zz zz zz

High altitude pulmonary oedema Neurogenic pulmonary oedema Re-expansion pulmonary oedema.

Pathophysiology zz

Fig. 4.139  Cardiac resynchronisation therapy by pacing

5. Furosemide—A potent venodilator 40 to 80 mg IV relieves pulmonary congestion even before the commencement of diuresis. 6. Nitroglycerin (5 µg/minute) potentiates the effect of furosemide. Avoid hypotension and keep the systolic pressure above 90 mm of Hg. 7. Nitroprusside is more useful in pulmonary oedema resulting from valvular regurgitant lesions or systemic hypertension. 8. Dobutamine-dopamine-phosphodiesterase inhi­bi­tors are used in the presence of cardiogenic shock. 9. Aminophylline—250 to 500 mg slow IV is given in some cases to relieve bronchoconstriction and to augment myocardial contractility. 10. Mechanical aids on: (a) Rotating tourniquets, (b) Phle­bo­to­my. 11. Treat the precipitating cause.

Non-cardiogenic Pulmonary Oedema The oedema occurs due to damage of pulmonary capillary lining which results in leakage of proteins followed by fluid. This is associated with surfactant dysfunction.

zz zz

Clinical Features zz zz zz

zz

zz

zz zz zz zz zz

Ch-4c.indd 290

Chest trauma Aspiration Pulmonary contusion Smoke inhalation Pneumonia

Mild dyspnoea due to respiratory failure Normal auscultatory findings in early stages Hypoxaemia persists despite oxygen administration (intrapulmonary shunting) Chest X-ray—reveals normal heart size with diffuse alveolar infiltrate Clinical features of aetiological factor.

SYSTEMIC HYPERTENSION (FIG. 4.140) Recommendations of the Eighth Joint National Committee (JNC 8) zz

zz

Aetiology 1.  Direct Injury to Lungs

Intrapulmonary shunt with hypoxaemia Decreased pulmonary compliance Hyaline membrane and pulmonary fibrosis formation

zz

zz

Once again age factor is taken into account. Age ≥ 60 years, initiate therapy to achieve the goal SBP < 150 and DBP < 90 mm Hg. Age ≤ 60 years, initiate therapy to achieve the goal of SBP < 140 and DBP < 90 mm Hg. Age ≥ 18 years with chronic kidney disease or diabetes mellitus, initiate therapy to achieve the goal of SBP < 140 and DBP < 90 mm Hg. General non-black population including those with DM, initial treatment should include thiazide type diuretic/calcium channel blocker/ACEI or ARB. General black population including those with DM, initial treatment should include a thiazide type diuretic or CCB.

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Cardiovascular System zz

zz

Start one drug and then add the second drug before achieving the maximum dose of initial drug. Begin with two drugs either as separate pills or in the form of single pill combination.

European Society of Hypertension (ESH) and European Society of Cardiology (ESC) Hypertension Guidelines 2013 Category

Systolic BP mm Hg

Diastolic BP mm Hg

Optimal

< 120

< 80

Normal

120–129

80–84

High normal

130–139

85–89

Grade 1

140–159

90–99

Grade 2

160–179

100–109

Grade 3

≥ 180

≥ 110

Isolated systolic HTN

≥ 140

< 90

Primary (Essential)—94% Secondary—6%

Fig. 4.140  Systemic hypertension zz

zz

zz

zz

zz zz

Age ≥ 18 years with CKD, initial antihypertensive treatment should include ACEI or ARB to improve kidney outcome. This applies to all CKD patients with hypertension regardless of race or DM status. If the goal BP (< 140/90 mm Hg) is not achieved within a month treatment, increase the dose of initial drug or add a second drug from the above list (CCB, ACEI, and ARB). If the goal BP is not achieved with two drugs, add a third drug from the above list. If the goal is not achieved with three drugs from the above-mentioned list, antihypertensives from other class can be used. Do not combine ACEI with ARB in the same patient. Use of beta-blocker is restricted to IHD, acute coronary syndrome, MI, atrial fibrillation prevention and control of ventricular rate, cardiac failure, aortic aneurysm, and late stages of pregnancy.

Strategies in the usage of Antihypertensive Drugs zz

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Start one and titrate to the maximum dose before adding the second drug.

Renal (4%) Vascular Renal artery stenosis Parenchymal Glomerulonephritis (acute/chronic) Chronic pyelonephritis Polycystic kidneys Amyloidosis Diabetes. Endocrine (1%) Acromegaly Hyperthyroidism Hypothyroidism Hyperparathyroidism Cushing’s syndrome Conn’s syndrome Pheochromocytoma. Miscellaneous (1%) Drugs: zz Steroids —— Anabolic steroids —— Corticosteroids —— Oral contraceptive pills zz Cyclosporine zz Beta receptor agonists zz Sympathomimetics (Cold remedies/Nasal drops) zz NSAIDs. zz Coarctation of aorta.

Causes of Isolated Systolic Hypertension zz zz

Atherosclerosis (old age) Coarctation of aorta

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Manual of Practical Medicine zz zz

Severe AR Thyrotoxicosis.

Investigations

Factors Influencing Prognosis zz

zz

zz

zz

Used for risk stratification —— Levels of systolic and diastolic BP (grade I-III) —— Men > 55 years —— Women > 65 years —— Smoking —— Total cholesterol 250 mg% —— Diabetes mellitus —— Family history of premature CVD. Other factors adversely influencing prognosis —— Reduced HDL cholesterol —— Raised LDL cholesterol —— Micro-albuminuria in diabetes/HT —— Impaired glucose tolerance —— Obesity —— Sedentary lifestyle —— Raised fibrinogen —— High-risk socio-economic group —— High risk ethnic group —— High risk geographic region. Target organ damage (TOD) —— LVH —— Proteinuria or slight elevation of plasma creatinine (1.2–2 mg%) —— Radiological evidence of atherosclerotic plaque (carotid, femoral, iliac, aorta) —— Generalised or focal narrowing of retinal arteriole. Associated clinical conditions (ACC) —— Cerebrovascular disease (infarcts, haemorrhages, TIA) —— Heart disease (MI, angina, CCF, coronary revascularisation) —— Renal disease (nephropathy, renal failure—P. creatinine > 2 mg%) —— Vascular disease (dissecting aneur ysm, symptomatic arterial disease) —— Advanced hypertensive retinopathy (grade III and IV). Risk Stratification to Quantify Prognosis

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Investigation of hypertension (all patients) Urine analysis: Protein, glucose, haematuria zz Plasma urea/creatinine zz Chest radiograph (cardiomegaly, heart failure, rib notching) zz ECG (left ventricular hypertrophy, ischaemia) zz Plasma electrolytes (hypokalaemic alkalosis in the absence of diuretic therapy may indicate primary or secondary hyperaldosteronism) zz Plasma cholesterol/triglycerides. zz

Other risk factors and disease history

Grade I

Blood pressure (mm Hg) Grade II

Grade III

I. No other risk factor

Low risk

Medium risk

High risk

II.  1 to 2 risk factors

Medium risk

High risk

Very high risk

III. 3 or > risk factors or TOD or diabetes

High risk

High risk

Very high risk

IV. ACC

Very high risk

Very high risk

Very high risk

Investigation of hypertension (patients suspected of having secondary hypertension) zz Intravenous urogram, ultrasound (if renal disease is suspected) zz Radionuclide renography or renal arteriography (if there is evidence of renal artery stenosis) zz 24 hours urine catecholamines (vanillylmandelic acid—VMA) zz Plasma renin activity and aldosterone (if Conn’s syndrome suspected) zz Urinary cortisol, dexamethasone suppression test (if signs of Cushing’s syndrome is present) zz Angiography/MRI (if coarctation is suspected). When to Suspect Secondary Hypertension Young patient with hypertension (20 to 40 years) No family history of hypertension zz Postural fall of blood pressure zz Malignant hypertension zz Resistant or refractory hypertension. Evidence of underlying secondary cause (signs or symp­toms) zz Signs and symptoms of renal parenchymal disease zz Truncal obesity and thin limbs (Cushing’s syn­drome) zz Paroxysmal hypertension, sweating, palpitation, fear of impending death (pheochromocytoma) zz Disparity in upper and lower limb pulses (coarc­tation of aorta) zz Renal artery bruit (renal artery stenosis): This condition is diagnosed by doing a rapid sequential IVP. There is a delayed appearance and delayed clearance of the contrast media on the affected side zz Episodes of muscle weakness and tetany—Hyperaldosteronism. zz Symptoms suggestive of thyroid disease. zz Skin stigmata of neurofibromatosis—Pheochromocytoma zz Palpation of enlarged kidney—Polycystic kidney. zz Diminished and delayed femoral pulses and reduced femoral BP—Aortic coarctation. zz zz

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293

Cardiovascular System Left-right arm BP difference—Aortic coarctation, subclavian artery stenosis. zz Auscultation of chest murmurs—Aortic coarctation, aortic disease. Malignant hypertension: This presents with mani­festa­ tions of hypertensive encephalopathy (severe head­ ache, vomiting, visual disturbances, transient para­­l­ysis, convulsions, coma), attributed to spasm of cerebral vessels and cerebral oedema. Other presenta­tions are sudden cardiac decompensation and rapidly declining renal function. The characteristic vascular lesion is fibrinoid necro­sis of the walls of the small arteries and arterioles, which can be reversed by effective antihypertensive therapy. About 1% of hypertensive patients develop malig­nant hypertension and men are more affected than women. In the absence of effective antihypertensive therapy, life expectancy after diagnosis of malignant hyperten­sion is two years, and with effective anti­­hyper­tensive therapy, at least half of the patients survive for more than five years. Most deaths are due to CCF, renal failure or cerebral haemorrhage. zz

Management General Principles zz In presence of mild hypertension, a trial of non-drug therapy (diet, weight reduction, exercise and relax­ ation), must be given for a period of 3–6 months. zz Drug therapy must be instituted when there is a persistent elevation of diastolic blood pressure of more than 95 mm Hg in males and more than 100 mm Hg in females or when diastolic blood pres­ sure is more than 90 mm Hg in any individual with increased risk factors like smoking, DM, family history of hypertension, hyperlipidaemia, or with increased risk of complications secondary to hyper­ tension, or with evidence of end organ damage. zz Drug therapy must be instituted with as few drugs as possible, in the minimum optimal dosage so as to avoid drug interactions, minimise adverse effects of the drugs and to improve patient compliance.

Non-Drug Therapy zz

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Diet —— Weight reduction in obese and overweight patients (Aim: BMI < 25 kg/m2) —— Avoid excess salt consumption (advised to restrict salt intake to 3 to 4 gm/day; normal daily salt consumption is about 10 gm/day) —— Avoid alcohol

Lifestyle Modification—Management of Hypertension Modification

Recommendation

Approximate reduction – SBP

Weight reduction

BMI 19–25 kg/m2

5–20 mm Hg/10 kg

Diet

Low fat, vegetables and fruits

8–12 mm Hg

Sodium restriction

< 6 gm of sodium chloride

4–8 mm Hg

Physical activity

Brisk walking 40 min/day

4–8 mm Hg

Alcohol restriction

Avoid or limit consumption

2–4 mm Hg

Fat restriction (saturated, mono and polyun­ saturat­ed fatty acids each 10%, cholesterol less than 300 mg/day) —— Calcium, magnesium and potassium supple­ men­­tation —— Fresh food preferred to processed food (as processed food has increased salt content and decreased potassium content. Exercise and Relaxation —— Regular exercise programme (isotonic exercise) —— Avoid isometric exercise —— Meditation. Smoking —— Smoking should be stopped as it constitutes the single most important and effective risk reduction. ——

zz

zz

Drug Therapy Strategy for drug therapy in hypertension Step-wise approach is no longer advocated zz Confirm that hypertension is present on repeated measure­ments zz Determine whether drug therapy is required zz Thiazide diuretic may be initiated as first line treat­ ment, especially in the elderly (especially in those with isolated systolic hypertension) zz β-adrenoceptor antagonists can be used in combination with a thiazide especially relevant in presence of angina zz Calcium antagonists and α-blockers may be used when β-adrenoceptor antagonists are contraindi­cated or not tolerated zz Young hypertensive—(Renin ↑) Use beta-blockers and ACE inhibitors zz Elderly hypertensive—(Renin ↓) Use diuretics and calcium channel blockers zz Angiotensin converting enzyme inhibitors may be used where first line treatment fails, or may be used as an alter­native to β-adrenoceptor antagonist or calcium antagonist zz

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zz zz zz

zz

zz zz

β-blockers, calcium channel blockers and ACE inhi­ bitors can be used individually as first line drugs There is an individualised approach to drug therapy Always select a single appropriate drug Start with minimal dose of drug and then titrate to achieve optimal dose If the drug in optimal dose does not give the desired result, in order to avoid adverse effect of that drug as a result of increasing its dose, another appro­priate drug can be added to achieve the desired effect Treatment is life long In the course of treatment, 25% of mild hyper­tensives can become normotensives for a duration of one year or so without drugs. The patient requires frequent monitoring at this stage as the BP may rise at a later date and patient will require re-intro­duction of the antihypertensive drugs. Drug Therapy for Hypertension

BP classification

Drugs advocated

Pre-hypertension

Life-style modification and no drugs

HTN – Stage 1

Thiazide, ACEI, ARB, BB, CCB

HTN – Stage 2

Combined use of above drugs

Diuretics zz

zz

zz

zz

zz

Thiazides can be used only when renal function is intact Loop diuretics can be used in presence of impaired renal function Long acting diuretics (chlorthalidone, indapamide, metolazone) are preferable for 24 hour control of BP Metolazone is useful in patients with normal renal function Potassium sparing diuretics may be used in border­line hypertension (must be avoided in renal failure and in combination with ACE inhibitors).

Adverse Effects of Thiazides zz

zz zz zz zz zz zz

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Hyperglycaemia (due to decreased insulin secretion as a result of hypokalaemia induced by the diuretic, increased insulin resistance due to increased cate­chol­ amines, and increased hepatic glycogenolysis) Hyperlipidaemia Hyperuricaemia Hypercalcaemia Hypokalaemia Hyponatraemia Hypomagnesaemia.

β-blockers β-blockers may be cardioselective or non-cardio­selective. Non-cardioselective β-blockers are: Without intrinsic sympathomimetic activity (pro­ prano­lol, nadolol, timolol, sotalol, tertalol). zz With intrinsic sympathomimetic activity (pindolol, carte­lol, alprenolol, oxprenolol, dilevalol, penbuto­lol). Cardioselective β-blockers are: zz Without intrinsic sympathomimetic activity (ateno­lol, metoprolol, bevantolol, bisoprolol, betaxolol) zz With intrinsic sympathomimetic activity (Acebuto­ lol, celiprolol). β-blockers with added alpha blocking activities are: zz Labetalol (used in the dose of 200 to 1200 mg/day; useful in pheochromocytoma, hypertensive crisis and acute aortic dissection; to be used with caution in pregnancy; may cause postural hypotension, paraesthesia, tremor, choles­tatic jaundice, positive antinuclear antibody. zz Bucindolol. zz Carvedilol. Ultra short acting β-blockers are: zz Esmolol zz Flestolol and they are useful for intraoperative control of hyper­ tension as their dose can be easily titrated due to their short half-lives. Lipophilic β-blockers penetrate the CNS and dreams are common (propranolol, metoprolol, oxpre­nolol, labetalol). Hydrophilic β-blockers have a prolonged action, and dreams are uncommon (atenolol, sotalol, nadolol, practolol). zz

Routes of elimination of β-blockers are as follows: By liver (propranolol, metoprolol, labetalol) zz By kidney (atenolol, sotalol, nadolol). zz

The following are indications for β-blockers: Young hyperkinetic hypertensive zz Hypertension with IHD zz Marked anxiety, perioperative stress zz Thyroid disorder with hypertension. zz

β-blockers with ISA can be used in hypertensives with: Hyperlipidaemia zz Peripheral vascular disease zz In presence of bradycardia. zz

The following are contraindications for β-blockers: Complete heart block zz Bronchial asthma zz Hyperlipidaemia zz Peripheral vascular disease zz Diabetes mellitus (use with caution). zz

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Cardiovascular System Doses of commonly used β-blockers are: Metoprolol (100 to 200 mg/day) zz Atenolol (50 to 100 mg/day) zz Pindolol (15 to 30 mg/day) zz Oxprenolol (160 to 320 mg/day) zz Nebivolol (5 to 10 mg/day). It is selective β1-blocker and it has added endothelial nitrous oxide mediated vasodilator effect. zz

Other indications for β-blockers are: i. Migraine ii. Tremors iii. MVPS iv. TOF v. To prevent reinfarction vi. In patients with family history of sudden death vii. Congestive cardiac failure (Class II and Class III— carvedilol) viii. Thyrotoxicosis.

Centrally Acting Adrenergic Inhibitors The drugs belonging to this category are: a. Methyldopa (500–2000 mg) b. Clonidine (0.2–2 mg) c. Guanabenz (4–16 mg). zz These drugs (b and c) have a favourable effect with lipid metabolism and have no effect on carbo­hydrate and uric acid metabolism. zz The cardiovascular response to exercise is pre­serv­ed. zz It reduces left ventricular hypertrophy. zz Rebound hypertension can occur with sudden with­ drawal of drug. zz It can cause postural hypotension. zz Tachyphylaxis can occur with prolonged use, espe­ cially with Methyldopa. zz Long-term use can result in sodium retention (except guanabenz). The following are the adverse effects noticed: a. Dry mouth, drowsiness, sexual dysfunction (com­mon for all drugs). b. Depression, drug fever, galactorrhoea, haemolytic anae­mia, positive antinuclear antibody (for methyl­dopa). The following are the indications for using these drugs: a. Hypertension with hyperlipidaemia (clonidine, guana­­benz) b. Pregnancy (methyldopa) c. Hypertension with left ventricular hypertrophy d. Clonidine may be used in diagnosis of pheochromo­ cytoma and for GH assay.

Ch-4d.indd 295

Peripherally Acting Adrenergic Inhibitors The drugs belonging to this category are: a. Reserpine (0.01–0.5 mg/day): An effective and in­expen­sive drug useful in mild hypertension; post­ ural hypoten­sion common; sodium retention occurs and has to be used with diuretics; side effects are peptic ulceration, depression, drowsiness, suicidal tenden­cies, nasal congestion, weight gain, impo­tence, broncho­spasm, dysrrhythmias and extrapyramidal symptoms. b. Guanethidine (10–300 mg/day) used in severe hyper­ tension when other drugs fail; postural hypo­tension common; sodium retention may occur and has to be used with a diuretic; side effects are impotence, retrograde ejacu­lation, diarrhoea, weakness, nasal congestion, bradycardia, azotaemia.

Alpha Adrenergic Inhibitors The drugs belonging to this category are: a. Prazosin (6–15 mg) b. Terazosin (5–20 mg) c. Doxazosin (1–16 mg). zz These are powerful vasodilators zz They cause postural hypotension zz They reduce cholesterol, LDL, VLDL and increase HDL zz Dose modification is necessary in hepatic insuf ­fi ciency. zz Useful in renal insufficiency zz Phentolamine and Phenoxybenzamine are used in controlling hypertension in pheochromocytoma and are used perioperatively in surgery for pheochromo­­cytoma. Indications for using these drugs are: Hypertension with hyperlipidaemia zz CCF/shock zz Angina with hypertension zz Hypertension with cardiac arrhythmias zz Hypertensive crisis zz Pheochromocytoma zz Hypertension with Raynaud’s phenomenon zz Hypertension with benign prostatic hypertrophy zz Hypertension with COPD/pulmonary hyperten­sion. zz

Calcium Channel Blockers The drugs belonging to this category are: a. Verapamil (120–480 mg/day) b. Diltiazem (90–360 mg/day) c. Nifedipine (10–180 mg/day) d. Amlodipine (5–10 mg/day)

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Fig. 4.141  Mechanism of action—Cilnidipine

e. f. g. h.

Nicardipine (20–40 mg/day) Isradipine (2.5–10 mg/day) Felodipine (5–20 mg/day) Nitrendipine (5–20 mg/day).

d. Hypertension with angina e. Hypertension with cardiac arrhythmias. The pharmacological effects of these drugs are as follows:

i.  Cilnidipine (5–10 mg /day) (Fig. 4.141) Cilnidipine—Novel 4th generation CCB with L and N type calcium channel inhibitory action. It has greater renoprotective effect and 24 hours SBP reduction. Renoprotective effect is due to reduction in glomerular pressure caused by dilatation of both afferent and efferent arterioles. It inhibits the sympathetic neurotransmitter release by N type Ca(2+) channel blocking property causing suppression of cardiac sympathetic overactivity and prevents reflex tachycardia (cardioprotection) by blocking platelet activation, it reduces the incidence of arterial thrombosis and that prevents myocardial and cerebral infarction. Dose—5 to 10 mg daily. j.  Benedipine—a triple L, T, and N-type calcium channel blocker. It is reno- and cardioprotective. The indications of calcium channel blockers are: a. Hypertension with renal dysfunction b. Hypertension with COPD c. Hypertension with peripheral vascular disease

Ch-4d.indd 296

Parameters

Cilnidipine

Amlodipine

Role in proteinuria

Reduces proteinuria 50%

Reduces proteinuria but less effective

Ankle oedema and tachycardia

No

Yes

Role in renoprotection

Yes

No

Role in cardioprotection

Yes

No

Role in neuroprotection

Yes

No

Characteristics

Diltiazem Verapamil  Nifedipine Nicardipine

Heart rate

D

D

I

I

Myocardial contractility

D

DD

D

–

Nodal conduction

D

DD

–

–

Peripheral vasodilation

I

I

II

II

D = Decreased    I = Increased

Adverse effects of calcium channel blockers are: Headache zz Hypotension zz Flushing zz Bradycardia zz Dizziness zz Dysrrhythmias zz Palpitation zz Constipation zz Sexual dysfunction and depression (low incidence) zz Ankle oedema. All calcium channel blockers are metabolised in liver and hence dose modification is required in cirrhosis liver. zz

ACE Inhibitors The drugs belonging to this category are: a. Captopril (25–75 mg/day) b. Enalapril (5–40 mg/day) c. Lisinopril (5–40 mg/day) d. Bendopril (5–40 mg/day) e. Fosinopril (10–40 mg/day) f. Quinapril (2.5–10 mg/day)

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297

Cardiovascular System g. Ramipril (1.25–10 mg/day) h. Imidapril (5–10 mg/day). The advantages of ACE inhibitors are: Improved general well-being zz Absence of mental depression, sleep disturbance zz Absence of fatigue, sexual dysfunction zz Does not precipitate CCF, bronchospasm, nasal conges­ tion, brady­cardia, peripheral vascular disease, flushing zz Does not cause hyperglycaemia, hyperuricaemia, hyper­lipidaemia, hypokalaemia, fluid retention, tachy­ phylaxis, reflex tachycardia, rebound hyper­tension. zz

ACE inhibitors can be used in the following situations: CCF zz Renal insufficiency (creatinine less than 3 mg) zz Diabetic nephropathy (it can reverse the early microalbu­minuria of diabetic nephropathy) zz Hypertension with LVH zz Hypertension with hyperlipidaemia zz Renovascular hypertension (avoid in bilateral renal artery stenosis). Adverse effects of ACE inhibitors are: zz Angioedema zz Cough zz Loss of taste zz Potassium retention zz Skin rashes zz Proteinuria zz Neutropenia. zz

AT2 Receptor Blockers They inhibit the renin angiotensin system via specific blockade of the AT2 receptors. In contrast to ACE inhibitors, they do not increase bradykinin levels, which may be responsible for adverse effects such as cough. Drugs are: zz Candesartan—8 to 16 mg od zz Irbesartan—75 to 150 mg od zz Losartan—25 mg od, can be used bid zz Valsartan—80 mg od zz Eprosartan—200 to 400 mg od, can be used bid zz Telmisartan—20 to 40 mg od zz Olmesartan—20 mg zz Azilsartan—a new angiotension receptor blocker. Dosage 40/80 mg OD.

Directly Acting Vasodilators The drugs used in this category are: Hydralazine (25–300 mg/day) zz Minoxidil (10–100 mg/day) zz Sodium nitroprusside (0.3–1 mg/kg/min IV) zz

Ch-4d.indd 297

Diazoxide (50–150 mg IV bolus rapidly). These drugs induce sodium and water retention and reflex tachycardia. They are effective when combined with β-blockers and diuretics. They may be used in the following situations: a. Mild and moderate hypertension b. CCF c. Renal hypertension d. Pregnancy (hydralazine) e. Refractory hypertension f. Renal failure g. Diazoxide and sodium nitroprusside are useful in hyper­tensive crisis.

zz

Refractory hypertension: Refractory or resistant hyper­­ tension is defined as failure to achieve a blood pressure of 140/90 mm Hg despite the use of a rational triple-drug regimen of the following drugs: zz Oral diuretic (equivalent to 25 mg of hydrochlo­ rothiazide or chlorthalidone or 320 mg of furo­semide or 10 mg of metolazone per day) plus zz Sympathetic inhibitor (propranolol 320 mg/day or atenolol 100 mg/day or clonidine 0.6 mg/day or prazosin 20 mg/day or methyldopa 2 g/day) or Other agents (ACE inhibitors like captopril 200 mg/day or benazepril 40 mg/day) or Angiotensin II receptor blocker (losartan potassium 100 mg/day) or Calcium channel blocker (verapamil 480 mg/day or nifedipine 120 mg/day or diltiazem 360 mg/day) plus zz Direct vasodilator (hydralazine 100 mg/day or minoxi­ dil 20 mg/day). Most causes of resistant hypertension are due to noncompliance on part of the patient in adhering to a strict diet and drug dosage schedule, or due to use of other medications and substances that may interfere with blood pressure control (NSAIDs, nasal decongestants, OCPs, steroids, carbeno­xolone) or presence of under­lying renal artery stenosis or other causes of secondary hypertension (endocrine hypertension). A systematic approach to the problem, keeping the above factors in mind, usually reveals the cause of resistant hypertension. The correction of these factors usually result in adequate control of blood pressure. The adverse effects of these drugs are: Hydralazine (headache, nausea, emesis, tachy­cardia, postu­ral hypotension, positive antinuclear antibody, SLE)

zz

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Manual of Practical Medicine Minoxidil (weight gain, hypertrichosis, hirsutism, pericardial effusion). Vasodilators act on arteries and veins. The relative action of vasodilators on arteries and veins are as follows: zz Sodium nitroprusside A=V zz Alpha blockers A=V zz Diazoxide A>V zz ACE inhibitors A>V zz Hydralazine A >> V zz Minoxidil A >> V zz Calcium channel blockers A >> V zz Nitroglycerin V>A Abbreviations: A = Artery; V = Vein zz

Potassium Channel Openers

Dose Pinacidil (12.5 mg bid up to maximum of 75 mg/day) zz Nicorandil (20 mg od). zz

Antihypertensives and Uric Acid and Glucose Metabolism and Electrolyte Changes Uric acid

Drugs

LV mass

Sexual dysfunction

Postural hypotension

I

–

–

β-blockers

Inconsistent

I

–

Labetalol

D

I

I

Clonidine

D

I

–

Methyldopa

D

I

I

Reserpine

D

I

–

Diuretics

α-blockers

D

–

I

ACE inhibitors

D

–

–

Calcium channel blockers

D

low

+/–

Abbreviations: D = Decreased; I = Increased

Drugs are diazoxide, minoxidil, pinacidil, nicorandil, croma­kalim and lomakalim. These drugs open potas­ sium channels of vascular smooth muscle, causing their relaxation and thereby vasodilatation. Peripheral arterial vasodilatation decreases peri­pheral vascular resistance, thereby decreasing blood pressure. It causes reflex tachycardia.

Drugs

Effects of Antihypertensives on LV Mass, Sexual Dysfunction and Postural Hypotension

Glucose

Electrolytes K

Mg

Diuretics

I

I

D

D

β-blockers

I

I

–

–

Labetalol

I

I

–

–

ACE inhibitors

–

–

I

D

Calcium channel blockers

–

I

–

–

ACE inhibitors and calcium channel blockers have some favourable effect on lipid metabolism.

Renin Inhibitors Aliskiren (150–300 mg) Remikiren zz Enalkiren They are orally used in the management of hypertension and diabetic nephropathy. zz zz

Special Considerations in Antihypertensive Therapy zz

zz

Abbreviations: D = Decreased; I = Increased

Central adrenergic inhibitors have no effect on the above parameters.

zz

Antihypertensives and Lipid Metabolism Drugs

Ch-4d.indd 298

Total cholesterol

VLDL

Triglycerides

LDL

HDL

Diuretics

↑

↑

↑

↑

↓

b-blockers (without ISA)

↑

↑

↑

↑

↓

b-blockers (with ISA)

–

–

↓

–

↑

Methyldopa

–

↑

↑

–

↓

Reserpine

↑

–

↑

↑

↓

Clonidine

↓

↓

↓

↓

↑

a-blockers

↓

↓

↓

↓

↑

Guanabenz

↓

↓

↓

↓

↑

zz

zz

Pregnancy —— Safe drugs are hydralazine, methyldopa, cloni­dine, metoprolol, prazosin. —— Drugs that can be used with caution are labetalol, *propranolol, diazoxide, nifedipine, nitroprus­side. —— Drugs to be avoided are thiazides, ACE inhibitors. Elderly —— Drugs preferred are diuretics and calcium channel blockers. —— Adrenergic inhibitors to be used with caution. Anaesthesia —— Short-acting β-blockers like esmolol is preferred for control of hypertension perioperatively. The alternative drugs are sodium nitroprusside and trimethaphan. Renal failure —— Drugs preferred are diuretics (frusemide), calcium channel blockers, ACE inhibitors, β-blockers (propranolol, metoprolol), α-blockers. Ischaemic heart disease —— Calcium channel blockers and β-blockers are preferred

* It can cause IUGR if given early in pregnancy

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Cardiovascular System In presence of CCF, ACE inhibitors, α-blockers are used. —— If ejection fraction is < 30%, β-blockers can be used with caution, but calcium channel blockers are contraindicated. zz Diabetes mellitus —— Preferred drugs are ACE inhibitors, calcium channel blockers and α-blockers. zz Arrhythmias Sinus bradycardia Nifedipine, α-blockers Sinus tachycardia β-blockers SVT Verapamil, β-blockers AV block Nifedipine zz COPD —— Calcium channel blockers, ACE inhibitors, α-block­ers. zz Peripheral vascular disease —— Calcium channel blockers, α-blockers. zz Subarachnoid haemorrhage —— Nimodipine. zz Aortic dissection —— Acute (nitroprusside, esmolol, propranolol, labeta­ lol, nifedipine). —— Chronic (calcium channel blockers, β-blockers, methyl­dopa, clonidine, reserpine). zz Hyperlipoproteinaemia —— Clonidine, guanabenz and α-blockers have a favourable effect on lipid metabolism. —— Other drugs that can be used are ACE inhibitors, calcium channel blockers and β-blockers with ISA. zz Left ventricular hypertrophy —— Drugs like α-blockers, reserpine, clonidine, a methyldopa and ACE inhibitors have been shown to reduce left ventricular hypertrophy. zz Hypertensive emergencies—Preferred parenteral drugs: —— Hypertensive encephalopathy and stroke— Nitroprusside, nicardipine, labetalol —— Acute LVF—Nitroglycerine, enalaprilat, loop diuretics ——

Compelling Indications for Antihypertensive Drugs Disorder

Ch-4d.indd 299

——

—— ——

——

MI/Unsable angina—Nitroglycerine, nicardipine, labetalol, esmolol Adrenergic crisis—Phentolamine, nitroprusside Postoperative hypertension—Nitroglycerine, nitroprusside, labetalol, nicardipine Preeclampsia/eclampsia—Hydralazine, labetalol, nicardipine.

Management of Hypertensive Crisis It is not appropriate to attempt to cause an instan­ taneous fall in blood pressure. Too rapid a fall may cause cerebral damage, including blindness and may sometimes precipitate coronary or renal insufficiency. Even in the presence of cardiac failure or hypertensive encephalo­pathy, a controlled reduction over a period of 30 to 60 minutes to a level of about 160/100 to 110 mm of Hg is adequate. IV antihypertensive agents are preferred in hypertensive encephalopathy and oral antihypertensive agents in cardiac failure. The drugs used in the management of hyper­­tensive crisis are: zz Sodium nitroprusside (0.3–1 µg/kg/min up to a maximum of 6 µg/kg/min as an IV infusion) zz Labetalol (2 mg/min up to a maximum of 200 mg IM or IV) zz Hydralazine (5–10 mg aliquotes, repeated half hourly up to a maximum of 300 mg) zz Oral clonidine loading—Initial dose of 0.2 mg followed by 0.1 mg every hour to a total dose of 0.7 mg. Check the BP in every 15 minutes. After 6 hours a diuretic can be given. By this method, reduction of diastolic BP up to 20 mm of Hg can be achieved. zz Diazoxide (50–150 mg IV bolus rapidly, as it has high affinity to bind to albumin, up to a maximum of 600 mg/day) zz Nicardipine IV infusion 5 to 15 mg/h zz Enalaprilat IV bolus 1.25 to 2.5 mg 6th hourly zz Nitroglycerine IV drip is useful in the management of hypertensive crisis associated with ischaemia. zz Fenoldopam—0.1 to 0.3 µg/kg/min IV infusion zz Esmolol—500 µg/kg/min IV bolus followed by 50 to 300 µg/kg/min IV infusion zz Phentolamine 5 to 10 mg q5-15 minutes IV bolus zz Methyldopate—250 to 500 mg IV bolus.

Diuretics

BB

ACEI

ARB

CCB

Aldo-Ant

Heart failure

*

*

*

*

—

*

Post-MI

—

*

*

—

—

*

High risk CAD

*

*

*

—

*

—

Complications of Hypertension

Diabetes

*

*

*

*

*

—

Chronic KD

—

—

*

*

—

—

Recurrent stroke

*

—

*

—

—

—

Adverse effects of hypertension principally involve the central nervous system, the retina, the heart and the kidneys.

Do not use sublingual nifedipine as it could cause excessive reduction in BP resulting in adverse effect such as stroke or MI.

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Manual of Practical Medicine Central Nervous System Hypertension induced complications of central nerv­ous system are: zz Carotid atheroma and transient cerebral ischaemic attacks zz Cerebral infarction zz Cerebral haemorrhage Fig. 4.142 zz Subarachnoid haemorrhage zz Hypertensive encephalopathy (it is characterised by very high blood pressure and neurological symp­ toms like transient disturbances of speech or vision, paraesthesiae, disorientation, fits and loss of consci­ ous­ness. Papillo­edema is common. The neurological deficiency is usually reversible if hypertension is properly controlled) zz Cognitive impairment and dementia.

Fig. 4.142: CT brain and MRI brain: Acute intracerebral haemorrhage involving left capsuloganglionic region with intraventri­cular extension

Retina The optic fundi reveal a gradation of changes linked to the severity of hypertension. They provide a clue to the arteriolar damage occurring elsewhere. There are four grades of hypertensive retinopathy depending on the severity and duration of hypertension. Cardiovascular System Hypertension induced complications of cardiovas­cular system are: zz Left ventricular hypertrophy (LVH) as a result of pressure overload. LVH is reversible with certain anti­hyper­tensive agents. zz Left ventricular failure zz Coronary artery disease zz Aortic aneurysm zz Aortic dissection (Fig. 4.143). Kidneys Hypertension can lead to damage of the renal vessels. Longstanding hypertension can cause proteinuria and pro­gressive renal failure. Microalbuminuria is an earlier marker of hyper­ tensive nephropathy. The pathological change noticed in longstanding hypertension is benign nephrosclerosis. Fibrinoid nec­ ro­­­­sis is noticed in malignant hypertension.

ACUTE CORONARY SYNDROME (ACS) Acute coronary syndrome (ACS) includes unstable angina, and non-ST elevation myocardial infarction (NSTEMI).

Ch-4d.indd 300

Fig. 4.143: Dissection involving ascending and descending aorta

ACS is a spectrum of disease characterised by either one of the following: zz New-onset angina zz Angina at rest zz Progression of angina of increasing frequency or severity zz Angina in response to lower levels of exertion. ACS most often represents acute atherosclerotic plaque rupture with exposure of thrombogenic sub-endothelial matrix. Thrombus formation, which may be episodic in nature and it is the mechanism by which it interferes with coronary blood flow (Fig. 4.144).

Unstable Angina It is due to dynamic obstruction of coronary artery—spasm and or rupture of plaque.

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Cardiovascular System All ACS patients should be placed on aspirin, β-blocker, nitrate and clopidogrel immediately. Low risk patients—On observation if the patient remains pain-free with normal ECG and normal levels of cardiac markers, submit them for stress ECG. If the stress test is negative, consider alternative diagnosis. If the stress test is positive, continue medication and invasive testing when required. Intermediate and high risk patients—Patient has to be admitted in the intensive care unit and to be managed with anti-ischaemia, antiplatelet and anticoagulant group of drugs. In the meantime coronary angiography is planned.

Antiplatelet Therapy Aspirin (loading dose of 325 mg followed by 75 to 150 mg/day after lunch) reduces subsequent MI and cardiac death. zz Clopidogrel (loading dose 300 mg followed by 75 mg/ day) in aspirin intolerant patients. Added benefit in reducing the motality is achieved by combining both aspirin and clopidogrel and can be used for a minimum of one month if PCI is planned or maximum of 9 months. zz Glycoprotein (GP) IIb/IIIa antagonists—abciximab (ReoPRO) or eptifibatide (Integrilin) or tirofiban (Aggrastat) should be considered for high risk patients. They should be used in conjunction with heparin. If early invasive strategy is planned any one of the molecule can be used. If early invasive strategy is not planned, one of the small molecule either eptifibatide or tirofiban can be used. zz

Fig. 4.144  Acute coronary syndrome

It is defined as angina pectoris or equivalent ischaemic discomfort with either one feature. zz It occurs at rest or with minimal exertion usually lasting > 10 minutes. zz It is severe and of new onset within the prior 4 to 6 weeks. zz It has a crescendo pattern of pain—distinctly severe, prolonged and more frequent than before. Unstable angina is distinguished from non-STelevation myocardial infarction by the absence of elevated serological markers of myocardial necrosis. It is also distinguished from ST-elevation MI by the absence of persistent ST-segment elevation.

Pathogenesis zz

zz

zz

Plaque rupture or erosion with superimposed nonocclusive thrombus (most common) Progressive mechanical obstruction—either rapidly advancing coronary atherosclerosis or restenosis following percutaneous coronary intervention. Increased discrepancy between myocardial oxygen demand and supply.

Management (Fig. 4.145) Immediately assess the following: Clinical evaluation—history and physical exami­nation zz 12-lead ECG recording zz Measurement of cardiac specific markers—troponin and CK-MB. zz

Ch-4d.indd 301

Anticoagulant Therapy Dalteparin—(Fragmin) 120 IU/kg SC 12 h (Maximum 10,000 IU bid) zz Enoxaparin—(Lovenox) 30 mg IV bolus followed by 1 mg/kg SC bid zz Heparin (unfractionated—UFH) 60 to 70 U/kg (maximum 5000 U) IV followed by infusion 12 to 15 u/ kg/h (Initial maximum 1000 U/h) titrated to achieve a PTT 1.5 to 2.5 times control. Compared with UFH, LMWH produces more predictable anticoagulant response because of the better bioavailability, longer half-life and dose independent clearance. Enoxaparin 1 mg/kg bid subcutaneously is the only LMWH found to confer greater cardiac benefit. zz

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Fig. 4.145  Acute management of unstable angina or non-ST elevation myocardial infarction

Risk Stratification of ACS Features

High risk

Intermediate risk

Low risk

Clinical history

Accelerating tempo of ischaemic symptoms in preceding 48 hours

Prior MI, peripheral or cerebrovascular disease, CABG or prior aspirin use

Classical pain

Prolonged ongoing > 30 min rest pain

Prolonged > 20 min rest angina, now resolved, with high likelihood of CAD, rest angina < 20 min relieved with SL-TNG

Clinical findings

Pulmonary oedema, worsening MR, S3, hypotension, tachycardia, bradycardia, Age > 75 years

Age > 70 years

ECG

Transient ST changes > 0.05 mV, new bundle branch block or VT

T-wave inversions > 0.2 mV Pathological Q-waves

Normal or unchanged ECG

Biochemical cardiac markers

Elevated troponin or CK-MB (TnT or TnI > 0.1 ng/mL)

Borderline elevation (TnT > 0.01 but < 0.1 ng/mL)

Normal

New-onset or progressive angina in the past 2 weeks with moderate or high likelihood of CAD:

CRP (c-reactive protein) levels > 3 mg/L represent a high risk group. Thrombolytic therapy is not indicated in ACS.

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303

Cardiovascular System GP IIb/IIIa Receptor Inhibitors in ACS-IV Features

Abciximab

Eptifibatide

Tirofiban

Drug type

Monoclonal antibody

Cyclic heptapeptide

Nonpeptide

Dosage

0.25 mg IV bolus then 0.125 mg/kg/min (max 10 μg/min) × 12 hr-ACS planned for PCI

180 μg/kg bolus then 2 μg/kg/min × 24–48 hours

0.4 μg/kg/min for 30 min, then 0.1 μg/ kg/min × 24–48 hours

Metabolism

Cellular catabolism

Renal—modify dose in renal failure

Renal—modify dose in renal failure

Recovery of platelet inhibition

48–96 hours

4–6 hours

4–6 hours

Reversibility

Platelet transfusion

None

None

Pros and Cons of Indirect Thrombin Inhibitors Indirect thrombin inhibitors

Pros

Cons

Unfractionated heparin

•  Short half-life •  Low cost •  Rapid reversal of anti-coagulant effect

•  Increased risk of major bleeding •  Increased risk of Heparin induced thrombocytopaenia (HIT)

Low molecular weight heparins

•  Stable and predictable pharmacokinetics •  Monitoring usually not required •  Lower incidence of HIT

•  Longer half-life •  Weight-based dose •  Restriction in renal failure •  Questionable reversibility

Bivalirudin—0.1 mg/kg bolus followed by 0.25 mg/kg/h IV infusion.

Pros and Cons of Warfarin Pros

Synthetic Heparin Derivatives zz

zz

Fondaparinux: It inhibits factor Xa but not thrombin. Dose is 2.5 mg SC qd and monitoring is not required. It is contraindicated in severe renal failure. Idraparinux: It has a half-life of 80 hours and is administered SC on a weekly basis.

Direct Thrombin Inhibitors zz

zz

zz

Argatroban: It has a short half-life—40 to 50 minutes and can be given only by IV. It is excreted by the liver and dose modification is required in hepatic failure. Lepirudin: This direct thrombin inhibitor is derived from leech salivary extract. It is given as IV and is excreted through the renal route. Use with caution in renal failure. Bivalirudin: It is also administered through IV and dose modification is required in renal failure. This agent is mainly used in invasive cardiology.

Vitamin K Antagonist zz

Ch-4d.indd 303

Warfarin: It is given orally. Therapeutic anticoagulation is achieved only after a few days and average duration of action is 2 to 5 days. Monitoring is required.

Cons

•  Oral dosing

•  Increased risk of major bleeding

•  Many years of clinical usage

•  Need for periodic INR monitoring

•  Low cost

•  Teratogenicity and skin necrosis

Newer Oral Anticoagulants Rivaroxaban: It is an orally administered factor Xa inhibitor. It is partly renally excreted. Routine monitoring is not needed and there is no specific reversing agent. zz Dabigatran: It is an orally administered factor IIa inhibitor. It is entirely renally excreted and routine monitoring is not required. There is no specific reversing agent. Discontinue 3 to 5 days before surgical procedure. zz Apixaban: It is an orally administered factor Xa inhibitor. There is no specific reversing agent. It is metabolized by CYP3A4. zz

Pros and Cons of Newer Oral Anticoagulants Pros

Cons

•  Oral administration •  Rapid onset of action •  Monitoring is not needed •  Excellent efficacy

•  More costly •  Compliance essential because of the short duration of action •  No antidote



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Newer Drugs in Angina

Coronary Angiography

Partial fatty acid oxidation inhibitors: Trimetazidine: Heart utilizes glucose when fatty acid oxidation is inhibited and it results in reduction of free radicals generation. This change over to glucose oxidative pathway reduces intracellular acidosis and increases ATP production and limits the deleterious effects of ischaemia. It is contraindicated in closed angle glaucoma. Dose—20 mg bid or tid.

Coronary angiography is performed for high/intermediate risk patients (Figs 4.146A and B). CABG: Left main disease, triple vessel disease, LV dysfunction or diabetes mellitus PCI: 1 or 2 vessel disease—GP IIb/IIIa inhibitors followed by PCI. If coronary angiography is normal consider alter­native diagnosis.

zz

Na+ channel blockers: Ranolazine: It blocks late sodium inward current and prevents Na+ and Ca2+ overload of ischaemic myocytes. It is used in chronic stable angina as add-on therapy. Dose: 500 to 1000 mg bid orally. It is contraindicated in hepatic impairment, drugs causing enzyme inhibition and QT prolongation. zz Ivabradine: It is useful to control the heart rate without myocardial suppression in chronic stable angina in patients with normal sinus rhythm who have contraindication or intolerance to beta-blockers. It is contraindicated in extreme sinus bradycardia (60 beats/min), cardiogenic shock, acute MI, hypotension, sick sinus syndrome, sinoatrial block, complete heart block, hepatic and renal impairment. Dose: 2.5 to 7.5 mg bid. zz

MYOCARDIAL INFARCTION (MI) Irreversible necrosis of part of the heart muscle is almost always due to coronary atherosclerosis.

Incidence 5/1000 per year. Fifty percent of deaths due to MI occur within 1 to 2 hrs after the onset of symptoms.

Risk Factors zz

Comparison between Warfarin and Dabigatran Attribute

Warfarin

Dabigatran

Mechanism of action

Inhibition of vitamin K dependent coagulation factors (II, VII, IX, X, protein C and S)

Inhibition of thrombin

100%

6-7%

Oral bioavail­ability

Ch-4d.indd 304

zz

Half-life

30–60 hours

12–18 hours

Metabolism

Hepatic

Renal (80%)

Time of onset

24–72 hours

1–2 hours

Protein binding

100%

35%

Antagonist

Vitamin K

None

Monitoring

Needed

Not needed

Dose modification

Required for each individual

In renal failure

Interaction with diet

Interacts with food rich in vitamin K (e.g. cabbage, spinach)

No interaction

Interaction with drugs

Interacts with amiodarone, alcohol antifungals, antibiotics, and dose modification is required

Dose modifica­tion with ketoconazole and amiodarone

Cost factor

Cost effective

Costly

zz

zz

Category I (For which interventions have been proved to lower CVD risks) —— Raised LDL cholesterol —— Reduced HDL cholesterol —— Atherogenic diet —— Cigarette smoking —— Hypertension —— LVH —— Thrombogenic factors Category II (For which interventions are likely to lower CVD risks) —— Diabetes mellitus —— Physical inactivity —— Increased triglycerides —— Small dense LDL —— Obesity Category III (Associated with increased CVD risk that, if modified, might lower risk) —— Psychosocial factors —— Increased Lipoprotein a (normal level—0–3 mg/dl) —— Hyperhomocysteinemias —— No alcohol consumption —— Oxidative stress —— Post-menopausal status Category IV (Associated with increased CVD risk which cannot be modified) —— Age —— Male gender

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Cardiovascular System

A

B Figs 4.146A and B  (A) Blood supply of the heart; (B) Recanalisation methods in coronary artery disease —— ——

Low socioeconomic status Family history of early onset CVD.

Symptoms Anginal pain is of greater severity and is associated with nausea, vomiting, sweating and extreme distress.

Ch-4d.indd 305

Painless infarcts are common in diabetics and in the elderly, due to autonomic neuropathy.

Signs zz zz

Tachycardia, bradycardia, VPCs, gallop There may be hyper or hypotension

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Manual of Practical Medicine zz zz zz zz

Cold and clammy extremities Cyanosis may be present Mild pyrexia (< 38.5°C) Features of complications (LV failure, pulmonary oedema, arrhythmias).

Syndrome X zz

zz zz

Ischaemic chest pain in the presence of normal coronary arteries It is probably due to microvascular disease of the heart Prognosis is good when compared with classic CAD patients.

Investigations ECG (Figs 4.148A and B) May be normal initially and hence serial ECGs must be taken. zz ST-elevation and T-wave inversion with patho­logical Q-waves are typically seen in leads adjacent to the infarcted segment of myocardium. zz Reciprocal ST depression or T-wave inversion in opposite leads. zz A non-Q-wave infarct may occur and has a high risk of mortality (as they are prone to develop dangerous arrhythmias and recurrent angina). zz

Troponin T and I reach a reliable diagnostic level in plasma by 12 to 16 hrs, maximal activity by 24–32 hrs, returns to normal in 10–12 days. —— Troponin I : 0 to 0.4 ng/mL —— Troponin T: 0 to 0.1 ng/mL Cardiac troponins are detected in the serum by using monoclonal antibodies. These antibodies have negligible cross reactivity to skeletal muscle. Cardiac troponins I and T start to rise within 3 to 4 hours after myocardial infarction and remain raised for 4 to 10 days (Fig. 4.147). zz Other causes of elevated cardiac troponins: —— Cardiac causes: „„ Cardiac contusion/surgery „„ Myocarditis „„ Cardiomyopathy „„ Heart failure „„ Cardioversion „„ Percutaneous coronary intervention „„ Cardiac amyloidosis „„ Radiofrequency ablation „„ Supraventricular tachycardia „„ Post-cardiac transplantation —— Non-cardiac causes: „„ Primary pulmonary hypertension „„ Pulmonary embolism

Chest X-ray Signs of heart failure or pulmonary oedema. Cardiac Enzymes CPK-MB: This cardiac isoenzyme starts rising within 4 to 6 hrs after development of acute MI, peaks during the 2nd day (4-fold rise) and disappears in 2 to 3 days. Other causes of total CK elevation: —— Skeletal diseases—Polymyositis, muscle dys­ trophy, myopathies —— Electrical cardioversion —— Skeletal muscle damage—trauma, convulsions, immobilisation —— Hypothyroidism —— Stroke —— Surgery zz AST: Starts rising on the 1st day, peaks in 2 to 3 days (3-fold rise) and disappears by 3rd day. zz LDH : Starts rising by second day, peaks around 3 to 1 4 days (3-fold rise) and disappears in 10 days. zz Troponin T: Cardiac troponin T is a regulatory contractile protein not normally found in blood. Its detection in the circulation has been shown to be a sensitive and specific marker for myocardial cell damage. zz

Ch-4d.indd 306

Fig. 4.147  Enzyme levels in acute MI

A

B Figs 4.148A and B  ST changes in MI

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307

Cardiovascular System Cerebrovascular stroke „„ High dose chemotherapy „„ Sepsis and septic shock „„ Renal failure „„ Critically-ill patients „„ Scorpion envenomation „„ Ultra-endurance exercise (marathon) Myoglobin It is increased within 2 hrs of onset of symptoms and remains increased for at least 7 to 12 hrs. Normal level is 20 to 100 µg/L. „„

zz



Investigation

STEMI

Non-STEMI

Unstable angina

ECG

ST elevation

Normal / ST depression T-wave inversion

Normal /ST depression T- wave inversion

Cardiac biomarkers

Raised

Raised

Normal

zz

zz

zz

zz

It is an alternative to thrombolytic therapy in acute MI with ST elevation or resent onset LBBB with acute MI. Primary PCI is ideal in acute MI if door to balloon time is < 90 minutes Treatment is optimal if angioplasty is performed within 12 hours of onset of symptoms or if the symptoms persist PCI is preferred over thrombolysis in patients: —— Age 40% of LV is infarc­ted and rendered non-functional. It carries a high mortality rate (80–90%). The criteria for diagnosing cardiogenic shock are: zz Signs of failure like thready pulse, cold and clammy extremities and pallor zz Systolic BP < 80 mm Hg 2 zz Cardiac index < 1.8 L/min/m zz Left ventricular filling pressure > 18 mm Hg zz Urine output less than 20 to 30 mL/h zz Presence of tachycardia and S3 and S4 gallop rhythm zz Features of pulmonary oedema. Treatment of cardiogenic shock with drugs like dopamine, dobutamine, norepinephrine, amrinone or various combina­tions of these agents or with intraaortic balloon (or external) counter-pulsation and use of anti­coagulants help to lower the mortality. Emergency PTCA or CABG can reduce the mortality by about half. The prognosis, in the presence of cardiac failure, when untreated, is assessed by using the Killip classi­fication. Killip Classification

Ch-4d.indd 307

Primary PCI

Class

Features

Incidence

Mortality

I

No heart failure

40%

0.5%

II

Mild to moderate heart failure (S3; rales no more than half way up the back)

40%

10–20%

III

Severe heart failure (pulmonary oedema)

10%

30–40%

IV

Cardiogenic shock

10%

80–90%

Emergency Surgery It is essential in the following situations: Papillary muscle rupture zz Ventricular septal defect zz Ventricular aneurysm zz Ventricular free wall rupture zz Intractable pump failure zz Intractable ventricular arrhythmias. zz

Arrhythmias Nearly all patients with acute MI have arrhythmias. In many cases, it is mild and of no haemodynamic significance. Common arrhythmias seen in acute MI are: zz Ventricular fibrillation: This is a major cause of death within one hour of developing MI zz Ventricular tachycardia zz Accelerated idioventricular rhythm zz Ventricular ectopics zz Atrial fibrillation: Common and frequently tran­sient. May cause a rapid ventricular rate and hypotension zz Atrial tachycardia zz Sinus bradycardia: Should be treated if there is associated hypotension zz Heart block: Following inferior wall MI is often temporary and may resolve without treatment, but is more serious leading sometimes to asystole when occurring following anterior wall MI.

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Manual of Practical Medicine Treatment of Arrhythmias Sinus bradycardia: No treatment if the patient is stable. If heart rate is below 50/min and patient sympto­matic, injection atropine (0.6–1.0 mg) IV may be given. zz Sinus tachycardia: The underlying aetiology of tachy­ cardia is detected (infection, anxiety, peri­carditis, hypovolaemia, left ventricular failure, pain) and treated appropriately. zz Atrial fibrillation: May be treated with digoxin, calcium-channel blockers or β-blockers-which reduce the ventricular rate. If AF is resistant to these drugs and patient is symptomatic, cardio­version may be attempted. Digoxin is indicated in AF with heart failure and calcium channel blockers (verapamil) and β-blockers are indicated in AF without heart failure. zz Atrial flutter: Cardioversion is the preferred treatment. zz Supraventricular tachycardia: Sustained SVT should be treated with intravenous verapamil or adenosine. If it does not revert to sinus rhythm cardioversion may be attempted if concomitant failure is present. zz Junctional tachycardia: Rapid and sustained junc­ tional tachycardia should be treated in a manner similar to that for SVT. zz Premature ventricular contractions and ventricu­ lar tachycardia: These may be treated by giving inj. Lidocaine IV in a dose of 1 to 4 mg/kg body weight bolus, followed by an infusion at 2 to 4 mg/min. Other drugs which may be used are procainamide, amiodarone, metopro­lol, tocainide, quinidine or mexiletine. If ventricular tachycardia is not controlled by these drugs, then a synchronised DC shock should be administered. VPC: K—4.5 mEq and Mg—2.5 mEq—β-blocker is indicated. The criteria for treating premature ventricular contractions has been discussed in the chapter on ECG, under significant ventricular extrasystoles. zz Ventricular fibrillation: Immediate unsynchronised car­dio­version is the treatment of choice. Drugs that may be tried are lidocaine or bretylium. Non-pharmacologic therapy for VT/VF: —— It includes automatic ICD and catheter ablation. —— ICDs provide automatic recognition and treat­ ment of ventricular arrhythmias. —— ICD is very useful in primary prevention of sudden cardiac death (SCD). zz

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Fig. 4.149  Implantable cardiac defibrillator

Sudden cardiac death is common in hyper­ trophic cardiomyopathy, congenital long QT syndrome, family history of SCD and CAD with low EF. —— ICD is useful in most patients with LVEF of < 35% for more than 3 months. —— ICD implantation is essential to protect against SCD prior to cardiac transplantation (Fig. 4.149). zz Heart blocks: First degree heart block, mobitz type I block and asymptomatic complete heart block need not be treated. Mobitz type II and symptomatic complete heart block must be treated with the use of a permanent pacemaker.

Pacemakers Pacemakers supply electrical initiation to contraction. They may dramatically benefit even a very old patient. The pacemaker lies subcutaneously where it may be programmed through the skin as needs change, e.g. for different rates. They last for 7 to 15 years. Indications for Temporary Pacemaker zz zz zz

Symptomatic bradycardia, uncontrolled by drugs. Suppression of drug-resistant VT and SVT. Acute conduction disturbances: —— After acute anterior MI, prophylactic pacing is required in: „„ Second or third degree AV block; „„ Bi- or tri-fascicular block. —— After acute inferior MI, if patient is symptomatic.

Indications for Permanent Pacemaker zz zz

2° (Mobitz type II) and 3° heart block. Symptomatic bradycardias (e.g. sick sinus syn­drome).

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Cardiovascular System zz

zz

Occasionally useful in suppressing resistant tachy­arrhythmias. Persistent bi-fascicular block after MI (this remains controversial).

Postinfarct Angina This may occur in 50% of patients having residual stenosis in the infarct related vessel. This may be treated by controlling the concomitant failure or by IV nitroglycerine, if there is no contraindication to its use. Coronary angiography and mechanical revasculari­ sation can be done.

Myocardial Stunning It is a temporary and reversible post-ischaemic systolic and/or diastolic ventricular dysfunction in which the myocardium is still viable. This condition may be reversed by thrombolytic therapy, PTCA or CABG.

Pericarditis This may occur in the early or late stage of MI. In the early stage, it is particularly common on the second or third day after MI. In the late stage, occurring weeks or even months after MI, it is due to probably an autoimmune reaction to the necrotic myocardium. It is known as ‘postmyo­ cardial infarct syndrome’ or Dressler’s syndrome and is characterised by persistent fever, pericarditis and pleurisy.

Treatment zz zz

zz

Anticoagulants are contraindicated. Pericarditis occurring immediately after MI is treated by using NSAIDs. Steroids are contra­indicated, as aneurysm formation or cardiac rupture may occur due to poor healing of the infarcted area. Dressler’s syndrome is treated with NSAIDs initially, and if there is no response, then steroids may be used.

Cardiac rupture is common in females, in the first week after MI, during the first infarct, in the elderly, in the absence of LVH, when associated with hyper­ten­sion and in patients receiving NSAIDs and steroids. There is electromechanical dissociation (electrical activity persists with pump failure and a non-record­able pulse and BP).

Thromboembolism Thrombosis forms on the endocardial surface of freshly infarcted myocardium and may lead to sys­temic embolism. Deep vein thrombosis may lead to pulmonary embolism.

Treatment Prevention of thrombus formation is done by use of anticoagulants.

Ventricular Aneurysm Predisposing Factors zz zz zz zz

Decreased left ventricular ejection fraction. Anterior wall myocardial infarction. Congestive cardiac failure. Large regional wall motion abnormality.

A LV aneurysm (Figs 4.150 and 4.151) may develop causing cardiac failure, ventri­cular arrhythmias, mural thrombus and sys­temic embolism. Its occurrence is particularly common when there is persistent occlusion of the infarct related vessel and should be suspected when there is persistent ST elevation in the ECG. True LV aneurysm must be differentiated from false LV aneurysm, occurring due to cardiac rupture and subsequent formation of an organised haematoma

Mechanical Complications zz

zz

zz

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Papillary muscle damage, with onset of severe MR and acute pulmonary oedema. A loud PSM and S3 may be heard. Rupture of the interventricular septum leading to a left to right shunt through a VSD. A loud PSM may be heard. In contrast to MR, however, an acquired VSD causes right heart failure rather than acute pulmonary oedema. Rupture of the ventricle leading to cardiac tam­ponade.

Fig. 4.150  Acute infarct in left MCA territory with post MI LV clot

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Manual of Practical Medicine Comparison of Anterior and Inferior Wall Myocardial Infarction Features Extent of necrosis Extent of coronary atherosclerosis Complications –  Ventricular septal rupture – Aneurysm –  Free wall rupture –  Mural thrombus –  Heart blocks –  Bundle branch blocks Prognosis Diagnosis – Symptoms

Inferior MI Small Large

Apical, easily repaired Common Uncommon Common Uncommon Common

Basal, difficult to repair Uncommon Rare Uncommon Common Uncommon Better than that of anterior MI

Worse than that of inferior MI Gastrointestinal symptoms unusual

–  Physical examination

– ECG – Echocardiogram

Anterior MI Large Small

Gastrointestinal symptoms (nausea, vomiting, hiccough) common Tachycardia; hypotension uncommon. Jugular Bradycardia; hypotension common. Jugular venous distention common. 20% have S3 venous distention less common than with inferior MI. 50% have S3 Features of anterior wall MI Features of inferior wall MI Abnormal left ventricular wall motion is Abnormal left ventricular wall motion is inferior in location. anterior in location. No abnormal right Right ventricular abnormal wall motion present in ventricular wall motion approximately one-third of patients.

Right Ventricular Infarction In approximately 30% of patients with Q-wave inferior wall MI, there is associated right ventricular infarc­tion. Rarely, it can occur with anterior wall MI.

Clinical Features zz zz zz zz zz zz zz zz

Fig. 4.151  LV aneurysm

Treatment zz

covered by the pericardium. False LV aneurysms occur due to cardiac rupture following MI, due to injury or due to previous cardiac surgery. True LV aneurysm can be differentiated from the false LV aneurysm, by use of 2D Echo, where, false LV aneurysm has a narrow orifice, and true LV aneurysm has a wide orifice, connecting it to the heart. False LV aneurysm must be surgically corrected even in the absence of symptoms or signs. True LV aneurysm may be surgically corrected if there is associated refractory failure or systemic embolisation in spite of adequate anticoagulation.

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Hypotension Pulsus paradoxus Raised JVP Kussmaul’s sign Clear lungs RV S3 and S4 TR murmur Enlarged, tender liver.

zz

Diuretics are contraindicated. IV fluids are given to counteract the hypotension.

Management zz zz zz

zz

Bed-rest Nasal O2 Morphine given in an intravenous form (≤ 1 mg per minute) to a maximum dose of 10 to 15 mg. It acts as a pulmonary venodilator and also as an analgesic to alleviate anxiety. Nitrates may be given sublingually for rapid action of relief of pain by coronary vasodilation. It also helps to reduce the preload of the heart, being a predominant

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Cardiovascular System venodilator. If pain persists after adminis­tration of sublingual nitrates, IV infusion of nitroglycerine may be given, provided the sys­tolic BP is maintained above 100 mm Hg. zz Aspirin is given orally in the dose ranging from 100 to 300 mg. zz Thrombolytic therapy (Streptokinase, Urokinase, Tissue plasminogen activator) may be given and is particularly useful if given within 6 hrs of onset of symptoms, but may be given up to 12 hrs after onset of symptoms. Ideal—door to needle time 30 min.

Thrombolytic agents for Myocardial Infarction Agents with fibrin specificity: —— Alteplase (rt-PA) 15 mg IV bolus followed by 0.75 mg/kg IV infusion (up to 50 mg) over 30 minutes then 0.5 mg/kg (up to 35 mg) by IV infusion over 60 minutes (maximum dose 100 mg IV over 90 minutes) —— Reteplase (r-PA) 10 mg IV bolus over 2 minutes followed by another 10 mg IV bolus after 30 minutes. —— kg-30 mg, 61–70 kg -35 mg, 71-80 kg-40 mg, 81–90 kg- 45 mg, >90 kg-50 mg) Agents without fibrin specificity: —— Streptokinase—1.5 million units IV infusion over 60 minutes —— Urokinase: Because of the development of antibodies, patients who were previously treated with strepto­kinase should be given an alternate thrombolytic agent.

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Contraindications for Thrombolytic Therapy —— Absolute contraindications: —— Active bleeding —— Defective haemostasis —— Recent major trauma —— Tenecteplase (TNK-tPA) 0.5 mg/kg IV bolus ( 10 minutes —— H/O CNS tumour, aneurysm, AV malformation —— Active peptic ulcer —— Aortic dissection —— Acute pericarditis —— Active inflammatory bowel disease —— Active cavitary lung disease —— Pregnancy

Relative contraindications: Systolic BP > 180 mm Hg —— Diastolic BP >110 mm Hg —— Bacterial endocarditis —— Haemorrhagic diabetic retinopathy —— H/O intraocular bleeding —— Chronic warfarin therapy —— Severe renal or liver disease —— Severe menstrual bleeding: Beta blockers can be used in LV dysfunction with low ejection fraction whereas calcium channel blockers should not be used. ACE inhibitor is the ideal choice in the presence of LV dysfunction and cardiac failure with normal renal function. zz Heparin may be given in a dose of 5000 U, 12 hourly, subcutaneously, as prophylaxis against develop­ment of deep vein thrombosis and 12,500 U, 12 hourly, subcutaneously, as prophylaxis against development of mural thrombus or exten­sion of the coronary thrombus, for a period of 7 to 10 days. zz β-blockers are started immediately, or after two weeks and given for a minimum duration of two years, if there is no contraindication for their use, as these agents (atenolol, metoprolol, proprano­ lol) help in reducing morbidity and mortality sig­ni­­ ficantly. β-blockers can be given even if the ejection fraction as determined by Echo is Familial > Primary amyloidosis.

Clinical Features

Fig. 4.156  Restrictive cardiomyopathy

Hypereosinophilic syndrome (Loffler’s endocarditis) Carcinoid syndrome zz Radiation zz Drugs—serotonin, ergotamine Amyloidosis is the most common cause of restrictive cardiomyopathy. Primary amyloidosis is the most common type to affect the heart and it is nothing but plasmacell disorders (AL type). It is associated with bad prognosis. Cardiac involvement is uncommon in secondary amyloidosis (AA type). Familial form is related to mutation of TTR protein (ATTR-M). Senile cardiac amyloidosis is due to TTR normal protein deposition due to ageing (ATTR Wild). zz zz

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X-ray: Mild cardiomegaly. ECG: Low voltage; conduction defects. Doppler echo: Abnormal diastolic function; sym­metrical thickened LV walls and a normal or slightly decrea­s­ed systolic function. Cardiac catheterisation: Same findings as above plus ele­ vated left and right sided filling pressures. Radionuclide studies: Normal or mildly decreased systolic function. CT and MRI: Detect thickened pericardium in constric­ tive pericarditis. Endomyocardial biopsy: Interstitial infiltration or fibro­­sis.

Hypertrophic Obstructive Cardiomyopathy (Fig. 4.157) Hypertrophic cardiomyopathy is defined as left ventricular hypertrophy that develops in the absence of causative haemodynamic factors. Other Names zz zz zz

Hypertrophic obstructive cardiomyopathy (HOCM) Asymmetric septal hypertrophy (ASH) Idiopathic hypertrophic sub-aortic stenosis (IHSS)

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Manual of Practical Medicine to systolic anterior motion of anterior leaflet of mitral valve (SAM).

Symptoms Dyspnoea, angina, syncope, palpitation, sudden death.

Signs Jerky pulse, double or triple apex, S3, S4, late systolic murmur (outflow obstruction + MR) AF common when associated with MVP.

Differential Diagnosis Fig. 4.157  Hypertrophic obstructive cardiomyopathy midventricular type

Pathophysiology Most common genetic cardiovascular disorder in humans zz Autosomal dominant inheritance due to sarcomeric protein mutation zz Asymmetrical septal hypertrophy zz Myofiber disarray—fibrosis (interstitial and replacement) zz Thickened septal vessels (Fig. 4.158). It can be familial (autosomal dominant) or sporadic. In familial cases, abnormality of beta myosin heavy chain gene on chromosome 14 is found. There is asym­ metrical, elaborate ventricular hypertrophy of septum or apex with malalignment of myocardial fibres. The stiff, non-compliant ventricle impedes diastolic filling. Asymmetric hypertrophy of septum (ASH) may also cause dynamic LV outflow tract obstruction and MR due zz

ECG: Shows LVH and LBBB; deep broad Q-waves and arrhythmias (SVT, AF, VT) seen. X-ray: Mild to moderate cardiac enlargement. Echo: Asymmetrical septal hypertrophy (septum: Left ventricular posterior free wall is 1.3 or more : 1) and SAM. Cardiac catheterisation: Small, banana like or spadeshaped LV cavity; thickened papillary muscle and trabeculae; Cavity obliteration in systole; Dynamic LV outflow obstruction. Radionuclide studies: Vigorous systolic function and asymmetric septal hypertrophy. Contrast MRI: It is superior to echocardiogram in providing accurate measurement of regional hyper­ trophy and fibrosis.

Management zz

zz zz zz zz zz zz

zz zz zz

zz

zz

B A Figs 4.158A and B Hypertrophic obstructive cardiomyopathy is characterized by misalignment and disarray of the enlarged myofibrils and myocytes

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ABCD – Amiodarone, Beta- blocker, Calcium channel blocker (verapamil/diltiazem), Disopyramide. The treatment of choice is cardiac transplantation. Beta blocker for angina Amiodarone for arrhythmia Septal myectomy or myotomy In chronic AF, anticoagulation Avoid diuretics, digitalis, β-agonists, nitrates, vasodilators like nifedipine IE prophylaxis when associated with MR Alcohol ablation treatment Insertion of an implantable cardioverter defibrillator in high risk patients Verapamil, diltiazem, disopyramide improve the symptoms of HCM by augmenting the diastolic ventricular filling IE prophylaxis when there is prior history of IE.

Sudden Death is Common in those who have: zz zz

Ventricular tachycardia (non-sustained) Family history of sudden death

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Cardiovascular System zz zz zz zz zz

History of syncope Previous history of resuscitation Marked ventricular hypertrophy Abnormal BP response to exercise Genetic mutations at risk.

zz zz

Infiltrations and Granulomas zz zz

Primary Cardiomyopathies zz zz zz zz

zz

Idiopathic Familial Eosinophilic endomyocardial disease Endomyocardial fibrosis.

zz zz

Secondary Cardiomyopathies

zz

zz

Myocarditis

zz

Bacterial, fungal, viral, protozoal, metazoal, ricket­tsial.

zz

Metabolic

zz zz

zz

Aetiology is unclear. Symptoms and signs are similar to other forms of dilated cardiomyopathy. It is common in multiparous women of >30 years age. zz Incidence—1:2000 and 1:15,000 deliveries Risk Factors

Glycogen storage disease Mucopolysaccharidoses.

zz zz

Connective Tissue Disorders zz zz zz

Alcohol Radiation Drugs (lithium, cyclophosphamide, doxorubicin, dauno­­rubicin).

Peripartum Cardiomyopathy (PPCM)

Hyper and hypothyroidism Hyper and hypokalaemia Nutritional deficiency—thiamine, protein Hemochromatosis.

Familial Storage Disease zz

Muscular dystrophy Myotonic dystrophy Friedreich’s ataxia Refsum’s disease.

Sensitivity and Toxic Reactions

Causes

zz

Amyloidosis Sarcoidosis Malignancy (leukaemias, lymphomas, malignant melanoma, carcinoma of lung or breast).

Neuromuscular

zz

zz

Progressive systemic sclerosis Dermatomyositis.

zz

SLE Polyarteritis nodosa Rheumatoid arthritis

zz zz zz

Increased maternal age Increased parity Twin pregnancy Malnutrition Use of tocolytic therapy for premature labor Preeclampsia or toxaemia of pregnancy.

Differential Diagnosis: Cardiomyopathies

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Features

Dilated

Hypertrophic

Restrictive

Ejection fraction (Normal >55%)

60%

25–50%

LV diastolic dimension (Normal 60 mm

Often decreased

RA

RA > LA

—

 Variation of RA pressure with respiration

Absent

Present

Present

—

 Ventricular diastolic pressures

Equal in RV and LV

LV > RV by more than 5 mm Hg

RV > LV

—

  PCWP

< 18 mm Hg

> 18 mm Hg

Low

—

  Pulmonary artery pressure

< 50 mm Hg

> 50 mm Hg

Low

Not helpful

May be helpful

Not helpful

Biopsy of myocardium

No

Abbreviations: JVP, Jugular venous pressure; RA, Right atrium; LA, Left atrium; PCWP, Pulmonary capillary wedge pressure

Criteria for Diagnosis zz Development of cardiac failure during last trimester of pregnancy or within 6 months of delivery. zz Absence of determinable cause for cardiac failure zz Demonstrable impairment in LV systolic function. Management is similar as for other forms of DCM. Selective use of vasodilators like hydralazine and avoid ACE inhibitors during pregnancy. Anticoagulation is necessary. Avoid future pregnancy as the condition can recur. Endocardial Fibroelastosis This is characterised by elastic and fibrous thickening of the endocardium. It commonly involves LV and LA. RV and RA are less frequently involved; It is one of the cardiac disorders causing CCF in infancy. Endocar­dium has a smooth, glistening white surface consisting of dense layers of elastic fibres. Patients have features suggestive of myocardial failure (dyspnoea, orthopnoea and cough); They may have holo­ systolic murmur of MR. Chest X-ray shows cardiomegaly; ECG shows LVH; Echo shows LV dila­ta­tion with poor contractility. Death usually occurs within lst year of life.

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Patients can be treated symp­tomatically for CCF and valve replacement may be done for MR.

PERICARDITIS zz zz zz

Acute: < 6 weeks Subacute: 6 weeks–6 months Chronic: > 6 months

Aetiologic Classification (Figs 4.159 to 4.162) Infections zz zz

zz

Mycobacterium tuberculosis Bacterial: Staphylococcus, Streptococcus, Pneumococcus, Haemophilus, Neisseria, Chlamydia, etc. Viral: CMV, HIV, coxsackie virus, echovirus, adenovirus

Malignancies zz

Primary—Mesiothelioma, angiosarcoma, rhabdomyo­ sarcoma, etc.

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Cardiovascular System

Fig. 4.159  Pericardial effusion (X-ray chest)

Fig. 4.161  Constrictive pericarditis. Calcified pericardium (6 mm) leading to gross dilatation of RA and mild dilatation of LA with compression of RV and LV

Fig. 4.160  Thickened and calcified pericardium

Fig. 4.162  Pericardial effusion (ECHO) Abbreviations: LV, Left ventricle; RV, Right ventricle; AV, Antrioventricle; LA, Left atrium; EFF, Efferent

zz

Metastatic—lung cancer, breast cancer, lymphoma, leukemia, stomach cancer, melanoma, etc.

Connective Tissue Disorders zz zz zz zz

Systemic lupus erythematosus Rheumatoid arthritis Scleroderma Behcet’s disease

Iatrogenic zz zz

Other Conditions zz zz zz

Metabolic Disorders zz zz

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Hypothyroidism Chronic renal failure

Percutaneous coronary intervention Pacemaker, ICD, cardiac resynchronization therapy, CPR, etc.

zz zz zz zz

Chest wall injury—blunt/penetrating Aortic dissection Myocarditis/pericarditis Post myocardial infarction: Dressler’s syndrome Chylopericardium Cardiac failure Sarcoidosis

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Manual of Practical Medicine zz zz

Infectious mononucleosis Post-irradiation

Idiopathic zz

No identifiable cause

Management zz

zz

zz

zz

Aspirin or indomethacin are useful; When the res­ ponse is not satisfactory, steroids can be used. Anticoagulants are contraindicated (haemopericar­ dium or tamponade may occur). Steroids are best avoided in pericarditis following MI because of myocardial aneurysm formation and rupture. In chronic pericarditis, pericardiectomy should be consi­dered.

CARDIAC TAMPONADE The accumulation of fluid in the pericardium sufficient to cause serious obstruction to the inflow of blood to the ventricles results in cardiac tamponade.

Causes zz zz zz zz zz zz zz

Neoplastic disease Idiopathic pericarditis Uraemia Tuberculosis Cardiac surgery Trauma Haemopericardium

Diastolic collapse of right ventricular free wall and right atrium is the characteristic feature of cardiac tamponade. Echocardiographic classification based on pericardial separation zz zz zz zz

Minimal: 5 mm (50–100 mL) Small: 5-10 mm (100–250 mL) Moderate: 10–20 mm (250–500 mL) Large: > 20 mm (> 500 mL)

Management If manifestations of tamponade appears, pericardio­ centesis must be carried out at once and is life saving. A small catheter advanced over the needle inserted into the pericardial cavity may be left in place to allow draining of the pericardial space if fluid reaccumulates. Surgical drainage through a limited thoracotomy may be required in recurrent tamponade or when tissue diagnosis is needed. If pericardial drainage is delayed, IV saline is given to maintain adequate ventricular filling along with parenteral inotropic support to stabilise the patient. Do not use diuretics, nitrates or any other pre-load reducing agents.

CARDIAC ARREST Causes

Clinical Features

Anatomical/Mechanical

The symptoms depend upon the rapidity of accumu­ lation of fluid. As small as 200 ml can produce the critical state when fluid develops rapidly or more than 2 litres in slowly developing effusions. Patient presents with severe dyspnoea, chest tightness and dizziness. In striking contrast to elevated venous pressure (prominent × descent), arterial hypotension, and pulsus paradoxus, cardiac pulsation often are impalpable (Beck’s triad). Kussmaul’s sign, pericardial knock and 3rd heart sound are rare.

Coronary artery Atherosclerosis disease Ischaemic heart disease Anomalous left coronary artery from pulmonary artery (ALCAPA). Kawasaki disease Myocardial disorders Primary Hypertrophic obstructive cardiomyopathy Secondary Dilated cardiomyopathy Infiltrative cardiomyopathy Myocarditis Valvular heart Aortic stenosis, disease Pulmonary stenosis Mitral valve prolapse syndrome Cardiac failure Cardiac shock

Beck’s Triad zz zz zz

Hypotension Raised JVP Muffled or absent heart sounds.

Electrocardiography Low voltage complexes with or without electrical alternans (Fig. 4.163).

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Echocardiogram

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Cardiovascular System

Fig. 4.163  Electrical alternans

Electrical zz zz zz zz zz

zz

Wolff-Parkinson-White syndrome Romano-Ward syndrome (Long QTc) Jervell-Lange-Nielsen syndrome (Long QTc) Electric shock. Metabolic: —— Hypoxia —— Hypercapnia —— Hypocalcaemia —— Hypomagnesaemia —— Hypokalaemia —— Hyperkalaemia. Toxins: —— Antiarrhythmics —— Digitalis —— Cocaine —— Adrenaline.

Cardiopulmonary Resuscitation (Basic Life Support) Cardiopulmonary resuscitation (CPR) was developed to rescue patients with acute circulatory or respiratory failure or both. The ABCs of basic life support are: zz Airway

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Breathing Circulation. and are essential for successful resuscitative efforts.

zz zz

When one encounters an unconscious patient, the following procedures are recommended: zz Determine responsiveness by gently shaking the patient. Do not shake the head or neck unless trauma to this area has been excluded zz Position the patient on a firm, flat surface zz Assess patency of airway and presence of respiration. Place the palm of one hand on the patient’s forehead and apply firm pressure to tilt the head backward. At the same time, place the index and middle fingers of the other hand under the chin and displace the mandible anteriorly. This will raise the tongue away from the posterior pharynx. If a neck injury is suspected, the neck tilt should be avoided and the modified jaw thrust, by grasping the angles of the mandible with the fingers of both hands and moving the mandible anteriorly is done. With the airway thus made patent, the presence of spontaneous respiration is looked for. zz Assisted ventilation is started when there is no spontaneous respi­ration. Gently pinch the nose closed with the index finger and thumb of the hand kept on the forehead. Make a tight seal over the patient’s mouth and ventilate twice with slow, full breaths

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Manual of Practical Medicine (1–1.5 sec­onds each). A two second pause should be interspersed between breaths. Alter­native­ly, an Ambu bag may be used for ventilation. Indicators of adequate ventilation are the rise and fall of the chest and detection of escaping air during expi­ration. zz Palpate the carotid pulse for at least 5 seconds. If a carotid pulse is palpable, assisted ventilation should be continued at a rate of 12 breaths per minute. If carotid pulse is not palpable, then cardiac resus­citation should be started. zz Cardiac resuscitation is started by placing the patient on a firm surface. An initial blow to the chest over the sternum is delivered. Chest compressions are performed by placing the heel of one hand on the back of the other and placing it 1 inch above the xiphoid process of the sternum, with the shoulders directly above the hands and the elbows in a locked position. With the heel of the hand, the sternum is compressed 3 to 5 cm, the thrust being applied straight down towards the spine. Basic life support should be stopped for 5 seconds at the end of the first minute and every 2 to 3 minutes thereafter to determine whether the patient has resum­ed spontaneous breathing or circulation. The procedure should be continued till advanced cardiac life support is made available for revival. CPR should be continued for a minimum period of 30 minutes. If, however, the pupils become dilated and fixed and the patient does not regain consciousness, CPR may be discontinued. CPR need not be done in end organ failure or multisystem failure.

up to 3 to 6 weeks before the procedure, and for 1 week after the procedure. 2. Atrial flutter is one of the easiest rhythms to convert to sinus rhythm. Cardioversion frequently requires less than 50 joules. 3. Re-entrant SVTs require 25 to 100 joules for cardio­version. 4. Ventricular tachycardia requires synchronised cardio­ version of 20 to 50 joules to be applied. If however the pulse and blood pressure are not recordable, 200 joules, followed by 360 joules (if no response) should be delivered. 5. Ventricular fibrillation requires repeated unsyn­ chronised cardioversion, starting with 200 joules, fol­ low­ed by 3 to 4 applications of 360 joules. If there is no response, then the following man­oeuvres may be carried out: CPR—Establish IV access—Epinephrine 1:10,000, 0.5 to l mg. IV stat—Intubation—DC shock of 360 joules— Lidocaine 1 mg/kg. IV stat—DC shock of 360 joules— Bretylium 5 mg/kg. IV stat—DC shock of 360 joules— Bretylium 10 mg/kg. IV stat—DC shock of 360 joules— Repeat Lidocaine and Bretylium—DC shock of 360 joules. Sodium bicarbonate in a dose of 0.5 mEq/kg body weight may be administered intermittently every 10–15 minutes to counteract the developing acidosis. Immediate cardioversion is mandatory if the arrhy­thmia causes angina, hypotension or heart failure.

Contraindications to Cardioversion zz

Cardioversion (DC Shock) Cardioversion or DC shock is a safe means of termi­nating various tachyarrhythmias and restoring sinus rhythm. Cardioversion is only effective for re-entrant arrhy­th­ mias, including atrial and ventricular fibrillation, but not for those caused by abnormal automaticity.

zz

Indication for DC Shock

zz

1. Atrial fibrillation is one of the most common indications for cardioversion. A minimum of 100 joules is required. Patients are unlikely to maintain sinus rhythm if atrial fibril­lation is of longstanding duration or the echocardio­graphically determined left atrial dimension exceeds 4.5 cm. Cardioversion is more like­ ly to be complicated by systemic emboli in patients with atrial fibrillation of more than 3 days’ duration and hence anticoagulants should be administered for

Ch-4d.indd 322

zz

zz

zz

zz

zz

zz

Digitalis toxicity: Elective cardioversion should not be performed in the presence of potentially toxic levels of digoxin. If cardioversion is necessary, then prophylactic lidocaine therapy should be given and cardioversion should begin at low energy levels. Repetitive, short-lived tachycardias. Multifocal atrial tachycardia or other automatic arrhy­thmias. Patients with sick sinus syndrome, complete AV block or on β-blockers (as cardioversion may poten­tiate severe bradycardia). Patients with supraventricular arrhythmias in hyper­ thyroidism should be made euthyroid before elective cardioversion. Patients with AF secondary to mitral stenosis must have the underlying problem (MS) corrected before attempting to revert AF to sinus rhythm. In patients with pacemaker (as pacemaker may be damaged). Tachyarrhythmias developing immediately after car­­ diac surgery (as they cannot maintain sinus rhythm). AF of long-standing duration (> 1 year duration).

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CARDIAC SURGERY zz

zz

zz





zz zz zz

Valvuloplasty: This procedure is useful in mitral and pulmonary stenosis if the valves are pliable, noncalcified, and no associated regurgitation. Valvotomy: Closed valvotomy is rarely performed now. Open valvotomy is performed under cardiopulmonary bypass through a median sternotomy. Valve replacements: Mechanical valves: They may be of the ball-cage (StarrEdwards), tilting disc (Bjork-Shiley), or double tilting disc (St Jude) type. These valves are very durable but the risk of thromboembolism is very high; patients require life long anticoagulation. Xenograft: They are made from porcine valves or pericardium. These valves are less durable and may require replacement every 8–10 years. Anticoagulation is not required unless there is AF. Homografts: They are cadaveric valves and they are very useful in young patients and in the replacement of infected valves. Complications of prosthetic valves: 1. Systemic embolism 2. Infective endocarditis 3. Haemolysis 4. Structural valve failure 5. Cardiac arrhythmias Correction of congenital defects CABG Cardiac transplantation.

CARDIAC TRANSPLANTATION Cardiac transplantation is the therapy of choice for end stage heart disease, who are unlikely to survive for the next 6–12 months as evidenced by a decrease in ejection fraction of less than 20% or presence of serious ventricular arrhythmias. Optimal candidates for transplantation are those who do not show evidence of end stage organ damage from cardiac failure and do not suffer from other systemic illnesses like collagen vascular disease or HIV. Longstanding pulmonary hypertension, recur­rent pulmonary emboli or pulmonary infarction carries a high risk of intraoperative death. Patients who are dopamine/dobutamine dependent to maintain an adequate cardiac output are those who get the highest priority for a donor heart.

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A suitable donor is obtained by doing ABO match­ ing and lymphocyte cross matching. He should also test negative for cytomegalovirus infection. The donor heart is removed, except for posterior wall of RA, SVC and IVC. The LA along with the pulmonary veins are also left in situ. The donor heart is then sutured to the posterior wall of the two atria of the recipient’s heart, the rest of the heart having been incised and removed. Rejection of cardiac transplant is characterised by perivascular infiltration of killer T-lymphocytes, which may later migrate into the myocardium. This can be assessed by repeated percutaneous transvenous RV endomyocardial biopsies via the right internal jugular vein, every 3 months. Prolongation of isovolumetric relaxation time by echo may also provide an early clue to rejection. Immunosuppressive therapy is given with cyclos­porine, azathioprine and prednisolone. There is an increased risk of development of malignancy due to this. The donor sinus node controls the rate of the transplanted heart. The controlling sinus node has no innervation by the autonomic nervous system and maintains a constant heart rate of 100–110 beats per minute. The ECG taken after transplantation shows two P-waves (one from the recipient’s SA node and the other from the donor’s SA node). The P-wave from the recipient’s SA node is dissociated from the QRS complexes as the impulse does not cross the suture line, whereas the P-wave arising from the donor SA node precedes the QRS complex. Chronic rejection may occur in the form of accel­erated atherosclerosis of the coronary arteries, affect­ing both the proximal and distal vessels and is the most important cause of death. Angina is rare, as the transplanted heart is devoid of autonomic innervation.

Contraindications to Cardiac Transplantation zz zz zz zz zz zz zz zz zz zz



Age more than 65 years Active infection DM with end-organ disease Pulmonary function < 60% predicted or COPD Serum creatinine > 2 mg/dL or Creatinine clearance < 40 mL/minute Serum bilirubin > 2 mg/dL Elevated transaminases > 2 × normal value Pulmonary artery systolic pressure > 60 mm of Hg Transpulmonary gradient > 15 mm of Hg (TPG = Mean pulmonary artery pressure minus capillary wedge pressure)

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5

Respiratory System

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ANATOMICAL LANDMARKS The trachea bifurcates at the level of angle of Louis anteriorly and between the 4th and 5th thoracic spines posteriorly. The second costal cartilage is connected to the angle of Louis. The ribs are counted downwards from the second rib. Angle of Louis is the transverse bony ridge at the junction of the body of the sternum and the manu­brium sterni. Major interlobar fissure (Fig. 5.1) is marked by a line drawn from T2 spine along the medial border of the scapula, with the arm kept hyperabducted, to the 6th rib at its costochondral junction, crossing the 5th rib at the mid axillary line. It corresponds to the upper border of the lower lobe. Minor interlobar fissure (Fig. 5.1) is marked by a horizontal line drawn from the sternum at the level of 4th costal cartilage to meet the first line of the major interlobar fissure. It marks the boundary between the upper and middle lobes.

Right side

Left side

Upper

Apical (1) Posterior (2) Anterior (3)

Upper

Apical (1) Posterior (2) Anterior (3)

Middle

Lateral (4) Medial (5)

Lingular

Superior (4) Inferior (5)

Lower

Apical (6) Medial basal (7) Anterior basal (8) Lateral basal (9) Posterior basal (10)

Lower

Apical (6) Anterior basal (7) Lateral basal (8) Posterior basal (9)

BRONCHOPULMONARY SEGMENTS Each main bronchus divides into three lobar bronchi. On the right side, one each to the upper lobe, middle lobe and lower lobe. On the left side, one each to upper lobe, lingular lobe and remainder of the lower lobe. Then these divide into segmental bronchi to individual segments. The bronchopulmonary segments of the lungs on both the left and right side is given in the next column with their numbers.

Borders of the Lung The apices of the upper lobes of both the lungs rise 2 to 3 cm above the clavicles. From the apices of the upper lobe the inner margins of the lungs and their covering pleura start towards the sternum, meeting each other in the midline at the sternal angle. On the right, the margin of the lungs continue down the sternum as far as the 6th costal cartilage and then run outwards and downwards to meet the mid axillary line at the 8th rib, the scapular line at the 10th rib and the para vertebral line at the T10 vertebrae. The landmark of the left lung is the same except that the lung border turns away from the sternum at the 4th instead of 6th costal cartilage due to the position of the heart.

Pleural Border

Fig. 5.1  Surface marking of major (right and left) fissures and minor fissure (right)

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At the apices and along the inner margins of the lungs, the pleura lies close to the lungs to follow the same surface marking; but at the lower border of the lung, the pleura extends 4 to 5 cm anteriorly and 9 to 10 cm posteriorly below the lung, lying at the level of 8th rib in the mid clavicular line, 10th rib at the mid axillary line and 12th rib at the scapular line. Upper lobes of the lung are accessible from the front, lower lobes from the back and all the three lobes in the axilla.

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PULMONARY CIRCULATION zz zz zz zz

Thin walled (single layer of smooth muscle) Low pressure with less autonomic influence Response to hypoxia—vasoconstriction Pulmonary vein supplies the respiratory part of the airway (respiratory bronchiole to alveoli).

SYSTEMIC CIRCULATION (BRONCHIAL CIRCULATION) zz zz zz zz

zz zz

Thick walled (double or triple layered smooth muscle) High pressure with significant autonomic influence Response to hypoxia—vasodilatation It supplies the air conducting part—entire airway up to terminal bronchiole Bronchial circulation—1–2% of cardiac output Due to high pressure, bronchial bleeding can cause massive haemoptysis.

SYMPTOMS AND SIGNS Cough It is the reflex act of forceful expiration against a closed glottis that helps in clearing the airways including foreign body.

Mechanism of Cough It is brought about by contraction of respiratory muscles against the closed glottis with a resultant increase in intrathoracic pressure followed by opening of the glottis with forced expiration at very high air flow rate in the upper airways.

Types of Cough zz

zz

zz

zz

zz

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Dry cough: Pleural disorders, interstitial lung disease, mediastinal lesions. Productive cough: Suppurative lung disease, chronic bronchitis, pulmonary TB. Short cough: It is seen in upper respiratory tract infections (common cold). Brassy cough: Cough with metallic sound produced by compression of the trachea by intrathoracic space occupying lesions. Bovine cough: Cough with loss of its explosive nature, e.g. tumours pressing on recurrent laryngeal nerve.

zz

zz

Prolonged and paroxysmal cough: It is present in chronic bronchitis and whooping cough. Barking cough: It is found in epiglottal involvement as well as in hysterical and nervous individuals.

Cough syncope (Post-tussive syncope): It is due to raised intrathoracic pressure, which reduces venous return to the heart, thereby diminishing cardiac out­put, resulting in cerebral hypoperfusion and syncope. Nocturnal cough: It is present in the following con­ditions: Chronic bronchitis zz Left sided failure zz Bronchial asthma zz Aspiration zz Tropical eosinophilia zz Post-nasal drip. zz

Drug induced cough is present in drug therapy with ACE inhibitors.

Sputum It is a mixture of tracheobronchial secretion, cellular debris, micro-organisms and saliva. The character of sputum is determined by its amount, colour, chronol­ogy, consistency and smell. Saliva contains squamous cells. Sputum contains epithelial cells. If sputum con­tains epi­thelial cells and eosinophils then suspect. zz Bronchial asthma zz Allergic bronchopulmonary aspergillosis (ABPA).

Amount Bronchorrhoea: When the quantity of sputum produc­tion is >100 mL/day, it is termed as bronchorrhoea. Copious sputum production is seen in conditions like: 1. Bronchiectasis 2. Lung abscess 3. Empyema rupturing into the bronchus 4. Necrotising pneumonia 5. Alveolar cell carcinoma. Copious sputum production upon changes in posture is seen in bronchiectasis and lung abscess. This pos­tural relationship to cough is due to irritation of the healthy bronchial mucosa. Large amount of colourless sputum is present in alveolar cell carcinoma.

Chronology Chronic bronchitis: Sputum production is more in the early morning for many years.

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Manual of Practical Medicine Bronchial asthma: Sputum production is more either in the morning or at night. Recent onset of sputum production signifies severe infection.

Colour of the Sputum zz

zz

zz zz

zz zz zz

Green or yellow coloured thick sputum indicates bacterial infections. The green colour to sputum is imparted by the enzyme myeloperoxidase (verdo­per­oxidase) Black coloured sputum is present in coal worker’s pneumoconiosis Rusty sputum is present in pneumococcal pneu­monia Red currant jelly sputum is seen in Klebsiella pneumonia Pink frothy sputum is present in pulmonary oedema Blood stained sputum is present in tuberculosis Anchovy sauce sputum is present in ruptured amoebic liver abscess.

Consistency Serous: It is clear, watery and frothy. It is seen in bronchoalveolar carcinoma. It may be pink, as occurs in pulmonary oedema.

Frank haemoptysis: It is the expectoration of blood only. Massive and fatal blood loss may occur. Frank haemoptysis daily suggests bronchogenic carcinoma. Haemoptysis in suppurative lung disease: Large quantities of foul smelling sputum and blood suggests suppurative lung disease. Spurious haemoptysis: Haemoptysis present secondary to upper respiratory tract infection, above the level of larynx. Pseudohaemoptysis: It is due to pigment, prodigiosin produced by gram-negative organism, Serratia marces­cens. Endemic haemoptysis: Present in infection with Para­ gonimus westermani (lung fluke).

Severity of Haemoptysis Mild 500 mL blood loss per day (or) rate of blood loss > 150 mL/hr (or) 100 mL blood loss per day for more than 3 days.

Mucoid: It is clear, greyish white or black in colour and frothy. It may be seen in conditions like chronic bron­chitis and chronic asthma.

If there is > 500 mL blood loss per day, aggressive intervention (rigid bronchoscopy or surgery) is advo­ cated. If the blood loss is sub-massive, after subsidence of haemoptysis, fibreoptic bronchoscopy is indicated.

Mucopurulent or purulent: Yellowish or greenish brown in colour, seen in bacterial infection.

Causes of Haemoptysis

Bronchial asthma: Macroscopically the sputum is ‘worm like’, which are remnants of casts of bronchus. Microscopically, the sputum consists of: a. Eosinophils b. Desquamated epithelium c. Curschmann spirals (whorled mucous plugs) d. Charcot-Leyden crystals (crystalloid debris of eosino­ phil membrane) e. Creola bodies (exfoliated cells due to disruption of muco­sal integrity).

Odour of Sputum Offensive and foetid: a. Lung abscess b. Bronchiectasis c. Anaerobic bacterial infection.

Haemoptysis It is defined as expectoration of blood, or bloody sputum.

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Types of Haemoptysis

Infection a. Tuberculosis b. Lung abscess c. Bronchiectasis d. Pneumonia e. Fungal infection (aspergillosis, nocardiosis, blasto­mycosis). Differences between Haemoptysis and Haematemesis Haemoptysis

Haematemesis

1. Cough precedes haemoptysis

Nausea and vomiting precedes haematemesis Not frothy pH acidic Mixed with food particles

2. Frothy due to admixture of air 3. pH alkaline 4. Mixed with macrophage and neutrophil 5. Melena absent 6. Bright red in colour 7. Previous history of respiratory disease 8. Diagnosed by bronchoscopy

Melena present Dark brown in colour due to acid haematin Previous history of peptic ulcer disease Diagnosed by gastroscopy

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Respiratory System Neoplasm zz zz zz

Bronchogenic carcinoma Bronchial adenoma Metastatic tumour to lung.

Cardiovascular Disorders zz zz zz zz zz

Mitral stenosis Pulmonary hypertension Aortic aneurysm Arteriovenous malformation Pulmonary embolism.

Congenital zz zz

Bronchial cyst Sequestration of lung —— Intralobar —— Extralobar.

Collagen Vascular Disorder zz zz zz

Vasculitis Wegener’s granulomatosis Goodpasture’s syndrome.

Traumatic zz

zz

Non-iatrogenic —— Blunt injury —— Inhalation of toxic gases or acid aspiration. Iatrogenic —— Diagnostic Biopsy procedure —— Therapeutic Anticoagulants Radiation fibrosis.

Miscellaneous

zz

Grading of Dyspnoea Modified Medical Research Council Dyspnoea Scale Grade 0 Breathless with strenuous exercise. 1 Short of breath when hurrying on the level or walking up a slight hill. 2 Walking slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at own pace on the level. 3 Stop for breath after walking about 100 yards or after a few minutes on the level. 4 Too breathless to leave the house or breathless when dressing. Sherwood Jones Classification Grade I: Able to do household work: With moderate difficulty zz With great difficulty. Grade II: Confined to chair or bed and: zz Able to get up with moderate difficulty zz Able to get up with great difficulty. Grade III: Totally confined to chair or bed. Grade IV: Moribund. zz

Bleeding disorders.

Receptors involved in Mechanism of Dyspnoea

Haemoptysis is uncommon in:

zz

zz

zz

Metastatic lesions of the lung except in secondaries due to choriocarcinoma and renal cell carcinoma. Viral infection.

Dyspnoea It is defined as the undue awareness of respiratory effort or of the need to increase the effort. Increased work of breathing is required in: Thickened pleura zz Pleural effusion zz Pneumothorax zz Airway resistance. zz

Increased demand of breathing is present in con­ditions like: zz Hypoxia zz Anaemia

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Acidosis Thyrotoxicosis. Increased respiratory effort is needed in: zz Breath-holding zz Paralysis of respiratory muscles. zz

zz zz

zz

J receptors, situated at the alveolo-capillary junc­tion, are responsible for rapid shallow breathing and they are stimulated by pulmonary congestion, oedema or micro­emboli. The stretch receptors in thoracic cage and lung. The chemoreceptors in the carotid arteries, aorta and reticular substance of medulla which respond to oxygen lack, carbon dioxide excess and decrease in pH. Receptors in the respiratory muscle which are imme­ diate cause of appreciation of dyspnoea.

Clinical Aspects of Dyspnoea Onset of dyspnoea can be as follows: Dyspnoea occurring within: Minutes Pneumothorax zz Pulmonary oedema due to cardiac arrhythmias zz

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Major pulmonary embolism Inhalation of foreign body Laryngeal oedema.

Hours zz Asthma (but can also be acute) zz Left heart failure zz Pneumonia. Days Pneumonia zz Adult respiratory distress syndrome zz Left heart failure zz Repeated pulmonary embolism. zz

Weeks Pleural effusion zz Anaemia zz Muscle weakness zz Tumours. zz

Months Pulmonary fibrosis zz Thyrotoxicosis zz Muscle weakness.

zz

Erosion of adjacent ribs and vertebrae, producing a constant chest pain.

Upper Retrosternal Pain It is a momentary pain which increases in intensity on coughing and subsides when the cough becomes productive. It is seen in acute tracheitis.

Mid or Lower Retrosternal Pain It is constrictive in character and may be present in: Acute mediastinitis zz Mediastinal tumour zz Mediastinal emphysema zz Reflux esophagitis zz Achalasia cardia. zz

GENERAL EXAMINATION

zz

Years zz Muscle weakness zz Chronic obstructive pulmonary disease zz Chest wall disorders.

zz zz zz zz

Chest Pain Pleural Pain It is caused by stretching of the inflamed parietal pleura. Present in all forms of pleurisy. It is a stabbing type of catchy pain occurring with deep inspiration or coughing and relieved by shallow breathing or lying on the affected side. Detailed description is dealt with in chapter on pain. Time of Onset Sudden onset Spontaneous pneumothorax, pulmo­ nary embolism Gradual onset Pneumonia.

Pancoast Syndrome Pancoast syndrome is caused by either a superior sulcus tumour (Pancoast tumour) or superior sulcus infiltrative disorder, e.g. pulmonary tuberculosis. The components of this syndrome are: zz Compression of C , T , T nerve roots resulting in 8 1 2 shoulder and arm pain. zz Compression of the cervical sympathetic chain and stellate ganglion, producing Horner’s syndrome.

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zz

zz

zz zz zz zz

Build Nourishment Dyspnoea Cyanosis (Mode of onset of respiratory disorder determines the presence or absence of cyanosis. In acute respiratory disease, lesser area of involve­ment can result in cyanosis, as occurs in lobar pneu­monia. In chronic lung disorder, unless bilateral extensive involvement is present, cyanosis may be absent) Anaemia may occur when there is: —— Haemoptysis —— Excessive sputum production and protein loss —— Loss of appetite leading to malnutrition Jaundice may be seen with: —— Pulmonary infarction —— Iatrogenic (drugs) —— Liver secondaries (obstructive jaundice) —— Pneumonia (pneumococcal) Clubbing Lymphadenopathy Eye Pedal oedema (cor pulmonale, hypoproteinaemia due to protein loss in sputum).

Clubbing (Fig. 5.2) It is a selective bulbous enlargement of the distal portion of the digit due to increased subungual soft tissue. The normal angle between the nail and the nail-bed is 160° and is known as the Lovibond angle. The minimum duration required for clubbing to manifest is 2 to 3 weeks. Clubbing first appears in the index finger.

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Fig. 5.2  Clubbing

Grading of Clubbing Fig. 5.3  Testing for fluctuation

Grade I Obliteration of the angle between the nail and the nail-bed and positive fluctuation test (Fig. 5.3) Grade II Parrot beak appearance Grade III Drumstick appearance Grade IV Hypertrophic osteoarthropathy.

Schamroth’s Sign When the dorsum of the distal phalanges of the fingers of both hands are approximated to each other, a diamond shaped gap (Fig. 5.4) is made out due to the presence of the Lovibond angle. This gap dis­appears with oblitera­tion of this angle, as occurs with clubbing.

Hypertrophic Osteoarthropathy It is a painful swelling of the wrist, elbow, knee, ankle, with radiographic evidence of sub-periosteal new bone formation. It can be familial or idiopathic. Other common disorders that can produce it are: a. Bronchogenic carcinoma b. Cystic fibrosis c. Neurofibroma d. AV malformation.

Theories of Clubbing 1. Neurogenic: Vagal stimulation causes vasodilata­tion and clubbing 2. Humoural: GH, PTH, oestrogen, PG, bradykinin cause vasodilatation and clubbing 3. Ferritin: Decreased ferritin in systemic circulation causes dilatation of AV anastomosis and hyper­trophy of the terminal phalanx 4. Hypoxia: Persistent hypoxia causes opening of deep AV fistulae of the terminal phalanx

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Fig. 5.4  Normal nail-bed angle

5. Platelet derived growth factor: This factor which is released secondary to infection anywhere in the body, also causes vasodilatation and this is the latest and most acceptable theory for clubbing.

Causes of Clubbing Congenital/Familial* Note: *Congenital hypertrophic pulmonary osteoarthropathy—pachydermoperiostosis. Acquired zz zz zz

Unidigital or pandigital Unilateral or bilateral Differential.

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Manual of Practical Medicine zz

zz

zz

Unidigital clubbing: It is seen in: —— Tophaceous gout —— Local injury —— Sarcoidosis. Unilateral clubbing: It is seen in: —— Aneurysmal dilatation of aorta, subclavian or innomi­­nate arteries —— Brachial AV fistula —— Hemiplegia —— Pancoast tumour. Differential clubbing: It is seen in PDA with reversal, with cyanosis and clubbing occurring in the lower limbs only.

Pulmonary and Thoracic Causes zz zz zz

zz zz zz zz zz zz zz

Bronchogenic carcinoma (rare in adenocarci­noma) Metastatic lung cancer Suppurative lung disease: —— Bronchiectasis —— Cystic fibrosis —— Lung abscess —— Empyema Interstitial lung disease Long standing pulmonary tuberculosis Chronic bronchitis Mesothelioma Neurogenic diaphragmatic tumour Pulmonary AV malformation Sarcoidosis.

Cardiovascular Causes zz zz zz zz

Cyanotic congenital heart disease Bacterial endocarditis Atrial myxoma Eisenmenger’s syndrome.

Gastrointestinal Causes zz zz zz zz

Cirrhosis of liver (more common in biliary cirrhosis) Ulcerative colitis Crohn’s disease GIT malignancy.

Miscellaneous zz zz zz zz

Syphilis Syringomyelia Acromegaly Thyrotoxicosis.

Pseudo-clubbing It may be seen in: Hansen’s disease due to resorption of tissue

zz

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zz

zz zz

Vinyl chloride worker due to focal tissue reaction to the chemical Leukaemia due to tissue infiltration Hyperparathyroidism due to bone resorption. Examination of the Eye

Signs

Diseases

Horner’s syndrome

Pancoast tumour

Iridocyclitis

Tuberculosis and vascular disorder collagen

Phlycten

Tuberculosis (Primary)

Chemosis and dilatation of retinal and conjunctival veins

Superior vena cava syndrome and hypercapnoea

Choroid tubercle

Tuberculosis (Miliary)

Papilloedema

Chronic obstructive pulmonary disease and SVC obstruction

Colour blindness

Ethambutol (Red-green colour blindness)

EXAMINATION OF THE NECK Scalene Lymph Node It is a group of nodes in a pad of fat on the surface of scalenus anterior muscle just in front of its insertion into the scalene tubercle of the lst rib.

Significant Node It is one which is round in shape, 0.5 cm in diameter and firm in consistency. It is: 1. Large and fixed in secondary involvement from a primary lung malignancy. 2. Hard and craggy, matted, with or without sinus formation in healed and calcified tuberculous lymphadenopathy. Other significant lymph nodes to be palpated are: 1. Supraclavicular lymph node (presence of left supracla­ vicular node or Virchow’s node is known as Troisier’s sign) 2. Cervical lymph node 3. Axillary lymph node (parietal pleura involvement with infiltration into subcutaneous tissue and skin, breast and upper limb disorders).

Lymphatic Drainage of the Lung and Pleura a. Parietal pleura to axillary lymph node b. Whole of right lung and left lower lobe to right supraclavicular lymph node c. Left upper lobe to left supraclavicular lymph node (Troisier’s sign).

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Respiratory System Note: Genito-urinary system and gastrointestinal system malignancies also involve the left supraclavicular lymph node due to retrograde permeation.

zz zz zz zz

Aortic aneurysm Haematoma Mediastinal sclerosis Post-irradiation.

Presence of Veins over the Chest Wall In superior vena cava (SVC) syndrome look for presence of distended veins over the chest wall (Fig. 5.5). If the obstruction to SVC is above the level of azygos vein, collateral venous circulation on the anterior sur­face of chest wall is less prominent as the intercostal veins drain into the azygos vein. If the obstruction to SVC is at or below the level of azygos vein, collateral veins on the chest become promi­ nent as these collaterals carry blood caudally to the IVC.

EXTERNAL MANIFESTATIONS OF RESPIRATORY DISEASES zz zz zz zz zz zz

Causes of SVC Obstruction Malignant Causes zz

zz zz zz zz zz

Bronchogenic carcinoma —— Small cell carcinoma 40% —— Squamous cell carcinoma 25% —— Adenocarcinoma15% —— Large cell carcinoma 12% —— Unclassified8% Hodgkin’s lymphoma Thymoma Mediastinal germ cell tumour Neuroblastoma Metastasis from carcinoma breast or prostrate.

Non-malignant Causes zz zz

Mediastinal fibrosis (TB, syphilis and histoplasmo­sis) Thrombosis induced by interventional procedures (Pace­maker catheter, Le Veen shunt, Swan-Ganz catheter, CV access devices)

zz

Asterixis—respiratory failure Halitosis—suppurative lung disease Gynaecomastia—INH, digoxin, bronchogenic carci­noma Horner’s syndrome—pancoast tumour Small muscle wasting—pancoast tumour External markers of tuberculosis: —— Tinea versicolor —— Lupus vulgaris —— Erythema nodosum —— Scrofuloderma (caused by atypical mycobacteria, M. scrofulaceum) —— Epididymo-orchitis External markers of cor pulmonale —— Raised jugular venous pressure —— Pedal oedema —— Ascites —— Liver enlargement.

EXAMINATION OF THE RESPIRATORY SYSTEM Inspection of Upper Respiratory Tract zz

zz

zz

Oral cavity —— Oral hygiene —— Dental caries —— Oral thrush —— Tonsils. Nose —— Deviated nasal septum —— Nasal polyps may be seen in „„ Wegener’s granulomatosis „„ Allergic asthma „„ ABPA „„ Cystic fibrosis. Pharynx—Post-nasal drip, lymphoma deposits.

Inspection of Lower Respiratory Tract Fig. 5.5  SVC obstruction

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All the findings in the clinical examination should be com­ pared on both sides in the following areas: zz Supraclavicular area

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Infraclavicular area Mammary region Axillary region Infra-axillary region Suprascapular region Interscapular region Infrascapular region.

Position of Trachea Trail’s sign: It is the undue prominence of the clavicu­lar head of sternomastoid on the side to which the trachea is deviated. The pre-tracheal fascia encloses the clavicular head of sternomastoids on both sides. When the trachea is shifted to one side, the pre-tracheal fascia covering the sternomastoid on that side relaxes, making the clavi­cular head more prominent on the side of tracheal deviation.

Chest Deformities 1. Flat chest: The anteroposterior to transverse diameter ratio is 1 : 2. Seen in pulmonary TB and fibrothorax 2. Barrel chest : The anteroposterior to transverse diameter ratio is 1 : 1. Seen in physiological states like infancy and old age and in pathological states like COPD (emphysema). 3. Pigeon chest (Pectus carinatum) (Fig. 5.6): It is forward protrusion of sternum and adjacent costal cartilage, seen in Marfan’s syndrome, in childhood asthma and rickets. 4. Pectus excavatum (funnel chest, cobbler’s chest) (Fig. 5.7): It is the exaggeration of the normal hollowness over the lower end of the sternum. It is a developmental defect. The apex beat shifted further to the left and the ventilatory capacity of the lung is restricted. It is seen in Marfan’s syndrome. 5. Harrison’s sulcus: It is due to the indrawing of ribs to form symmetrical horizontal grooves above the costal

Position of Apex Beat The apex beat is shifted to the side of mediastinal shift.

Symmetry of Chest Normal chest is symmetrical and elliptical in cross section. The normal anteroposterior to trans­verse diameter ratio is 5 : 7. The normal subcostal angle is 90°. It is more acute in males than in females. Look for the following: Drooping of the shoulder zz Hollowness or fullness in the supraclavicular and infracla­vicular fossae zz Crowding of ribs zz Kyphosis (forward bending of the spine) zz Scoliosis (lateral bending of the spine). zz

Fig. 5.6  Pectus carinatum

Acquired scoliosis can be differentiated from congeni­ tal scoliosis as follows: zz If the convexity of the spine and the lung lesion are on the same side, it is most likely that the scoliosis is congenital. zz If the convexity of the spine is on one side and the lung lesion is on the opposite side, it indicates an acquired scoliosis. This dictum may not always be true. The skin over the chest wall is examined for the following: Engorged veins and subcutaneous nodules (sarcoid and malignancy) zz Intercostal scar (drained pleural effusion, empyema or pneumothorax) zz Discharging sinuses (TB) zz Empyema necessitans in which there is an inter­costal swelling close to the sternum. zz

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Fig. 5.7  Pectus excavatum

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Respiratory System margin, along the line of attachment of diaphragm due to hyperinflation of the lungs and repeated strong contraction of the diaphragm as occurs in chronic respiratory disease in childhood, childhood asthma, rickets and blocked nasophar­ynx due to adenoid enlargement. 6. Rickety rosary: It is a bead like enlargement of costo­ chondral junction, e.g. rickets. 7. Scorbutic rosary: It is the sharp angulation, with or without beading or rosary formation, of the ribs, arising as a result of backward displacement or pushing in of the sternum, e.g. vitamin C defi­ciency.

Spinal Deformity Kyphoscoliosis (Figs 5.8 and 5.9): It is a disfiguring or disabling defor­mity of the spine, producing a shift of the

apex beat. It reduces the ventilatory capacity of the lung and increases the work of breathing. Ankylosing spondylitis: In this condition, there is a diminished volume of the lung and the capacity of the chest and thereby the capacity of lung to expand is restricted.

Movement of the Chest It is described in terms of rate, rhythm, equality and type of breathing.

Rate zz

zz

zz

The normal respiratory rate in relaxed adults is 14 to 18 breaths per minute The type of breathing in women is thoraco-abdominal and in men is abdomino-thoracic The ratio of pulse rate to respiratory rate is 4 : 1.

Tachypnoea: It is an increase in respiratory rate more than 20 per minute. Conditions causing tachypnoea are: zz Nervousness zz Exertion zz Fever zz Hypoxia zz Respiratory conditions —— Acute pulmonary oedema —— Pneumonia —— Pulmonary embolism —— ARDS —— Metabolic acidosis.

Fig. 5.8  Kyphosis

Bradypnoea: It is a decrease in the rate of respiration. Conditions causing bradypnoea are: zz Alkalosis zz Hypothyroidism (myxoedema) zz Narcotic drug poisoning zz Raised intracranial tension. Hyperpnoea: It is an increase in depth of respiration. Conditions causing hyperpnoea are: zz Acidosis zz Brainstem lesion zz Hysteria.

Rhythm Inspiration: It is an active process brought about by the con­traction of the external intercostal muscles and the diaphragm (Fig. 5.10). Expiration: It is a passive process and it depends upon elastic recoil of the lungs. Fig. 5.9  Scoliosis

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Accessory muscles of inspiration (Fig. 5.10) are the scaleni, trape­zius and pectoral muscles.

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Fig. 5.10  Muscles of inspiration

Fig. 5.11  Muscles of expiration

Accessory muscles of expiration (Fig. 5.11) are abdominal muscles and latissimus dorsi.

Abnormal Breathing Patterns Abnormal breathing patterns may be regular or irregular (Fig. 5.12). Regular abnormal breathing patterns Cheyne-Stokes breathing: It is characterised by hyperpnoea followed by apnoea. It occurs in cardiac failure, renal failure, narcotic drug poisoning and raised intracranial pressure. zz Kussmaul’s breathing: It is characterised by increase in rate and depth of breathing. It occurs in meta­bolic acidosis and pontine lesions. zz

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Irregular abnormal breathing patterns Biots breathing: It is characterised by apnoea between several shallow or few deep inspirations. It occurs in meningitis. zz Ataxic breathing: It is characterised by irregular pattern of breathing where both deep and shallow breaths occur randomly. It occurs in brainstem lesions. zz Apneustic breathing: It is characterised by pause at full inspiration, alternating with a pause in expi­ration, lasting for 2 to 3 seconds. It occurs in pontine lesions zz Cogwheel breathing: It is an interrupted type of breathing pattern, seen in nervous individuals. zz Pursed lip breathing: This form of breathing is seen in patients with COPD especially with emphysema. The patient breathes out against a pursed lip as this zz

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Respiratory System

Fig. 5.13  Methods of palpating trachea

Fig. 5.12  Abnormal respiratory patterns

manoeuvre helps in increasing the intrabronchial pressure above the surrounding alveoli and pre­vents its collapse.

PALPATION The position of the trachea is confirmed by slightly flexing the neck so that the chin remains in the mid­line. The index finger is then inserted in the supra­sternal notch and the tracheal ring is felt. Slight shift of trachea to the right is normal (Figs 5.13 and 5.14).

Tracheal Tug-Oliver’s Sign

Confirmation of Apical Impulse

This sign is elicited by standing behind the patient. The chin of the patient is raised and the cricoid carti­lage is held up on deglutition on either side with fingers of both hands. The sign is said to be positive when a downward tug is felt by the fingers during cardiac systole. This sign is present in aortic arch aneurysm.

The shift of the apical impulse and trachea in the absence of chest deformity indicates mediastinal shift. External mass lesions like thyroid, thymus, lymph ­nodes causing displace­ ment of trachea must be kept in mind while ascertaining tracheal position.

Inspiratory Tracheal Descent

The position of apical impulse is altered in: Scoliosis (scoliosis with right sided convexity will displace the cardiac impulse further to the left) zz Funnel-shaped depression of the sternum zz Enlargement of ventricle zz In the absence of the above conditions, the shift of trachea and apical impulse is due to disease of the lung altering the position of the mediastinum.

Tracheal descent with inspiration can be seen in the suprasternal region in chronic obstructive air way diseases.

zz

False-positive sign: In mediastinal tumour attached to aortic arch. False-negative sign: In non-pulsatile aortic aneurysm (when thrombosed).

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Fig. 5.14  Assessing tracheal position

zz

The trachea is ‘pushed’ to the opposite side in con­ditions like: Pleural effusion

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Manual of Practical Medicine zz zz

Pneumothorax Tumour.

The trachea is ‘pulled’ to the same side in conditions like: Fibrosis zz Collapse of the lung. zz

The trachea may be shifted to the same side in the presence of pleural effusion in the following condi­tions: zz Mesothelioma zz Empyema or effusion following pre-existing fibrosis zz Mass with collapse and pleural effusion.

Measurement of the Chest Expansion This is done using an inch tape. The normal circum­ference of the chest and its expansion with deep inspiration is measured. In males, the measurement is done at the level of the nipple and in the females the measurement is done below the breasts. Normal expansion of the chest is 5 to 8 cm In severe emphysema, it is less than 1 cm Non-respiratory cause giving rise to poor chest expan­sion— Ankylosing spondylitis.

Fig. 5.15  Assessment of upper thoracic expansion

Assessing Symmetry of Chest Expansion Equality of expansion of the upper part of thorax is done by facing the patient’s back and placing both hands over the patient’s supraclavicular fossae. The extent of upward movement of the hands, during quite respiration, is compared on both sides (Fig. 5.15). Equality of expansion of the mid and lower part of thorax is assessed as follows.

Fig. 5.16  Assessment of anterior thoracic expansion

Assessment of Anterior Thoracic Movement (Fig. 5.16) The examiner faces the patient and keeps his finger tips of both the hands on either side of the patient’s rib cage so that the tips of the thumb approximate each other in the midline without touching the chest wall. After a deep breath, the degree of expansion is com­pared on both sides by movement of the thumb away from the midline.

Assessment of Posterior Thoracic Movement A similar procedure is carried out over the posterior aspect of the patient’s chest (Fig. 5.17). The difference in chest expansion can be assessed by holding a loose fold of skin in between the thumbs,

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Fig. 5.17  Assessment of posterior thoracic movement

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Respiratory System

Friction Fremitus It is a palpable pleural rub.

Vocal Fremitus It is a vibration felt by the hand when the patient is asked to repeat ninety-nine or one-one-one, by putting the vocal cord into action. Identical areas of the chest are compared on both sides. It is felt with the flat of the hand or with the ulnar border of the hand for accurate localisation. It is increased in consolidation. It is decreased in pleural effusion.

Special Clinical Features of Importance Fig. 5.18  Method 2 for assessing chest expansion

approximated in the midline, whereby even a slight difference in chest expansion can be assessed easily. (The skin fold disappears on the side of good expansion) (Fig. 5.18). Minimal difference in chest expansion of the two hemi­ thoraces can be assessed in a cooperative patient, without dyspnoea in the following way. The patient is asked to expire fully thereby obtaining the residual lung volume, and then to inspire to his full capacity thereby attaining total lung capacity. The difference in expansion of each hemithorax can then be assessed.

Tenderness over the Chest Wall It may be due to: Empyema zz Local inflammation of parietal pleura, soft tissue and osteomyelitis zz Infiltration with tumour zz Non-respiratory cause (amoebic liver abscess). zz

Detection of Subcutaneous Emphysema Spongy crepitant feeling on palpation suggests sub­­­cuta­ neous emphysema. It is present in: zz Injury to chest wall and rib zz Pneumothorax zz Rupture of oesophagus.

Tactile Fremitus These are palpable added sounds (rhonchi are better felt than crackles).

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General restriction of expansion COPD zz Extensive bilateral disease zz Ankylosing spondylitis zz Interstitial lung disease zz Systemic sclerosis (hide bound chest). zz

Asymmetrical expansion of the chest Pleural effusion zz Pneumothorax zz Extensive consolidation zz Collapse zz Fibrosis. zz

In all these above conditions, diminished expansion occurs on the affected side.

PERCUSSION OF THE LUNG FIELDS General Principles Position of the Patient The sitting posture is the best position of choice for percussion. Supine posture is not desirable because of the alteration of the percussion note by the underlying structure on which the patient lies. zz Anterior percussion: The patient sits erect with the hands by his side zz Posterior percussion: The patient bends his head forwards and keeps his hands over the opposite shoulders. This position keeps the two scapulae further away so that more lung is available for percussion zz Lateral percussion: The patient sits with his hands held over the head.

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Fig. 5.19  Percussion areas

Objectives of Percussion It is done to find out the degree of resonance over the symmetrical areas of the two sides of the chest and to map out areas in which percussion note is abnormal.

Cardinal Rules of Percussion zz

zz

zz

zz

zz

The pleximeter: The middle finger of the examiner’s left hand should be opposed tightly over the chest wall, over the intercostal spaces. The other fingers should not touch the chest wall. Greater pressure should be applied over a thick chest wall to remove air pockets The plexor: The middle or the index finger of the examiner’s right hand is used to hit the middle phalanx of the pleximeter The percussion movement should be sudden, origina­ t­ing from the wrist. The finger should be removed immediately after striking to avoid damping Proceed from the area of normal resonance to the area of impaired or dull note, as the difference is then easily appreciated The long axis of the pleximeter is kept parallel to the border of the organ to be percussed.

Areas of Percussion (Fig. 5.19) Anterior Chest Wall zz

zz

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Clavicle: Direct percussion is used and percussion is done within the medial 1/3rd of the clavicle (Fig. 5.20) Supraclavicular region (Kronig’s isthmus): It is a band of resonance 5 to 7 cm size over the supra­clavicular fossa. It is bounded medially by scalenus muscle of the neck,

Fig. 5.20  Direct percussion—clavicle

zz zz

laterally by the acromion process of scapula, anteriorly by the clavicle and posteriorly by the trapezius. The percussion is done by standing behind the patient and the resonance of the lung apices is assessed by this method. Hyper resonance in this area indicates emphysema. Im­paired resonance in this area indicates pulmonary TB or malignancy in the lung apex Infraclavicular Second to sixth intercostal spaces. However, the percussion note cannot be compared due to relative cardiac dullness on the left side.

Lateral Chest Wall Fourth to seventh intercostal spaces.

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Respiratory System

Posterior Chest Wall zz zz zz

Percussion on the Left Side

Suprascapular (above the spine of the scapula) Interscapular region Infrascapular region up to the eleventh rib.

Surface anatomy: Draw two parallel vertical lines, one from the left 6th costochondral junction and another from the 9th rib in mid axillary line. Then connect the two lines above from the left 6th costo­chondral junction to the 9th rib in mid axillary line and below along the left costal margin. It forms a semilunar space and is tympanitic on percussion.

Types of percussion note

Lesions

1. Tympanitic

Hollow viscus

2. Subtympanitic (skodiac resonance or boxy quality)

Above the level of pleural effusion

3. Hyper-resonant

Pneumothorax

4. Resonant

Normal lung

5. Impaired

Pulmonary fibrosis, cavity with surrounding fibrosis

6. Dull

Consolidation, collapse, pleural thickening

Boundaries of Traube’s space: Right side Left lobe of the liver Left side Spleen Above Left lung resonance Below Left costal margin Content Fundus of stomach

7. Stony dull

Pleural effusion, empyema, parenchymal lung disorder with pleural thickening

zz

Crack Pot Resonance A type of tympanitic note which can be produced by clasping the moist hands loosely together and striking it against the knee. It may be elicited over a large cavity communicating with a bronchus.

Normal Percussion Note in Diseased Lung zz zz zz zz

Chronic bronchitis Bronchial asthma Interstitial lung disease Diffuse emphysema.

Percussion on the Right Side

Traube’s space is obliterated in: Left sided pleural effusion zz Massive splenomegaly zz Enlarged left lobe of liver zz Full stomach zz Fundal growth zz Massive pericardial effusion. Traube’s space is shifted upwards in: Left diaphragmatic paralysis zz Left lower lobe collapse zz Fibrosis of the left lung. zz

Special Features of Clinical Importance Percussion Tenderness It is present in empyema and inflammation of parietal pleura.

Liver dullness can be percussed from the right 5th intercostal space downwards in the midclavicular line up to the right costal margin.

Straight Line Dullness

Tidal Percussion

This is done to demonstrate the shift of fluid in pleural effusion and hydropneumothorax. In hydropneumo­thorax shifting occurs immediately, whereas it is very slow in case of pleural effusion. The immediate shift of fluid can be demonstrated by the dull area percussed in the axilla in the sitting posture, becoming resonant on lying down on the healthy side.

This is done to differentiate upward enlargement of liver or subdiaphragmatic abscess from right sided parenchymal or pleural disorder. If on deep inspiration, the previous dull note in the fifth right intercostal space on the mid clavicular line becomes resonant, it indicates that the dullness was due to the liver, which had been pushed down by the right hemidiaphragm with deep inspiration. If the dullness persists on the other hand, it indicates under­lying right sided parenchymal or pleural pathology, in the absence of diaphragmatic paralysis.

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Traube’s Space

It is present in hydropneumothorax. Shifting Dullness

“S” Shaped Curve of Ellis In moderate sized pleural effusion, the uppermost level of dullness is highest in the axilla and lowest in the spine, and tends to assume the shape of the letter “S”. Hence the name.

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Manual of Practical Medicine One school of thought is that, this phenomenon is due to capillary suction between the two layers of the pleura, drawing the fluid up maximally in the axillary region. Another school of thought is that this phenomenon is only a radiological illusion.

AUSCULTATION General Principles of Auscultation zz

zz

zz

zz

As most normal lung sounds are low pitched, the bell is normally preferred over the diaphragm. Stretch­ing of the skin under the diaphragm during breathing is apt to produce scratching sound similar to a pleural rub. In order to avoid time consumption and practical difficulty, diaphragm is used. The patient should be asked to breathe with his mouth open. This is to prevent sound being pro­duced from a partially closed nose. Avoid auscultation within 2 to 3 cm from the midline in the upper part of the chest, since breath sounds in these areas may normally have a bronchial character. If the chest is hairy, moisten the chest wall with water and apply the chest piece tightly to avoid sounds produced by the friction with hair.

Auscultatory Areas Anterior: From an area above the clavicle down to the 6th rib. Axilla: Area up to the 8th rib. Posterior: Above the level of the spine of the scapula down to the 11th rib.

Technique of Auscultation zz

zz

zz

When abnormal breath sounds are heard, the extent to which the abnormal sound is heard should be mapped from normal to abnormal zone. Note also the area at which the character changes. In case of patient with pleural pain, it is better to test vocal resonance and to avoid frequent deep breathing. Auscultation after coughing is a useful procedure. It helps differentiate coarse crepitation and low pithced rhonchi from pleural rub. Coughing does not alter pleural rub, but may alter the character of rhonchi and crackles.

Importance of Auscultation zz zz

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To assess the character and intensity of breath sounds Presence or absence of any added sounds

zz

zz

Character of vocal resonance (voice sounds and whis­ pering sounds) Miscellaneous sounds.

Breath Sounds Breath sounds are produced by vibrations of the vocal cords due to turbulent flow of air.

Vesicular Breath Sound It is low pitched, rustling in nature and is produced by attenuating and filtering effect of the lung paren­chyma. Duration of the inspiratory phase is longer than the expiratory phase in a ratio of 3 : 1. There is no pause between the end of inspiration and the beginning of expiration. Conditions with diminished vesicular breath sounds: Bronchial asthma (silent chest) zz Tumour zz Pleural effusion (small) zz Pleural thickening zz Collapsed lung with occluded bronchus zz Emphysema. zz

Bronchial Breath Sound It is produced by passage of air through the trachea and large bronchi, heard over an area of diseased, airless or consolidated lung interposed between the bronchi and chest wall. Character: It is loud and high pitched, with an aspirate or guttural quality. The duration of inspiration is shortened whereas that of expiration is prolonged and sometimes, the duration of inspiration and expiration are equal. There is a pause between inspiration and expiration. Types of Bronchial Breathing zz zz zz

Tubular Cavernous Amphoric.

Tubular They are high pitched and present in: Pneumonic consolidation zz Collapsed lung or lobe when a large draining bron­chus is patent zz Above the level of pleural effusion (in a partially collapsed lung with a patent bronchus). zz

Cavernous They are low pitched and heard in the presence of thickwalled cavity with a communicating bronchus.

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Respiratory System Amphoric They are low pitched, with a high tone and a metallic quality and present in: zz Large superficial smooth-walled cavity zz Bronchopleural fistula zz Tension pneumothorax.

Bronchovesicular Breath Sound zz

zz

zz

zz

zz

Intermediate in character between vesicular and bronchial breathing Louder, longer, higher in pitch than inspiratory sound with hollow character Normally heard over and above the upper part of the sternum, near the 3rd and 4th dorsal spines between the scapulae and at times over the lung apices Mechanism: Normal lung tissue is interposed between a large bronchus and chest wall Disorders causing bronchovesicular breathing— consolidation in induction and resolution phase.

Absent Breath Sounds zz zz zz zz zz zz zz

Pleural effusion (massive) Thickened pleura (fibrothorax) Collapsed lung or lobe when bronchus is occluded Pneumothorax Near fatal asthma (silent chest) Pneumonectomy Agenesis of lung.

Added Sounds Crackles They are non-musical, interrupted added sounds of short duration. They are explosive in nature. Types zz

zz

Fine: They are less loud, short in duration and arise from the alveoli. Coarse: They are low pitched, loud and arise from the bronchus and bronchioles.

Crackles may be: Early inspiratory as in chronic bronchitis zz Mid inspiratory as in bronchiectasis zz Late inspiratory as in asbestosis, pulmonary fibro­ sis, pneu­monitis, interstitial lung disease, pulmo­nary oedema. zz Expiratory as in chronic bronchitis, pulmonary oedema. zz

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Mechanism of Crackles zz

zz

Bubbling or flow of air through secretions in the bronchial level Sudden opening of successive bronchioles and alveoli with rapid equalisation of pressure causing a sequence of explosive sounds.

Crackles without sputum production indicates inter­ stitial lung disease. Crackles with sputum production indicates parenchymal lung disease. Fine localised crackles are a sign of parenchymal infiltration. If heard over the apices of the lungs, it may be an early sign of pulmonary tuberculosis. Medium or coarse crackles are a sign of respiratory disorder. Fine end inspiratory crackles over both lung bases may be an early sign of LVF. Coarse crackles (death rattle) can occur as a termi­nal event in gross pulmo­nary edema.

Rhonchi They are musical, continuous added sounds. They may be low pitched (sonorous), arising from large airways or high pitched (sibilant), arising from small airways.

Types of Wheeze (Figs 5.21A to D) Fixed monophonic wheeze: It is a single note of constant pitch, timing and site. It results from air passing through a localised narrowing of airway. It is seen in incomplete obstruction of principal or lobar bron­chus, as in: zz Tumours zz Foreign body zz Bronchial stenosis zz Intrabronchial granuloma. Random monophonic wheeze: It is a random single note, which is scattered, occurring in inspiration and expiration and varying in duration, site and pitch, e.g. bronchial asthma. Expiratory polyphonic wheeze: This is a complex musical sound of multiple notes with all its components starting together, conti­nu­ing to finally end in expiration due to expira­tory compression of large central airways, e.g. emphy­sema. Sequential inspiratory wheeze: It is due to the opening of distal airways which has become abnormally opposed during pre­v ious expiration, e.g. pulmonary fibrosis, fibrosing alveolitis, asbestosis.

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A

B

C

D

Figs 5.21A to D  Types of wheeze: (A) Fixed monophonic wheeze, (B) Random polyphonic wheeze, (C) Expiratory polyphonic wheeze, (D) Sequential inspiratory wheeze (squawks)

Voice Sounds Vocal Resonance It is a voice sound heard with the chest piece of the stethoscope. The change in vocal resonance can be either quantitative—diminished or increased (Bronchophony/ whispered pectoriloquy) or qualitative (aegophony). Types Bronchophony: Voice sounds appear to be heard near the earpiece of stetho­scope and words are unclear, e.g. consolidation, cavity commu­nicating with a bronchus, above the level of pleural effusion. It is normally heard in proximity to the trachea. zz Aegophony: Voice sound has a nasal or bleating quality. On saying ‘E’, it will be heard as ‘A’ (E to A sign), e.g. consolidation, above the level of pleural effusion, cavity. The phenomenon—aegophony is useful to differentiate crackles due to alveolar fluid collection zz

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zz

from that of interstitial pulmonary fibrosis. It is present in parenchymal consolidation (alveolar fluid), but not in IPF. Whispering pectoriloquy: The patient is asked to whisper words at the end of expiration, and this whispered voice is transmitted without distortion so that the individual sylla­bles are recognised clearly, e.g. pneumonic consolidation.

Miscellaneous Sounds Pleural rub: It is a superficial, localised squeaking or grating sound best heard with firm pressure of stetho­ scope. They are not altered by coughing. They are associated with pain. Pleuro-pericardial rub: It is present in pleurisy adja­cent to the pericardium. It is due to roughened pleural surface adjacent to the pericardium being moved across one another by cardiac pulsation.

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345

Differentiation between Pleural Rub and Crackles Rub a. Superficial and loud b. Continuous c. Localised d. Unaffected by cough e. Pressure with stetho-scope over the chest increases the sound f. Associated with pain and tenderness

Crackle Not superficial or loud Discontinuous Heard over a wide area Intensified or abolished by cough No effect No pain or tenderness

Other Features of Clinical Significance Heimlich’s manoeuvre: Laryngeal obstruction by a foreign body in an adult can be dislodged by a sudden inward and upward forceful compression of the upper abdomen, by standing behind the patient. Post-tussive suction: It is a sucking sound, heard over the chest wall during inspiration, following a bout of cough, over the area of amphoric breath sound. It occurs in the presence of thin-walled superficial, collaps­ible, communicating cavity. Succussion splash: Splashing sound heard over the chest either with the stethoscope or unaided ear applied to the chest wall when the patient is shaken suddenly by the examiner (Fig. 5.22). This is done by asking the patient to lie down laterally with the healthy side in the dependent position. Percuss and determine the air-fluid level in the paraspinal region and keep the stethoscope over that region. Then grasp the non-dependent shoulder and shake it suddenly, when a sound like that of splashing water can be heard (Fig. 5.23). Succussion splash can be heard in hydropneumo­thorax (Fig. 5.24), diaphragmatic hernia. It is normally heard over the fundus of stomach filled with air and fluid. Coin sound: It is the metallic quality of a coin sound produced on one side of the chest, that can be appreciated on the diametrically opposite side of the chest wall, by use of a stethoscope on that side. It is heard in tension pneumothorax and at the air fluid level of hydropneumothorax. DeEspine’s sign: It is the presence of high pitched tubular breathing and whispering pectoriloquy over the thoracic spine below T3 in adults and T4 in children and infants. It is due to transmission of bronchial breath sound through a mass or central pneumonia in the middle or posterior mediastinum. Bronchial breath sounds may be heard normally over the midline in the back up to T3 in adults and T4 in children.

Fig. 5.22  Succussion splash

Fig. 5.23  Succussion splash—lateral decubitus position

Others Stridor It may be laryngeal or tracheal in origin. Laryngeal stridor: It is a high pitched, crowing sound better heard during inspiration, e.g. obstruction of the larynx by foreign body, laryngeal oedema. Tracheal stridor: It is a low pitched sound best heard in inspiration.

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Fig. 5.24  Right hydropneumothorax

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Manual of Practical Medicine Signs in Common Respiratory Disorders Pathology

Mediastinal shift

Percussion note

 Breath sounds

Vocal resonance

Added sounds

1. Consolidation

Midline

Dull

Tubular

Increased

Indux fine crackles Redux coarse crackles

a. Major bronchus obstruction

Same side

Dull

Diminished or absent

Reduced or absent

None

b. Peripheral bronchus obstruction

Same side

Dull

Tubular

Increased

None

3. Fibrosis

Same side

Impaired

Diminished or bronchial

Variable

None or fine crackles

4. Cavity

Midline or same side (if associated fibrosis present)

Impaired Impaired

Cavernous Cavernous

Increased Increased

Fine or coarse crackles Fine or coarse crackles

5. Bronchiectasis

Midline

Impaired

Vesicular or cavernous** Normal or increased or tubular***

Persistent coarse leathery crackles

6. Pleural effusion or empyema

Opposite side

Stony dull

Diminished or absent (tubular above level of effusion)

Reduced or absent (increased above level of effusion)

Pleural rub may be heard above the level of effusion

7. Pneumothorax

Opposite side

Hyper-resonant

Diminished or absent (amphoric in valvular pneumothorax)

Reduced or absent (may be increased in valvular pneumothorax)

None

8. Bronchitis

Midline

Resonant

Vesicular

Normal

Rhonchi and crackles

9. Emphysema

Midline

Hyper-resonant

Diminished

Normal or decreased

Rhonchi may be heard

10. Bronchial asthma

Midline

Resonant

Vesicular with prolonged expiration

Normal

Inspiratory and expiratory rhonchi

2. Collapse due to

a. Thick-walled b. *Thin-walled

  *In thin-walled superficial, collapsible cavity, amphoric breath sound may be heard instead of cavernous breath sound. **In bronchiectasis associated with large cystic cavities. ***In bronchiectasis associated with surrounding consolidation.

Hamman’s Mediastinal Crunch It is clicking, rhythmical sound synchronous with the cardiac cycle, which may be heard with or without the aid of stetho­scope, e.g. mediastinal emphysema.

CAVITY

zz zz zz

Thin-walled Cavity zz zz zz

Cavity can be defined as a gas containing space within the lung surrounded by a wall whose thickness is > l mm. A gas containing space possessing a wall of 15 mm Malignant The nature of wall of cavity gives a clue to the under­lying disorder: zz Irregular or nodular—carcinoma zz Shaggy—acute lung abscess zz Smooth—in other cavitary lesions.

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FIBROSIS

INVESTIGATIONS

Types of Fibrosis

Sputum Examination

zz

zz zz

Focal, e.g. pneumoconiosis 1 cm, consider progressive massive fibrosis (PMF) Replacement, e.g. pulmonary TB, bronchiectasis Interstitial, e.g. fibrosing alveolitis.

Upper Lobe Fibrosis zz zz zz zz zz zz

Pulmonary TB Ankylosing spondylitis Silicosis Sarcoidosis Rheumatoid arthritis Radiation.

Lower Lobe Fibrosis zz zz zz zz zz

Asbestosis Fibrosing alveolitis Bronchiectasis Scleroderma Loeffler’s syndrome.

In patients with symptom of cough with expectoration, sputum examination forms an important investiga­tion. In patients who do not bring out sputum, inha­lation of droplets of normal saline can bring about its production and help in its analysis. Sputum should be initially examined macroscopically and the following characters to be noted: zz Quantity zz Consistency zz Colour zz Presence of blood zz Odour. Sputum should then be subjected to the following examination: zz Gram’s stain and acid fast stain zz Cytology including malignant cells zz Culture and sensitivity zz Presence of hyphae, Charcot-Leyden crystals, Cursch­ mann’s spirals, Creola bodies.

Lung Function Tests

Differentiation between Active and Passive Collapse Features

Active collapse

Passive collapse

Droop of shoulder; hollowing of supraand infra-clavicular fossa

Present

Absent

Trachea

Pulled to same side

Pushed to opposite side

Percussion note

Dull

Subtympanitic or skodiac resonance

Breath sounds

Absent

Tubular

VF/VR

Absent

Increased

Cause

Luminal or extraluminal obstruction

Pleural effusion, pneumothorax

These tests are done to assess the ventilatory capacity of the patient.

Bed Side Lung Function Tests zz

zz

zz

Differentiation between Fibrosis and Collapse

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Features

Fibrosis

Collapse

1. Onset

Chronic

Sudden

2. Clubbing

Present

Absent

3. Percussion

Impaired

Dull

4. Breath sounds

Decreased

Absent

5. Added sounds

Crackles

None

Duration of expiratory airflow: This is assessed by placing the diaphragm of the stethoscope over the trachea and asking the patient to breathe out after maximal inspiration. Normally the duration of the expiratory sound heard is 4 seconds. The duration of the expiratory sound heard over the trachea should not exceed 6 seconds. If the duration exceeds 6 seconds, it indicates obstructive pulmonary disease. Breath-holding test: In this test, the patient’s vital capacity is tested by asking the patient to take a deep inspiration, and then to count numbers while holding his breath. Normally, a patient can do this up to a count of 40. Snider’s test: It is a crude assessment of airway resistance. The patient is asked to blow out a candle in a single breath, with his mouth open, which is kept at a distance of 15 cm from the patient.

Spirometry The spirometer is used to assess lung function. These tests are done to differentiate obstructive from restrictive lung

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Manual of Practical Medicine disease. It is used to assess the initial dis­ability and exercise tolerance, and to assess sub­­­se­­­­­quent improve­ment with therapy. Spirometry is the measure of airflow during inspiration and expiration. The test is performed in the sitting position and airflow is recorded as forced and sustained expiration followed by forced and sustained inspiration. Three efforts which have less than 5% variability between each other are selected and the best effort is used for interpretation.

Spirometry Measurements

Obstructive Abnormality zz zz

FEV1% = FEV1 (observed)/FEV1 (predicted) = < 80% FEV1/FVC % = FEV1 (observed)/FVC (observed) = < 75%.

Restrictive Abnormality FVC% = FVC (observed)/FVC (predicted) = < 75% FEV1/FVC% = FEV1 (observed)/FVC (observed) = Normal (> 75%). The parameters assessed by spirometry are: zz Forced expiratory volume in one second (FEV ) 1 zz Forced vital capacity (FVC) zz Vital capacity (VC). zz zz

Forced Vital Capacity (FVC) Total volume of air expired with a maximal effort after deep inspiration. Forced Expiratory Volume (FEV1) Volume of air expired in the first second after deep inspiration. Maximal Expiratory Flow Rate (MEFR) Mid-portion of expiration (25–75 %). Peak Expiratory Flow Rate (PEFR) Volume of air forcibly expired during first 10 seconds after deep inspiration. All the above parameters are read as normal or abnormal, when compared to predicted values. Predic­ted values vary as per age, sex, height and ethnic group.

Patterns of Abnormal Ventilatory Capacity Test

Obstructive lung disease Restrictive lung disease

1.

FEV1

Markedly decreased

2.

VC

Decreased or normal

3.

FEV1/VC (80%) Decreased (70–75%)

Decreased Decreased Normal (> 75%)

Normal vital capacity In men = 4.8 L In women = 3.1 L FEV1 (Fraction of vital capacity expired in one sec) = 83% of vital capacity.

Lung Volume Estimation Abnormalities of lung volume in obstructive and restric­­tive ventilatory defects can be assessed by (Fig. 5.25): a. Helium dilution technique b. Whole body plethysmography.

Fig. 5.25  Lung volumes (FEV1—Fraction of vital capacity expired in first second)

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Respiratory System

Peak Expiratory Flow Rate This can be assessed at the bed side by using a peak expiratory flow rate meter for monitoring the severity of airway obstructive disease and their response to therapy. Results are compared with tables prepared on normal controls according to age, height, sex and race.

CHEST X-RAY

part of the right lung above the impression formed by the azygos vein is known as the azygos lobe) zz Achalasia: Chest X-ray air/fluid level behind the heart. Some of the important and common chest X-ray find­ ings and their differential diagnosis are discussed.

Causes of Bilateral Hilar Enlargement zz zz zz

This is the single most important investigation in respiratory medicine and provides essential inform­ation concerning the underlying respiratory disease process in many patients. It is a mirror that manifests many systemic disorders. Some patients may have serious or advanced respiratory disease with a normal chest X-ray. These condi­tions may be: zz Bronchitis zz Bronchial asthma zz Bronchiectasis zz Interstitial lung disease zz Solitary or multiple pulmonary nodules of size < 0.5 mm. zz Endobronchial TB zz Bronchial adenoma zz Right middle lobe collapse zz Acute pleurisy zz Pleural effusion (< 300 mL) zz Miliary TB—cryptic miliary zz Pulmonary embolism without infarction zz Viral and mycoplasma pneumonia zz Sarcoidosis zz Allergic alveolitis zz Connective tissue disorder—SLE zz Pneumocystis carinii pneumonia. In an apparently normal chest X-ray, look for the following: A small apical pneumothorax zz A fluid level behind the heart due to a hiatus hernia zz Right middle lobe collapse with loss of clarity of the right heart border zz Left lower lobe collapse with absence of the out­line of the left diaphragm behind the heart (sail sign) zz A deviated trachea zz Paratracheal lymphadenopathy zz Air beneath the diaphragm zz Rib notching zz Mastectomy zz Dextrocardia with the film reversed. zz Cervical ribs zz Azygos lobe (It is formed by azygos vein that crosses the upper lobe of the right lung in a curved line resembling an inverted comma, to drain medially into the SVC. The zz

Ch-5.indd 349

zz zz zz zz zz

Sarcoidosis Lymphoma Tuberculosis Pulmonary hypertension Pulmonary embolism Septal defects (increased pulmonary flow) Silicosis Lymphangitis carcinomatosis.

Causes of Unilateral Hilar Enlargement Bronchial carcinoma Sarcoidosis zz Lymphoma zz Pulmonary embolism. The left hilum may be up to 2 cm higher than the right. zz zz

Unilateral Hypertransradiant Hemithorax zz zz

zz zz zz

zz zz zz zz zz

zz

Poor technique Scoliosis (hypertransradiant hemithorax to side to which the patient is turned) Mastectomy Poliomyelitis (atrophy of pectoral muscles) Poland’s syndrome (unilateral congenital absence of pectoral muscles) Pneumothorax Compensatory emphysema Obstructive emphysema Unilateral bullae Macleod’s syndrome (late sequelae of childhood bronchiolitis) Congenital lobar emphysema.

Hemithorax Opacity zz

zz

With no mediastinal shift —— Consolidation —— Pleural effusion (small) —— Mesothelioma. With mediastinal shift to opposite side —— Pleural effusion (moderate to large) —— Diaphragmatic hernia.

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Manual of Practical Medicine zz

With mediastinal shift to same side —— Collapse —— Post-pneumonectomy —— Lymphangitis carcinomatosa —— Pulmonary agenesis and hypoplasia.

zz zz zz

zz zz

Widespread Alveolar Opacities zz zz

zz

zz zz zz zz zz

Pulmonary oedema Pneumonia (tuberculosis, histoplasmosis, Pneumo­cys­tis carinii, influenza, chickenpox, viral pneumo­nias, broncho­pneumonia) Haemorrhage (trauma, anticoagulants, haemophi­lia, leukaemia, DIC, Goodpasture’s syndrome) Fat emboli Alveolar cell carcinoma Haematogenous metastases Lymphoma Sarcoidosis.

Honeycomb Lung (Air Containing Cysts 0.5–2.0 cm in Diameter) zz zz zz zz

Collagen disorders (rheumatoid lung, sclero­derma) Extrinsic allergic alveolitis Sarcoidosis Pneumoconiosis

zz

Cystic bronchiectasis Cystic fibrosis Drugs (nitrofurantoin, busulphan, cyclophospha­mide, bleomycin and melphalan) Histiocytosis X Cryptogenic fibrosing alveolitis Neurofibromatosis.

Miliary Mottling (0.5–2 mm Opacities) zz zz

zz zz zz zz zz zz zz zz zz

Miliary tuberculosis Fungal diseases (miliary histoplasmosis, coccidio­ idomy­co­sis, blastomycosis and cryptococcosis) Coal miner’s pneumoconiosis Sarcoidosis Acute extrinsic allergic alveolitis Fibrosing alveolitis Haemosiderosis Silicosis Pulmonary eosinophilic syndrome Pulmonary alveolar proteinosis Lymphangitis carcinomatosis.

Solitary Pulmonary Nodule (Fig. 5.26) This is defined as a spherical intrapulmonary roentgeno­­ graphic density of 3 cm are called mass lesions.

Causes of Solitary Pulmonary Nodule Inflammatory (50%)

Malignant (40%)

Benign (5%)

Others (5%)

Tuberculoma

Bronchogenic carcinoma

Hamartoma

Hydatid cyst

Histoplasmoma

Alveolar cell tumours

Chondroma

Ascariasis

Coccidioidoma

Solitary metastasis

Fibroma

Mycetoma

Cryptococcosis

Bronchial adenoma

Lipoma

Infarct

Actinomycosis

Lymphoma

Myxoma

AV malformation

Nocardiosis

Sarcoma

Endometriosis

Amyloidosis

Neurogenic tumours

Mucoid impaction

Non-specific granuloma Lipoid pneumonia

Dermoid cyst

Chronic lung abscess

Features of Benign and Malignant Solitary Pulmonary Nodule Clinical features

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Types of nodule Benign

Primary malignancy

Solitary metastasis

Age

Under 35 years

Over 35 years

Any

Size of SPN

Tendency to be smaller

Tendency to be larger

Either

Margin

Sharp

Ill-defined

Sharp

Calcification

Frequent

Rare

Rare

Doubling time

Less than 30 days or More than 500 days

30–500 days

30–500 days

History of smoking

Not related

Strong relation

Not related

Extrapulmonary malignancy

Not usually

Not usually

Usually

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Respiratory System

Fig. 5.27  Left midzone—thick-walled, irregular cavity

Fig. 5.26  Solitary pulmonary nodule

Multiple Medium Sized Pulmonary Nodules (5–10 mm) zz zz zz zz zz zz zz zz

zz

Metastasis (breast, thyroid, kidney, GIT, testes) Abscesses (Staphylococcus aureus) Coccidioidomycosis Histoplasmosis Sarcoidosis Wegener’s granulomatosis Rheumatoid nodules Caplan’s syndrome (rheumatoid arthritis with pneu­mo­coniosis) Silicosis.

zz

zz

zz zz

zz

zz zz zz

Characteristics of Blebs, Bullae and Cysts Features

Bleb

Bulla

Cyst

Site

Within visceral pleura

Arises within secondary lobule

Lung parenchyma or mediastinum

Size

1–2 cm

1 cm – 75% of lung 2–10 cm

Lining

Elastic laminae of pleura

Connective tissue septa

Epithelium

Associated disorder

Spontaneous pneumothorax

Bronchogenic carcinoma

Respiratory infection

zz

Unilateral Elevated Hemidiaphragm zz zz zz zz zz zz zz

Lung Cavities (Fig. 5.27) zz zz

zz

zz zz zz

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Staphylococcus aureus (thin-walled and multiple) Klebsiella pneumoniae (thick-walled and with ragged inner lining, common in upper lobes) Tuberculosis (thin-walled and smooth, common in upper lobes) Aspiration Aspergillosis Hydatid cyst

Carcinoma of the bronchus (thick-walled; pre­dilection for the upper lobes; cavitation common in squamous cell carcinomas) Metastases (thin or thick-walled; seen especially in secondaries from a squamous cell carcinoma, carcinoma colon and from a sarcoma) Pulmonary infarction Cystic bronchiectasis (thin-walled; common in lower lobes) Infected emphysematous bulla (thin-walled with air fluid level) Bronchogenic cyst Wegener’s granulomatosis (thick-walled) Rheumatoid nodules. Traumatic lung cyst (thin-walled and peripheral).

zz

zz

Phrenic nerve palsy Pulmonary collapse Pulmonary infarction Chronic pleural disease (fibrothorax) Eventration of the diaphragm Gaseous distension of the stomach or splenic flexure Subphrenic inflammatory disease (subphrenic abscess, sub­pulmonic effusion) Scoliosis (the raised hemidiaphragm is on the side of the concavity) Massive hepatomegaly or splenomegaly.

Bilateral Elevated Hemidiaphragm zz zz zz

Poor inspiratory effort Obesity Bilateral basal pulmonary collapse

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Manual of Practical Medicine Types and Causes of Respiratory Failure Type I Acute PaO2 ↓↓

Chronic

Type II Acute

Chronic

PaO2 ↓

PaO2 ↓

PaO2 ↓

PaCO2 ↔

PaCO2 ↔

PaCO2 ↑

PaCO2 ↑

pH ↔

pH ↔

pH ↓

pH ↓ or ↔

HCO 3 ↔

HCO 3 ↔

HCO 3 ↔

HCO 3 ↑

–

Asthma Pulmonary oedema Pulmonary embolus ARDS Pulmonary fibrosis

zz zz zz zz zz zz zz zz

–

Emphysema ‘pink puffer’ Lymphatic carcinomatosis Respiratory muscle paralysis

–

–

Examples Acute epiglottitis Chronic Severe acute bronchitis ‘blue asthma bloater’ Primary alveolar hypoventilation

Small lungs (fibrotic lung disease) Ascites Pregnancy Pneumoperitoneum Hepatosplenomegaly Large intra-abdominal tumour Bilateral subphrenic abscesses Bilateral subpulmonary effusions.

CT SCAN zz

zz

zz

zz zz

Valuable in determining the size and position of pulmonary nodules (30/min), sweating, pulsus paradoxus (>10 abnormal; >20, profound obstruction), altered level of consciousness, and an inspiration-expiration ratio of 1 : 3 or 1 : 4.

Exercise-induced Asthma

Chronic Asthma Symptoms may be chronic unless controlled by appro­ priate therapy. It may simulate chronic bronchitis.

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Corticosteroid Resistant Asthma

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Manual of Practical Medicine Life-threatening Features zz zz zz zz zz zz zz zz zz

Patient cannot speak Central cyanosis Exhaustion, confusion, altered consciousness Bradycardia Silent chest Unrecordable peak flow Severe hypoxaemia (< 8 kPa) A normal or high CO2 tension (5–6 kPa) A low pH or high [H+].

Investigations Chest X-ray Chest X-ray should be taken to rule out other causes of wheezing and also to rule out the presence of pneumo­ thorax in all cases of severe acutet asthma. Pulmonary function tests (PFT) PFT shows obstructive type of lung disease. FEV1 following 2 puffs of beta agonist shows an increase by 15% or greater than the previous level. Peak expiratory flow (PEF) Serial recordings of PEF may show overnight fall (morning dip) and subsequent rise during the day in patients with asthma. There are increased eosinophils in sputum and blood. Serum IgE is elevated in atopic asthma. Exhaled nitric oxide Non-invasive test to measure eosinophilic airway inflammation zz Elevated levels are reduced by inhaled corticosteroids zz Test of compliance with therapy. zz

Differential Diagnosis of Asthma � zz zz zz zz zz zz zz zz zz zz zz zz zz zz zz zz zz

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Chronic bronchitis Emphysema Cystic fibrosis Viral bronchiolitis Bronchial stenosis Mechanical airway obstruction Foreign body aspiration Endobronchial tumour Cardiac failure Superior vena cava syndrome Substernal thyroid Vocal cord dysfunction Pulmonary embolism Pulmonary eosinophilia Drugs—ACEI, β-blockers Systemic vasculitis Carcinoid syndrome Allergic bronchopulmonary aspergillosis.

Management of Bronchial Asthma zz zz zz zz

Treatment of infection Avoidance of allergens and other precipitating factors Drugs Hyposensitisation.

Drugs Used in Asthma A. Drugs used for prevention of asthma Sodium cromoglycate: This acts by preventing medi­ ator release from mast cells. It is useful in children with atopic asthma and should be given for at least four weeks in a dose of 20 mg through a ‘Spinhaler’ or 5 to 10 mg from a metered dose inhaler 4 times daily. Nedocromil sodium: This is an anti-inflammatory drug with similar properties to those of sodium cromoglycate. Adminis­tered by a metered dose inhaler in a dose of 4 mg, 2 or 4 times daily. Ketotifen: This is less effective than the above two drugs and causes profound drowsiness. The recom­mended dose is 1 to 2 mg twice daily with food. B. Drugs used to reverse bronchospasm β-Adrenergic Agonists —— Short duration „„ Epinephrine „„ Isoetharine „„ Isoproterenol. —— Intermediate duration „„ Metaproterenol „„ Terbutaline „„ Albuterol „„ Pirbuterol „„ Bitolterol „„ Fenoterol. —— Long duration „„ Salmeterol „„ Formoterol.

Inhaled Glucocorticoids —— Beclomethasone diproprionate —— Triamcinolone acetonide —— Flunisolide —— Budesonide —— Fluticasone proprionate

Dose/µg/puff 42 100 250 200 44, 110, 220

1. Adrenergic stimulants: The drugs under this category are: � Catecholamines (epinephrine, isoproterenol, iso­etha­rine, rimiterol and hexoprenaline). � Resorcinols (metaproterenol, terbutaline and feno­terol). � Saligenine (salbutamol).

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357

Respiratory System Salmeterol 50–100 µg BD Formoterol 12–24 µg BD Bambuterol 10–20 mg OD These are long acting selective β2 agonist with long duration of action, preferably used along with inhaled corticosteroids. They produce airway dilatation through stimulation of beta receptors by stimulating adenyl cyclase enzyme with the resultant formation of cyclic AMP from ATP. Catecholamines: These are short acting drugs, most effective by parenteral or inhalational routes. Epi­ neph­rine (0.3–0.5 mL of 1 : 1000 solution subcuta­ neously) and isoproterenol are non-β2 selective and hence have additional positive chronotropic and inotropic effects on the heart. Epinephrine has alpha stimulating effect whereas isoproterenol does not stimulate alpha receptors and is the most preferred drug of this group. Resorcinols: Terbutaline 5 mg three times daily orally or by MDI. Saligenines: Salbutamol 2 to 4 mg three times daily orally or by MDI. 2. Anti-cholinergics: Ipratropium bromide by MDI. This drug is especially useful in drug induced asthma, e.g. β-blockers. 3. Methyl xanthines – Oral theophylline – IV aminophylline (In children 9–16 years and adult smokers—a loading dose of 6 mg/ kg followed by an infusion of 1 mg/kg/h for 12 hours and 0.8 mg/kg/h thereafter. In nonsmokers—same loading dose if patient has not received the drug previously, followed by 0.1– 0.5 mg/kg/h as an infusion). Theophylline has got a narrow therapeutic window. Ideal serum level is 10–20 µg/mL; if the serum level exceeds 30 µg/mL, seizures, arrhythmias may occur. Theophylline clearance is decreased in the following conditions: —— Concurrent use of erythromycin, cimetidine, allo­ puri­nol, or propranolol —— Febrile illness —— Neonates and elderly —— Acute and chronic liver disease. Theophylline clearance is increased in the following conditions: —— Concurrent use of phenytoin, phenobarbitone —— Cigarette smoking —— In children. �

Ch-5.indd 357

C. Anti-inflammatory drugs —— Beclomethasone dipropionate (200 µg), twice daily by MDI —— Budesonide (200 µg), twice daily by MDI —— Oral prednisolone. —— Methyl prednisolone IV 125 mg stat, followed by 40 to 60 mg IV 6th hourly which corresponds to an equivalent dose of 60 mg prednisolone 6 to 8 hourly. —— Fluticasone—For prophylaxis 250 µg BD (inhala­ tion by puffs). Can be increased up to 1000 µg. —— Fluticasone and salmeterol combination. D. Leukotriene antagonists —— Montelukast (10 mg QID) —— Zafirlukast (20 mg BD) They provide effective control of mild persistent asthma and less effective when compared to inhaled corticosteroids. E. 5-Lipoxygenase inhibitor: Zileuton 600 mg qid is primarily reserved for severe asthma. It causes elevation of liver enzymes. Monthly estimation of ALT is essential. F. Anti-IgE therapy: Omalizumab is a monoclonal antibody against IgE and has a role in the manage­ment of moderate and severe persistent asthma. As add-on therapy, this drug is useful to reduce the dose of oral and inhaled steroids without a decline in quality of asthma control. Omalizumab 30 to 700 IU/ml SC based upon the patient’s baseline IgE level. G. Alternative medications: Methotrexate, cyclosporine, tacrolimus, and mycophenolate mofetil have been tried. H. Future therapies: —— Blocking antibodies to IL-5 —— Inhibitors of phosphor diesterase (PDE-4) and nuclear factor kappa light chain (NF-kB) enhancer of activated B cells and P38 MAP kinase (mitogen activate protein). —— DNA vaccination —— T cell peptide fragments of allergens. Symptoms Step 1 Intermittent

Step 2 Mild persistent Step 3 Moderate persistent Step 4 Severe persistent

< 1 time a week Asymptomatic and normal PEF between attacks ≥ 1 time a week but < 1 time a day Daily Use β2 agonist daily Attacks affect activity Continuous Limited physical activity

Night-time symptoms ≤ 2 times a month

PEF

> 2 times a month

≥ 80% predicted Variability 20–30%

> 1 time a week predicted

> 60% < 80% Variability > 30%

Frequent

≤ 60% predicted Variability >30%

≥ 80% predicted Variability < 20%

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Manual of Practical Medicine Management

Long-term preventive

Asthma Classification of severity The presence of one of the features of severity is sufficient to place a patient in that category.

Step 2 Mild persistent

Nocturnal asthma Treatment with anti-inflammator y drugs (corticosteroids) zz Sustained-release theophylline or a β agonist or 2 both zz Long acting β agonists. 2 zz

Acute severe asthma High concentration oxygen therapy zz High dose β agonists by nebuliser 2 zz Systemic corticosteroids zz If no response with above treatment, ipratropium bromide by nebuliser or IV aminophylline (250 mg over 20 minutes) or IV β2 agonists zz Monitor treatment with pulse oximetry zz Assisted ventilation when needed zz Treatment with 70 to 80% helium (balanced oxygen) may be beneficial. This gas mixture reduces airway resistance and improves the effect of aerosolised bronchodilators. zz

Step 3 Moderate persistent

Step 4 Severe persistent

Indications for Assisted Ventilation Coma Respiratory arrest zz Exhaustion, confusion, drowsiness zz Deterioration of ABG tensions despite therapy PaO2 < 8 kPa and falling (60 mm Hg) PaCO2 > 6.5 kPa and rising (50 mm Hg) pH < 7.3 and falling. zz zz

Treatment Long-term preventive

Quick relief

Step 1 Intermittent None needed

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1. Short-acting bronchodilator: inhaled β2 agonist as needed for symptoms, but less than once a week 2. Intensity of treatment will depend on severity of attack 3. Inhaled β2 agonist or cromoglycate before exercise or exposure to allergen

Quick relief

1. Short-acting Daily medication: bronchodilator: 1. Either inhaled inhaled β2 agonist as corticosteroid, 200–500 needed for symptoms, µg, cromoglycate, not to exceed 3–4 nedocromil or sustained times in one day release theophylline 2. If needed, increase inhaled corticosteroids up to 800 µg 3. Either long acting inhaled β2 agonist or sustained release theophyline or long acting β2 agonist tablets can be added Daily medication: 1. Inhaled corticosteroid 800–2000 µg and if needed 2. Long-acting bronchodilator: Either long acting inhaled β2 agonist tablets can be added

1. Short-acting bronchodilator: inhaled β2 agonist as needed for symptoms, not to exceed 3–4 times in one day or long acting β2 agonist or sustained release theophylline

Daily medication: 1. Inhaled corticosteroid 800–2000 µg or more 2. Long-acting bronchodilator: Either long acting inhaled β2 agonist or sustained release theophyline or long acting β2 agonist tablets added 3. Corticosteroid tablet long-term

1. Short-acting bronchodilator: inhaled β2 agonist as needed for symptoms

Step down: Review treatment in every 3–6 months. If control is sustained for 3 months step-wise reduction in treatment has to be done. Step up: If control is not achieved, consider step up.

Obstructive Sleep Apnoea-Hypopnoea Syndrome (OSAHS) OSAHS is the co-existence of unexplained daytime sleepiness with atleast 5 obstructed breathing events (apnoea/hypopnoeas–breathing pauses ≤10 seconds in which there is continued breathing but ventillation is reduced by atleast 50% from baseline during sleep) per hour of sleep (Fig. 5.29).

Risk Factors for OSAHS zz zz zz

Gender—male/female 2 : 1 Obesity—>120% ideal body weight Neck size—collar size >17 inches in males, >15 inches in females

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Respiratory System

zz

zz

zz

type where as in obstructive type airflow is reduced or absent but the respiratory effort is intact) Overnight polysomnography (PSG or sleep study)— the gold standard for the diagnosis of OSAHS Sleep study includes EEG, EMG, electro-oculo­graphy, ECG and oxyhaemoglobin saturation along with assessment of respiratory airflow and effort Increased risk of DM, HTN, depression, impotence, motor vehicle accidents and death due to cardiovascular events.

Indications for Sleep Study zz zz zz

Fig. 5.29  Common sites of airway collapse Abbreviations: LW, Laryngeal wall zz

zz zz

zz

Upper airway anatomy: —— Macroglossia —— Lateral peritonsillar narrowing —— Elongation/enlargement of soft palate —— Tonsillar hypertrophy —— Nasal septal deviation —— Retrognothia, micrognathia —— Narrowing of the hard palate —— Class III/IV modified Mallampati airway Genetic factors/Genetic diseases: Downs syndrome, Apert’s syndrome, Achondroplasia Endocrine disorders: —— Hypothyroidism —— Acromegaly Drugs—Alcohol, sedative or hypnotic use

Mallampati Airway Classification (Fig. 5.30) Class I II III IV zz

zz zz zz

zz zz

Ch-5.indd 359

Visible structures with mouth maximally open and tongue protruded Hard palate, soft palate, uvula, tonsillar pillars Hard palate, soft palate, uvula Hard palate, soft palate, base of uvula Hard palate

Apnoea (cessation of breathing) or hypopnoea (shallow breathing >30% reduction in baseline airflow associated with 4% decrease in oxygen saturation) followed by excessive daytime somnolence 2 to 4% of middle aged adults have OSAHS Loud-snoring is the most common symptom of OSAHS Morning headaches, intellectual deterioration, loss of libido, nocturnal arousals, nocturia, enuresis and chronic fatigue are common symptoms Obesity and nasal obstruction are common Apnoea may be central, obstructive or a combination of both (Airflow and respiratory effort absent in central

zz zz zz

Snoring with excessive daytime sleepiness Titration of optimal nasal CPAP therapy Unexplained pulmonary hypertension Unexplained polycythaemia Daytime hypercapnia Poorly controlled hypertension.

Apnoea-hypopnoea Index (AHI) (Number of episodes per hour of sleep) AHI is used to quantify the severity of OSAHS—Mild (5–15), moderate (16–30), severe (> 30)

Complications zz zz zz zz zz zz zz

Hypoxaemia and hypercapnia Polycythaemia and COPD Cor pulmonale Systemic HTN, heart failure and stroke Diabetes mellitus—aggravation of DM/insulin resistance Hepatic dysfunction—abnormal LFT, steatosis, fibrosis Anaesthetic complications.

Management zz

zz zz

zz zz

zz

zz

zz

Gold standard investigation is overnight polysomnography. Gold standard treatment is CPAP. Mild OSAHS—oral appliances like mandibular repositioning device Oxygen supplementation should be used when needed Positive airway pressure —— CPAP is used to deliver air via a nasal or oral mask —— BiPAP—Bilevel positive airway pressure can also be used but more expensive than CPAP Tracheostomy is indicated in life-threatening significant alveolar hypoventilation. Uvulopalatopharyngoplasty is the most common surgical treatment Genioglossus advancement, hyoid myotomy with suspension and maxillo-mandibular advancement are other surgical procedures.

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Fig. 5.30  Mallampati classification

Chronic Obstructive Pulmonary Disease (COPD) COPD is a disease state characterised by expiratory airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases (Fig. 5.31). A diagnosis of COPD should be considered in any patient who has symptoms of cough, sputum produc­tion, or dyspnoea, and/or a history of exposure to risk factors for the disease. COPD includes chronic bronchitis and emphysema. The diagnosis is confirmed by spirometry. The presence of a post-bronchodilator FEV1 < 80% of the predicted value in combination with an FEV1/FVC < 70% confirms the presence of airflow limitation that is not fully reversible. A low peak flow is consistent with COPD, but it has poor specificity since it can be caused by other lung diseases. Presence of chronic air flow obstruction is essential to entertain the diagnosis of COPD. Chronic bronchitis without airflow obstruction is not included within COPD.

Chronic Bronchitis This is a condition associated with excessive tracheo­ bronchial mucous production sufficient to cause cough with expectoration on most days for at least 3 months a year for more than two consecutive years. It can be subdivided into: zz Simple chronic bronchitis (describes a condition with mucoid sputum production). zz Chronic mucopurulent bronchitis (persistent or re­cur­ rent purulent sputum production in the absence of local suppurative disease). zz Chronic bronchitis with obstruction/chronic asth­ matic bronchitis (severe dyspnoea and wheezing in

Ch-5.indd 360

Fig. 5.31  Pursed lip breathing—COPD

association with inhaled irritants or infections in the setting of bronchitis).

Emphysema It is defined as distention of the air spaces distal to the terminal bronchiole with destruction of alveolar septa. Types of Emphysema (Fig. 5.32) Centriacinar emphysema: There is destruction and enlarge­ ment of central or proximal part of respiratory unit—the acinus. There is predominant involvement of upper lobe and apices. It is commonly seen in male smokers in association with chronic bronchitis. Panacinar emphysema: There is uniform destruction and enlargement of acinus. It is predominant in lower basal zones. It is associated with α1-antitrypsin defi­ciency.

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Respiratory System Differentiating Features between Emphysema and Chronic Bronchitis Features

Predominant emphysema (Pink puffer)

Predominant bronchitis (Blue bloater)

1. Age of onset

6th decade

5th decade

2. Cough

After dyspnoea

Before dyspnoea

3. Dyspnoea

Severe

Mild

4. Sputum

Scanty, mucoid

Copious, purulent

5. Infections

Less common

Common

6. Respiratory insufficiency

Often terminal

Repeated attacks

7. Chest X-ray

Hyperinflation ± bullous changes; small heart

Increased bronchovascular markings; large heart

8. PaCO2 (mm Hg) PaO2 (mm Hg)

35–40 65–75

50–60 45–60

9. Pulmonary hypertension

Mild

Moderate to severe

10. Cor pulmonale

Preterminal stage

Common

11. Diffusing capacity

Decreased

Normal to slight reduction

zz

Fig. 5.32  Types of emphysema

Paraseptal emphysema: This involves only the distal acinus. It is found near the pleura and often causes spontaneous pneumothorax. Irregular: There may be any type of involvement. Special Varieties of Emphysema Compensatory emphysema: Normal lung tissue under­­ goes hyperinflation as a compensatory mecha­nism, in response to the damage occurring in part of the same lung or opposite lung. Here, alveolar septae are preserved. Mediastinal emphysema: This occurs as a result of escape of air rapidly into the mediastinum following rupture of over­ distended alveoli. It may occur in the following conditions: zz Severe bronchial asthma zz Rupture of emphysematous bullae zz Rupture of oesophagus. The escaped air tracks up into the subcutaneous tissues of the neck, manifesting as subcutaneous emphysema.

Predisposing Factors for COPD zz zz zz zz zz zz

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Smoking Environmental pollution (dust, smoke) Genetic predisposition Infection (bacterial or viral) α1 antitrypsin deficiency (for emphysema) Occupational exposure (fumes, etc.)

Exposure to dampness, fog and sudden change in temperature.

Pathogenesis COPD is characterised by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. Macrophages, T-lymphocytes (CD8+), and neutrophils are increased in various parts of the lung. Activated inflammatory cells release a variety of mediators—leukotriene B4 (LTB4), interleukin 8 (IL-8), tumour necrosis factor α (TNF- α), and others capable of damaging lung structures. In addition to inflamma­tion, an imbalance between proteinases and antiproteinases and oxidative stress play a role in the pathogenesis of COPD. The elastase—anti-elastase hypothesis: Elastin, the principal component of elastic fibres, is a highly stable component of extracellular matrix that is critical to the integrity of the lung. The balance between elastase and anti-elastase determines the susceptibility of the lung to destruction resulting in air space enlargement. Protease–antiprotease hypothesis holds that des­truc­­tion of alveolar walls in emphysema is due to an imbalance between proteases and their inhibitors in the lung. In α1-antitrypsin deficiency (a major protease inhibi­­ tor), emphysema develops at a younger age especially in smokers. Impaction of smoke particles in bronchioles leads to inflam­matory cell aggregation, increased elastase and decrea­sed α1-antitrypsin resulting in centriacinar emphysema seen in smokers.

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Manual of Practical Medicine Clinical Features The hallmark of COPD is expiratory airflow obstruction that is not fully reversible. The main symptoms are cough, sputum production, and exertional dyspnoea. Nocturnal symptoms are unusual in COPD unless associated with cardiac failure. Physical examination reveals prolonged expiration, use of accessory muscles of respiration, chest hyper-resonance on percussion, enlarged thoracic volume and decreased breath sounds. Clubbing is not a feature of COPD. Signs of cor pulmo­ nale may be present. Marked tachypnoea, cyanosis, paradoxical abdominal motion may signify the need for assisted ventilation. Chest radiographs are not sensitive for the diagnosis of COPD. Spirometry is the only reliable means for diagnosis and classification of COPD. COPD exacerbation is caused by H. influenzae, S. pneumoniae, and M. catarrhalis. Systemic Features of COPD Systemic features Cachexia

Possible mechanism

Muscle wasting

Apoptosis of skeletal muscle due to TNF-α Chronic hypoxia

Polycythaemia Anaemia Depression Cardiovascular Osteoporosis

Complications Pneumothorax, respiratory failure and cor pulmonale.

Investigations Chest X-ray Shows hypertranslucency, low flat diaphragm or bullae. Translucency extends anteriorly up to the 7th rib and posteriorly up to 9th rib. Widened intercostal spaces and tubular heart are seen. Lung function tests Air flow obstruction with reduction in FEV 1, and FEV1/FVC zz Diffusing capacity decreases zz Increase in TLC, FRC, and RV. zz

Arterial blood gases and oximetry • Resting or exertional hypoxaemia Gold Classification of COPD

TNF-α, IL-6, leptin

TNF-α TNF-α, IL-6 CRP, fibrinogen abnormalities Effect of corticosteroid therapy

Development of systemic features indicate poor prognosis with survival < 1 year.

FEV1 /FVC < 70% is diagnostic of COPD except stage 0 at risk Stages: All stages may or may not have chronic symptoms. 0: At risk—Normal spirometry—Chronic symptoms like cough and sputum production I: Mild COPD—FEV1­— > 80% predicted II: Moderate COPD—FEV1—50 to 80% predicted III: Severe COPD—FEV1—30 to 50% predicted IV: Very severe—FEV1— < 30% predicted or < 50% predicted with chronic respiratory failure or clinical signs of right heart failure

Reid Index

Management

The ratio of the thickness of the submucosal glands to that of the bronchial wall is expressed as Reid index. In normal individuals, it is 0.44 ± 0.09 In chronic bronchitis, it is 0.52 ± 0.08 If the submucosal layer thickness is > 50% of bron­chial wall thickness it is highly suggestive of chronic bronchitis. High index is commonly associated with symptoms.

Stage 0 at risk—Avoidance of risk factors and influenza vaccination Assess willingness to quit smoking—advise, assist and arrange to follow-up: zz Mild COPD: Add short acting β2 agonists Fenoterol/ Salbutamol/Terbutaline zz Moderate COPD: Add one or more long acting bronchodilators—Formoterol/Salmeterol and if needed add either short acting (Ipratropium bromide/Oxitropium bromide) or long acting (Tiotropium) anticholinergics. zz Severe COPD: Add inhaled glucocorticosteroids (Beclomethosone/Budesonide/Fluticasone/ Triamcinolone and if the response is not satisfactory, add systemic glucocorticosteroids (Prednisone/ Methyl-prednisolone). zz N-acetyl cysteine can be used for its mucolytic and antioxidant properties

Prognosis – BODE Index (B-BMI; O-obstruction; D-Dyspnoea; E-Exercise capacity) Points on BODE index Features FEV1 Distance walked in 6 minutes in meter MRC dyspnoea scale Body mass index

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Inference: Mortality rate at 4 years: Score 0 to 2—10%; Score 7 to 10—80%.

0 ≥65 ≥350

1 50–64 250–349

2 50–64 150–249

3 3 ≥35

0–1 > 21

2 ≥ 21

3

4

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Respiratory System zz

Very severe COPD: Long-term O 2 , Ventilatory assistance, management of cardiac failure, consider surgical management.

All the drugs can be administered in the form of metered dose inhaler or dry powder inhaler or MDI with a spacer device or reservoir or delivery of the drug by a nebuliser. Methylxanthines (Aminophylline, or theophylline SR) can be added when necessary. Oxygen should be administered to maintain a PaO2 >60 mm Hg or SaO2 >90%. Patients with chronic respiratory failure need oxygen >16 hours/day, 2 to 3 L/minute and it has been shown to increase survival. Antibiotics are needed only when there is respiratory infection. In acute exacerbation, only parenteral steroid is useful and inhaled steroids are not useful. Intravenous α1-antitrypsin (A1AT) augmentation therapy may benefit select patients with A1AT deficiency (< 50 mg/dL) and COPD. Vaccinations—Influenza and pneumococcal vaccinations reduce serious illness and mortality in patients with COPD. Psychoactive drugs—Patients with COPD often suffer from depression and anxiety. Low dose benzodiazepines (alprazolam 0.25–0.5 mg PO tid) produce significant anxiety reduction. Long-term oxygen therapy: Indications COPD-Hypoxaemia-Oedema zz FEV < 1.5 L, FVC < 2 L 1 zz PaO < 55 mm of Hg (7.3 kPa); PaCO > 45 mm Hg 2 2 (6 kPa)

zz zz zz

zz

zz

Respiratory arrest Altered sensorium Unstable cardiovascular function—hypotension, shock, failure Sepsis, pulmonary embolism, massive pleural effusion, barotraumas NIPPV failure.

Surgical management Bullectomy zz Lung volume reduction surgery—resection of damaged portion of lung. Improves exercise tolerance but does not improve life expectancy. zz Lung transplantation FEV < 35% (PaO < 60 mm Hg 1 2 and PaCO2 > 50 mm Hg). zz

Bronchiectasis Bronchiectasis is defined as permanent dilatation of bronchi and bronchioles due to destruction of smooth muscle and elastic tissue by chronic necrotizing infections. Persistent and irreversible dilatation and distortion of medium sized bronchi (5th to 9th generation) by more than 2 mm. Bronchiectasis may be due to bronchial distention occur­ring as a result of chronic obstruction and recur­rent infection.

zz

Indications for non-invasive positive pressure ventilation (NIPPV) This mode is advocated only in patients with normal mental status, stable cardiovascular function, fairly cooperative and without respiratory arrest. zz Severe dyspnoea with the use of accessory muscles and paradoxical abdominal motion zz Acidosis pH < 7.35 and hypercapnia PaCO > 45 mm 2 Hg (> 6.0 kPa) zz Respiratory rate > 25/minute. Indications for invasive mechanical ventilation Dyspnoea with the use of accessory muscles and paradoxical abdominal motion zz Respiratory rate > 35/minute zz Hypoxia – PaO < 5.3 kPa (40 mm Hg) or PaO /FiO 2 2 2 < 200 mm Hg zz Severe acidosis – pH < 7.25 and hypercapnia PaCO > 2 60 mm Hg (> 8 kPa) zz

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Factors Predisposing to Bronchiectasis Congenital zz zz

Primary Secondary —— T ra c h e o b ro n c h o m e g a l y ( Mo u n i e r- Ku h n synd­rome) —— Bronchomalacia (William-Campbell syndrome) —— Pulmonary sequestration (intralobar, extra­lobar) —— Kartagener’s syndrome (bronchiectasis, sinusi­ tis, situs inversus) —— Young’s syndrome (idiopathic obstructive azoo­spermia) —— Yellow nail syndrome (lymphoedema, yellow nails and pleural effusion) —— Cystic fibrosis —— α anti-trypsin deficiency 1 —— Immunodeficiency syndromes (hypogammaglobulinaemia). —— Chandra-Khetarpal syndrome—Levocardia, sinusi­ t is and bronchiectasis, but no ciliary abnormality.

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Manual of Practical Medicine Acquired zz



zz

zz

Infections: Measles, whooping cough, bronchitis, bron­ chiolitis, pneumonia, endobronchial tuber­culosis. Adenovirus, influenza and HIV infections can also predispose to bronchiectasis. Bronchial obstruction: Foreign body, tumour (adenoma/carcinoma), lymph nodes, left atrium, aneurysm (causes may be inside the lumen, on the wall or outside the wall). Associated immune disorders: Ulcerative colitis, SLE, rheumatoid disease, ABPA.

Pathogenesis The bronchial dilatation in bronchiectasis is associated with destructive and inflammatory changes in the walls of medium sized airways, often at the level of segmental or subsegmental bronchi. Inflammation is primarily mediated by neutrophils and it leads to upregulation of enzymes, such as elastase and matrix metallo­proteinases. The normal structural component of the wall, including cartilage, muscle and elastic tissue are destroyed and replaced by fibrous tissue. The dilated airway frequently contain pools of thick purulent material while more peripheral airways are often occluded by secretion or obliterated and replaced by fibrous tissue.

Fig. 5.33  Bronchiectasis specimen

Types (Figs 5.33 and 5.34) zz zz zz

Cylindrical bronchiectasis Saccular (cystic) bronchiectasis Varicose bronchiectasis.

Clinical Features Persistent, recurrent cough and large quantity of purulent sputum production; haemoptysis; persistent coarse leathery crackles, with or without bronchial breathing (associated consolidation). Any combination of crackles, rhonchi and wheezes can occur. Clubbing of fingers and toes are present. Bronchiectasis is common in left lower lobe because the lower lobe bronchus is longer and narrower. Middle lobe and lingual are next frequently involved. Involve­ ment of upper lobe is uncommon. Sequestration of Lung It is a region of lung parenchyma that has an incomp­lete or no connection with the airways and is supplied by an aberrant artery arising from aorta or one of its branches. When it shares common visceral pleural investment with the adjacent normal lung tissue, it is called intralobar sequestration. When it has its own pleural lining, it is called extralobar sequestration.

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Fig. 5.34  CT chest—Cystic bronchiectasis of right lung

Upper Lobe Bronchiectasis This involves posterior and apical segments of upper lobe. It is common in tuberculosis, cystic fibrosis and ABPA. It also occurs in post-radiation fibrosis. Mid Lung Field Bronchiectasis zz zz

Non-tuberculous mycobacterium (MAC) Dyskinetic—immotile cilia syndrome.

Lower Lung Field Bronchiectasis zz zz zz

Chronic recurrent aspiration End stage fibrotic lung disease Recurrent immunodeficiency-associated infections.

Central Airway Involvement zz zz

ABPA Mounier-Kuhn and William-Campbell syndrome.

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Respiratory System Dry Bronchiectasis (Bronchiectasis Sicca) Only haemoptysis is present; there is no sputum pro­ duction; usually seen in upper lobe involvement in tuberculosis. Middle Lobe Bronchiectasis (Brock’s Syndrome) This is a term applied to recurrent atelectasis of the right middle lobe (RML) in the absence of endobron­ chial obstruc­tion. After several episodes of atelectasis, bronchiectasis and chronic fibrosis of the RML may develop. It is usually sequelae to primary pulmonary tuberculosis resulting from obstruction of middle lobe bronchus by TB lymph nodes. Right middle lobe is involved because: zz RML bronchus originates as a narrow and often slitlike lumen. zz RML bronchus is surrounded by a network of lymph nodes draining both middle and lower lobes, which with infection enlarge and compress the bron­chus. zz RML bronchus before bifurcating into medial and lateral segments, runs a longer course (0.75 cm). zz RML is separated by fissures and by a pleural envelope from the upper and lower lobes and lacks collateral ventilation.

Pseudo (Reversible) Bronchiectasis It is a temporary bronchial dilatation occurring in an area of lung affected by pneumonic consolidation, tracheobronchitis or lung collapse.

Complications zz zz

zz zz zz zz zz zz

Haemoptysis—may be life threatening. Metastatic abscess (brain, pericardium, etc.). Metastatic brain abscess can occur due to spread of septic emboli through paravertebral Batson venous plexus. Pneumothorax. Cor pulmonale and right ventricular failure Amyloidosis Recurrent pneumonia at the same site Pyothorax Lung abscess.

Sputum examination This is done for identifying the infecting organisms. Classi­cally, a 3-layered sputum is seen (upper layer — frothy and watery, middle layer—turbid and muco­puru­ lent, lower layer—purulent and opaque). Chest X-ray (Fig. 5.35) It shows ring shadows, tram track sign, gloved finger appea­rance, evidence of fibrosis or cor pulmonale. CT scan (Fig. 5.36) It is a non-invasive diagnostic test: zz Thick sections—more specific zz Thin sections—more sensitive. CT findings Airway dilatation—tram track or signet-ring sign zz Lack of bronchial tapering—presence of tubular structures within 1 cm from pleural surface (Diameter of bronchus greater than 1.5 times that of the adjacent pulmonary artery branch) zz Cysts (Normal wall of the bronchus should be less than half the width of the accompanying pulmonary artery) zz Bronchial wall thickening in dilated airways with inspissated secretions—tree in bud pattern. Bronchiectasis of proximal airways is suggestive of ABPA. Whereas nodular bronchiectasis suggests Mycobac­terium avium complex infection. Bronchography (Fig. 5.37) It provides excellent visualisation of bronchiectatic airways, which helps in confirming diagnosis and for planning surgery. FOB: It is very useful in focal bronchiectasis to reveal endobronchial obstruction. PFT: Pulmonary function tests can also be performed. zz

Investigations Assessment of ciliary function A pellet of saccharine is placed on anterior chamber of nose. The time taken for it to reach the pharynx, so that the patient can taste it, is noted. Normally, it should not exceed 20 minutes. It is greatly prolonged in patients with ciliary dysfunction.

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Fig. 5.35  Right sided bronchiectasis

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Manual of Practical Medicine surgical resection (when disease is localised) or bronchial artery embolisation (when disease is widespread) may be resorted to. —— Treatment of chronic hypoxaemia and cor pul­mon­ale with long-term supplemental oxygen. —— Aerosolised recombinant DNAse which decreases viscosity of sputum by breaking down DNA released from neutrophils has been shown to improve pulmonary function. Surgery: Surgery is done only for localised disease when the remaining lung and/or the other lung is normal and when there is no systemic causal factor. Surgery is contraindicated in extremes of age and in bilateral extensive lesions. Lung transplantation should be considered if the disease is widespread.

zz

zz

Fig. 5.36  CT scan—bronchiectasis right lung

Preventive measures Reversal of underlying immunodeficiency (administer gamma globulin) zz Vaccination (Influenza/pneumococcal) zz Smoking cessation zz Suppressive antibiotic therapy—to minimise microbial load and to reduce frequency of exacerbations. zz

Modes of antibiotic usage Oral antibiotics daily for 1 to 2 weeks/months zz Rotating schedule of antibiotics zz Macrolides daily or three times/week. They have additional anti-inflammatory effect and reduce gram- negative biofilms zz Inhalation of aerosolised antibiotics zz Intermittent IV antibiotics for severe bronchiectasis/ resistant pathogens. zz

Fig. 5.37  Bronchogram—bronchiectatic changes

Management Control of infections by using appropriate antibiotics. The infection is mostly due to P. aeruginosa and H. influenzae and the antibiotics have to be continued for 10 days. zz Improved clearance of tracheobronchial secretions by adequate hydration, chest physiotherapy with percussion, vibration and postural drainage.   Mucolytics are also tried (adequate hydration, acetyl cysteine, bromhexine). Percussion therapy should not be attempted when the patient has haemo­ptysis. zz Reversal of air flow obstruction by bronchodilators. zz Elimination of underlying problem (immunoglob­ ulin replacement, ATT, steroids for ABPA). zz Treatment of complications: —— Massive haemoptysis—when this is not control­ led with conservative measures (bed rest, antibiot­ics, blood transfusion), other options like zz

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Cystic Fibrosis Cystic fibrosis (CF) is the most common, autosomal reces­s ive disorder, with the basic defect in the gene located on the long arm of chromosome 7, which results in the deficiency of cystic fibrosis transmembrane conduc­t ance regulatory protein (CFTCR). CFTCR is a chloride channel activator, activated by a combination of phos­phorylation of protein kinase A and binding of ATP. This genetic defect results in a reduction in the movement of ions in and out of cell and a reduction in the amount of water in the secretions. In lungs, CF airway epithelia exhibit both increased transport rates for Na+ and decreased ion permeability for Cl–; there is raised transepithelial electric potential difference. CF epithelia do not respond to β agonists or agonists of protein kinase c, with chloride secretion as normal airway epithelia do. There is hyperabsorption of Na+.

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Respiratory System CF is a multisystem disease involving lung, pan­creas, sweat glands, and urogenital tract.

Clinical Features Respiratory/Cardiovascular zz Bronchitis, bronchopneumonia, bronchiectasis, lung abscess, ABPA zz Atelectasis zz Sinusitis, nasal polyposis zz Pulmonary hypertension zz Cor pulmonale and congestive heart failure zz Haemoptysis zz Pneumothorax zz Respiratory failure. Gastrointestinal Intestinal zz Meconium ileus zz Volvulus zz Ileal atresia zz Rectal prolapse zz Intussusception zz Faecal impaction zz Pneumatosis intestinalis. Pancreatic Nutritional deficit and growth failure due to pan­ creatic insufficiency zz Steatorrhoea zz Diabetes mellitus zz Recurrent pancreatitis. zz

Hepatobiliary Atrophic gallbladder, cholelithiasis zz Loss of bile salts zz Focal biliary cirrhosis zz Portal hypertension —— Oesophageal varices —— Hypersplenism —— Haemorrhoids zz

Reproductive system Males: Sterility: Absent or defective vas deferens, epididymis and seminal vesicles (in about 99% of males). zz Females: Decreased fertility: Increased viscosity of vaginal secretions. zz

Skeletal Retardation of bone age zz Demineralisation zz Hypertrophic osteoarthropathy. zz

Others Salt depletion zz Heat stroke zz Salivary gland hypertrophy zz Retinal haemorrhage zz Hypertrophy of apocrine glands. zz

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Complications zz

zz zz zz zz zz

Recurrent respiratory infections (Pseudomonas, staphylo­cocci, Burkholderia and H. influenzae). Pneumothorax Massive haemoptysis Respiratory failure Cor pulmonale ABPA (in 20%).

Differential Diagnosis zz

zz

zz

Primary ciliary dyskinesia may lead to bronchiec­tasis, sinusitis, and infertility. Sweat chloride value is normal. Shwachman syndrome—Pancreatic insufficiency, cyclic neutropenia and lung disease may simulate CF, but sweat chloride value is normal. Young syndrome (bronchiectasis, sinusitis and azoospermia) in men lacks GI symptoms and has normal sweat chloride levels.

Investigations Chest X-ray Hyperinflation, leading to changes of bronchiectasis later. Evidence of mucus impaction, destructive emphy­­­ sematous changes with cystic change, fibrosis may also be seen. Sweat test Pilocarpine iontophoresis stimulates sweat secretion. If sweat chloride > 70 mEq/L, on two different occa­sions, diagnosis of CF is confirmed. Normal value of sweat chloride is less than 50 mEq/L. Other conditions with increased sweat chloride value: • Addison disease • Untreated hypothyroidism. Pulmonary function tests It shows evidence for small and large airway obstruc­tion.

Management Appropriate antibiotics (tobramycin or genta­micin aerosol) for Pseudomonas infection for 2 to 3 weeks. Oral ciprofloxacin 500 mg BD or ofloxacin 200 to 400 mg BD can be given for minor infections. For major infection, oral and single or double IV drugs can be used. Antipseudomonal antibiotics: —— Ceftazidime 2 gm IV q8hrly —— Cefepime 2 gm IV q12hrly —— Tobramycin 3 mg/kg/day —— Gentamicin 5 mg/kg single* dose A combination of semi-synthetic pencillin or cephalospo­rin with anti-pseudomonal activity and an aminoglycoside has to be given.

zz

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Manual of Practical Medicine * Aminoglycoside has to be given in single dose except in: —— Pregnant patients —— Infective endocarditis —— Burns involving more than 20% of body —— Cystic fibrosis —— Anasarca —— Creatinine clearance < 20 mL/min zz Human recombinant DNAse—decreases sputum visco­sity and increases airflow. Alfa dornase acts by digesting extracellular DNA from dead neutrophils, and it has shown to improve pulmonary function and to decrease risk of respiratory tract infections. The recommended dose of dornase α is 2.5 mg (one ampule)/day inhalation by using a jet nebuliser. zz Uridine triphosphate (UTP)—a chloride channel activator. zz Amiloride inhaler: It is a sodium channel blocker which inhibits sodium reabsorption into the respi­ ratory epithelial cells and thereby reduces sputum viscosity and improves lung function. Dose: 3 ml of 10–3 mol solution as inhalation. zz Mucolytics: Adequate hydration + acetylcysteine, carbocysteine can be tried. Ambroxol hydrochloride 30 to 60 mg TDS and brom­hexine can be tried. Other uses of acetyl cysteine: —— Antidote to paracetamol poisoning, ratol poisoning and carbon tetrachloride poisoning —— Combined use of nitroglycerine and N-acetyl cysteine in the management of unstable angina. —— In colposcopy to clean the cervix and to remove cervical mucus prior to colposcopy. —— To prevent radiographic contrast induced reduction in renal function. —— In cystitis caused by cyclophosphamide, it is used to irrigate the bladder. Hypertonic saline inhalation – 4 mL of 7% saline bid. Inhalation of bronchodilator is essential to avoid saline induced bronchospasm. zz Clearing pulmonary secretions by chest percus­sion and breathing exercises. High frequency per­cus­sion jackets are also used. – zz β -agonists (may facilitate Cl secretion). 2 zz α -antitrypsin inhalation helps in restoring anti­ 1 pseudo­monas properties. zz Treatment of complications (oral steroids for ABPA, oxygen therapy in cor pulmonale, treat­m ent of pneumo­thorax by surgery, chemical pleuro­desis, thoracoscopy with CO2 laser abla­tion). zz Gene therapy: ‘CF’ gene could be packaged within a liposome or incorporated by genetic engineering into a modified viral vector and delivered to the respiratory epithelium with the aim of correcting the defect. zz Either sequential single lung transplant or heart lung transplant can be done.

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Tuberculosis It is a pulmonary and systemic disease caused by Mycobac­ terium tuberculosis. Transmission is by drop­let nuclei of 1 to 5 µ in dia­meter which deposit on the alveoli. There is increased incidence of tuberculosis in HIV positive patients. Natural History of Tuberculosis Most primary tuberculous infections heal spontane­ously TB affecting various organs

Time taken after primary infection

Miliary TB or TB meningitis

Within 6 months

Pleural effusion

Within 6–12 months

Progressive primary tuberculosis with cavity

Within 1–2 years or even later

Skeletal tuberculosis

1–5 years after primary infection

Genito-urinary and skin tuberculosis

5–15 years after primary infection

Primary Tuberculosis The initial infection usually occurs in the lung or may be in the tonsil or GI tract. Ghon’s focus is a subpleural focus usually at the lower border of upper lobe or upper border of lower lobe. It is because most inspired air is distributed to these areas of lung. The combination of primary or Ghon’s focus and the draining lymph nodes is known as Ghon’s complex or Primary complex. The initial infection resolves spon­­­ taneously in most individuals. Remnants of the healed lesions appear on chest X-ray as calcified paren­­­­chymal nodules (Ghon’s lesions) often asso­ciated with calcified hilar nodes (Ranke’s complex). In a small percentage of patients, the initial infection progresses and manifests as: zz Rupture into pleural space causing tuberculous pleurisy zz Extensive caseous pneumonia zz Enlargement of tuberculous lymph nodes resulting in bronchial obstruction (collapse consolidation lesions—Epituberculosis) zz Rupture of TB focus into a bronchus leading to endobronchial tuberculosis zz Rupture into a pulmonary blood vessel causes haema­ togenous spread, resulting in acute dissemi­nation. The factors causing ‘breakdown’ of previously healed lesions are: zz Malnutrition zz Alcoholism zz Poorly controlled diabetes mellitus zz Silicosis zz Immunosuppression (by disease or drugs) zz Post-partum period zz Post-gastrectomy and jejunoileal bypass surgery zz Chronic haemodialysis.

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Respiratory System Clinical Features Fever, fretfulness, loss of appetite, cough, wheeze; sputum production is rare in children. Usually there are no detectable clinical signs except occasional crackles and wheezes. Erythema nodosum (bluish red, raised, tender lesions over shin and thigh), phlyctenular conjunc­tivitis (1–3 mm shiny yellow or grey bleb at limbus) may be associated with primary infection. These are manifes­ tations of hypersensitivity reactions (Fig. 5.38).

Miliary Tuberculosis This is produced by acute dissemination of TB bacilli via bloodstream resulting in the appearance of discrete nodular shadows about the size of a millet seed (2 mm).

Clinical Features High pyrexia with drenching night sweats, tachy­cardia, loss of weight, anaemia; usually no physical signs in the chest; a few crackles may be heard; hepatosplenomegaly often present; choroid tubercles on fundus examination. Death takes place in untreated patients. Hepatosplenomegaly, lymphadenopathy and meningism may also be present. Sputum for AFB is negative in more than 80% of cases.

zz

zz zz zz zz

Chest X-ray: Symmetrical miliary mottling (it takes 3–6 weeks for radiological appearance) Culture of sputum, urine, bone marrow (Fig. 5.39). Liver biopsy in difficult cases Mantoux test: May be negative Transbronchial and bone marrow biopsy are useful.

Post-primary Pulmonary Tuberculosis The lesions are usually situated in the posterior segment of upper lobes or apical segment of lower lobe because of high ventilation perfusion ratios with elevated alve­olar PO2 relative to other zones. Simon Focus It is present in the apical or posterior segment of upper lobe. Seedling of bacilli in this area is favoured by high PO2 of the region. Caseous material contains 1 × 104 bacilli per gram whereas 1 × 109 (100 crores) organisms are harboured in a cavitary lesion. Tenacious sputum is more infectious than thin sputum.

Clinical Features

It is seen in elderly and also in females. There are no choroid tubercles and tuberculin test may be negative. It is usually an autopsy diagnosis. It is associated with neutropenia, pancyto­penia, leukemoid reaction. Patient may have hepatosplenome­galy. Chest X-ray is usually normal (size of tubercles < 0.5 mm).

Insidious onset of cough and sputum; initially there are no physical signs; later, crackles over lung apex, signs of consolidation, cavity or fibrosis develop. Pleural effusion (hypersensitivity reaction) or sponta­neous pneumothorax are other types of presentation. Haemoptysis is due to the rupture of a hypertrophied bronchial vessel (Rasmussen’s aneurysm). Haemoptysis is also due to erosion of blood vessel in the wall of the cavity or aspergilloma formation in an old cavity.

Fig. 5.38  Bilateral pulmonary tuberculosis

Fig. 5.39  Miliary mottling both lung fields

Cryptic Miliary Tuberculosis

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Investigations

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Manual of Practical Medicine Complications zz zz zz zz zz zz zz zz zz zz zz zz

Pleurisy Pneumothorax Empyema, pyopneumothorax TB laryngitis TB enteritis COAD like picture Respiratory failure, RV failure Blood-borne dissemination Aspergilloma Poncet’s disease (polyarthritis) TB of spine (Pott’s disease) Scar carcinoma.

Non-reactive Miliary TB zz zz

zz zz zz

Acute septicaemic form Due to massive haematogenous dissemination of tubercle bacilli Pancytopenia is more common Incidence—very rare and is rapidly fatal Postmortem—multiple necrotic non-granulomatous lesion.

Lymph Node TB (Tuberculous Lymphadenitis) zz

zz

zz

Most common presentation of extrapulmonary tuberculosis Common site: Posterior cervical and supraclavicular nodes Nodes are matted and non-tender.

Endobronchial and Laryngeal Tuberculosis It is usually associated with extensive cavitary disease. Laryngeal TB is extremely infectious. Chest X-ray is normal; sputum AFB is positive.

TB Meningitis TB meningitis presents with headache, lethargy, confusion. CSF shows lymphocytic pleocytosis, glucose 50,000 bacilli/ml of sputum. zz In smear negative cases, culture of sputum or broncho­alveolar lavage fluid or fasting gastric wash­ ings or laryngeal swabs should be done. zz Culture and drug sensitivity tests using ‘BACTEC’ radiometric method. In this method, 14C labelled palmitic acid is incorporated into a liquid culture medium. Growth of mycobacteria is detected by the liberation of 14CO2, produced as a result of meta­ bolism of palmitic acid by the viable mycobacteria, which in turn can be measured.   Mycobacterial growth can be detected in 5 to 8 days and it can be differentiated from other mycobacteria in another 3 to 5 days. This is the only method to detect live bacilli. zz DNA probe technology can provide a rapid (within hours) method of detecting the presence of myco­ bacteria in cultured material and in clinical speci­ mens as well. zz Polymerase chain reaction (PCR) technique is a sensitive and specific assay performed on clinical specimens. zz ELISA testing for IgG antibodies has a specificity of 97% and a sensitivity of 65%. It only denotes past infection, but not useful as diagnostic aid.

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Respiratory System zz zz

Drug susceptibility testing to anti-TB drugs Molecular method for identifying genetic mutations for resistance to drugs.

Sputum collection zz Cannot bring out sputum by coughing: Sputum induction by ultrasonic nebulization of hypertonic saline zz Children: Early morning gastric lavage. Tuberculin test 1 to 5 U of PPD is injected intradermally using a 27 G needle on the flexor aspect of the fore arm. The extent of induration is measured 48 to 72 hours later. Interpretation 0–4 mm Negative 5–9 mm Doubtful (may be due to atypical mycobacteria) 10 mm or more Positive zz ≥ 5 mm size: Close contact with TB patients and in patients with fibrotic lesions on chest radiography zz ≥ 10 mm size: Recently infected persons ≤ 2 years and patients with high risk medical conditions such as DM, HIV, CKD and haematological disorders. In HIV infected individuals, 5 mm is considered positive. Tuberculin negative patients should be vaccinated with BCG. False-negative tuberculin tests (i.e. negative skin tests occurring in patients with tuberculosis). IFN γ release assays Principle: Measuring the IFN γ release from T cells in response to stimulation with the highly TB specific antigens—ESAT- 6 and CFP-10. zz T-Spot –TB – ELISA assay zz Quantiferon–TB gold – ELISA Advantages Less cross reactivity due to BCG vaccination zz No boosting phenomenon zz Logistical convenience and less number of patient visit zz

Conclusion To detect latent TB < 5 years of age – tuberculin skin test > 5 years of age – IFN γ release assay (IGRA). Causes zz Infections (measles, mumps, chickenpox, typhoid, leprosy) zz AIDS zz Hodgkin’s disease, lymphoma, leukaemia, sarcoi­dosis zz Protein malnutrition zz Miliary tuberculosis, TB meningitis zz Immunosuppressive drugs

Ch-5.indd 371

zz zz zz zz

Newborn and elderly Faulty storage or dilution of PPD Errors of administration and recording Live viral vaccinations.

BCG Vaccination (Bacillus Calmette-Guérin) It is a live, attenuated bacterial vaccine given at lower deltoid (0.1 mL) intradermally. It is given for tuberculin negative individuals and hence converts the skin test positive.

Complications Local secondary infection, cold abscess or swelling of regional nodes and rarely disseminated BCG in immunosuppressed individuals. Not to be given in patients with extensive dermatosis.

Management of Tuberculosis First line drugs Second line drugs • Rifampicin • Injection Aminoglycosides • INH (streptomycin/kanamycin/ • Pyrazinamide amikacin) • Ethambutol • Capreomycin • PAS • Ethionamide • Kanamycin • 3rd generation fluoroquinolones (gatifloxacin/moxifloxacin/ levofloxacin) • Viomycin • Cycloserine Some important WHO definitions must be understood for the proper therapy. zz New case: A patient who has never had treatment for TB or who has taken antituberculosis drugs for less than one month. zz Relapse: A patient previously treated for TB who has been declared cured or treatment completed, and is diagnosed with bacteriologically positive (smear or culture) tuberculosis. zz Treatment after failure: A patient who is started a re-treatment regimen after having failed previous treatment. zz Treatment after default: A patient who returns to treatment, positive bacteriologically, following interruption of treatment for two months or more. zz Chronic case: A patient with TB who is sputum positive at the end of a standard retreatment regimen with essential antituberculosis drugs. zz MDR–TB: A patient who has active tuberculosis with bacilli resistant atleast to both rifampicin and isoniazid.

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Manual of Practical Medicine Essential Anti-tuberculosis Drugs (mg/kg body weight) Essential drugs

Daily

Three times weekly

Isoniazid (H)

5

10

Rifampicin (R)

10

10

Streptomycin (S)

15

15

Ethambutol (E)

15

30

Pyrazinamide (Z)

25

35

Thioacetazone (T)

2.5

Not applicable

Treatment Regimens in Special Situations Pregnancy Most antituberculosis drugs are safe for use in pregnancy. Do not use streptomycin which is ototoxic and nephrotoxic to the foetus. Pregnancy – 2HRE + 7HR Breastfeeding All antituberculosis drugs are compatible with breastfeeding. The baby should be given prophylactic isoniazid for at least three months (till the mother is declared noninfectious). BCG vaccination of the newborn should be postponed until the end of isoniazid prophylaxis. Vitamin K should be given at birth to the infant of a mother taking rifampicin. Oral Contraception Rifampicin reduces the effectiveness of oral contracep­tives by inducing hepatic enzymes. The individual should adopt another form of contraception or an oral contraceptive pill containing a higher dose of estrogen (50 µg) may be taken. HIV Infection Thioacetazone is contraindicated in those who are HIV infected.

Liver Disorders Isoniazid, rifampicin and pyrazinamide are all asso­ciated with hepatitis. Out of these three drugs rifampicin is least toxic and pyrazinamide is the most hepatotoxic. Acute hepatitis: If possible, avoid TB treatment until the acute hepatitis has resolved. If not possible, treat with 3 SE + 6 HR (if hepatitis has resolved in three months). If the hepatitis has not resolved, SE should be continued for a total of 12 months. Established chronic liver disease: Do not use pyrazinamide. Recommended regimens are the following: 2 SHRE followed by 6 HR; or 9 RE; or 2 SHE followed by 10 HE. Renal Failure Streptomycin and ethambutol are excreted by the kidneys. Thioacetazone is partly excreted by the kidneys. Avoid these drugs in renal failure. The safest regimen for patients with renal failure is 2 HRZ followed by 4 HR. Mode of Action in Interruption of TB Treatment Interruption less than 1 month—Prolong the duration to compensate the missed doses. Interruption for 1 to 2 months—Do sputum for AFB 3 times – smear negative – prolong therapy to compensate for missed doses. If smear positive – treatment received < 5 months – prolong therapy to compensate for missed doses; treatment received > 5 months—If on category I regimen – start category II; If already on category II regimen—refer to specialised centre to rule out resistance and to decide the type of regimen. Drugs acting in acid medium: Pyrazinamide—acts on intracellular organisms. Drugs acting in alkaline medium: Streptomycin—acts on extracellular organisms.

Reserve Antituberculosis Drugs Thrice weekly regimens are not recommended for reserve antituberculosis drugs.

Ch-5.indd 372

Reserve drugs

Mode of action

Average (mg/kg)/day

Minimum (mg)

Maximum (mg)

Amikacin (Am)

Bactericidal

15

750

1000

Capreomycin (Cm)

Bactericidal

15

750

1000

Kanamycin (Km)

Bactericidal

15

750

1000

Ciprofloxacin (Cx)

Bactericidal

10–20

1000

1500

Ofloxacin (O)

Bactericidal

10–15

600

800

Cycloserine (Cs)

Bacteriostatic

10–20

500

750

Ethionamide (Et)

Bactericidal

10–20

500

750

PAS

Bacteriostatic

150

8g

12 g

Protionamide (Pt)

Bactericidal

10–20

500

750

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Respiratory System Recommended Treatment Regimens Category I •  New sputum smear positive patients •  New sputum smear negative •  New extra-pulmonary TB Treatment regimen: •  Two months intensive phase—H3 R3 Z3 E3 (four drugs at thrice weekly schedule) •  Four months continuation phase—H3 R3 (Two drugs at thrice weekly) Category II •  Relapse after treatment •  Treatment failure •  Treatment after default •  Sputum smear-negative or extra-pulmonary disease and who can have recurrence Treatment regimen: •  Three months intensive phase—2 months H3 R3 Z3 E3 S3 and one month H3 R3 Z3 •  Five months continuation phase—H3 R3 E3

Management of Chronic and Multidrug Resistant Cases X DR–TB X DR–TB means extremely drug resistant TB. It is due to multi-drug resistant (MDR) strains that are resistant to all fluoroquinolones and to at least one of three second line injectable agents (Amikacin, kanamycin, capreomycin). Management Guidelines •  Use any first-line agents that are effective. •  Use any one susceptible injectable agent for 12 months or for the whole treatment period. If the strain is resistant to all injectables, select an agent which has not been used previously. •  Use a later generation fluoroquinolone such as moxifloxacin. •  Use all second line oral agents (PAS, cycloserine, ethionamide, prothionamide). •  Use 2 or more of the following drugs: Clofazimine, amoxi/clavulanic acid, clarithromycin, imipenem, linezolid and thioacetone (drugs of unclear role). •  Consider high dose INH in case of low level resistance. •  Adjuvant surgery to be planned in case of localised disease. •  Enforce strict therapy, comprehensive monitoring and strong infection control measures.

Management of Chronic and Multidrug Resistant Cases (MDR–TB) Sl No. Resistant to Duration 1.

2.

3. 4.

Ch-5.indd 373

H (INH)

Preferred drugs

RZE (Fluoroquinolone addition may strengthen the regimen in patients with extensive disease) R 12–18 HZEQ (Streptomycin for 2 months may (Rifampicin) months strengthen the regimen in patients with extensive disease) H+R 20 months ZEQ + S or another injectable agent All first line drugs

6 months

20 months Any one injectable agent (amikacin, kanamycin, capreomycin) + ethionamide, cycloserine, PAS, and quinolone

Sample Regimen: Accurate Dosage of Antituberculosis Drugs with Fixed Dose Combinations According to Weight Bands Weight in kg 30–39

40–54

55–70

> 70

HRZE (75 mg + 150 mg + 400 mg + 275 mg)

2

3

4

5

HRZS (HRZ-75 mg + 150 mg + 400 mg)

2

3

4

5

0.5

0.75

1

1

2

3

4

5

1.5

2

3

3

HR–(150 mg + 150 mg)

2

3

4

5

Category II add E – 400 mg

2

4

6

6

Initial phase—Daily

S-Streptomycin 1g vial – for 2 months Continuation phase—Daily HR – (75 mg + 150 mg) Category II add E 400 mg Continuation phase—Thrice weekly

Name of the drug

Dosage

Side effects

Rifampicin

10–20 mg/kg; 450 mg if < 50 kg; 600 mg if > 50 kg

Hepatitis, orange urine, flulike syndrome, cutaneous syndrome, inactivates oral contraceptives, thrombocytopenia

INH

10 mg/kg; In adults 300 mg

Hepatitis, B6 deficiency, neuropathy, agranulocytosis, rarely INH cysts

Ethambutol

25 mg/kg × first 8 weeks 15 mg/kg later.

Optic neuritis

Pyrazinamide

20–35 mg/kg; in adults, < 50 kg—1.5 gm > 50 kg—2 g

Arthralgia, hepatitis, hyperuricaemia

Drugs acting on intracellular, extracellular organisms in both acid and alkaline medium are: INH, Rifam­picin—acts on persistors also. Drugs crossing blood-brain barrier: INH, Rifampicin and Pyrazinamide; Streptomycin crosses the blood-brain barrier poorly. It takes 3 weeks for sputum conversion if regimens containing rifampicin are used and 3 months for regi­mens without rifampicin. Other Antituberculous Drugs zz zz zz zz zz

Rifabutine Sparfloxacin Clarithromycin Azithromycin Clofazimine

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374

Manual of Practical Medicine Principles of Chemotherapy zz zz

zz zz

zz

zz

zz

zz

zz

zz

zz

zz

zz

zz zz

Always multidrug regimen should be used In almost all short regimens INH and rifampicin are included Rifampicin is the most potent sterilising drug Ethambutol and thioacetazone are added along with powerful drugs to prevent emergence of resistant bacilli DOT—Directly observed treatment means that an observer watches the patient swallowing their tablets. DOT ensures accountability of TB services and helps to prevent emergence of drug resistance. DOT is recommended in the initial phase of treat­ment, at least for all smear positive cases and the continuation phase of rifampicin containing regimens. INH alone is used to prevent: —— Development of active TB in immunodeficient individuals —— Progression of infection to primary complex in those recently infected —— Transmission to close contacts at high risk Contact lenses may be irreversibly stained during rifampicin therapy Antiretroviral drugs interact with rifampicin—reduces the effect of both drugs Blood glucose level is labile when on pyrazinamide therapy Streptomycin is contraindicated in: —— Known hypersensitivity —— Auditory nerve impairment —— Myasthenia gravis Cross-resistance between kanamycin and amikacin is usual. Among aminoglycosides streptomycin is least nephrotoxic Streptomycin should be avoided during pregnancy and children Capreomycin has no cross resistance with other aminoglycosides Ethionamide and PAS have anti-thyroid effect PAS is best avoided in renal failure as it may exacerbate acidosis.

Corticosteroid Therapy in TB zz zz

zz

zz zz zz

Ch-5.indd 374

TB meningitis In seriously ill patients, before chemotherapy becomes effective TB in serous sacs (peritonitis, pericarditis and pleural effusion to prevent fibrosis and adhesions and to facilitate absorption of fluid) Genitourinary TB To control drug hypersensitivity reaction Rarely for regression of lymph nodes during chemo­therapy.

Reserve Antituberculosis Drugs—Side Effects Name of the drugs

Side effects

Kanamycin and Amikacin

Ototoxicity, deafness, vertigo, nephrotoxic

Capreomycin

Tinnitus, vertigo, lesser risk of deafness, renal damage, cutaneous reactions, hypokalaemia, hypocalcaemia, hypomagnesaemia, hepatitis

Ethionamide (or protionamide)

Metallic taste, anorexia, nausea, epigastric discomfort, vomiting, excessive salivation, hypoglycaemia, hallucinations, depression, hepatitis, goitre-hypothyroidism, gynaecomastia, impotence, acne, headache, menstrual disorders, peripheral neuropathy

Ofloxacin and ciprofloxacin

Anorexia, nausea, vomiting, dizziness, headache, mood changes, rarely convulsions, injury to growing cartilage and impair growth

Cycloserine

Headache, dizziness, slurred speech, confusion, depression, insomnia, tremor, convulsions, avoid in epileptics and mental illness

P-Aminosalicylic acid (PAS)

Anorexia, nausea, vomiting, abdominal discomfort, hypokalaemia, hepatic dysfunction, hypothyroidism and goitre

HIV and Tuberculosis TB has a rapidly progressive and often a fatal course in HIV positive patients. Increased re-activation of latent PT occurs. Mantoux test is false-negative. Smear may be negative and hence culture is vital. There are many atypical features. There is higher frequency of miliary tuberculosis, hilar adenopathy, extrapulmonary involve­ment. There is lower frequency of focal infil­trates and cavities.

Congenital TB It is very rare. TB in the mother is invariable. Infant presents with failure to thrive, hepatosplenomegaly and lymphadeno­pathy, obstructive jaundice due to glands in the porta hepatis. Treatment is by using 3 drug regimen and steroids.

Pneumonia Exudative solidification of lung tissue is known as pneumonic consolidation.

Classification zz zz

Community acquired pneumonia (CAP) Health care associated pneumonia (HCAP) —— Nosocomial (hospital acquired) pneumonia (HAP) —— Ventilator associated pneumonia (VAP)

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Respiratory System

Pathological Stages in the Development of Pneumonia zz

zz zz zz

Stage of congestion—indux crepitus (fine crackles) heard Stage of red hepatisation  Tubular type of bron Stage of grey hepatisation  chial breathing heard Stage of resolution—Redux crackles appear, fine crackles become coarse.

Predisposing Factors Bronchopneumonia zz zz

Extremes of age Immunosuppression (disease or drugs).

Lobar Pneumonia zz

zz zz

Disorders of swallowing, coughing and impairment of airway defence mechanisms (old age, convul­sions, chronic bronchitis, bronchiectasis, neurolog­ical disorders, trauma) Fluid accumulation in alveoli (CCF, ARDS, burns) Impaired phagocytosis and compromised immunity (hypo­­-­gammaglobulinaemia, AIDS, diabetes, lymph­o­­ ­ma, mye­loma, functional asplenia, sickle cell anaemia).

Clinical Features Fever, tachypnoea, pleuritic pain, cough with sputum (rusty in pneumococcal pneumonia), haemoptysis, con­ fu­­sion, signs of consolidation.

Investigations zz zz zz

zz

zz

zz zz

Sputum examination (Gram’s stain and culture) Blood culture Serology for Mycoplasma, Chlamydia, Legionella and viral infections. Examination of pleural fluid in parapneumonic effusions Chest X-ray shows evidence of consolidation (homo­ genous opacity) of the affected lobe or segment (Fig. 5.40). May show evidence of pleural effusion. Second chest X-ray is a must in all cases of pneumonias after 7 to 10 days to assess the response to therapy and to find out if there is development of any complication. PCR – Legionella, Mycoplasma, Chlamydia Urine antigen test for Legionella and Pneumococcus.

Assessment of Prognosis zz



Ch-5.indd 375

PSI—pneumonia severity index 20 variables like age, existing illness, physical and laboratory findings are taken into account to derive

Fig. 5.40  Opaque left hemithorax without mediastinal shift massive consolidation

5 classes of patients. Treat class I and II as OP, class III as IP and class IV and V at ICU. This formula is not very useful for practical application. zz CURB 65 (Age > 65 years) C — Confusion U — Urea > 7 mmol/L R — Respiratory rate > 30/minute B — BP – Systolic < 90, Diastolic < 60 mm of Hg Score – 0  Out-patient 2 In-patient 3  Intensive care unit

Complications zz zz zz zz zz

zz zz zz zz zz

Circulatory failure Septicaemia Parapneumonic effusions/empyema Respiratory failure Metastatic infections (meningitis, endocarditis, arthri­tis) Lung abscess ARDS, renal failure, multiple organ failure Pneumothorax, especially with Staph. aureus Thromboembolic disease Pyrexia due to drug hypersensitivity.

Causes of Unresolved Pneumoniae zz zz zz zz zz

Incorrect microbiologic diagnosis Inadequate dose or wrong choice of antibiotics Endobronchial obstruction (poor local host defences) Immuno-compromised states (disease or drugs) Malignancy.

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376

Manual of Practical Medicine Causes of Recurrent Pneumoniae in the Same Segment zz zz zz zz

Foreign body Neoplasia (benign or malignant) Sequestration of lung Bronchiectasis.

Special Characteristics of Various Pneumonias Pneumococcal Pneumonia Production of rusty sputum is characteristic and the patient may be icteric. It usually involves a lobe and pleuritic reaction is common.

Common Causes of Immunosuppression and Associated Lung Diseases Causes

Pathogens involved

Neutropaenia

Cytotoxic drugs Agranulocytosis Acute leukaemia

S. aureus Gram –ve bacteria Candida albicans and Aspergillus fumigatus

T-cell defect with or without B-cell defect

Lymphoma, CLL Immunosuppressive drugs, Bone marrow transplants Splenectomy

Antibody production

CLL, Myeloma

Candida albicans Tuberculosis Pneumocystis carinii CMV Gram –ve bacteria S. aureus Pneumococcus H. influenzae Pneumococcus H. influenzae

Staphylococcal Pneumonia This is common in cystic fibrosis and influenza. Multi­ple, thin-walled staphylococcal abscesses are common (pneu­ matoceles). Pneumothorax is a complication. It occurs in extremes of age and in immunosuppressed patients. Klebsiella Pneumoniae Massive consolidation and excavation of upper lobe with expectoration of chocolate coloured sputum (brick red currant jelly). Lobes characteristically increase in size and it simulates tuberculosis. Legionella Pneumonia This is transmitted through infected water from cis­ terns, vapour or venti­lation systems. Patient is toxic with haemoptysis; CNS or renal problems, myoglobin­uria may be present. Diag­nosis by serology or immuno­­fluorescence. Viral Pneumonia (Atypical Pneumonia) Prodromal symptoms precede the onset of pneumonia by one week. Despite extensive radiological findings, respiratory signs and symptoms are minimal. Haemop­ tysis and parapneu­monic effusions are rare. Common viruses causing pneumonia are varicella, H. simplex, CMV, measles, influenza, adeno­virus and RSV. Actinomycosis A. israelii, an anaerobe can cause suppurative pneu­monia when local defences are impaired. Chest wall sinuses and empyema are common with the sinuses discharging pus containing sulfur granules. Mycoplasma Pneumonia Presents with dry cough, erythema multiforme, arthral­gia, myalgia. Predilection to lower lobe. Cold agglutinins positive. Pneumonia due to Chlamydia C. psittaci causes psittacosis or ornithosis. Patient has pneumonia, systemic illness, hepatosplenomegaly. Patchy consolidation is common. Diagnosed by sero­logy.

Ch-5.indd 376

Empirical Antibiotic Treatment of Community-Acquired Pneumonia Out-patients Previously healthy (not on antibiotic in the past three months): Clarithromycin 500 mg PO bid or azithromycin or doxycycline 100 mg PO bid Comorbidities with history of antibiotics use in past three months: Use respiratory fluoroquinolone moxifloxacin 400 mg PO od or gemifloxacin 320 mg PO od or levofloxacin 750 mg PO od or A β-lactam amoxicillin 1 gm tid or amoxicillin/clavulanate 2 gm bid or ceftriaxone 1–2 gm IV od or cefpodoxime 200 mg PO bid or cefuroxime (500 mg PO bid plus a macrolide) In-patients (non-ICU) Moxifloxacin 400 mg PO or IV od or gemifloxacin 320 mg PO od or levofloxacin 750 mg PO or IV od A β-lactam ceftriaxone 2 gm IV od or cefotaxime 1–2 gm IV tid or ertapenem 1 gm IV od plus a macrolide Oral clarithromycin or azithromycin or IV azithromycin 1 gm once and then 500 mg od. In-patients (ICU) A β-lactam ceftriaxone 2 gm IV od or cefotaxime 1–2 gm IV tid or ampicillin/sulbactam 2g IV tid plus Azithromycin or fluoroquinolone as mentioned above for in-patients (non-ICU). Note: Pseudomonas infection— an anti-pneumococcal, anti-pseudomonal β-lactam piperacillin/tazobactam 4.5 gm IV qid, cefepime 1–2 gm IV bid, imipenem 500 mg IV qid, meropenem 1 gm IV tid, plus either ciprofloxacin 400 mg IV bid or levofloxacin 750 mg IV od plus an aminoglycoside either amikacin or tobramycin. CA-MRSA (Community acquired methicillin resistant Staphylococcus aureus) Add linezolid 600 mg IV bid or vancomycin 1g IV bid.

Nosocomial Pneumonia Pneumonia developing in a patient who has been hospitalised for >48 hours. Infection by S. aureus, Pseudomonas and anaerobes are common. Factors predisposing to nosocomial pneumonia Aspiration of nasopharyngeal secretions zz Gastroesophageal aspiration zz Bacteria introduced by interventions (endotracheal tube, ventilators, nebulisers). zz

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Respiratory System Empirical Antibiotic Treatment of Health Care Associated Pneumonia MDR (Multidrug–resistant) pathogens—patients without risk factors: •  Ceftriaxone 2 gm IV od, or levofloxacin 750 mg IV od, moxifloxacin 400 mg IV od, ciprofloxacin 400 mg IV tid or •  Ampicillin/sulbactam 3 gm IV qid or Ertapenem 1 gm IV od MDR (Multidrug–resistant) pathogens – patients with risk factors: •  A β-lactam—Cefepime 2 gm IV bid, ceftazidime 2g IV tid, or Piperacillin/tazobactam 4.5 gm IV qid, imipenem 500 mg IV qid or meropenem 1 gm IV tid plus •  A second agent active against gram-negative bacteria •  An aminoglycoside–gentamycin/tobramycin/amikacin or Levofloxacin 750 mg od or ciprofloxacin 400 mg IV tid plus An agent active against gram-positive bacteria Linezolid 600 mg IV bid or vancomycin 1 gm IV bid

zz

zz

Reduced host defences (steroid, post-operative state, anaesthesia) Bacteraemia (sepsis).

Ventilator-associated Pneumonia It is either due to non-multidrug resistant organisms or due to multidrug resistant organisms.

Clinical Features zz zz zz zz zz

Fever with leukocytosis Increase in respiratory secretions Pulmonary consolidation New or changing radiographic infiltrate Set of diagnostic criteria—None.

Complications zz zz zz

Death Need for increased ventilatory support Necrotising pneumonia.

Pneumonia in Immunocompromised Host This may be caused by P. carinii, M. tuberculosis. Onset is less rapid. Symptoms are more than signs. May be bilateral. Pneumocystis Carinii Pneumonia Occurs in immunocompromised hosts (AIDS, trans­plant recipients). It is an interstitial pneumonia. It presents with dry cough, tachypnoea, fever. Diagnosis is by clinical setting, sputum examination (methana­mine silver stain) and lung tissue histopathology. Chest X-ray may be normal or show ground glass appearance; may spare lower zones.

Ch-5.indd 377

Management zz

zz zz zz

Appropriate antibiotics for 1 to 2 weeks as given in boxes. Treatment of complications. Ventilatory support when needed. Prevention by pneumococcal vaccine (Pneumovax, 1 dose of 0.5 mL SC/IM repeated after 5–10 years).

Lung Abscess It is a localised infectious suppurative necrosis of lung tissue of >2 cm in diameter.

Predisposing Factors zz

zz zz zz zz zz zz

Aspiration of infected material (oropharyngeal surgical procedures, dental sepsis, coma, drugs, alcohol, anaes­thesia, bulbar palsy, seizures, acha­lasia cardia). Inadequately treated pneumonia. Bronchial obstruction (tumour, foreign body). Pulmonary infarction. Septic emboli. Spread of infection from adjacent organs, e.g. liver. Infection of congenital or acquired cysts.

Abscesses vary in size and number. Aspiration abs­ cesses are more common on right, reflecting the more vertical right bronchus. Posterior segment of right upper lobe or apical segment of either lower lobe are commonly involved. Chronic abscesses are often surrounded by a reac­tive fibrous wall. Common Organisms Anaerobes, staphylococci, Pseudomonas, Legionella sp, Streptococcus pneumoniae, M. tuberculosis, Nocar­dia sp.

Clinical Features Fever, malaise, weight loss, cough with copious, puru­lent sputum, haemoptysis, clubbing. Position of the patient

Site of aspiration

•  Supine posture

Posterior segment of right upper lobe and apical segment of right or left lower lobe.

•  Prone position

Right middle lobe and left lingular lobe.

•  Sitting upright

Posterior or lateral basal segment of either lower lobe.

In epilepsy, any lobe can be involved because of bizarre posturing.

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378

Manual of Practical Medicine Differential Diagnosis zz zz zz zz zz zz zz

Cavitating lung cancer Infected bulla or cyst Pulmonary hamartoma Cavitating pneumoconiosis Infected hydatid cyst Tuberculous, fungal, actinomycotic infections Hiatus hernia.

Suspect and exclude malignancy in cavitary lesions involving the non-dependent portion of the lung such as right middle lobe or anterior segment of the upper lobe.

Investigations zz

zz zz zz

Chest X-ray: Shows thick-walled cavity with fluid level which moves in decubitus film. Sputum examination and culture. Radioactive Indium-111 labelled leucocyte uptake. CT-chest.

Management zz zz zz

zz zz

zz



Appropriate antibiotics for 4 to 6 weeks. Physiotherapy and postural drainage. Rigid bronchoscopy for adequate suction of secre­ tions from bronchial tree. Fibreoptic bronchoscope should be avoided as the suction channel is small and the flood of pus may drown the patient. Intercostal tube drainage—very rarely. Surgery: If there is failure of medical therapy in spite of bronchoscopic clearance, surgical resec­tion is advised. Presence of obstructing carcinoma is an indication for surgery in addition to the defin­itive management according to the staging and general condition of the patient. Failure of medical management–causes (In these cases do bronchoscopy and CT chest to identify the cause) —— Failure to drain pleural collections —— Inappropriate antibiotics —— Obstructed bronchus —— Giant abscess: > 6 cm —— Resistant pathogen —— Immunocompromised individuals.

Pleural Effusion Pleural effusion is the accumulation of serous fluid in the pleural cavity.

Decreased plasma oncotic pressure (except in con­ genital hypoalbuminaemia) zz Increased capillary permeability due to local inflam­­ mation, toxins or vasoactive substances as occurs in collagen-vascular diseases, pancreatitis, pulmonary emboli and pneumonitis. zz Increase in pleural space oncotic pressure as a result of: —— Protein leak through capillaries —— Protein exudation due to local pleural inflam­ mation. —— Defective lymphatic resorption. When pleural space oncotic pressure approaches that of plasma (32 cm H2O), fluid absorption is impaired. zz Simple transfer of ascitic fluid across diaphragm­ atic defects and also through transdiaphragmatic lymphatics as occurs in cirrhosis and Meig’s syn­drome. zz Increased negativity of pressure in the pleural space also results in pleural effusion as occurs in atelectasis zz Obstruction of lymphatics: Pleural fluid, on aspiration in normal persons is 3 to 20 mL. Normal protein content is below 1.5 gm/dL. zz

Causes of Pleural Effusion Causes of Transudative Pleural Effusions Congestive heart failure

Acute diuresis resulting in high PF/serum protein ratio

Hepatic hydrothorax

Usually associated with ascites

Nephrotic syndrome

Small, bilateral and subpulmonic

Peritoneal dialysis

Acute onset within 72 hours after dialysis-large right effusion

Hypoalbuminaemia

Anasarca—serum albumin < 1.5 gm/dL

Urinothorax

Associated with ipsilateral obstructive uropathy

Atelectasis

Small effusion caused by increased intrapleural negative pressure

Constrictive pericarditis

Due to pulmonary and systemic venous hypertension—bilateral

Trapped lung

As a result of remote inflammation

SVC obstruction

Due to venous hypertension or obstruction to thoracic lymph flow

Subarachnoid pleural fistula

CSF leak into pleural space after disc surgery

Myxoedema

Associated features of hypothyroidism

Exudates zz

Mechanism of Pleural Fluid Formation zz

Ch-5.indd 378

Elevation of venous pressure (rare in pure RV failure)

zz

zz

Neoplasms: Metastatic disease, mesothelioma Infectious diseases: Bacterial, viral, fungal, para­sitic, tuberculous Pulmonary embolism

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Respiratory System zz

zz

zz zz

zz

zz zz zz zz zz zz zz

Collagen vascular diseases (rheumatoid arthri­tis, SLE, Wegener’s granulomatosis) Gastrointestinal disease (oesophageal perforation, pan­c reatic disease, diaphragmatic hernia, intraabdominal abscess, endoscopic sclerotherapy) Uraemia Meig’s syndrome (ovarian fibroma, ascites, right sided pleural effusion) Drug-induced: Bromocriptine, amiodarone, nitro­ furan­toin, dantrolene Chylothorax, haemothorax Ovarian hyperstimulation syndrome. Post-coronary artery by-pass surgery Asbestos exposure Radiation therapy Intravascular insertion of central lines Transplant surgery.

Features

Exudates

Transudates

Colour

Amber coloured

Colourless

Consistency

Sticky

Non-sticky

On shaking

Froth +

No froth

On standing

Clots

Does not clot

On aspiration

Slow flow

Flows fast

Specific gravity

> 1018

< 1018

Cells

++

a few lymphocytes

Light’s criteria • Pleural fluid protein/ > 0.5 serum protein • Pleural fluid LDH/serum > 0.6 LDH • Pleural fluid LDH > 2/3 of upper normal value of serum

< 0.5

Glucose

< 60 mg/dL

> 60 mg/dL

LDH

> 200 IU/L

< 200 IU/L

< 0.6 < 2/3 of upper normal value of serum

If the clinical suspicion is strongly in favour of transudate in a case of exudative effusion, do serum-pleural fluid protein gradient. Exudative criteria can be ignored if the gradient is >3.1 gm/dL.

Pleural Fluid Analysis If pleural fluid is found to be an exudate, the following tests should be done. zz Glucose level: If 1000/mm , the fluid is an 3 exudate. If TC >10,000/mm , consider —— Empyema —— Parapneumonic effusion —— Pancreatitis —— Pulmonary embolism —— Collagen vascular diseases —— Malignancy —— Tuberculosis. zz Differential cell count —— Increased neutrophils „„ Pulmonary infection „„ Pulmonary embolisation „„ Intra-abdominal abscess —— Increased lymphocytes „„ Tuberculosis „„ Malignancy „„ Chylothorax „„ Lymphoma „„ Yellow nail syndrome „„ Sarcoidosis „„ Rheumatoid disease „„ Acute lung rejection —— Increased eosinophils „„ With peripheral eosinophilia  Hodgkin’s disease  Fungal infection  Parasitic (paragonimiasis)  Benign asbestos pleural effusion  Polyarteritis nodosa  Tropical eosinophilia  Churg-Strauss syndrome.  Drugs—dantrolene, nitrofurantoin „„ Without peripheral eosinophilia  Trauma  Pulmonary infarction  Pneumothorax  Haemothorax  Rarely in carcinoma. —— ——

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Manual of Practical Medicine Mesothelial cells: Presence of mesothelial cells is against the diagnosis of tuberculosis and diag­nos­ tic of mesothelioma and adenocarci­noma. zz pH of the pleural fluid: If pleural fluid pH is 140 pg/mL zz Pleural fluid adenosine deaminase (large form) >70 U/L indicates tuberculous effusion and a value of < 40 U/L is against the diagnosis. If the small form of ADA is elevated, it is sug­ges­tive of lymphoma. zz Pleural fluid should be sent for Gram’s stain and culture, smear for AFB, culture for AFB. zz Pleural fluid cytology should be done to find out malignant cells. zz N-terminal pro brain natriuretic peptide (NT-proBNP) >1500 pg/mL is diagnostic of effusion secondary to congestive heart failure. ——

Clinical Features

zz

zz zz

zz

zz

Tracheal and mediastinal shift to the opposite side (fluid >1500 cc). When mediastinal shift does not occur, think of parenchymal collapse, previous media­ s­tinal fixation or mesothelioma (Figs 5.41 and 5.42). Obliteration of costophrenic and cardiophrenic angles. Fluid that is located laterally may result in a smooth, semicircular opacity abutting the pleural surface mimicking a mass lesion. There may be a collection in interlobar fissure (vanish­ing tumour of lung) which diappears on treat­ ment with diuretics. Subpulmonic effusion of about 1000 ml may appear only as an elevated diaphragm. X-ray in lateral decubitus position confirms the diagnosis by layer­ing the fluid and reveals the true diaphragmatic shadow.

Fig. 5.41  CT scan—irregular, lobulated appearance of pleural mesothelioma

Pleuritic chest pain (before effusion develops); dysp­noea (the degree of which depends on the rate and the size of accumulation); tracheal and mediastinal shift to the opposite side; diminished or absent breath sounds and stony dull percussion note; aegophony and bron­chial breath sounds just above the level of effusion due to the relaxed lung.

Investigations Chest X-ray Minimal amount of fluid that can be detected in the PA view is 300 mL. Smaller quantities of fluid are detected in lateral decubitus position (in this posi­ tion, fluid layers along the dependent chest wall). zz Dense uniform opacity in the lower and lateral parts of the haemithorax shading off above and medi­ally into transluscent lung (Ellis ‘S’ shaped curve). zz

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Fig. 5.42  CT mediastinal window—pleural effusion right side with passive lung collapse

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Respiratory System

Parapneumonic Effusion

Contd...

It is a pleural effusion associated with bacterial pneu­mo­­ nia, lung abscess or bronchiectasis. Complicated parapneumonic effusions are those effu­sions which require tube thoracostomy for their reso­lution. Empyema is pus in pleural cavity and this term is reserved for effusions in which the Gram’s stain of the pleural fluid is positive. In a patient with bacterial pneumonia, lateral decu­ bitus film may show the presence of free pleural fluid. If the fluid separates the lung from the chest wall by >1 cm in the decubitus film, a diagnostic thora­centesis should be performed. Any of the following is an indication for tube thora­ costomy in patients with parapneumonic effusion. zz Presence of gross pus in pleural space zz Organisms visible on Gram’s stain of the pleural fluid zz Pleural fluid glucose level < 50 mg/dL zz Pleural fluid pH below 7.0 and 0.15 units lower than arterial pH. If the pH is >7.3, antibiotics alone are sufficient. If the pH is 40mg/dl, pH >7.2 LDH 1000 U/L, glucose < 60 mg/dl and Gram’s stain demon­strates organisms.

Treatment Control of infections with appropriate antibiotics (amino­gly­cosides penetrate less well or they may be inactivated by the infected pleural fluid) zz Adequate drainage of pus by: —— Using a wide bore needle/Abram’s punch biopsy needle (for taking biopsy also). Aspiration may be required daily or 2 to 3 times per week. —— Closed tube thoracostomy at the most dependent part of empyema. Tube thoracostomy fails „„ if the pus is too thick „„ if a bronchopleural fistula develops „„ if the pus is loculated. —— Thoracostomy with decortication: This procedure is done if tube thoracostomy fails and when the patient is surgically fit. The fibrous wall (rind, peel, cortex) of empyema cavity is stripped off the parietal and visceral pleura. —— Open drainage with rib resection is done if the patient is unfit for decortication. zz

Malignant Effusions Malignant effusions commonly occur in carcinoma of lung, breast and lymphomas. Effusions are usually haemorrhagic and rapidly accumulating.

Chylothorax When thoracic duct is disrupted and chyle accumu­lates in pleural space, chylothorax occurs. When the lesion is above D5 level, a left-sided chylothorax occurs and if the lesion is below D5 level, a right-sided chylothorax results. Causes zz Trauma zz Tumour-lymphomas zz Tuberculosis zz Lymphangioleiomyomatosis zz Congenital absence of thoracic duct

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zz zz

Yellow nail syndrome Filariasis

Chylous fluid is milky and has a triglyceride level of >110 mg/dL; CT may show mediastinal nodes. Detection of dye or radio activity after the patient eats butter with a lipophilic dye (Sudan III) or radio-iodine labelled triglyceride confirms the diagnosis. Chylothorax should be differentiated from pseudo­ chylous effusion. In chronic effusion due to TB or rheumatoid arthritis, fluid rich in cholesterol mimick­ing chyle accumulates. Addition of ethylether to a sample of the turbid pleural fluid clears it by dissolving triglyceride if it is a chylous effusion. Demonstration of cholesterol crystals on a smear + history + a negative dye or radioiodine test can differentiate pseudochylous effusion from chylo­thorax. Treatment of choice is pleuroperitoneal shunt. Tube thoracostomy is contraindicated as it may lead to malnutrition and immunodeficiency.

Haemothorax Presence of blood in pleural cavity is called haemo­thorax. If the haematocrit of the pleural fluid is greater than 50% that of the peripheral blood, the patient has a haemothorax. Haemothorax is potentially lethal and warrants imme­ diate surgical intervention. Causes zz zz zz

Trauma Rupture of a blood vessel Tumour

Recurrent pneumothorax (due to rupture of vascular adhesions between visceral and parietal pleurae). If the pleural haemorrhage exceeds 200 mL/h, thora­ cotomy should be considered.

Pleural Effusion in AIDS This may be due to: Kaposi’s sarcoma zz Parapneumonic effusion zz Tuberculosis zz Cryptococcosis zz Lymphoma. zz

Causes of Bilateral Effusions zz

zz

With cardiomegaly —— CCF Without cardiomegaly —— Pulmonary infarction —— Hypoalbuminaemia —— Malignancy.

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Respiratory System Causes of Right Sided Effusions zz

zz

zz zz

Fluid retaining states (CCF, CRF, cirrhosis of liver with portal hypertension, etc.) Subdiaphragmatic causes (amoebic liver abscess, sub­ phrenic abscess) Meig’s syndrome Thoracic duct involvement below D5 level.

needle aspiration, thoracentesis, insertion of central intra­ venous catheters, intercostal nerve block, liver biopsy are leading causes for traumatic pneumo­thorax. Types zz

Causes of Left Sided Effusions zz zz zz zz zz

Pancreatitis Pericardial inflammation Oesophageal rupture Left sided subdiaphragmatic abscess Thoracic duct involvement above D5 level.

Management zz zz

zz

zz

Treat the underlying cause. If the effusion is symptomatic, pleural aspiration should be done. Do not aspirate more than 1000 mL of fluid in one sitting as it may lead to re-expansion of pulmonary oedema. Intercostal drainage for empyema, haemothorax (to find out rate of blood loss) Pleurodesis (using tetracycline, bleomycin, talc) for malignant effusions.

Pneumothorax This is the presence of air in the pleural space.

Spontaneous Pneumothorax Spontaneous pneumothorax is one which occurs with­out antecedent trauma to the thorax. zz Primary spontaneous pneumothorax: There is no underlying lung disease or sub-clinical disease and 50% recurs. These are due to rupture of apical, sub­ pleural blebs of 1 to 2 cm in diameter. More common in tall, thin individuals, especially smokers. zz Secondary spontaneous pneumothorax: There is underlying lung disease like COPD, bronchial asthma, tuberculosis, pneumonia, staphylococcal lung abscess, carcinoma lung, cystic fibrosis, fibrosing alveolitis, histiocytosis X, Marfan’s syndrome, Ehlers-Danlos syndrome.

Traumatic Pneumothorax This occurs following penetrating or non-penetrating chest injuries: Deceleration injury, rib fractures, oesophageal rupture, abdominal trauma, invasive procedures like transthoracic

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zz

zz

Closed: The communication between the lung and the pleura closes spontaneously as the lung deflates and does not reopen. When the air is reabsorbed, the lung gradually re-expands. Open: The communication is generally with a bron­ chus (bronchopleural fistula) and does not close when the lung collapses. Air pressure in the pleural cavity equals that of atmospheric pressure and the lung does not re-expand. Infection is common. Tension pneumothorax: The communication be­tween the pleura and the lung persists and it acts like a one way valve allowing air to enter the pleura during inspiration and coughing but prevents it from escaping. This usually occurs during mechani­cal ventilation or resuscitative efforts. This must be treated as a medical emergency.

There is positive pressure in the pleural cavity throughout the respiratory cycle.

Clinical Features Onset is sudden; progressively increasing dyspnoea, cyanosis, distended neck veins, mediastinal shift, hypotension, dimi­nished breath sounds, hyper-reso­nant percussion note, diminished VF, VR. Mediastinal emphysema may be detected by hear­ ing mediastinal crunch (Hamman’s sign) co-existent with cardiac systole and diastole.

Catamenial Pneumothorax It is a rare condition occurring in women aged more than 25 to 30 years. Repeated attacks on the right side are common in association with menstruation. Attacks usually occur within 48 hours of onset of menstru­ation. This is treated by ovulation suppressing drugs, surgical exploration or pleurodesis.

Complications Acute: Tension pneumothorax, bilateral pneumo­thorax, acute respiratory failure, haemothorax and pyothorax. Bilateral pneumothorax is rare and cannot be detected unless a chest X-ray is taken. Haemothorax is potentially lethal; at least 200 mL of blood should be there to obscure costophrenic angle on an X-ray. Late: Failure to re-expand and recurrence.

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Manual of Practical Medicine Investigations

zz

Chest X-ray: Pneumothorax is evident as an area devoid of lung markings peripheral to the edge of the collapsed lung. It is better demostrated in an expi­ratory film when the lung is deflated (Fig. 5.39).

Management zz

zz

zz

zz

Small pneumothorax < 20% of hemithoracic volume can be left alone. Weekly X-ray is taken till full expansion occurs. Rate of absorption is 1.25% of hemithoracic volume per day. High pressure in the pleural cavity than in the capillaries facilitates absorption of air into the capillaries in interstitium. If lung is separated from lateral chest wall by >1/3 of the transverse diameter of hemithorax, active treatment is given. Site of intercostal tube insertion is second intercostal space in mid clavicular line to avoid internal mammary artery.

Management according to the aetiology: Primary spontaneous pneumothorax: Simple aspi­ ration is adequate. If lung does not re-expand or if there is recurrence, tube thoracostomy with instil­ lation of a sclerosant can be tried. Thoracoscopy or thoracotomy with pleural abrasion is almost 100% successful in preventing recurrences. zz Secondary spontaneous pneumothorax: Tube thora­ costomy and instillation of a sclerosant is done to achieve pleurodesis. Patients with primary or secondary spontaneous pneumothoraces with persistent air leak or an unexpanded lung after 6 days, should be subjected to open thoracotomy. zz

Traumatic pneumothorax: In haemopneumothorax one chest tube is placed in the superior part of the hemithorax to evacuate air and another should be placed at the inferior part of hemithorax to remove blood. Treatment can vary from observation, supplemental O2, aspiration, tube thoracostomy.

Tension Pneumothorax Patient is likely to die from inadequate cardiac output (decreased venous return) due to mediastinal shift or marked hypoxaemia (due to severely compromised venti­ lation). A large bore needle is inserted into the pleural space through second anterior intercostal space. Escape of large amount of air confirms diag­nosis. Needle should be left in that place until tube thoracostomy is later performed. Most common cause for pleural effusion, pneumothorax, empyema in our country is tuberculosis.

Interstitial Lung Disease Chronic interstitial pulmonary diseases are a heterogeneous group of disorders characterized predominantly by inflammation and fibrosis of the pulmonary interstitium (alveoli and alveolar epithelium, capillary endothelium, interstitium, perivascular and lymphatic tissues). Interstitial lung disease develops as a result of patho­ logic response of the lungs to a wide variety of insults.

Causes zz zz

zz

zz

zz zz

zz

Infections (viral infections, Mycoplasma) Drugs: Cytotoxic drugs (bleomycin, methotrexate), nitro­ f urantoin, penicillin, amiodarone, hydrochloro­­thiazide Collagen-vascular disorders: SLE, scleroderma, rheu­ ma­toid arthritis Exposure to organic dusts: Farmer’s lung (micropoly­ spora faeni), pigeon breeders (droppings/feather) Irritants: Asbestosis, silicosis Idiopathic interstitial pneumonitis (cryptogenic fib­ros­ ing alveolitis) Inherited diseases—Tuberous sclerosis, neurofibro­ matosis, Niemann Pick’s disease, Gaucher’s disease.

Clinical Features

Fig. 5.43  Pneumothorax right side with passive lung collapse

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Common in 5th to 7th decades with a slight male prepon­derance. Symptoms like non-productive cough, exertional dyspnoea, fatigue, clubbing, cyanosis are common; late inspiratory ‘velcro’ crackles unaltered by coughing at lung bases are heard; features of RV failure and loud P2 may be present.

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Respiratory System Idiopathic Interstitial Pneumonias Clinical diagnosis Clinical features Usual interstitial Idiopathic pulmonary fibrosis pneumonias (UIP) Non-specific interstitial pneumonias (NSIP) Respiratory Common in men and smokers—40–60 bronchiolitis— interstitial years lung disease Acute interstitial Preceded by viral URI, severe exertional pneumonia dyspnoea, widespread pneumonic consolidation, diffuse alveolar damage on biopsy, poor prognosis. Desquamative interstitial Common in men and smokers, pneumonia (DIP) 40–60 years, insidious onset of dyspnoea, clubbing in 50%, alveolar infiltration with macrophages and septal thickening on biopsy, prognosis generally good. Cryptogenic organizing Presents as clinical and radiological pneumonia (bronchiolitis pneumonia, markedly elevated ESR, obliterans organizing absent clubbing, biopsy reveals fibroid pneumonia – BOOP) proliferation of immature collagen Excellent response to corticosteroids. Lymphocytic interstitial Common in women, slow onset over pneumonia (LIP) years, associated with connective tissue disorders or HIV, response to corticosteroids—unclear

Investigations Chest X-ray: Shows an interstitial or alveolar filling pattern or both; honeycombed appearance or swiss cheese appearance may be seen in later stages; RV enlargement and dilated central pulmonary arter­ ies may be seen; in acute alveolitis, ground glass appearance is present. zz Pulmonary function test: Shows classical restric­tive defect. DLCO is reduced. zz High resolution CT scan: HRCT is highly sensitive. zz ABG analysis: Shows arterial hypoxaemia. zz Cytology of bronchoalveolar lavage fluid – Increased Sarcoidosis lymphocytes Extrinsic allergic alveolitis – Neutrophilia Cryptogenic fibrosing alveolitis pneumoconiosis – Organisms Pneumocystis carinii/fungal infections – Lipoprotein- Alveolar proteinosis aceous material – Iron laden Pulmonary haemosiderosis macrophages zz Other investigations: —— Non-specific elevation of LDH, C-reactive protein and ESR —— Anti-nuclear antibodies, rheumatoid factor to rule out SLE and rheumatoid arthritis —— Angiotensin converting enzyme level is elevated in sarcoidosis. zz

Ch-5.indd 385

Management zz

zz zz

zz

Treat the primary cause in diseases where cause is known Bronchodilators and prophylaxis for infection Avoid exposure to allergens in extrinsic allergic alveolitis The drugs of choice are immunosuppressives (steroids, cytotoxic drugs).

Prednisone in a dose of 1 to 1.5 mg/kg/day for 2 to 3 weeks followed by a maintenance dose of 15 to 20 mg on alternate days. If the patient does not respond, cyclo­ phosphamide 100 to 120 mg/day is started. Monitor the response to treatment with chest X-ray, ABG and lung function tests.

Bronchogenic Carcinoma Lung cancer remains the number one cause of cancer deaths among men. Heavy smokers (> 25 cigarettes/ day) experience a risk that is 20 times greater than that of non-smokers. Five percent of cancer deaths are due to passive smoking.

Common Types of Lung Cancer zz zz zz zz

Squamous cell carcinoma or epidermoid (50%) Small cell carcinoma or oat cell carcinoma (25%) Large cell carcinoma (15%) Adenocarcinoma (10%)

Squamous cell and small cell carcinomas are centrally placed tumours; Large cell and adenocarcinoma are peripherally placed tumours.

Predisposing Factors Smoking Asbestos exposure zz Occupational hazards (mining, industrial gases, arsenic, chromium, nickel, radon, vinyl chloride, synthetic rubber) zz Air pollution (sulphur dioxide, carbonaceous parti­cu­ late matter) zz Familial predisposition zz History of COPD, diffuse pulmonary fibrosis, sclero­ derma, sarcoidosis zz Less intake of fruits and vegetables containing beta carotene which is a precursor of vitamin A. Vitamin A deficiency predisposes to carcinoma lung. Other dietary factors—Selenium, vitamin E and C deficiency, high dietary fat/cholesterol intake. zz Individuals with increased aryl hydrocarbon hydro­ xylase (genetically determined) which converts zz zz

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Manual of Practical Medicine

A B Figs 5.44A and B  Pancoast tumour—Right upper lobe carcinoma presenting with Horner’s syndrome

hydrocarbons to more active carcinogens, are at a risk of developing lung cancer.

zz

Clinical Features Thoracic manifestations Cough, haemoptysis, dyspnoea (due to collapse or pleural effusion) pleuritic chest pain, recurrent and slow­ly resolving pneumonia, fixed monophonic wheeze. zz Pancoast tumour (superior sulcus tumour): It presents with pain in shoulder and arm, unilateral Horner’s syndrome, small muscle wasting of the hand, rib and vertebral erosion and is usually due to a squamous cell carcinoma (Fig. 5.44). zz Symptoms due to SVC obstruction, more common with small cell carcinoma. zz Recurrent laryngeal nerve palsy and dysphagia may also occur.

—— Eaton-Lambert syndrome (Myasthenic syn­drome). Others —— Hypertrophic pulmonary osteoarthropathy —— Nephrotic syndrome —— Weight loss.

zz

Investigations To confirm diagnosis Chest X-ray: It may show unilateral hilar enlarge­ ment, peripheral opacity, collapse, pleural effusion, rib erosions, mediastinal widening, elevated hemi­ diaphragm (due to phrenic nerve palsy) (Fig. 5.45). zz Bronchoscopy: Central tumours may be visualised. Bron­chial washings can be obtained to find out malignant cells. zz

Extrathoracic manifestations Symptoms due to blood borne metastasis such as sei­ zures, focal neurological deficits, jaundice, bone pain are common. Paraneoplastic manifestations Endocrine —— Inappropriate ADH secretion (small cell carci­noma) —— Ectopic ACTH secretion (small cell carcinoma) —— Hypercalcaemia (squamous cell carcinoma) —— Carcinoid syndrome —— Gynaecomastia. zz Neurological and muscular —— Myopathy, myositis —— Neuropathy —— Dementia —— Cerebellar degeneration zz

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Fig. 5.45  Right lung—mass lesion

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Respiratory System zz

zz

Sputum cytology: Microscopic examination of sputum and bronchoscopic brushings. Biopsy and histopathological examination: —— Biopsy of the parenchymal lesion by bronchos­ copy or percutaneous biopsy. —— Pleural biopsy in the presence of pleural effusion. —— Lymph node biopsy.

In the presence of metastasis Liver function tests zz Isotope bone scan zz Mediastinoscopy zz USG abdomen zz CT of brain, abdomen and thorax (Fig. 5.46). zz

Squamous cell or epidermoid carcinoma Central tumour; it may cavitate; usually well-differen­ tiated; radiosensitive. Small cell or oat cell carcinoma APUD cell origin; most malignant type; usually widely spread before diagnosis; central tumour; paraneoplasic manifestations common; chemotherapy is beneficial. Large cell carcinoma Peripheral tumour; less well-differentiated; meta­stasise early. Adenocarcinoma Peripheral tumour; may present as pneumonic consolidation; associated with asbestosis. Not related to smoking. Alveolar cell carcinoma, one of the subtypes, is associated with profuse, mucoid sputum production (bronchorrhoea).

Management Small cell lung cancer (SCLC) Limited stage—For patients with good performance status Combination chemotherapy + chest radiotherapy zz Extensive stage (good performance status) Combination chemotherapy zz All stages—Complete tumour responders Prophylactic cranial radiotherapy zz Poor performance status—All stages. zz

Modified dose combination chemotherapy and pallia­tive radiotherapy. Non-small cell lung cancer Resectable (stage I, II, IIIa and selected T3, N2 lesions) zz Surgery zz Radiotherapy for ‘non-operable’ patients zz N —postoperative radiotherapy. 2 Non-resectable (N2, M1) Confined to chest: High dose chest radiotherapy (RT) if possible zz Extrathoracic: RT to symptomatic local sites; chemo­­ therapy for good performance status patients. zz

All patients Radiotherapy for brain, spinal cord metastasis, nerve palsies, obstructed airway, haemoptysis in nonsmall cell cancer, in small cell cancer resistant to chemotherapy, SVC obstruction, chest wall inva­sion, bone metastasis zz Appropriate diagnosis and treatment of other medi­ cal problems zz To stop smoking. zz

Prognosis Non-small cell carcinoma: 2-year survival rate with­out spread—50%; with spread 10%. Small cell carcinoma: 1 year in treated and 3 months in untreated patients.

Mediastinal Mass

Fig. 5.46  CT scan—irregular thick-walled cavity in left lung (carcinoma)

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Mediastinum is divided into four compartments with reference to the lateral chest radiograph. zz Superior mediastinum: Above the line joining D 5 vertebra and the upper end of the body of the sternum. zz Anterior mediastinum: Bounded by thoracic inlet supe­riorly, sternum anteriorly, anterior peri­cardium posteriorly. It contains upper oesophagus, trachea, thymus, aortic arch, adipose tissue and lymphatics.

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Manual of Practical Medicine zz

zz

Middle mediastinum: Contains pericardium and its contents, lower part of trachea, carina, main bronchi and associated lymph nodes. Posterior mediastinum: It reaches from posterior pericardium to vertebral column, posterior rib including paravertebral gutters. It contains oeso­phagus, descending aorta, sympathetic ganglia and peripheral nerves.

Investigations zz

zz

Common Mediastinal Masses

zz

Superior Mediastinum zz zz zz zz zz

Thymic tumour Retrosternal goitre Dermoid cyst Lymphoma Aortic aneurysm.

Anterior Mediastinum zz zz zz zz zz zz

zz

zz

Chest X-ray: Benign tumours are well-circumscribed and malignant tumours show irregular margin and present with mediastinal widening. Fluoroscopic exami­nation of hemi­di­ a­phragm is to be done to rule out phrenic nerve palsy. CT scan: Very useful in defining mediastinal masses (Figs 5.47 and 5.48). MRI scan: It can image in any plane and it has the ability to differentiate between blood vessels and soft tissue. It is also useful in detecting spinal cord exten­sion in a posterior mediastinal tumour (Fig. 5.49). Mediastinoscopy: This is helpful in taking biopsy of lymph nodes from anterior mediastinum. Investigations to rule out other causes: Broncho­ scopy for carcinoma bronchus, thyroid scintigraphy, barium swal­low, angiography.

Thymoma Hodgkin’s and non-Hodgkin’s lymphomas Aortic aneurysm Pericardial, bronchogenic, thymic cysts Intrathoracic goitre Mesenchymal tumours (lipoma, fibromas, lymph­ angio­mas and their malignant counterparts).

Middle Mediastinum zz zz zz zz zz zz

Pericardial cyst, bronchogenic cysts Lymphomas Granulomatous lesions (TB, sarcoidosis, histoplasmosis) Carcinoma bronchus Hiatus hernia Metastasis.

Posterior Mediastinum zz zz zz zz

Neurogenic tumours Paravertebral abscess Alimentary tract duplications, enteric cyst Aortic aneurysm.

Fig. 5.47  CT mediastinal window—anterior mediastinal mass

Symptoms and Signs zz

zz zz zz

zz

zz zz

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Compression of trachea—stridor, dyspnoea, brassy cough, collapse Compression of oesophagus—dysphagia Phrenic nerve involvement—diaphragmatic para­lysis Left recurrent laryngeal nerve involvement— hoarse­ ness of voice, bovine cough SVC obstruction—headache, facial and arm oedema, cya­nosis, non-pulsatile neck vein distension, dilated anasta­motic veins of the chest Sympathetic trunk involvement—Horner’s syn­drome Pericardial involvement (effusion or inflammation).

Fig. 5.48  CT mediastinal window—posterior mediastinal mass (neurofibroma)

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Respiratory System Management Benign tumours: Surgical removal (cysts may get infected; benign tumours may turn malignant).

Malignant tumours Treatment for lymphoma or leukaemia zz Radiotherapy for malignant thymoma zz Radiotherapy for nodes from carcinoma lung zz Radiotherapy alone or radiotherapy + chemotherapy for SVC and tracheal obstructions. zz Treatment of other primary causes (TB, histoplas­ mosis, etc.) zz

Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome is a clinical syndrome of severe dyspnoea of rapid onset, hypoxaemia and diffuse pulmonary infiltrates leading to respiratory failure. Diagnostic Criteria for ARDS (Fig. 5.50) zz zz zz

Fig. 5.49  Venogram—extensive collaterals in SVC obstruction due to mass lesion

zz

Acute onset Oxygenation—PaO2/FiO2 ≤ 200 mm Hg Chest X-ray—bilateral alveolar or interstitial infiltrates Absence of left atrial hypertension or pulmonary capillary wedge pressure—PCWP ≤ 18 mm of Hg

Fig. 5.50  Pathogenesis of ARDS

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Manual of Practical Medicine Diagnostic Criteria for Acute Lung Injury zz

Same as ARDS but the PaO2/FiO2 ≤ 300 mm of Hg.

ARDS consists of three phases (Figs 5.51A and B): zz

zz

zz

Exudative phase: This phase lasts for about seven days. Injury involving alveolar capillary endothelial cells and type I pneumocytes cause exudation of highly proteinaceous fluid into the interstitial and alveolar spaces. The oncotic pressure is normal. Proliferative phase: This phase lasts for about two weeks (8th–21st days). This phase is characterised by prominent interstitial inflammation and early fibrosis. Fibrotic phase: Many ARDS patients recover lung function four weeks after initial lung injury. Some will enter a fibrotic phase that may require long-term support on mechanical ventilation.

Clinical Settings Associated with the Development of ARDS zz zz zz zz zz zz

Aspiration of gastric contents Pneumonia Severe sepsis Major trauma DIC Near drowning

zz zz zz zz zz zz zz zz zz zz zz zz

Inhalation of smoke, irritant (oxygen) or toxic gases Fat or air embolism Massive burns Cardiopulmonary bypass Pancreatitis Narcotic administration Preeclampsia Head injury, increased ICT Shock, sepsis Radiation, drugs Tumour lysis syndrome Malaria.

Clinical Features Tachypnoea followed by dyspnoea, cyanosis, extensive crackles over both lung fields.

Investigations zz zz

zz

zz zz

ABG analysis: Demonstrates hypoxaemia. Chest X-ray: Diffuse, extensive alveolar shadowing bilaterally and more peripherally. Haemodynamic measurements: Pulmonary artery occlusive pressure 18 mm Hg suggests hydrostatic pulmonary oedema. Pulmonary compliance: Decreased to 55 to 60 mm Hg using an FiO2 of 0.6 or less). PEEP helps in the redistribution of capillary blood flow resulting in improved V/Q matching and the recruitment of previously collapsed alveoli and prevention of their collapse during exhalation. This results in improved PaO2 which helps in the reduction of FiO2. Improvement of lung function occurs in 30 to 60 minutes. Oxygenation can also be improved by increasing mean airway pressure with inverse ratio ventilation (Inspiration: Expiration ratio > 1:1). Prone position ventilation can also be tried. —— Low tidal volume (6 mL/kg predicted body weight) —— High frequency ventilation—ventilating at high respiratory rates (5–20 cycles/second and low tidal volume (1–2 mL/kg) —— Partial liquid ventilation with perflurocarbon —— Lung replacement therapy with extracorporeal membrane oxygenation zz zz

A

B Figs 5.51A and B  Stages of ARDS

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Respiratory System zz

zz

zz

zz

zz

zz

Sedation and muscle paralysis to prevent the patient from fighting the ventilator and oxygen utilisation. If cardiac output cannot be preserved, inotropic agents, vasodilators or both can be used. Cyclo-oxygenase inhibitors, protease inhibitors, antioxidant therapy, antitumour necrosis factor or interleukin-1 receptor antagonists are being evaluated. Nitric oxide inhalation (reduces pulmonary artery pressure and improves oxygenation). Minimize left atrial filling pressures with fluid restriction and diuretics. Extracorporeal membrane oxygenation (ECMO) can be tried as alternative therapy.

Mechanical Ventilation Ventilators are specially designed pumps that can support the ventilatory function of the respiratory system and improve oxygenation through application of high oxygen content and positive pressure. Indications for Mechanical Ventilation zz zz zz zz zz zz

Respiratory rate > 35/min Inspiratory force < 25 cm of H2O Vital capacity < 10 to 15 mL/kg PaO2 < 60 mm Hg with FiO2 > 60 % PaCO2 > 50 mm Hg with pH < 7.35 Absent gag or cough reflex.

Modes of Ventilation A volume-cycled ventilator is used in most clinical circumstances. These ventilators deliver a pre-set tidal volume irrespective of change in the lung compliance. Hence, when there is a non-compliant lung, baro-trauma can be caused to the lung. To protect the patient against this undesirable side effect, a pressure limit is set. Control mode ventilation (CMV): This mode is selected in a patient who does not have any spontaneous breathing as in coma or paralysis. The required volume and rate is set and delivered by the ventilator. The patient is not allowed to take spontaneous breath in this mode. Assist-control mode ventilation (ACMV): This is the commonly used mode of ventilation in patients who need assisted ventilation. In this mode, the required tidal volume and respiratory rate are set and delivered by the ventilator. In addition, all spontaneous breathing effort by the patient are assisted by the ventilator. Ventilator-initiated breaths are delivered automatically when the patient’s spontaneous breath rate falls below the selected back-up rate. Synchronised-intermittent mandatory ventilation (SIMV): This mode is maintenance as well as weaning mode.

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Here, the required tidal volume and the respiratory rate are set and delivered by the ventilator in synchrony with the patient’s own respiratory effort. Potential advantages of SIMV include less respiratory alkalosis, fewer adverse cardiovascular effects due to lower intra-thoracic pressures, less requirement for sedation and paralysis, maintenance of respiratory muscle function, and facilitation of longterm weaning. Pressure support ventilation (PSV): This mode augments each patient triggered respiratory effort by specified amount of preset level of positive airway pressure (5–50 cm of H2O). This mode is primarily to augment spontaneous respiratory efforts during IMV modes of ventilation or during weaning trials. Continuous positive airway pressure (CPAP): CPAP is used to deliver air via a nasal or oral mask. Nasal continuous positive airway pressure (nCPAP) is the current treat­ ment of choice for most patients with obstructive sleep apnoea-hypopnoea syndrome (OSAHS). nCPAP pneuma­ ti­c ally splints open the upper airway and prevents collapse. CPAP is applied in spontaneously breathing patient before weaning from mechanical ventilation. Bilevel positive airway pressure (BIPAP) is more expensive than simple CPAP and can be used to treat patients with OSAHS and in patients who do not tolerate high levels of CPAP. All non-invasive positive pressure or mechanical ventilation devices may induce dryness of the airway, nasal congestion, rhinorrhoea, epistaxis, nasal bridge abrasions, skin reactions to the mask and aerophagia. Positive end expiratory pressure (PEEP): PEEP is defined as the maintenance of positive airway pressure at the end of expiration. It can be applied in the spontaneously breathing patient in the form of CPAP or to the patient who is receiving mechanical ventilation. PEEP usually increases lung compliance by opening the alveoli and oxygenation while decreasing the shunt fraction and ventilation perfusion mismatch. PEEP is used primarily in patients with hypoxic respiratory failure (e.g. ARDS, cardiogenic pulmonary oedema). Low levels of PEEP (3–5 cm of H2O) is useful in patients with COPD to prevent dynamic airway collapse from occurring during expiration. The main goal of PEEP is to achieve a PaO2 greater than 55 to 60 mm Hg with an FiO2 of 60%. Patients who receive significant levels of PEEP (i.e. > 10 cm H2O) should not have their PEEP removed abruptly since it can result in collapse of distal lung units. PEEP should be weaned in 3 to 5 cm H2O increments while oxygenation is monitored closely. Inverse ratio ventilation (IRV): It uses an inspiratory-toexpiratory ratio ≥ 1:1 instead of the normal 1:2 to 1:3 to stabilise terminal respiratory units (alveolar recruit­ment)

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392

Manual of Practical Medicine and to improve gas exchange primarily for patients with ARDS. The goals of IRV are: zz To decrease peak airway pressures zz To maintain adequate alveolar ventilation zz To improve oxygenation Indication for IRV: A PaO2 less than 60 mm Hg with FiO2 of greater than 60% and peak airway pressures greater than 40 to 45 cm of H2O or PEEP > 15 cm of H2O. Most patients need heavy sedation and often muscle paralysis during the implementation of IRV. Non-invasive mechanical ventilation: Non-invasive inter­ mit­tent positive pressure ventilation (NIPPV) increases pH, reduces PaCO2 reduces the severity of breathless­ ness in the first 4 hours of treatment, and decreases the length of hospital stay. Intubation rate is reduced by this intervention. However, NIPPV is not appropriate for all patients. Indications zz

zz

zz

Moderate-to-severe dyspnoea with the use of accessory muscles and paradoxical abdominal motion Moderate-to-severe acidosis (pH < 7.35) and hyper­ capnia (PaCO2 > 6 kPa, 45 mm of Hg). Respiratory frequency > 25 breaths/min.

Contraindications zz zz

zz

zz zz zz

zz

Respiratory arrest Cardiovascular instability (Hypotension, arrhythmias, MI) Impaired mental status, somnolence, non-cooperative patients High aspiration risk—viscous or copious secretions Recent facial or gastro-oesophageal surgery Craniofacial trauma, fixed nasopharyngeal abnor­malities Extreme obesity.

Complications of Mechanical Ventilation zz zz

zz

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Airway malpositioning and occlusion Acute increase in peak airway pressure —— Pneumo/haemothorax —— Occlusion of patient’s airway —— Bronchospasm —— Accumulation of condensate in ventilator circuit —— Worsening of pulmonary oedema Fighting or buckling the ventilator (Asynchro­nous breathing) ——  I nadequate ventilatory support, leak in the ventilatory circuit

Inadequate FiO2 (check the adjustments in the ventilatory system) Barotrauma or volutrauma —— Subcutaneous emphysema —— Pneumopericardium —— Pneumoperitoneum —— Pneumomediastinum —— Pneumothorax —— Air-embolism Cardiac arrhythmias Aspiration Pneumonia (nosocomial—>72 hr intubation) Upper GI bleed (gastritis or ulcer) Positive fluid balance and hyponatraemia Oxygen toxicity Tracheal stenosis Hypotension or organ hypoperfusion Mild to moderate cholestasis Acid-base complications (Metabolic/respiratory alkalosis). ——

zz

zz zz zz zz zz zz zz zz zz zz

Guidelines for Withdrawal of Mechanical Ventilation zz

zz zz zz zz zz zz zz

Mental status of the patient—Awake, alert and cooperative PaO2 more than 60 mm Hg with FiO2 less than 50% PEEP < 5 cm H2O Acceptable PaCO2 and pH Tidal volume > 5 mL/kg Vital capacity > 10 mL/kg Respiratory rate < 30/minute Stable vital signs after 1 to 2 hours spontaneous breathing trial.

Pulmonary Hypertension Normal pulmonary artery pressures are as follows: • Systolic pressure 15–25 mm Hg • Diastolic pressure   5–10 mm Hg • Mean pressure 10–15 mm Hg Pulmonary hypertension is present when pulmonary artery systolic pressure is >30 mm Hg, and pulmonary artery mean pressure is >20 mm Hg.

Basic Mechanism zz zz zz zz

Genetic and environmental factors Increased pulmonary blood flow Pulmonary vascular resistance Left heart resistance to blood flow

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Respiratory System

Clinical Classification of Pulmonary Hypertension (Venice 2003) zz

zz

zz

zz

zz

Pulmonary arterial hypertension (PAH) —— Idiopathic pulmonary arterial hypertension (IPAH) —— Familial pulmonary arterial hypertension (FPAH) —— Associated pulmonary arterial hypertension (APAH) „„ Collagen vascular disease „„ Congenital systemic to pulmonary shunts „„ Portal hypertension „„ HIV infections „„ Drugs and toxins „„ Others—(glycogen storage disorders, haemo­ globinopathies, myeloproliferative disorders, splenectomy) —— Associated with significant venous or capillary involvement „„ Pulmonary veno-occlusive disease „„ Pulmonary capillary haemangiomatosis Pulmonary venous hypertension —— Left-sided atrial or ventricular heart disease —— Left-sided valvular heart disease Pulmonary hypertension associated with paren­chymal lung disease or chronic hypoxaemia —— COPD (Chronic obstructive pulmonary disease) —— ILD (Interstitial lung disease) —— Sleep disordered breathing —— Alveolar hypoventilation disorders —— Chronic exposure to high-altitude Pulmonary hypertension due to thrombotic or thromboembolic disease —— Thromboembolic obstruction of proximal pulmonary arteries —— Thromboembolic obstruction of distal pulmonary arteries —— Pulmonary embolism (tumour, parasites, foreign material) Pulmonary hypertension due to miscellaneous conditions —— Sarcoidosis —— Pulmonary langerhans cell histiocytosis —— Lymphangiomatosis

Functional Assessment of Pulmonary Hypertension Class I

No limitation of physical activity—No fatigue, dyspnoea, chest pain or syncope for ordinary physical activity

Class II

Comfortable at rest but symptomatic on ordinary physical activity

Class III

Marked limitation of physical activity—less than ordinary physical activity causes chest pain, undue dyspnoea, fatigue or near syncope

Class IV

Unable to carry out any physical activity—Dyspnoeic even at rest with signs of right heart failure

Six-minute walk test: It demonstrates oxyhaemoglobin desatu­ration on exertion.The distance achieved is lower than expected and it assists in quantifying functional limitations

Primary Pulmonary Hypertension (Fig. 5.52) It is genetically transmitted. The affected gene is in 2q33. Mutation occurs in BMPR2 locus (Bone Morphogenic Protein Receptor type 2). This genetic defect along with environmental triggers result in pulmonary vascular thickening and occlusion leading to primary pulmonary hypertension.

Investigations zz

Chest X-ray: In severe pulmonary hypertension, enlar­gement of RV and pulmonary arteries are seen. It may also show evidence of primary lung or cardiac diseases.

Clinical Features Cough, chest pain, haemoptysis, loud P2, TR murmur, RVH and features of RV failure later.

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Fig. 5.52  Primary pulmonary hypertension Abbreviation: BMPR-2—Bone morphogenetic protein receptor-type 2

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Manual of Practical Medicine zz

zz

zz

zz

zz

zz

zz

zz

zz

zz

zz zz

zz

zz

Ventilation-perfusion lung scan: This shows several segmental or greater-sized perfusion defects in throm­boembolism. In contrast, in PPH, perfusion scan is either normal or patchy. Pulmonary angiogram: It is indicated when there is suspicion of thromboembolism. ECG: Right ventricular and atrial enlargement, RBBB, RV strain pattern. Transthoracic echocardiogram to assess the cardiac status. Pulmonary function testing to assess COPD/ restrictive disorders. Arterial blood gas (ABG): Low PaO2 and elevated PaCO2 in case of parenchymal lung disease. Six minute walk test: Unexplained exercise induced desaturation suggests PH. Nocturnal oximetry: Nocturnal desaturation in case of sleep-breathing disorder. Transoesophageal echocardiogram: To identify intracardiac shunts. CT chest: To assess parenchymal and mediastinal lesions. MRI: To detect cardiac anomalies. Radionuclide ventriculography assesses RV and LV function. Right heart catheterisation: To confirm PAH and plan further management. —— Useful for accurate measurement of pulmonary arterial pressure, cardiac output and LV filling pressure —— Useful for drug testing with short acting pulmonary vasodilator (No/Adenosine) and the responders can be treated with calcium channel blockers. Lung biopsy: Histologic confirmation of pulmo­nary vasculitis, veno-occlusive disease and interstitial lung disease.

Management zz zz zz

Treat the underlying cause Correct hypoxaemia with oxygen Diuretics in RV failure.

Three pathways for treatment of PHT (Fig. 5.53): Nitric oxide – Soluble Guanyl Cyclase (Cyclic GMP Pathway) zz Prostacyclin pathway zz Endothelin pathway zz Vasodilators in PPH —— Calcium channel blockers —— Angiotensin-converting enzyme inhibitors

Epoprostenol and Treprostinil are the drugs approved for the treatment of pulmonary hypertension. —— Bosentan-endothelin receptor antagonist and sildenafil—an oral phosphodiesterase-5 inhibitor are also used in the treatment of pulmonary hypertension. —— Other drugs used: Endothelin receptor antagonists—ambrisentan, macitentan (both oral); PDE5 inhibitor tadalafil (oral); soluble guanylyl cyclase stimulator—Riociguat (oral). Caution: Sudden discontinuation of vasodilator/ prostacyclin during chronic use can result in rebound PH and death. Calcium channel blockers should be used only in vasodilator-responsive patients and not in nonresponders as it might cause hypotension, RVF and death. ——

Drugs for the Management of Pulmonary Hypertension S. No.

Dosage schedule

Nifedipine

20–60 mg tid (Maximum 240 mg/day)

2.

Diltiazem

90–120 mg tid (Maximum 720 mg/day)

3.

Bosentan

62.5–125 mg PO bid (Initiate 62.5 mg)

4.

Sildenafil

20 mg PO tid (caution – Hypotension)

5.

Epoprostenol

2–50 ng/kg/min – IV infusion

6.

Treprostinil

10–50 ng/kg/min – SC or IV infusion

7.

Iloprost

2.5–5 mcg 2–3 hourly inhalation

8.

Dobutamine, milrinone, digoxin

Inotropic agents as required

9.

Anticoagulants– Warfarin

Aim – INR 1.5–2.5

10.

Diuretics

Frusemide and spironolactone

zz

zz zz



zz

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Name of the drug

1.

zz zz

Prostacyclin (improves pulmonary haemodynamics, exer­cise tolerance and survival in PPH when given for more than 12 weeks) Acute inhalation of nitric oxide (in PPH) Creation of a small ASD by balloon septostomy (allows deoxy­genated blood to reach LV improving cardiac output). Atrial septostomy: It allows decompression of the right heart by creating a hole in the septum when the right heart pressure is greater than the left (right-toleft shunt). It is a palliative procedure and it improves left ventricular filling and cardiac output. This procedure is indicated in severe PPH refractory to maximal medical therapy and this serves as a bridge till the transplantation. Heart-lung transplant Surgical intervention in thromboembolism.

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Respiratory System

395

Fig. 5.53  Drugs used for pulmonary hypertension

Cor Pulmonale Cor pulmonale is enlargement of the right ventricle with or without failure, secondary to diseases of the lung, thorax, or pulmonary circulation. Corpulmonale, often referred as pulmonary heart disease, can be defined as altered RV structure and/ or function in the context of chronic lung disease and is triggered by the onset of pulmonary hypertension. Although RV dysfunction is also an important sequel of heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced EF (HFrEF), this is not considered as cor pulmonale.

zz zz

zz zz zz zz zz zz

Acute: It is due to thrombo-embolic episode. Chronic: It is due to various underlying causes.

zz

zz zz zz zz zz

COPD Chronic severe asthma Bronchiectasis Sarcoidosis ILD Cystic fibrosis

Pulmonary emboli Pulmonary vasculitis Primary pulmonary hypertension ARDS Sickle-cell disease Parasitic infestations.

Thoracic Cage Abnormality zz

zz

Pulmonary fibrosis Extensive tuberculosis Lung resection.

Pulmonary Vascular Disorders

Causes of Cor Pulmonale

Pulmonary Causes

Ch-5.indd 395

zz

zz

Kyphosis Scoliosis Thoracoplasty.

Neuromuscular Disorders zz zz zz

Myasthenia gravis Poliomyelitis Motor neuron disease.

Hypoventilation zz zz

Sleep apnoea Enlarged adenoids in children.

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396

Manual of Practical Medicine Clinical Features

Management

Features of RV failure and evidence of primary lung diseases.

zz zz zz

Investigations zz

zz

zz zz

zz

Chest X-ray: Prominent RA, RV and pulmonary artery. ECG: P-pulmonale, right axis deviation, RVH with strain pattern. Blood count: Secondary polycythaemia. Two-dimensional echocardiography for measuring RV thickness and chamber dimensions: RA/RV will be dilated (Fig. 5.54).

zz

Treat the primary lung disorder Diuretics Vasodilators Bronchodilators Control of infection.

Pulmonary Thromboembolism Pulmonary thromboembolism is due to detached thrombi from deep veins of leg (80%); of pelvic veins (10%); or other veins and right sided cardiac chambers (5%) and very rare causes air, fat, tumour cells, placental bits, amniotic fluid, and parasites—schistosomes (5%). Ninety percent of deaths occur within the first hour even before a diagnostic therapeutic plan is implemented. Pathophysiology of pulmonary embolism in shown in Figure 5.55.

Risk Factors for Deep Vein Thrombosis zz zz zz zz zz

zz zz zz zz

Fig. 5.54  Echo RA/RV dilated (Cor pumonale)

zz

Deficiency of antithrombin III, Protein C, and Protein S. Presence of lupus anticoagulant Homocystinuria Surgical procedures of more than 30 minutes duration. Prolonged bed rest following medical illness or surgery or fractures involving lower limbs Chronic deep venous insufficiency Malignancy predisposes to DVT Obesity Oral contraceptives Oestrogen therapy

Fig. 5.55  Pathophysiology of massive pulmonary embolism

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Respiratory System zz zz zz zz zz zz zz zz zz zz zz zz

Congestive heart failure Chronic lung disease Hypertension Diabetes mellitus Inflammatory bowel disorders Varicose veins Pregnancy/Postpartum Long distance air travel Cerebro-vascular disorder Indwelling central venous catheters Cigarette smoking Paroxysmal nocturnal haemoglobinuria —— Deep vein thrombosis usually develops in the region of a venous valve. —— Large extensive thrombi can develop within a few minutes. —— Larger leg veins (popliteal and above) are the common source of pulmonary emboli. —— Pulmonary emboli are uncommon in DVT that remains confined to calf veins. Pulmonary embolism is common in the first week of thrombus formation before its fibrinolysis/organisation. —— Pain, warmth, and swelling of legs denote deep vein thrombosis.

Fig. 5.56  CTPA—CT-pulmonary angiography (filling defectindicates pulmonary embolus)

Investigations zz

zz

zz

zz

zz zz

Ch-5.indd 397

Venography is the gold-standard technique for diagnosing DVT. However, non-invasive tests are preferred in symptomatic patients with suspected DVT. It is also contraindicated in renal dysfunction and dye allergy. CT venography: It allows visualisation of veins in the abdomen, pelvis and proximal lower extremities. MRI venography: It is non-invasive and sensitivity is good for the diagnosis of acute symptomatic proximal DVT. Contraindications for MRI include gadolinium allergy, severe claustrophobia. Certain implanted devices and cerebral aneurysm. PE specific testing (Figs 5.56 and 5.57): —— Contrast enhanced spiral chest CT —— Multidetector CT —— V/Q scanning: It needs administration of radioactive material (both inhaled and IV routes) —— MR angiography —— Pulmonary angiography—gold-standard for diagnosing PE. Plasma D-dimer ELISA—not specific Elevated cardiac biomarkers —— Serum troponin —— Plasma heart type fatty acid binding protein (a and b are due to RV microinfarction) —— BNP or NT pro-BNP—due to myocardial stretch.

Fig. 5.57  Saddle pulmonary embolism

Clinical Features The classical manifestations of pulmonary thrombo­ embolism are unexplained dyspnoea, tachycardia, central chest pain or pleurisy, haemoptysis developing in the second week of postoperative period, especially in patients with a predisposing condition like DVT. Chronic pulmonary thromboembolism manifests with exertional dyspnoea, and late signs of pulmonary hypertension as evidenced by loud P2, RV heave, and right heart failure. Chest X-ray reveals enlarged pulmonary artery trunk, prominent right ventricle and ECG reveals RV hypertrophy and strain. The clinical signs and the results of investigations vary depending on the size of pulmonary vessels involvedlarge (massive), medium (segmental), or pulmonary microvasculature.

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398

Manual of Practical Medicine Manifestations of Pulmonary Thromboembolism

Pathology

Symptoms

Large (massive) Reduced cardiac output, sudden loss of cerebral and coronary blood flow, acute right heart failure, altered ventilation perfusion ratio Sudden dyspnoea, tachycardia central chest pain sudden syncope

Microvasculature Pulmonary hypertension Failure of right heart

Pleurisy pain Breathlessness Haemoptysis

Dyspnoea and syncope only on exertion

Shock, raised JVP, tachycardia, hypotension, loud/widely split P2 gallop rhythm

Asymptotic or mild tachycardia mild dyspnoea

•  RS

Central cyanosis

•  Urine output •  Fever Investigations •  Chest X-ray

Reduced —

Pleural rub, crackles haemorrhagicpleural effusion Normal Low-grade fever

Asymptomatic late-loud P2 signs of RV failure Nil Normal —

Raised hemidiaphragm Wedge-shaped or linear opacities (Hampton’s sign) Pleural effusion

Prominent Pulmonary trunk And RV (Palla’s sign) Increased TCD

•  ECG

(SI QIII TIII) S in lead I Q in lead III Inverted T in lead III and chest leads VI to V4 Right axis deviation, AF Right bundle-branch block Reduced PaO2 Reduced PaCO2 Larger areas of defective perfusion

—

Right ventricular hypertrophy and strain

Reduced PaCO2

Reduced PaO2 on exertion

Segmental areas

—

Diagnostic

Diagnostic

—

Diagnostic

Diagnostic

—

Not required

Not required

Confirms diagnosis

Signs •  CVS

•  Blood gases •  Ventilation perfusion (V/Q lung scans) •  CT with contrast MRI, spiral CT •  P  ulmonary angiography •  Lung biopsy

Hilar prominence oligaemic lung fields (Westermark’s sign)

Management zz zz zz zz



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Size of vessels Medium (segmental) Pulmonary infarction with or without pleural effusion

Administer oxygen (up to 100%) Morphine 10 mg IV if patient is distressed Heparin—10,000 to 20,000 units IV bolus Follow it with heparin standard regimens 4 hours later Standard heparin regimens: —— Continuous intravenous—1000 units/hour —— Intermittent intravenous—5000 units 4th hourly or 7,500 units qid. —— Intermittent subcutaneous—5000 units 4th hourly or 10,000 units tid. „„ Low molecular weight heparin – Enoxaparin 1 mg/kg SC q12h or dalteparin – 200 IU/kg SC daily or tinzaparin 175 IU/kg SC daily (Or) „„ Fondaparinux – Anti Xa pentasaccharide Dose—100 kg—10 mg SC od (Or)

Newer anticoagulants Rivaroxaban (factor Xa inhibitor) or Dabigatran (direct thrombin inhibitor) Avoid intramuscular injection of heparin as it causes haematoma. Intramuscular injections must be avoided during heparin therapy. Subcutaneous low molecular weight heparin is equally effective except for the high cost. Heparin therapy is given for 10 days. zz Thrombolytic therapy with streptokinase or uro­ kinase may be useful in large vein DVT or massive embolism. zz Pulmonary embolectomy—Rarely indicated zz Venous interruption—Transvenous placement of filter in the inferior vena cava to protect against emboli greater than 2 mm in diameter. zz Oral anticoagulants like warfarin to be given for a period of three months afer heparin therapy. „„ „„

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Respiratory System Management of DVT

zz

Use one of the standard heparin regimens or low molecular weight heparin for 10 days. No bolus dose of heparin is required. Follow heparin therapy with oral anticoagulants for 3 months.

LUNG TRANSPLANTATION End-stage lung disease COPD zz Idiopathic pulmonary fibrosis zz Cystic fibrosis zz Primary pulmonary hypertension zz

Alpha-1 antitrypsin deficiency (emphysema) Eisenmenger’s syndrome.

Types zz

zz

zz

Indications

Ch-5.indd 399

zz

Single lung transplantation (right or left) through a thoracotomy Sequential single lung transplantation (through anterior thoracosternotomy) Heart-lung transplantation (through median ster­no­­­tomy).

Single lung transplantation is performed for non-infec­ tious lung disorders and for Eisenmenger’s syndrome (where heart defect is correctable at the time of trans­plant). There is a definite functional improvement. The lack of available donors to meet the demand makes single lung Tx popular.

Complications

Disease

Parameters for Tx

Improvement after Tx

Primary pulmonary hypertension

PHT, RV failure, Class III functional status, no response to vasodilators

Pulmonary artery and right heart pressures normalise

Early post-Tx period: Bleeding, bronchial dehiscence or stenosis, reimplantation pulmonary oedema, acute rejection, infection.

Eisenmenger’s syndrome

Near syncope, chest pressure, haemoptysis

Lung function tests become normal Functional improvement to class I or II

Late complications: Infections, renal insufficiency (cyclo­­ sporin), obliterative bronchiolitis (warrants sequen­tial bron­choscopy and transbronchial biopsy).

Cystic fibrosis

FEV1 < 20% haemoptysis, weight loss, frequent infections

Lung function tests normalise

Emphysema

FEV1 of 500 cc or less

40–60% after Tx

Interstitial lung disease

Low DLCO, PHT and RVF, hypoxaemia during exercise

TLC becomes 70–80%

Prognosis Single lung Tx: 1 year—73%, 2 years—65%, 3 years— 62%. Bilateral, sequential single lung Tx: 1 yr—70%, 2 yr—60%, 3 yr—55% (cystic fibrosis). Heart lung Tx (Eisenmenger’s syndrome): l yr—60%, 5 yrs—40%.

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CHAPTER

6

Abdomen

Ch-6.indd 401

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Manual of Practical Medicine

CLINICAL EXAMINATION Signs and Symptoms Dysphagia Difficulty in swallowing Aphagia Inability to swallow Odynophagia Painful swallowing Globus Sensation of a lump lodged in the pharyngeus throat Phagophobia Fear of swallowing Anorexia Loss of appetite or lack of desire to eat Sitophobia Fear of eating because of subsequent abdo­minal discomfort seen in regional enteritis and in chronic mesenteric vascular insuffi­c iency (abdominal angina). Nausea Feeling of imminent desire to vomit, usually referred to the throat or epigastrium. Vomiting Refers to the forceful oral expulsion of (emesis) gastric contents. Retching Denotes laboured rhythmic contrac­ tion of respiratory and abdominal muscu­lature that frequently precedes or accompanies vomi­ting. Hiccough or A phenomenon resulting from hiccup or sudden spasmodic, involuntary singultus contraction of diaphragm with the glottis remaining closed with the pro duction of short, sharp, inspi­ratory sounds. Regurgitation Appearance of previously swallo­wed food in the mouth without vomiting, e.g. acha­lasia cardia. Rumination Rumination is the repeated regurgita­ tion of food residue, which may be re-chewed and re-swallowed. Vomi­ ting is forceful expulsion of gastric contents due to contraction of gut and thoracoabdominal wall musculature and not under voluntary control. Regurgitation and rumination are due to the effortless passage of gastric contents into the mouth and these phenomena exhibit volitional control. Water brash Sudden filling of mouth with saliva produced as a reflex response to a variety of symptoms from upper GIT. Heart burn Sensation of warmth or burning located or pyrosis substernally or high in the epigas­ trium with radiation into the neck and occasionally to the arms.

Ch-6.indd 402

Belching Aerophagia Diarrhoea

Chronic repetitive eructations Air swallowing An increase in daily stool weight more than 200 g. Typically the patient may also describe an increase in stool liquidity and frequency of more than 3 bowel movements per day. If consis­ tency is liquid or semi­formed even one episode is considered as diarrhoea. Normal bowel frequency ranges from 3 times a week to 3 times a day depending on fibre content, medica­ tions, exercise and stress. Pseudo- Increased frequency of defaecation diarrhoea or without increase in stool weight above hyperdefaecation normal. It is seen in irritable bowel syndrome, hyperthyroidism (increased sym­pa­thetic activity) and proctitis. Faecal Involuntary release of rectal contents. incontinence It is more common when stool is liquid than solid. It reflects weakness of pelvic muscles resulting in abnormal function of anorectal sphincter. Acute diarrhoea Diarrhoea lasts for 1–2 weeks Persistent Diarrhoea lasts for 2–4 weeks diarrhoea Chronic Diarrhoea lasts for more than 4 diarrhoea weeks. Constipation Frequency of defaecation less than 3 times a week or the stool is hard or difficult to pass. Haematemesis Vomiting of blood Pseudohaemate- In patients with upper respiratory mesis bleed, the blood may be swallowed and later vomited as altered blood mimick­ing an upper GI bleed. Melaena Passage of stools rendered tarry and black by the presence of altered blood. About 60 mL of blood is necessary to cause melaena. After a single bout of bleeding, melaena per­sists for about 1 week. Blood must remain in the gut for about 8 hours to produce melaena. Maroon Passage of maroon coloured stool coloured stool occurs when the bleeding site is located in the distal small bowel or right colon. Haematochezia Passage of frank blood per rectum. It signifies bleeding from a source distal to ligament of Treitz, especially when bleed occurs from anorectum or left colon. Brisk upper GI bleed with rapid

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403

Abdomen

Jaundice

Azotaemia Oliguria Anuria

Proteinuria

intestinal transit may also result in bright red blood per rectum. Yellowish discolouration of skin, sclera and mucous membranes resulting from an increase in serum bilirubin concen­tration more than 3 mg/dL. Latent jaundice—serum bilirubin between 1 mg/dL and 2 mg/dL An increase in serum concentration of urea and creatinine. This refers to a urine output insuffi­ cient to sustain life, usually 150 pg/mL) with a raised basal gastric acid output of >15 mmol/hour (Normal BAO is 1.5–2.0 mmol/hr) Gastrinomas may be localised by measuring the uptake of a somatostatin analogue, 111Indium-Pentriotide (Octreo­scan) This condition is treated with a potassium-hydrogen ATPase inhibitor like omeprazole. The drug is started with a dose of 60 mg/day and then gradually tapered to 20 mg/day as symptoms subside. Since the long-term effects of omeprazole use are still unknown, it is worthwhile trying to excise the tumour, which is the definitive treatment for this condition If the tumour turns out to be malignant, then the prognosis is poor, 5-year survival being only 20%.

Endoscopy Upper Gastrointestinal Endoscopy Indications zz zz zz

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Dysphagia Caustic or foreign body ingestion Dyspepsia

zz zz zz zz

zz zz

Persistent nausea and vomiting Need to obtain small intestine biopsy Acute or chronic gastrointestinal bleeding Inflammatory bowel disease (as this may be associated with duodenal lesions mimicking a duodenal ulcer) Chronic abdominal pain Suspected polyp or cancer.

Contraindications zz zz zz zz

Perforated viscus suspected Patient in shock Combative or uncooperative patient Severe inflammatory bowel disease or toxic megacolon (colonoscopy).

Preparation of the Patient zz

zz

Patient should be fasted for 6 or more hours to ensure an empty stomach For emergency, nasogastric suction should be done before endoscopy procedure.

Therapeutic Oesophagogastroduodenoscopy zz

zz

zz

zz

In case of upper gastrointestinal bleeding, due to a variceal bleed, endoscopic injection of sclerosants (sclerotherapy) of oesophageal varices is the most widely accepted therapeutic oesophagogastro­ duodenoscopic procedure It is also used therapeutically for banding of oesophageal varices Laser therapy through endoscopy to relieve GI obstruction by malignant growth can be done palliatively Stenting procedure can be done, thereby providing a lumen through the stent for feeding patients with mechanical obstruction to oesophagus causing dysphagia.

Complications of Endoscopy zz zz zz zz zz zz

Perforation of viscus Bleeding Cardiac arrhythmias Reaction to medication (sclerosants) Vasovagal reaction Pulmonary aspiration.

Gastrointestinal Bleeding Haematemesis It is defined as the vomiting of fresh blood, either bright red or of coffee ground character.

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Melaena It is a tarry black, sticky, foul smelling stool (Other stool darkeners are iron and bismuth). Special Features zz

zz

zz

Approximately 60 mL of blood is required to produce single black stool. The blood loss > 60 mL produces melaena for more than 7 days. To produce melaena, the blood must remain in the gut for 8–14 hours.

Oesophageal varices 10% Others 5% (Leiomyoma, haemophilia, thrombocytopenia, EhlersDanlos syndrome, rupture of aorta into stomach, anticoagulants) Laboratory Findings zz

zz

zz

Haematochezia It is the passage of red or maroon blood from the rectum, usually signifies bleeding from a source distal to the ligament of Treitz. It can also occur from massive upper GI bleed from oesophagus, stomach and duodenum. Tilt Test • Tilting the head end of the body upwards at an angle of 75° for 3 minutes leads to accelerated heart rate and a drop in systolic blood pressure • Increase in heart rate of 30 beats/min and presence of faintness or syncope indicates decompensated blood loss and need for restorative measures. Assessment of Bleed Blood loss

Clinical features

500 ml

No systemic signs except in elderly and anaemic patients

1000 ml (20% reduction of blood volume)

Tachycardia, orthostatic hypotension, syncope, light headedness, nausea, sweating and thirst

2000 ml or more (40% reduction of blood volume)

Profound shock and possibly death

•  Drop in urine output 0.5 mL/min) Radio-labelled RBC: It is useful in determining low grade bleeding from GI tract and especially when the pathology is out of reach of the endoscope (>0.1 mL/min). Differentiation between Upper GI and Lower GI Bleed

Features

Upper GI bleed

Lower GI bleed

Site

Above the ligament of Treitz

Below the ligament of Treitz

Presentation

Haematemesis/melaena

Haematochezia

Nasogastric aspiration

Blood

Clear fluid

BUN/creatinine ratio

Increased (>25:1)

Normal (100 mmHg

120/min; systolic BP 125 milliosm/L Osmotic gap is calculated by the formula: 290 — 2 X stool (Na+ + K+ ) pH Carbohydrate in stool — acid pH Milk of magnesia — alkaline pH Poorly absorbable salt containing — neutral pH magnesium and sulfate, e.g. carbohydrate malabsorption, antacids and laxatives containing Mg++.

Secretory Diarrhoea Clinical Features

zz

Diarrhoea

Abnormal intestinal motility when an increased or decreased contact between luminal contents and mucosal surface.

zz zz zz zz

zz



Stool volume >1 litre/day Stool is watery in consistency Stool does not contain pus or blood Diarrhoea continuous, even when patient fasts for 24–48 hours but stops when agents causing fatty acid mal­absorption or laxatives are not ingested. Osmotic gap 70 years —— Hospitalization required patients.

Pathogens Salmonella Shigella Yersinia Campylobacter Clostridium difficile Giardia lamblia E. histolytica

Antibiotic Ampicillin, cotrimoxazole, amoxycillin Cotrimoxazole, amoxycillin, 4-fluoro- quinolones Tetracycline Erythromycin, tetracycline Vancomycin, metronidazole Metronidazole, tinidazole Metronidazole, tinidazole, secnidazole

Chronic Diarrhoea Diarrhoea of >4 weeks duration. Causes zz zz zz zz zz

zz

Differentiation between Small Bowel and Large Bowel Diarrhoea Features Volume of stool Colour of stool Smell of stool Nature of stool Type of stool Blood in stool WBCs in stool Location of abdominal pain Tenesmus Common pathogens

Small bowel diarrhoea Large Light Very foul Soupy and greasy Watery Rare Rare Mid abdomen (crampy and intermittent) Absent Vibrio cholerae E. coli Rota virus, Norwalk virus Campylobacter Giardia

Large bowel diarrhoea Small Dark Foul Mucinous or jelly like Mucoid Common Common Lower abdomen (gripping and continuous) Present Shigella E. histolytica

Amoebic dysentery 6–8 motions per day Relatively copious Offensive Dark red Blood and mucus mixed with faeces

Reaction Consistency

Acid Not adherent to the container

Microscopic examination a. RBC b. Pus cells c. Macrophage d. Eosinophils e. Parasite

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In clumps Scanty Very few Present Trophozoites of E. histolytica

Malabsorption Malabsorption refers to defective mucosal absorption of essential nutrients, electrolytes, minerals and vitamins. It can be due to defects in: zz Luminal phase zz Mucosal phase zz Transport phase of absorption of nutrients.

Luminal Phase Defect in Substrate Hydrolysis • Enzyme deficiency

Differentiation between Amoebic and Bacillary Dysentery Features Number of stools per day Amount Odour Colour Nature

Infection Inflammatory bowel disease Drugs Malabsorption Endocrine —— Zollinger-Ellison syndrome —— Hyperthyroidism —— Carcinoid —— Non-β cell pancreatic tumour —— Villous adenoma Motility disorder —— Irritable bowel syndrome —— Post-vagotomy syndrome.

Bacillary dysentery More than 10 per day Small quantity Odourless Bright red Blood and mucus (with minimal faecal matter) Alkaline Adherent to the container Discrete Numerous Numerous Absent Nil

• Enzyme inactivation • Rapid transit/ asynchrony

Chronic pancreatitis and pancreatic carcinoma Zollinger-Ellison syndrome Post-gastric surgery

Defect in Fat Solubilisation • Decreased bile salt • • •

Impaired biliary Bile salt deconjugat- ion, precipitation and binding Increased bile salt

Parenchymal liver disease synthesis Cholestatic jaundice secretion Bacterial over growth; Zollinger-Ellison syndrome Terminal ileal resection or loss disease

Defect in Luminal Availability and Processing • Lack of intrinsic factor Pernicious anaemia • Consumption of B12 Blind loop syndrome; due to bacterial over prolonged use of proton growth pump inhibitor

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Abdomen

Mucosal Phase Defect in Brush Border Hydrolysis Disaccharidase deficiency—primary or secondary. Defect in Epithelial Transport zz

zz

Isolated defects —— Hartnup disease, cystinuria, congenital vitamin B12 and folate deficiency Global defects —— Intestinal resection —— Diffuse mucosal disease „„ Coeliac disease „„ Tropical sprue „„ Crohn’s disease „„ Radiation „„ Ischaemia „„ Whipple’s disease „„ AIDS.

Defect in Epithelial Processing Abetalipoproteinaemia.

Transport Phase zz

zz

Lymphatic obstruction, lymphangiectasia, primary or secondary nodal disease Vascular intestinal ischaemia (atheroma, vasculitis).

Symptoms and signs Frothy stools, watery diarrhoea, weight loss Weight loss, muscle wasting, oedema, leuconychia Abdominal distension, borborygmi, watery diarrhoea, flatus Anaemia, glossitis, cheilosis, koilonychia, aphthous ulcer Anaemia, glossitis Anaemia, glossitis, neurological sequelae Hyperkeratosis, night blindness Rickets, osteomalacia, proximal myopathy Bruising and bleeding Paraesthesia, tetany Paraesthesia, tetany Poor taste, acrodermatitis, poor wound healing Watery diarrhoea

Small Intestine Biopsy Diseases

Biopsy findings

Coeliac disease (Figs 6.20A and B)

Subtotal or partial villous atrophy

Dermatitis herpetiformis Subtotal or partial villous atrophy Tropical sprue

Partial villous atrophy

Whipple’s disease

PAS-positive macrophages

Intestinal lymphomas

Infiltrate of abnormal lymphoid cells

Parasitic infections

Giardia, Strongyloides or coccidia may be seen

Lymphangiectasia

Dilated lymphatics

Drugs and Malabsorption Drugs

Mechanisms

Colchicine

Inhibits crypt cell division and disaccharidases

Neomycin and other related antibiotics

Reduces crypt cell replication, precipitates bile salts and micellar fatty acids; inhibits disaccharidases

Tuberculosis of Abdomen

Methotrexate

Folate antagonist ± direct toxicity

Cholestyramine

Binds bile salts

It commonly affects ileocaecal area in 70% of the patients. The other regions affected in decreasing order of frequency are ascending colon, jejunum, appendix, sigmoid colon, rectum, duodenum, stomach and oesophagus.

Laxatives, PAS, biguanides

Inhibits mucosal enzyme transport activity

Alcohol

Pancreatic insufficiency; direct enterocyte toxicity; chronic liver disease

Pathological Types

Diseases

Mechanisms

Ulcerative (60%)

Thyrotoxicosis

Hyperphagia and rapid transit

Hypothyroidism

Variable villous atrophy; pancreatic insufficiency

Addison’s disease

Unclear

Principles of Management zz zz

zz

zz

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Clinical Features Malabsorbed nutrients Fat Protein Carbohydrate Iron Folic acid Vitamin B12 Vitamin A Vitamin D Vitamin K Calcium Magnesium Zinc Bile salts

Correction of nutritional deficiencies Treatment of the underlying disorder.

Multiple superficial lesions confined largely to the epithelial surface (virulent process) The long axis of the ulcer is perpendicular to the long axis of the GI segment involved and hence it is prone for stricture formation (the long axis of the ulcer produced in enteric fever lies parallel to the long axis of the GI segment involved).

Systemic Disease Associated with Malabsorption

Hypoparathyroidism Minor mucosal changes; occasional monilial infection Diabetes mellitus

Pancreatic insufficiency; autonomic neuropathy; bacterial overgrowth

Collagen vascular disorders

Variable villous atrophy; amyloidosis; bacterial overgrowth

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A B Figs 6.20A and B  (A) Coeliac sprue-jejunal mucosal biopsy flat mucosal surface with absent villi; (B) Improvement after treatment

Lymphoglandular

Test of Malabsorption Nutrient tested Tests Fat Measurement of fat in a 5-day collection of stool The synthetic bile acid is given orally and its retention is measured at 7 days by whole body counting Carbohydrate

Protein

Vitamins

Lactose tolerance test: 50 g of lactose is given orally and blood samples are taken every 20 min for 2 hours Hydrogen breath test: 50 g of lactose is given orally and breath hydrogen is measured every hour for 4 hours Faecal clearance of endogenous α1 antitrypsin: This normal serum protein is excreted unchanged in the stool when there is any protein loss into the stool and is therefore measured in a 3-day collection of stool Vitamin B12 absorption: 0.5 µg of radiolabelled vitamin B12 is given orally followed 2 hours later by 1000 µg of non-radioactive vitamin B12 given by intramuscular injection. Urine is collected for 24 hours

Small intestinal culture

Normal value Excretion 90% (In severe ileal disease, retention is < 20%) Rise in blood glucose > 20 mg/dL Less than 10 ppm above baseline in any sample No α1 antitrypsin in the stool

Clinical Features Chronic abdominal pain (80–90%), diarrhoea and occasionally blood in the stool. Abdominal mass in the right iliac fossa may be palpated.

Complications Haemorrhage, perforation, obstruction, fistula formation and malabsorption.

More than 16% of radioactivity appears in the urine

3 cm in diameter suggests the probability of malignancy Gastric ulcer with pentagastrin fast achlorhydria indicates malignancy Improper preservation or refrigeration or ingestion of contaminated food leads to bacterial conversion of dietary nitrates to carcinogenic nitrites Biopsy must be performed in the management and follow-up of patients with isolated gastric ulcer.

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Abdomen

HEPATOLOGY AND PANCREAS Hepatic Segments The liver is divided into a functional right lobe and the left lobe by an imaginary line drawn between the gallbladder fossa and middle hepatic veins. For the purpose of func­ tional anatomy, the liver has been divided into 8 segments. Each of these segments can be considered as functional units, each with a branch of hepatic artery, portal vein, bile duct and drained by a branch of hepatic vein (Fig. 6.23).

Liver Function Tests Serum Enzymes Serum enzymes are markers of hepatocellular injury and necrosis. a. AST (SGOT) and ALT (SGPT): Serum transaminases are normally present in the blood (less than 40 units). There are indicators of liver cell damage. Their serial determination reflects the clinical activity of the liver disease. In jaundiced patients, values greater than 300– 400, suggest acute hepato­cellular disease. Values more than 1000 units are observed in viral hepatitis, toxic or drug-induced liver disease, prolonged circulatory collapse. Lesser degree of elevation is found in mild viral hepatitis, diffuse and focal chronic liver disease (chronic active hepatitis, cirrhosis, secondaries). Sometimes serial estimations may be needed. AST/ALT (SGOT/SGPT) ratio is most useful in detecting patients with alcoholic liver disease. AST/ ALT ratio is greater than 2 in them due to decreased concentration of ALT in the hepatocyte cytosol. Serum of alcoholic patients are deficient in pyridoxal-5’ phosphate, a co-enzyme necessary for the synthesis of transaminases especially ALT.



Uraemia depresses the aminotransferase levels. Higher degree of elevation of transaminases has a bad prognostic value. b. Lactic dehydrogenase (LDH): LDH-5 corresponds to the liver but the elevation of LDH-1 is more sensitive for myocardial infarction and haemolysis.

Tests of Biosynthetic Function a. Serum proteins: Liver produces all the serum proteins (especially albumin, prothrombin, fibrinogen) except gamma globulin. A serum albumin value of less than 3 (normal 3.5–5.0 gm/dL) and serum globulins greater than 4 gm/dL (normal 2.0–3.5 gm/dL) suggest a chronic or progressive liver disease. Increased globulin is as a result of increased stimu­lation of the peripheral reticuloendothelial compartment due to shunting of antigens past the liver and impaired clearance by Kupffer cells. Deficiency or absence of alpha 1 globulin is found in alpha 1 antitrypsin deficiency. Increase in albumin value of 2–3 gm towards normal with treatment implies improvement in hepatic function and a more favourable prognosis. Serum albumin has a long t ½ (18–20 days). Because of this slow turnover, serum albumin is not a good indicator of acute liver failure. b. Prothrombin time (PT): The liver synthesises all the clotting factors except factor VIII. The one stage PT which reflects the activities of prothrombin, fibrinogen and factors V, VII and X is dependent on both hepatic synthesis of these factors and availability of vitamin K. Factor VII is the rate limiting factor in this pathway. Prolongation of PT (normal 11.5–12.5 seconds) by 2 seconds or more is considered abnormal. Prolonged PT may also be present in congenital deficiencies of coagulation factors, consumption coagulo­pathy, drug intake and hypovitaminosis K. Prolongation of PT by more than 5–6 seconds heralds the onset of fulminant hepatic necrosis. Prolongation of PT with no response to vitamin K therapy indicates poor long-term prognosis. Prothrombin time is also prolonged in: i. Vitamin K malabsorption ii. Poor dietary intake of vitamin K iii. Antibiotic therapy (destruction of vitamin K producing commensals).

Tests of Cholestasis Enzymes zz

Fig. 6.23  Segmental anatomy of the liver

Ch-6.indd 435



Serum alkaline phosphatase (normal value 3–13 KA units or 30–120 IU/L): This is derived from three sources 1. Hepatobiliary system

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2. Bone 3. Intestinal tract. The hepatobiliary enzyme is differentiated from others by simultaneous estimation of 5’ nucleotidase, gamma-glutamyl transpeptidase or leucine aminopeptidase. Values more than 3–10 times the normal level are suggestive of hepatobiliary diseases (extra­ hepatic and intrahepatic biliary obstruction, druginduced cholestasis, primary biliary cirrhosis). Other causes of isolated alkaline phosphatase elevation: 1. Primary or metastatic tumour of liver or bone 2. Granulomatous liver disease 3. Hodgkin’s disease 4. Non-Hodgkin’s lymphoma 5. Liver abscess 6. CCF 7. Hyperthyroidism 8. Diabetes mellitus 9. Bone disease (Paget’s disease, osteomalacia) 10. Partial extrahepatic bile duct obstruction 11. Sclerosing cholangitis 12. Pregnancy. Persistent elevation of serum alkaline phosphatase >30 KA units or 300 IU/L indicates obstructive jaundice. zz 5′-Nucleotidase (normal value is 0.3–3.2 Bodansky units or 2–17 U/L): This enzyme is primarily located in the liver. Serum values are elevated in hepatobiliary diseases. In screening for liver metastases, it has a high predictive value. It is done to confirm the hepatic origin of an increased alkaline phosphatase level in children and pregnant women when there is coexisting bone disease. zz Leucine aminopeptidase: This is also useful in the diagnosis of biliary obstructive, space-occupying and infiltrative diseases of the liver. zz Gamma-glutamyl transpeptidase (normal value—5– 24 U/L): This enzyme is found in liver, pancreas and kidney. Elevated values are seen in liver, pancreas, cardiac, renal, pulmonary and biliary tract diseases. The values are elevated in alcoholic liver disease or in patients taking barbiturates or phenytoin. A GGT/AP value greater than 2.5 is suggestive of alcohol abuse. GGT is a potential marker of alcoholism. GGT correlates with alkaline phosphatase levels and it is one of the most sensitive indicators of biliary tract disease. MELD (Model for end stage liver disease) score: Designed to predict prognosis in liver disease and portal hypertension zz Assessing the need for liver transplantation zz It is calculated by using i. Prothrombin time in the form of INR zz

Ch-6.indd 436



ii. Serum bilirubin iii. Serum creatinine

MELD formula: 3.8 × log (total bilirubin mg/dL) + 11.2 × log (INR) + 9.6 log (creatinine mg/dL) Poor prognosis if the score is >18–21 PELD score: It is used for children 32. Serum Bilirubin Serum bilirubin is measured by van den Bergh’s diazo reaction. Unconjugated bilirubin requires the presence of alcohol for the diazo reaction and gives an indirect van den Bergh reaction. Conjugated bilirubin reacts directly without alcohol. Total serum bilirubin is measured with the diazo reaction carried out in alcohol, where both the conjugated and the unconjugated bilirubin react with the reagent. The conjugated bilirubin is then measured from the diazo reaction carried out without alcohol. The difference represents the concentration of the unconjugated bilirubin. Tests AST and ALT Alkaline phosphatase Serum albumin Prothrombin time Bilirubin GGT 5’ nucleotidase

Obstructive liver disease Parenchymal liver disease Mild increase Moderate to marked increase Markedly increased May be mildly increased Normal Normal Normal or increased Increased Increased

Decreased Increased Normal or increased Normal or increased Normal

Percutaneous Liver Biopsy Percutaneous liver biopsy is a safe procedure that can be per­formed with local anaesthesia under ultrasound guida­nce. Liver biopsy is of proven value in the following disorders: zz Hepatocellular disease of uncertain cause zz Prolonged hepatitis with the suspicion of autoimmune hepatitis zz Unexplained hepatomegaly zz Unexplained splenomegaly zz Pyrexia of unknown origin zz Hepatic filling defects on imaging zz Staging of lymphoma.

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Abdomen Sampling error can occur in focal infiltrative disorders such as metastases. Liver biopsy is not the initial procedure in the diagnosis of cholestasis. Assess the biliary tree for signs of obstruction. Significant ascites and prolonged INR are contraindications for percutaneous liver biopsy. In the above circumstances biopsy can be performed via the transjugular approach.

Noninvasive Tests to Detect Hepatic Fibrosis Fibro Test (Fibro Sure) The test incorporates haptoglobin, bilirubin, GGT, apolipoprotein A-1, and α2 – macroglobulin. The test has high positive and negative predictive values for diagnosing advanced fibrosis in patients with chronic hepatitis B and C, alcoholic liver disease and methotrexate induced fibrosis. Transient Elastography (TE) or Fibro Scan TE uses ultrasound waves to measure hepatic stiffness noninvasively. The test is useful to identify advanced fibrosis in chronic hepatitis C, primary biliary cirrhosis, haemochromatosis, non-alcoholic fatty liver disease, and recurrent chronic hepatitis after liver transplantation. Magnetic Resonance Elastography (MRE) MRE is superior to TE in staging liver fibrosis in patients with a variety of chronic liver disorders. Liver biopsy is the standard test for the assessment of hepatic fibrosis.

Jaundice Yellowish appearance of skin and mucous membranes resulting from an increase in bilirubin concentration in body fluids when serum bilirubin concentration exceeds 3 mg/dL. In latent jaundice, serum bilirubin level is between 1 and 2 mg/dL. Scleral tissue is rich in elastin and has a high affinity for bilirubin. Therefore, presence of scleral icterus is a highly sensitive index for detecting jaundice. It is best appreciated in natural light. Yellowish discolouration of carotenaemia spares the sclera.

Metabolism of Bilirubin One gm of haemoglobin yields 35 mg of bilirubin. Eighty per cent of the circulating bilirubin is derived from haem of haemoglobin which is in turn derived from senescent RBCs. Ten to twenty per cent of bilirubin comes from myoglobin, cytochromes and other haeme-containing proteins. Haem is oxidised to biliverdin which is then reduced to bilirubin. Bilirubin is insoluble in aqueous solutions. In blood, bilirubin is bound to albumin at a 1:1 ratio.

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Unbound bilirubin can cross blood-brain barrier and causes kernicterus in neonatal hyperbilirubinaemia. The processing of serum bilirubin by hepatocyte occurs in four steps namely hepatic uptake, cytosolic binding, conjugation and secretion. The albumin bound bilirubin dissociates and bilirubin is subsequently transported into the hepatocyte through a saturable protein carrier. In the hepatocyte, bilirubin binds to two cytosolic proteins ligandin and Z-protein. This limits the reflux of bilirubin back into the plasma. The conjugation of bilirubin involves its esterification with glucuronic acid forming bilirubin monoglucuro­nide and diglucuronide, the reaction being catalysed by the enzyme UDP-glucuronyl transferase. Bilirubin is rendered water soluble by this mechanism and hence it is eliminated from the body in bile and urine. Secretion of conjugated bilirubin into the bile from the hepatocyte is an active process against the concentration gradient involving a specific carrier. It is excreted in bile as a micellar complex with cholesterol, phospholipids and bile salts. It is later deconjugated and converted to urobilinogen by the colonic bacteria. By a process called enterohepatic circulation, a minor portion of bilirubin is reabsorbed. The rest is excreted in the stool (as stercobilinogen) and in urine (as urobilinogen).

Types 1. Hepatocellular jaundice (hepatic) 2. Haemolytic (prehepatic) 3. Obstructive (posthepatic).

Causes Hepatocellular Jaundice Viral hepatitis—A, B, C, D, E, G and TT virus Others—CMV, EBV, HSV, and Coxsackievirus Toxoplasma, Leptospira, Candida, Brucella, mycobacteria and Pneumocystis. Drugs zz zz zz zz zz zz zz zz zz zz zz

Halothane Phenytoin Carbamazepine INH, rifampicin Pyrazinamide Methyldopa Captopril, enalapril Amitriptyline Imipramine Ibuprofen Indomethacin

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Ketoconazole Fluconazole Zidovudine Paracetamol

Toxins zz zz zz

Alcohol Carbon tetrachloride Yellow phosphorus

Haemolytic Jaundice zz

zz

Intraerythrocytic —— Hereditary „„ RBC membrane disorders (spherocytosis) „„ Disorders of glycolysis (enzyme deficiencies) „„ Haemoglobinopathies. —— Acquired „„ Dyserythropoietic states (B 12 and folate deficiency) Extraerythrocytic —— Autoimmune —— Isoimmune —— Alloimmune —— Physical trauma „„ Prosthetic valve „„ Burns —— Chemical trauma (dapsone) —— Infections (malaria) —— Toxic factors —— Inflammations —— Neoplasms.

Obstructive Jaundice zz

zz

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Canalicular —— Alcohol —— Viral hepatitis —— Cirrhosis —— Lymphoma —— Bacterial sepsis —— Pregnancy —— Idiopathic —— Drugs „„ Erythromycin „„ Chlorpromazine „„ Chlorpropamide. Biliary —— Calculi —— Carcinoma pancreas —— Tumours „„ Benign „„ Metastatic —— Strictures —— Biliary cirrhosis.

An Approach to Jaundice If the physical examination shows: Excoriation, consider cholestasis or high grade biliary obstruction zz Greenish hue (due to biliverdin), suggests long standing liver disease like biliary cirrhosis, sclerosing cholangitis, severe chronic hepatitis or long-standing malignant obstruction zz Fever, epigastric or right hypochondrial tenderness, suggests choledocholithiasis, cholangitis or cholestasis zz Painless jaundice, suggests malignant biliary obstruction zz Enlarged tender liver, suggests acute hepatitis, rapidly enlarging hepatic tumour zz Palpable gallbladder, suggests distal biliary obstruction due to malignant tumour zz Splenomegaly, suggests portal hypertension or haemolytic jaundice zz Palmar erythema, facial telangiectasia, Dupuytren’s contracture are seen in chronic ethanol ingestion zz Evidence of hyperestrogenic state in cirrhosis (gynaecomastia, testicular atrophy, spider angiomata) zz Wasting or lymphadenopathy suggests malig­nancy zz Wasting and splenomegaly, suggests pancreatic tumour obstructing the splenic vein or a widely metastatic lymphoma zz Look for increased JVP, KF ring, xanthomata zz Look for primaries from thyroid, GIT, breast, etc. zz Hyperbilirubinaemia —— Predominantly unconjucated—>85% of total bilirubin —— Predominantly conjucated—>15% of total bilirubin. zz

Congenital Jaundice Crigler-Najjar Syndrome (Type I) It is an autosomal recessive disorder with severe unconjugated hyperbilirubinaemia due to total absence of bilirubin uridine diphosphate—glucuronyltransferase (UDPGT). This results in kernicterus and may cause cerebral damage. This condition is uniformly fatal in the neonatal period. Bilirubin level ranges from 24 to 25 mg/dL. When patients survive up to 2nd decade, encephalopathy develops. CN Type 1A zz

zz

Mutations in one of the common exons (2-5) of the UGT1 gene Defect in the spectrum of substrates involved in the glucuronide conjugation.

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Abdomen CN Type 1B

Diagnosis

Mutation in the bilirubin specific exon A1 Defect is limited to bilirubin conjugation.

zz zz

Diagnosis

zz zz zz

LFT/serum bile acids—normal zz Liver morphology/histology—normal zz No evidence of haemolysis zz Bile bilirubin fraction >90% unconjugated. Bilirubin conjugates are almost absent in bile. Diagnosis is based on clinical and laboratory findings and lack of response to phenobarbitone.

zz

zz

zz

Diagnosis is based on clinical and laboratory findings and response to phenobarbitone therapy.

Treatment Phenobarbitone, UV light, liver transplant.

Treatment zz

LFT/serum bile acids—normal Liver morphology/histology—normal No evidence of haemolysis Bile bilirubin fraction predominantly of monoglucoronides

Short-term—Phototherapy, tin protoporphyrin and plasmaphresis during emergencies. Definite treatment—Liver transplantation.

Crigler-Najjar Syndrome (Type II) It is an autosomal recessive disorder due to mild deficiency of UDPGT enzyme. This condition is compatible with normal life. Serum unconjugated bilirubin levels are in the range of 6–5 mg/dL. Kernicterus is uncommon.

Gilbert’s Syndrome It is an autosomal recessive disorder. There is mild un­conjugated hyperbilirubinaemia due to reduced glucuronyl transferase, mild haemolysis and defective bilirubin uptake. Patients have normal life expectancy. Serum bilirubin ranges from 1.3 to 3 mg/dl. Patients have normal liver serum tests and histology and there are no systemic symptoms.

Features

Haemolytic

Hepatocellular

Obstructive

1.

Mechanism

Increased bilirubin production

Hepatocellular failure

Bile duct obstruction

2.

Common cause

Haemolysis

Virus, drugs

Ca pancreas, gallstones

3.

Mode of onset

Rapid

Gradual

Gradual

4.

Symptoms

Anaemia, fever

Anorexia, nausea, vomiting, distaste to cigarette, coffee

Recurrent abdominal colic; fluctuating jaundice

5.

Skin

Mild yellow tinged

Orange tinged

Greenish yellow

6.

Urine

Colourless (absent bile pigments)

High coloured

Dark coloured (presence of bile pigments)

7.

Urobilinogen

++

+*

Absent

8. Pruritus

Nil

+

+++

9. Bradycardia

Nil

Rare

+

10. Motion

Normal

**Pale

Clay coloured

11.

Serum bilirubin

Unconjugated

Both (conjugated and unconjugated)

Conjugated

12.

AST and ALT

Normal

Grossly elevated

Slightly elevated

13.

Serum alkaline phosphatase

Normal

Slightly raised

Grossly elevated

14.

Coombs’ test Osmotic fragility

Positive Increased

– –

– –

15.

Spleen

++

+/–

–

16.

Gall-bladder

Not palpable

Not palpable

Palpable

*Urobilinogen is present normally in minimal quantities. In viral hepatitis, the quantum increases initially and disappears during the peak phase due to hepatocellular oedema and obstruction; it reappears during the recovery phase **Clay coloured stools are passed during the obstructive phase which reverts to normal colour in the recovery phase

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Dubin-Johnson Syndrome

Diagnosis zz zz zz

zz

LFT/serum bile acids—normal Liver morphology/histology—normal Bile bilirubin fraction—mostly diconjugates (monoconjugates slightly increased) Diagnostic clues include: —— Increase in serum bilirubin value on fasting —— Fall of bilirubin on taking phenobarbitone —— Increase in bilirubin value following IV nicotinic acid which raises the osmotic fragility of RBCs.

Patients when placed on a diet of 300 kcal without lipids for 24–48 hours, have an elevation of bilirubin by 100% or by 1.5 mg/dL.

Treatment Occasionally phenobarbitone in a dose of 180 mg/day in divided doses for 2 weeks can be given to enhance the activity of glucuronyl transferase.

Familial Defects in Hepatic Excretory Function 1. 2. 3. 4.

It is an autosomal recessive disorder resulting in conjugated hyperbilirubinaemia secondary to a defect in canalicular transport of organic anions. The liver is darkly pigmented. Histologically, a yellow black pigment is seen in lysozomes of hepatocytes. Liver may be slightly enlarged and tender. Serum bilirubin levels may rise up to 30 mg/ dL. Urine coproporphyrin I is more than coproporphyrin III (the reverse of normal). Bromsulphthalein excretion is normal at 45 minutes and there is secondary rise at 120 minutes. zz Black pigmented liver due to deposition of epinephrine metabolites that are not excreted normally zz Oral cholecystography—gallbladder not visualized zz Abnormality in urinary coproporphyrin excretion— Normally 75% of coproporphyrin in urine is isomer III. Total coproporphyrin content in urine is normal, but in DJS >80 % is isomer I. zz Avoid oestrogen in the management. Patients have normal life expectancy and usually no treatment is required.

Rotor Syndrome

Dubin-Johnson syndrome (DJS) Rotor syndrome (RS) Benign recurrent intrahepatic cholestasis (BRIC) Progressive familial intrahepatic cholestasis (FIC).

It is a conjugated hyperbilirubinaemia with non-pigmen­ ted liver. There is defective bilirubin uptake and reduced intrahepatic binding. Bilirubin level is usually less than

Differentiating Features of Hepatitis Viruses Features Genome Family Incubation period (days) Transmission Clinical Age group

HAV RNA Picorna 15–45

HBV DNA Hepadna 30–180

HCV RNA Flavi 15–150

HDV RNA Viroid 30–180

HEV RNA Calci 15–60

HGV RNA Flavi 14–35

Faeco oral

Blood, saliva, sexually

Blood

Blood, sexually

Faeco oral

Percutaneous

Young adults, babies, toddlers Occ. severe 0.1–1% Occasional (1–10%)

Any age

Similar to HBV

Young adults

Unknown

Severity Fulminant course Progression to chronicity Carrier Carcinoma

Children, young adults Mild 0.1% None

Moderate 0.1% 50%

Occ. severe 5–20% Common

Mild 1–2% None

Unknown Unknown Yes

None No

0.5–1% +

Variable ±

None –

Unknown Unknown

Prognosis

Excellent

0.1–30% + esp. in neonatal infection Worse with age, debility

Moderate

Acute—good; Chronic—poor

Good

Unknown

Recombinant vaccine

No

No

No

Hyperimmune serum globulin; interferon 40% effective

No interferon 50% effective

Prevention of HBV infection No

No

No

Prevention Active Passive

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Inactivated vaccine Immune serum globulin

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441

Abdomen 10 mg/dL. Here also, urine coproporphyrin I is more than III, but not to that extent seen in Dubin-Johnson syndrome. zz Oral cholecystography—gall bladder is visualized and normal zz Total coproporphyrin in urine is increased – but 2.5 mg/dL up to 20 mg/dL). High bilirubin level of 20–40 mg/dL is common in sickle cell anaemia, G6PD deficiency due to superimposed haemo­lysis Serum alkaline phosphatase level rarely exceeds 250 U/L Prolongation of the prothrombin time (severe syn­ thetic defect) Serological tests for HAV, HBV, HCV, CMV, EB viral infections: —— Acute infection of HAV is marked by anti-HAV IgM in serum. Later IgG replaces IgM and per­ sists for years conferring immunity —— HBsAg appears first and is a marker of active HBV infection, appearing before the onset of

Because of the non-specificity encountered in clinical samples tested for anti-HCV, a supple­ mentary recombinant immunoblot assay is also used. The most sensitive indicator of infection is the presence of HCV RNA, which can be detected by amplification techniques within a few days of exposure. zz Hypoglycaemia (nausea, vomiting, reduced CHO intake, poor hepatic glycogen) requiring hourly blood glucose estimation.

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Abdomen Complications of Endoscopy zz zz zz zz zz zz zz zz zz zz

Fulminant hepatic failure Cholestatic hepatitis Relapsing hepatitis (biochemical/clinical) Hyperbilirubinaemia (in Gilbert’s syndrome) Renal failure Henoch-Schonlein purpura Chronic hepatitis Cirrhosis (HBV, HCV, HDV) Hepatocellular carcinoma (HBV, HCV) Aplastic anaemia, pancreatitis, myocarditis, atypical pneumonia, transverse myelitis and peripheral neuropathy are rare complications.

Management zz zz zz

zz

Fig. 6.26  HBV-antigens and antibodies

zz

zz

zz

Bed rest Nutritious diet, glucose and fruit drinks Drugs are best avoided (sedatives, hypnotics, alcohol). Oral contraceptive pills can be resumed after clinical or biochemical recovery Healthy individuals with acute hepatitis B—99% of them recover and antiviral therapy is not likely to improve rate of recovery and is not required. Antiviral therapy with a nucleoside analogues (entecavir) or nucleotide analogues (tenofovir), the most potent and least resistance prone agents are recommended for severe fulminant hepatitis, but not mild or moderate acute hepatitis B. The treatment is recommended for reactivation of chronic hepatiris B presenting as acute on chronic liver disease. Therapy must be continued until 3 months after HBsAg seroconversion or 6 months after HBeAg seroconversion In acute hepatitis C, antiviral therapy with interferon alpha 3 million units subcutaneously thrice weekly helps in reducing the rate of chronicity HAV and HEV do not induce chronic hepatitis or cirrhosis and specific treatment is not available. Give supportive treatment and liver transplantation in the event of FHF IFN-α (standard or pegylated) SC for 6 months in HCV acute infection. Ribavirin can be added.

Prognosis Overall mortality is 0.5%. Prognostic Indicators zz

Fig. 6.27  Hepatitis C and its protein

Ch-6.indd 443

HAV and HEV infections have good prognosis; Prognosis is variable in HBV, HCV and HDV infections. HBV and HCV infections are associated with chronicity;

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Manual of Practical Medicine

zz zz

zz

zz

zz zz zz zz

HBV and rarely HCV infection may lead to malignancy. HEV can cause a high mortality in pregnancy Enormous increase of AST/ALT indicate bad prognosis Bilirubin levels more than 20 mg/dL suggests bad prognosis. However, enormous rise more than 40 mg/dL is common in patients with associated G6PD deficiency or sickle cell anaemia If the liver is not enlarged, it indicates fulminant hepatic necrosis Prothrombin time: It is a very sensitive index. Prolon­ gation of prothrombin time by 4–5 seconds indicates a bad prognosis Alarmingly elevated ESR—poor prognosis Recurring attacks of hypoglycaemia—poor prog­nosis Hepatorenal syndrome—poor prognosis Mortality is high in patients with other diseases like carcinoma, lymphoma or chronic liver disease.

Chronic Hepatitis It is defined as biochemical or serologic evidence of continuing inflammatory hepatic disease for more than 6 months, with symptoms and without steady improve­ment. Histologically, chronic hepatitis (CH) can be divided into three forms. Age and the virus type decide the incidence of chronic hepatitis. Hepatitis B—when infection occurs at birth, 90% develop chronic hepatitis whereas in adults only 1–5% develop chronic liver disease. In hepatitis C, 85–90% develop chronic hepatitis. Older Classification Chronic persistent hepatitis: It occurs typically with HBV, HCV, HBV-HDV infections. The portal tracts are infiltrated with inflammatory cells (lymphocytes, macrophages, plasma cells). The infiltrate is limited to portal tracts and does not spill out into the hepatic parenchyma.

zz

Diagnostic Approach in Patients Presenting with Acute Hepatitis

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HBsAg IgM anti- IgM anti- AntiHAV HBc HCV

Interpretation

+

Acute hepatitis B

–

+

–

Chronic active hepatitis: It commonly occurs with HBV, HCV, HBV-HDV infections and other non-viral causes like drugs, metabolic disorders and auto­immune hepatitis. Pathologically, it is characterised by piecemeal necrosis and fibrosis extending from the portal tracts into the hepatic parenchyma leading to cirrhosis. An exuber­ant portal inflammatory infiltrate spills out of portal tracts. zz Chronic lobular hepatitis: It refers to lobular inflammation with spotty necrosis. zz

Newer Classification The classification of chronic hepatitis is based on Cause zz Histologic activity or grade zz Stage or degree of progression zz

Cause: HBV, HBV plus HDV, HCV, autoimmune hepatitis, drug-induced chronic hepatitis and cryptogenic chronic hepatitis. Grade: This is based on histological activity. The histologic features assessed are: 1. Periportal necrosis including piecemeal necrosis and/ or bridging necrosis. 2. Intralobular necrosis 3. Portal inflammation 4. Fibrosis This is known as histological activity index or KnodellIshak score. Stage: This is based on the degree of fibrosis. Stage 0—No fibrosis Stage 1—Mild fibrosis Stage 2—Moderate fibrosis Stage 3—Severe fibrosis Stage 4—Cirrhosis Correlation between Earlier and Contemporary Classification of Chronic Hepatitis Old classification

Grade

Stage

Chronic persistent

Minimal or mild

0 or 1

Mild or moderate

1

Mild, moderate or severe

1, 2 or 3

+

–

–

–

Chronic hepatitis B

Chronic lobular

+

+

–

–

Acute HAV + chronic hepatitis B

Chronic active

+

+

+

–

Acute hepatitis A + B

–

+

+

–

Acute hepatitis A + B (HBsAg ↓)

–

+

–

–

Acute hepatitis A

–

–

+

–

Acute HBV (HBsAg ↓)

–

–

–

+

Acute hepatitis C

New classification

Causes of Chronic Hepatitis zz zz zz zz

Viral (HBV, HCV, HDV) Drugs (alpha-methyldopa, isoniazid) Alcoholic liver disease Non-alcoholic steatohepatitis

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445

Abdomen zz

zz

zz

Metabolic causes —— Primary biliary cirrhosis —— Sclerosing cholangitis —— Alpha-1-antitrypsin deficiency —— Wilson’s disease —— Haemochromatosis Autoimmune hepatitis —— Type I (antiactin/lupoid) —— Type II (anti-liver kidney microsomal) —— Type III (anti-soluble liver antigen). Cryptogenic.

Management of Chronic Hepatitis B zz

zz

zz

zz

zz

Chronic hepatitis B immune tolerant patients and chronic hepatitis B patients with low replication (102–104) should not be treated. Chronic hepatitis B (both HBeAg positive or negative) with HBV DNA > 20,000 IU/mL and/ or elevated ALT and liver biopsy revealing severe necroinflammation/fibrosis should be treated Patients with compensated cirrhosis with HBV DNA levels >2,000 IU/mL even with normal ALT levels should be treated Patients with compensated cirrhosis with HBVDNA levels 20,000 IU/mL

≤2 × ULN

Positive Negative

>20,000 IU/mL >2,000 IU/mL

Negative +/– +/–

≤2,000 IU/mL Detectable Undetectable

>2 × ULN >2 × ULN or changes in liver HP ≤ULN Any ALT Any ALT

+/–

Detectable

Any ALT

+/–

Undetectable

Any ALT

Treatment Strategy Patients without Cirrhosis Treatment is not recommended . consider treatment in older patients > 40 years and in patients with family history of hepatic carcinoma And ALT becomes elevated >2 × ULN or liver biopsy reveals changes Observe for 3–6 months if compensated and treat if no spontaneous

HBeAg loss or hepatitis B flare with icterus or clinical decompensation PegIFN α for 48 weeks or ETV/TAF/TDF for at least 12 months after HBeAg seroconversion. PegIFN α for one year or ETV/TAF/TDF for several years till HBsAg loss Monitor and treat if HBV DNA or ALT increases as above Patients with Compensated Cirrhosis HBV DNA >2000 IU/mL – Treat with ETV/TAF/TDF indefinite period HBV DNA 16 year old. Immunity lasts for 1 year. If booster is given after 6 months, immunity lasts for 10 years.

For HBV Pre-exposure prophylaxis (Health workers, doctors, para­ medicals): Three IM injections (deltoid, not gluteal) of Hepatitis B vaccine is recommended at 0, 1 and 6 months. Pregnancy is not a contraindication to vaccination. Vaccines available are zz Recombivax-HB (10 µg HBsAg) zz Engerix-B (20 µg HBsAg).

Dosage Recombivax-HB zz 2.5 µg HBs for children 10 years of age and adults zz 40 µg for dialysis patients and for immunosup­pressed. Post-exposure prophylaxis: A combination of vaccine and HBIG are recommended. Perinatal exposure of infants born to HBsAg positive mothers: A single dose of HBIG, 0.5 ml IM in the thigh

Ch-6.indd 447

Sexual contact: A single IM dose of HBIG (0.06 mL/kg) within 2 weeks + complete course of vaccination. It gives a protection of 80–90% for five years. Booster immunization is recommended for haemo­dialysis patients especially when anti-HBs levels fall < 10 mIU/mL.

Autoimmune Hepatitis Autoimmune hepatitis (AIH) is a chronic inflammation of the liver of unknown aetiology associated with circulating auto-antibodies and hypergammaglobulinaemia.

Clinical Features It occurs most often in women (10–30 years and late middle age). The common symptoms are fever, fatigue, intermittent jaundice, weight loss, and pruritus. They may present with urticaria, hepatosplenomegaly and lymphadenopathy. Patients may present with FHF or asymptomatic elevation of ALT or with signs of cirrhosis liver. Extrahepatic manifestations may be found in 30–50% of cases and that include autoimmune thyroiditis and haemolytic anaemia, Graves’ disease, ulcerative colitis, and rheumatoid arthritis.

Investigations zz

zz

zz zz

Elevated levels of serum aminotransferases (AST and ALT) Circulating autoantibodies (antinuclear antibody, anti-smooth muscle antibody, and liver-kidney microsomal antibody) Hypergammaglobulinaemia Liver biopsy—piecemeal necrosis or interface hepatitis.

Treatment zz zz

zz zz zz

zz

Prednisone alone 40–60 mg/day Prednisone and azathioprine 1–2 mg/kg/day till remission occurs (>1–2 years) Relapse (20–30% of cases) requires retreatment Life-long low dose therapy in some cases Salvage therapy in refractory cases—cyclosporine, tacrolimus, mycophenolate mofetil Liver transplantation for ESLD.

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Polycystic Liver Disease (Fig. 6.28) zz zz

zz

zz zz

zz

zz

It is genetically linked to chromosome 19 50% of cases are often associated with autosomal dominant polycystic kidney disease They are thin walled and contain clear or brown fluid due to altered blood Cyst may vary in size from pin’s head to a child’s head They never contain bile (no continuity with biliary tract) Complications—haemorrhage, infection and very rarely carcinoma. Surgery is very rarely necessary.

Clinical Features Patient may present with fever, pain, tenderness in right upper quadrant, chills, anorexia, nausea, vomiting or jaundice, 50% of patients have hepatomegaly. It may present as FUO, especially in the elderly.

Investigations zz zz zz zz

zz

Liver Abscess Liver is the organ commonly involved in the develop­ ment of abscesses. It may be solitary or multiple. Amoebic abscesses are single and pyogenic abscesses are multiple. In developing countries, abscesses are due to parasitic infection (amoebic, echinococcal, other protozoal or helminthic organisms). In developed coun­tries, abscesses are due to bacterial infection.

zz

Elevation of serum alkaline phosphatase (in 90%) Elevation of serum bilirubin (in 50%) Elevation of serum transaminases (in 45%) Leucocytosis, normochromic normocytic anaemia, hypo­albuminaemia *Chest X-ray occasionally shows elevation of right hemidiaphragm, right basal infiltration or a right pleural effusion Imaging studies—USG, CT scan (Fig. 6.29), gallium or indium labelled WBC scan, MRI.

Note: *Elevation of right hemidiaphragm is common in amoebic liver abscess (Fig. 6.30).

Causes zz

zz

zz

zz

zz

Organisms reaching the liver via the portal vein (amoebiasis, appendicitis, actinomycosis of right iliac fossa) Via arterial supply (septicaemia, pyaemia, facio­cervical actinomycosis, infected hydatid cyst) Direct invasion from adjacent structures (subphrenic abscess, empyema) Via biliary tree (ascending cholangitis due to stone, strictures) Direct penetrating injury.

Fig. 6.28  Polycystic disease—liver

Ch-6.indd 448

Fig. 6.29  Liver abscess. CT-guided drainage— collapsed abscess cavity

Fig. 6.30  X-ray—amoebic liver abscess with elevated right hemidiaphragm and minimal pleural effusion

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449

Abdomen Management of Pyogenic Abscess Antimicrobials according to aetiology. In haematoge­ nous spread of infection, S. aureus, Streptococcus milleri are involved. In abscesses following pelvic/ intraperitoneal source of infection, anaerobes or mixed flora are common. Abscesses due to E. histo­lytica, Candida are seen in immunocompromised patients zz Drainage of abscess using either percutaneous or pigtail catheter can be done. Failure of this pro­ cedure suggests —— Multiple abscesses —— Viscous abscess contents —— Associated diseases. If there is a lack of response to percutaneous drainage in 4–7 days, primary surgical intervention is needed. zz

Amoebic Abscess Symptoms and signs may be non-specific. Common in alcoholics. Most common site is posterosuperior quad­rant of right lobe of liver. Pus is chocolate coloured and anchovy sauce like (broken down liver cells, leuco­cytes, RBCs) or green in colour if admixed with bile (Figs 6.31A and B).

Complications Sterile pleural effusions Contiguous spread from liver zz Frank rupture into pleural space zz Hepatobronchial fistula (good prognosis) zz Rupture into peritoneum, pericardium (grave prognosis). Rupture can occur during medical therapy and may require surgical drainage. zz zz

Treatment Water sanitation; take fruits and vegetables after washing and after removing the skin. Cysts in water are disinfected by iodination zz Drugs: Metronidazole—800 mg orally or 500 mg IV tid for 10 days  or Tinidazole—2 gm orally OD for 3 days  or Ornidazole—2 gm orally. These drugs are given along with a luminal agent (paromomycin 500 mg tid for 10 days or dilox­anide furoate 500 mg tid for 10 days). zz Aspiration (Fig. 6.31) —— To rule out pyogenic abscesses especially if they are multiple —— Failure to respond clinically in 3–5 days —— Threat of imminent rupture zz

Ch-6.indd 449

Left lobe abscess to prevent rupture into pericardium or peritoneum —— Large abscesses of more than 10 cm in size Surgery in cases of bowel perforation and rupture of abscess into pericardium. ——

zz

Steatosis Microvesicular steatosis Acute fatty liver of pregnancy zz Reye’s syndrome (aspirin toxicity in children) zz Drugs —— Sodium valproate —— Tetracyclines —— Salicylates —— Yellow phosphorus zz Toxins: Bacillus cereus Macrovesicular steatosis zz Centripetal obesity—DM (type 2), insulin resistance, hyperinsulinaemia zz Drugs—glucocorticoids, oestrogen, tamoxifen, amio­ darone, methotrexate zz Nutritional—starvation, protein deficiency (kwas­ hiorkor), choline deficiency zz Liver disease —— Wilson’s disease, chronic hepatitis C (genotype 3) —— Indian childhood cirrhosis, jejunoileal bypass —— Alcoholic liver disease (initially micro- and then to macrovesicular) zz

Nonalcoholic Fatty Liver Disease It is a syndrome that encompasses several clinical entities that range from simple steatosis to non-alcoholic steatohepatitis (NASH). One to two per cent of simple steatosis patients have the risk of developing cirrhosis over a period of 20 years.

Figs 6.31A and B  Amoebic liver abscess drainage

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450

Manual of Practical Medicine NASH is defined as steatosis with hepatocellular ballooning and lobular inflammation. It may end up with fibrosis and end stage liver disease in the absence of significant alcohol consumption (Figs 6.32A and B). zz 25% progress to cirrhosis in 10–15 years zz 70% of cases of cryptogenic cirrhosis have NASH as the underlying aetiology zz NASH is associated with insulin resistance and metabolic syndrome (DM, HTN, dyslipidaemia and obesity) zz Abnormal ferritin values are seen in 50% of NASH patients and the increased level may be a marker of insulin resistance.

Nodules may vary from AST) Liver biopsy showing —— Macrovesicular steatosis —— Mallory hyaline changes —— Perivenular and perisinusoidal fibrosis.

zz zz

zz zz

Treatment zz zz

zz zz

Correct obesity by diet control and exercise Use thiazolidinediones to improve insulin sensitivity in DM Treat hyperlipidaemia with statins Liver transplantation for end stage liver disease.

Cirrhosis of Liver Cirrhosis is defined as an irreversible chronic injury of the hepatic parenchyma and include extensive fibro­sis in association with the formation of regener­ative nodules.

zz zz zz zz zz zz zz zz

zz

Viral hepatitis (HBV ± Delta virus, HCV) Alcohol Non-alcoholic steatohepatitis (NASH) Metabolic —— Haemochromatosis —— Wilson’s disease —— α antitrypsin deficiency 1 —— Diabetes mellitus —— Galactosaemia —— Tyrosinosis —— Fanconi’s syndrome —— Hereditary fructose intolerance —— Type IV glycogen storage disease Prolonged cholecystitis—intra- and extrahepatic Hepatic venous outflow obstruction —— Veno-occlusive disease, —— Budd-Chiari syndrome —— Constrictive pericarditis Disturbed immunity (lupoid hepatitis) Toxins and drugs: Methotrexate and amiodarone Intestinal bypass, gastroplasty Indian childhood cirrhosis/malnutrition Syphilis in neonates Cystic fibrosis Schistosomiasis Cardiac failure (chronic right- sided heart failure, tricuspid insufficiency) Cryptogenic—unknown aetiology.

Morphological Classification (Figs 6.33A and B) zz zz zz

Micronodular cirrhosis (Laennec’s cirrhosis) Macronodular cirrhosis (postnecrotic or viral) Mixed type.

Macronodular Cirrhosis (Nodule >3 mm) Causes zz

zz zz

A

Ch-6.indd 450

B Figs 6.32A and B  (A) Non-alcoholic steatohepatitis (NASH)— Early stage; (B) Late stage—chickenwire fibrosis

zz zz zz

Cryptogenic (most common cause is non-alcoholic fatty liver disease) Chronic viral hepatitis (post-necrotic) Wilson disease Alpha-1 antitrypsin deficiency Drug induced Alcoholic liver disease (late stage).

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451

Abdomen

A

B Figs 6.33A and B  (A) Macronodular cirrhosis; (B) Micronodular cirrhosis

Micronoular Cirrhosis (Nodules AST in chronic hepatitis B) Prolonged serum prothrombin time due to reduced synthesis of vitamin K dependent clotting factors Serum albumin is depressed and serum globulins are increased due to impaired protein synthesis by liver Leucopenia and thrombocytopenia due to hypersplenism and due to the effect of alcohol on the bone marrow Glucose intolerance (due to insulin resistance) Elevated ammonia level in hepatic encephalopathy Other abnormalities include hypomagnesaemia, hypo­phosphataemia, hyponatraemia, hypokalaemia and respiratory alkalosis Ultrasonography to find liver size and obstructive disorders of hepatobiliary tree Liver biopsy to confirm the diagnosis.

Treatment Treatment is purely symptomatic. Alcohol should be forbidden zz Diet enriched with proteins and amino acids zz Drugs must be administered with caution as almost all the drugs undergo metabolism through liver. —— Pentoxifylline (nonspecific TNF inhibitor): In severe alcoholic hepatitis, oral pentoxifylline reduces mortality, particularly from hepatorenal failure —— Glucocorticoids are helpful in patients with severe alcoholic hepatitis, but no role in established cirrhosis —— Glucocorticoid is restricted to patients with discriminant function (DF) value of >32 or MELD >20. Do not use in patients with active GI bleeding, renal failure and pancreatitis —— Acamprosate is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence, who are abstinent at treatment initiation. zz

Ch-6.indd 452

Aetiology zz

zz zz

zz

zz zz

Hepatitis B, C viral infections (especially among homosexuals and intravenous drug abusers) Chronic active hepatitis Drugs and toxins (arsenicals, INH, methotrexate, methyldopa) Alcoholic and primary biliary cirrhosis leads to postnecrotic cirrhosis in later stages Autoimmune hepatitis Non-alcoholic steato hepatitis.

Pathogenesis The liver is shrunken, distorted in shape. Nodules of variable size are seen.

Cryptogenic Cirrhosis The diagnosis of cryptogenic cirrhosis is reserved for those patients in whom no aetiology can be demon­strated. Clinical features, diagnosis and treatment are almost similar to alcoholic cirrhosis.

Biliary Cirrhosis There are two types of biliary cirrhosis: Primary biliary cirrhosis zz Secondary biliary cirrhosis. zz

Primary biliary cirrhosis is characterised by chronic inflammation and fibrous obliteration of intra­hepatic bile ducts. Secondary biliary cirrhosis is characterised by partial or complete obstruction of larger extrahepatic bile ducts. Aetiology and Pathogenesis of Primary Biliary Cirrhosis Aetiology unknown. Commonly seen in women of 30–50 years of age. Primary biliary cirrhosis is associated with auto­immune diseases like CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility sclerodactyly, telangiec­tasia), sicca syndrome, autoimmune thyroiditis. The autoantigen commonly involved is 74-kDa E2 compo­ nent of pyruvate dehydrogenase complex. An increased level of IgG antimitochondrial anti­body and increased levels of serum IgM, cryoproteins consisting of immune complexes are seen in 80–90% of patients.

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Abdomen Lymphocytes are prominent in the portal regions and surround damaged bile ducts. Secondary biliary cirrhosis is caused by postoperative strictures and gallstones.

Clinical Features Patients may be asymptomatic. Earliest symptom is pruritus. Other symptoms include jaundice, fatigue, melanosis, steatorrhoea, malabsorption of fat soluble vitamins, elevation of serum lipids resulting in xan­ thelasma and xanthomas. Later, signs of hepatocel­lular failure and portal hypertension develop. Fever and right upper quadrant pain (cholangitis/biliary colic) may occur in secondary biliary cirrhosis (Fig. 6.34).

Investigations Two- to five-fold increase in serum alkaline phosphatase and elevation of serum 5′ nucleotidase are seen. zz There may be an increased titre of more than 1 : 40 of antimitochondrial antibody. It is a specific and sensitive test. zz Elevated serum cholesterol and lipoproteins are seen. zz Raised serum bilirubin in terminal stages. zz Liver biopsy Stage 1: Necrotising inflammatory process (acute and chronic inflammatory cells) of the portal triads with destruction of medium and small sized bile ducts Stage 2: Ductule proliferation Stage 3: Expansion of periportal fibrosis due to scarring. Stage 4: Micro or macronodular cirrhosis. zz

Treatment No specific therapy for primary biliary cirrhosis. Colchicine in the dose of 0.6 mg orally twice daily. zz Methotrexate in a low dose and cyclosporine are used to slow the progression or arrest the disease zz Ursodiol 13–15 mg/kg/day is shown to produce symptomatic improvement and improvement in serum biochemical parameters zz Symptomatic treatment includes antipruritic agents and cholestyramine 8–12 gm/day for pruritus and hypercholesterolaemia zz Low fat diet for steatorrhoea zz Vitamin A, D, K supplements parenterally for correction of deficiencies zz Secondary biliary cirrhosis is treated by surgical means or endoscopic relief of the obstruction. zz

Ch-6.indd 453

Cardiac Cirrhosis Aetiology Prolonged severe right sided congestive heart failure may lead to chronic liver injury and cardiac cirrhosis. Pathogenesis In chronic right heart failure, retrograde transmission of elevated venous pressure leads to congestion of liver. Hepatic sinusoids become dilated and engorged with blood. Macroscopically the liver is referred to as ‘nutmeg liver’.

Clinical Features Liver is enlarged, firm, non-tender and non-pulsatile in spite of TR. Signs and symptoms of right heart failure are seen (Fig. 6.34).

Investigations Mild elevation of serum bilirubin and serum AST levels. Investigations for chronic heart disease (X-ray, ECG, echo).

Treatment Treat the underlying cardiovascular disorder.

Complications of Cirrhosis zz zz zz zz zz zz zz zz zz zz zz

Portal hypertension Ascites Hepatic encephalopathy Spontaneous bacterial peritonitis Hepatorenal syndrome Hepatocellular carcinoma Coagulopathy Hepatopulmonary syndrome Malnutrition Bone disorders—osteopenia, osteoporosis, osteo­malacia Haematological—anaemia, neutropenia, thrombo­ cytopenia, haemolysis.

Portal Hypertension Normal pressure in the portal vein is 10–15 cm saline or 7–10 mm Hg. Portal hypertension is present when the sustained elevation of portal pressure is >10 mmHg but the risk of variceal bleeding is greater only when it is >30 cm saline or >12 mm Hg.

Classification The obstruction to portal blood flow can occur at three levels: Portal vein (prehepatic) zz Intrahepatic (presinusoidal, sinusoidal, postsinu­soidal) zz Hepatic veins (posthepatic). zz

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Fig. 6.34  Clinical manifestations of cirrhosis

Clinical Features Patients may present with any of the complications of portal hypertension, namely zz Collateral circulation and varices zz Ascites zz Congestive splenomegaly, hypersplenism

Ch-6.indd 454

zz zz

Encephalopathy Congestive gastropathy.

Collateral Circulation (Varices) Extensive portal-systemic venous communications develop in order to decompress the high-pressure portal

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455

Abdomen venous system. Maintenance of portal hyper­tension after the collaterals are formed, is attributed to a resultant increase in splanchnic blood flow. Major Sites of Collaterals (Fig. 6.35) zz

zz

zz

zz

Oesophageal and gastric varices (left gastric vein and short gastric vein join with intercostal, diaphrag­matic, oesopha­geal and azygos veins of the caval system) Haemorrhoids (superior haemorrhoidal vein of the portal system to middle and inferior haemorrhoidal veins of the caval system) Caput medusae (remnants of the umbilical circu­lation of the foetus present in the falciform ligament may form a large paraumbilical vein) Other sites of anastomoses are retroperitoneal veins, lumbar veins, omental veins and veins over bare area of the liver.

Investigations zz

zz

zz

zz

Fibreoptic oesophagoscopy: Shows the presence of oesophageal and gastric varices Measurement of portal venous pressure by either percutaneous transhepatic skinny needle catheteri­ sation or through transjugular cannulation of the hepatic veins. Wedged hepatic venous pressure is high in sinusoidal and postsinusoidal portal hyper­tension USG abdomen: Features of portal hypertension, such as splenomegaly, collaterals, cause of liver disease (occasionally) or portal vein thrombosis can be detected. Portal vein size can be assessed (Normal portal vein size is 1 cm; when portal vein size is 2 cm, it is said to be dilated; when it is more than 3 cm, it is said to be aneurysmally dilated) Portal venogram: Site and the cause of portal venous obstruction can be detected and is also performed prior to surgical therapy.

Fig. 6.35  Portal venous system zz

Treatment of alcoholic hepatitis, chronic active hepatitis and other diseases results in fall in portal venous pressure and reduction in variceal size.

Prehepatic

Intrahepatic Presinusoidal Sinusoidal

Post­ sinusoidal

Schisto­ somiasis

Cirrhosis

Alcoholic hepatitis

Splenic Sarcoidosis arterio­venous cirrhosis fistula

Primary biliary disease

Veno-occlu- Tricuspid sive insufPericarditis ficiency

Constriction of the veins

Crypto­genic; Hepatic vein Tricuspid alcoholthrombosis Pericarditis induced cirrhosis

Portal vein thrombosis

Metastatic carcinoma

Complications zz zz zz zz zz zz

Variceal bleeding Congestive gastropathy Hypersplenism Ascites Renal failure Hepatic encephalopathy.

Management zz

Ch-6.indd 455

Beta-blockers like propranolol or nadolol can be used due to their vasodilatory effects on both the splanchnic arterial bed and the portal venous sys­ tem in combination with reduced cardiac output. Propranolol prevents recurrent bleeding from severe portosystemic gastropathy in cirrhotic patients.

Posthepatic

Inferior vena caval web

Congenital hepatic fibrosis

Variceal Bleeding Variceal bleeding occurs when portal venous pressure is more than 12 mm Hg. Mostly bleeding arises from oesophageal varices within 3–5 cm of the oesophago­gastric junction or from gastric varices.

Factors Predisposing to Bleeding zz zz zz

Large varices Endoscopic variceal stigma (red spots, red stripes) High portal pressure

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Liver failure Drugs (NSAIDs) Tense ascites. Modified Child’s Classification

Scores 1 2 Encephalopathy (degree) Nil Slight-moderate Ascites (degree) Nil Slight Bilirubin (mg/dL) 70 40–70 Prothrombin time (in seconds) ≤14 15–17 Scores are summed to determine Child’s class. Class A  5–7 (suitable for surgery) Class B  7–10 (marginal risk for surgery) Class C  more than 10 (unsuitable for surgery).

Variables

3 Moderate-severe Moderate-severe >3 < 2.8 < 40 ≥ 18

Usually there are no precipitating factors.

Clinical Features Symptoms and signs of shock (tachycardia, systolic BP 1.1/dL

1.1 (High gradient) ascites is due to portal hypertension SAAG: (Serum albumin – Ascitic fluid albumin Gradient)

Ch-6.indd 457

Conditions

Colour of ascitic fluid

Specific gravity

Protein in gm/lit

RBC >10,000/µL

WBC/µL

Other tests

Cirrhosis of liver

Straw coloured/ bile stained

1000 variable cells

Cytology, cell block, peritoneal biopsy

Tuberculosis hgic, chylous

Clear, turbid, >1.016

Variable

>25

7%

>1000 (70%) lymphocytes

Peritoneal biopsy, stain, culture for AFB

Pyogenic peritonitis

Turbid or purulent

If purulent >1.016

If purulent >25

Unusual

Predominantly polymorphs

Positive gram stain or culture

CCF

Straw coloured

Variable 1000 mg/dL) by chemical examination clinches the diagnosis. However, triglyceride concentration of >200 mg/dL is sufficient for the diagnosis. Causes Due to lymphatic obstruction from trauma, tumour, TB, nephrosis, pancreatitis, filariasis or congenital lym­phatic obstruction.

Mucinous Ascites Occurs in pseudomyxoma peritonei or colloid carci­noma of stomach or colon with peritoneal implants.

Investigations zz zz

zz

zz

Ascitic fluid analysis Plain abdomen X-ray: Demonstrates haziness of the abdomen with loss of psoas shadow Ultrasonogram of abdomen: It detects as little as 30 mL of ascitic fluid in the right lateral decubitus posi­tion. Loculated collections can also be identified CT scan abdomen: In addition to evaluation of intraabdominal anatomy, it detects small amounts of ascites also.

Management zz zz



zz

zz

zz zz zz

Daily weight chart, IO chart, bed-rest Indications for diuretics: —— Gross ascites —— Tense ascites with umbilical hernia —— For facilitating biopsy, scan or venogram Spironolactone can be given as single dose–100 mg od. Frusemide 40–80 mg/day may be added parti­ cularly in patients who have peripheral oedema. If adequate ascitic fluid is not mobilised, the dose of spironolactone and frusemide can be increased up to 400–600 mg and 120–160 mg/day, respectively. Fluid restriction up to 1500 mL/day and salt restric­ tion of 2 gm/day Paracentesis in severe distension causing respi­ratory embarassment Peritoneal shunt in intractable ascites Albumin can be infused Treat the cause.

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Abdomen

Refractory Ascites Refractory ascites is defined as ascites unresponsive to a sodium restricted diet and high dose diuretic treatment. It is of two types. 1. Diuretic resistant ascites 2. Diuretic intractable ascites. Diuretic Resistant Ascites Ascitic fluid cannot be mobilised or the recurrence cannot be prevented due to lack of response to 40 mmol sodium diet with intensive diuretic therapy (spirono­lactone 400 mg/day and frusemide 160 mg/day). Diuretic Intractable Ascites Ascitic fluid cannot be mobilised and the recurrence cannot be prevented due to the development of diuretic induced complications that preclude the use of an effective diuretic dosage. Renal impairment, hepatic encephalopathy or electrolyte disorder are the usual contraindications for effective diuretic therapy. In about 10–20% of patients with ascites, medical therapy is a failure. The conditions contributing to refractory ascites resulting in worsening of the pri­mary liver disease are: zz Active inflammation zz Portal or hepatic vein thrombosis zz GI bleed zz Infection zz SBP zz Malnutrition zz Hepatoma zz Superimposed cardiac and renal disease zz Hepatotoxic and nephrotoxic drugs.

Treatment zz

zz

Ch-6.indd 459

Peritoneovenous shunt (LeVeen or Denver shunt): PV shunt routes the ascitic fluid subcutaneously from the peritoneal cavity into the internal jugular vein through a pressure activated one-way valve. The complications are peritonitis, sepsis, DIC, CCF and ruptured oesophageal varices. Shunt may get occluded in 30% of the patients and may require replacement. Contraindications to this procedure are sepsis, CCF, malignancy and history of variceal bleeding Therapeutic paracentesis: The procedure involves removal of 4–6 litres of ascitic fluid until the abdomen is completely evacuated. Dietary sodium restriction and diuretics should be continued to prevent rapid reaccumulation of ascitic fluid. The procedure may be repeated every 2–4 weeks. But it may result in protein and opsonin depletion which can predispose to SBP.



zz

Albumin infusion is very costly and its replacement after large paracentesis remains controversial Liver transplantation: The 12 months survival of patients with ascites refractory to medical therapy is only 25%. The survival increases to 75% with liver transplantation.

Fulminant Hepatic Failure It is a rare syndrome in which hepatic encephalopathy results from sudden severe impairment of hepatic function. It occurs within 8 weeks of onset of preci­pitating illness, in the absence of preexisting liver disease.

Causes Any viral hepatitis (*HDV + HBV increases risk) *Drugs (paracetamol excess, INH, methyldopa, halothane) zz Fulminant Budd-Chiari syndrome zz Acute fatty liver of pregnancy zz Toxins—carbon tetrachloride zz Weil’s disease zz Wilson’s disease zz Reye’s syndrome. Note: *Poor prognosis. zz zz

Clinical Features Patients may present with neuropsychiatric changes, stupor, coma, symptoms and signs of cerebral oedema, profuse sweat­ing, haemodynamic instability, tachyar­ rhyth­mias, tachypnoea, fever, papilloedema, decere­ brate rigidity, deep jaundice, coagulopathy, bleeding, renal failure, acid-base disturbance, hypoglycae­ mia, acute pancreatitis, cardiorespiratory failure and infec­tions.

Poor Prognostic Indicators zz zz

zz

zz zz zz zz zz zz zz

Age 40 years If hepatic failure is due to halothane or non-A, non-B hepatitis Duration of jaundice of 1 week before the onset of encephalopathy Serum bilirubin >18 mg/dL Coma Rapid reduction in liver size Respiratory failure Prolongation of prothrombin time Factor V level 1.5 mg % 3. Absence of other causes of renal failure as evidenced by proteinuria >500 mg/dL, urine RBC >50/HPF and abnormal renal USG 4. No current or recent treatment with nephrotoxic drugs/ vasodilators 5. Absence of shock 6. Absence of sustained improvement of renal function following at least 2 days of diuretic withdrawal and volume expansion with albumin (Dose of albumin – 1 gm/kg/day–Maximum 100 gm/day). The kid­n eys are anatomically, histologically and function­ally normal.

Ch-6.indd 461



Hepatorenal syndrome occurs in 10% of patients.

Precipitating factors: SBP zz Large volume of paracentesis without volume expansion. zz

Defective clearance of vasoconstrictor substances by the liver leads to intrarenal vasoconstriction and ultimately hepatorenal syndrome. There are two types: zz Type I: Acute onset of rapidly progressive (3 mmHg when patient moves from supine to standing position. Exertional dyspnoea, clubbing and cyanosis

Investigations zz zz

Contrast enhanced ECHO Technetium –99m macro-aggregated albumin lung perfusion scan

Treatment zz

zz

zz zz

Clinical Features Patients may present with fever of unknown origin, abdominal pain, right upper quadrant abdominal mass, friction rub or bruit over the liver, haemorrhagic ascites or occasionally intra-abdominal bleeding. Paraneoplastic manifestations are: 1. Erythrocytosis (due to erythropoietin like sub­stance) 2. Hypercholesterolaemia 3. Hypercalcaemia (due to PTH like substance) 4. Hypoglycaemia 5. Acquired porphyria 6. Dysfibrinogenaemia 7. Cryofibrinogenaemia.

Investigations zz zz

Oxygen supplementation to maintain PaO2 >60 mm Hg Drugs like almitrine, methylene blue and even garlic powder which increase pulmonary vascular resistance and pulmonary arterial pressure are used. TIPS may be used Liver transplantation is the only effective mode of treatment.

Hepatocellular Carcinoma (Hepatoma) Hepatoma is 4 times more common in men. It commonly arises in a cirrhotic liver.

Aetiology zz

zz

zz zz zz zz zz

zz

Ch-6.indd 462

Chronic hepatitis B, C infection especially in a cirrhotic liver Aflatoxin B1 (loss, inactivation or mutation of the P53 gene) Haemochromatosis Alpha-1 antitrypsin deficiency Alcoholic cirrhosis; rarely in primary biliary cirrhosis Thorotrast, arsenic (causes angiosarcoma also) Oestrogens, androgens, anabolic steroids (causes adenoma also). Contraceptive steroids used for >8 years may increase the risk by 4-fold Non-alcoholic steatohepatitis (NASH).

zz

zz

zz zz zz

zz zz

Serum alkaline phosphatase: mildly elevated Tumour markers: —— Serum alpha fetoprotein >500 µg/L (Lens culinaris agglutinin reactive fraction of AFP is more specific); persistence of levels over 500–1000 µg/L in an adult with liver disease and without obvious GIT tumours or gonadal malignancies suggests hepatocellular carcinoma. Increasing levels suggest progression of the tumour or recurrence after hepatic resection/ chemother­apy/chemoembolisation —— Des-γ carboxy prothrombin (DCP) —— Others – Glypican-3 Imaging techniques: USG abdomen detects tumours of 2 to 3 cm in size; CT scan of the liver helps in the accurate evaluation of tumour and also to identify enlarged lymph nodes (Fig. 6.36) Liver biopsy: Diagnostic biopsy can be taken in an area localised by USG or CT. Risk of tumour cell migration along the biopsy track is small. Since the tumours are vascular, biopsies should be done with caution Detection of des gamma carboxyl prothrombin Cytology of ascitic fluid rarely shows malignant cells Laparoscopy or minilaparotomy can be done to take the biopsy under direct vision Investigations to rule out paraneoplastic syndrome Angiography: Celiac axis angiography can deter­mine operability in a patient with hepatoma or solitary metastasis to the liver.

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463

Abdomen

METABOLIC LIVER DISEASE Wilson’s Disease (Fig. 6.37) Wilson’s disease is an autosomal recessive disorder. The genetic defect is on chromosome 13. In 95% of patients, there is also an absence or deficiency of serum ceruloplasmin, the main copper transporting protein in blood, usually associated with the defect in cerulo­plasmin gene on chromosome 3.

Clinical Features (Fig. 6.38)

Fig. 6.36  CT scan—hepatoma left lobe

Management Surgical resection (hepatoma or single metastasis confined to one lobe) zz Hepatic artery embolisation with chemotherapy zz Alcohol ablation via USG-guided percutaneous injection zz USG guided cryoablation zz Immunotherapy using monoclonal antibodies tagged with cytotoxic agents zz Gene therapy with retrievable vectors containing genes which express cytotoxic agents zz Liver transplantation: Recurrence/metastasis in the transplanted liver is common. zz Newer drugs under trial • Tyrosine kinase inhibitors Target – Sorafenib VEGFR, PDGFR (Vascular endothelial growth factor receptor, platelet derived growth factor receptor) – Sunitinib VEGFR, PDGFR – Erlotinib EGFR (Epidermal growth factor receptor) – Linifanib VEGFR, PDGFR – Brivanib VEGFR, FGFR (Fibroblast growth factor receptor) zz Monoclonal antibody against VEGFR – Bevacizumab zz

Prognosis If untreated, patients usually die within 3–6 months of diagnosis. Monitor course of illness with serial USG, alpha-fetoprotein especially in HBsAg positive patients or patients with cirrhosis due to hepatitis C infection.

Ch-6.indd 463

The average age at presentation of liver dysfunction is 6–20 years, but it can manifest later in life. It can present as neuro-psychiatric disorder, chronic active hepatitis, fulminant hepatitis, cirrhosis of liver, acquired haemolytic anaemia, ophthalmic problems like sunflower cataracts and Kayser-Fleischer rings (copper deposits laid in the Descemet’s membrane around the periphery of cornea). Renal abnormalities are due to accumulation of copper within the renal parenchyma resulting in decreased GFR, proximal tubular defects resembling Fanconi’s syndrome, renal tubular acidosis, haema­turia and proteinuria.

Investigations zz zz

zz

zz

zz

zz

zz

Serum ceruloplasmin: Low, often less than 20 mg/dL. Serum copper level: Total serum copper often decreased but free copper is elevated. Free copper is calculated by finding the difference between total serum copper and the amount of copper bound to ceruloplasmin (0.047 µmol of copper/mg of cerulo­plasmin). Urine copper excretion: Levels greater than 1.6 mmol/ day is suggestive of Wilson’s disease. However, urine copper levels are high in other conditions like cirrhosis, chronic active hepatitis or cholestasis. Liver biopsy: It should be done for histology and for hepatic copper estimation. Hepatic copper concen­ tration more than 250 µg/gm of dry tissue is com­ patible with the diagnosis of Wilson’s disease. Kayser-Fleischer ring: It is present in all patients with Wilson’s disease who have neurological manifes­tation. It should be sought with slit-lamp examina­tion. Low serum alkaline phosphatase and elevated amino­transferase. Radiocopper loading test: In normal persons after giving radioactive copper, it disappears from serum within 4–6 hours. A secondary rise of radioactivity appears after the isotope is incorporated into ceruloplasmin production. In patients with Wilson’s disease, the secondary rise is absent since they cannot incorporate radiocopper into ceruloplasmin.

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Fig. 6.37  Wilson’s disease:  T2-weighted axial MRI demonstrates symmetric hyperintense signals in the putamen, posterior internal capsule, and thalami (arrows), “face of the giant panda” in midbrain with high signal in tegmentum and normal red nuclei (arrows), hypointensity of central tegmental tracts with hyperintensity of aqueductal opening to fourth ventricle (arrows). CT abdomen:  chronic liver disease (cirrhosis) with splenomegaly MRI abdomen:  diffuse hypointensities suggestive of copper deposition

Ch-6.indd 464

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465

Abdomen Zinc acetate – 50 mg of elemental zinc three times daily Trientine hydrochloride – 500 mg bid an hour before or two hours after food. Tetrathiomolybdate 120 mg/day (20 mg tid with meals and 60 mg at bed time 2 hours after dinner) along with zinc therapy. Anti-copper therapy must be life-long. Liver transplantation is ideal for end stage liver disease. Low copper containing diet should be taken. Foods rich in copper, like organ meats, shell-fish, dried beans, peas, whole wheat, and chocolate should be avoided.

Role of Trientine By binding to copper or by chelation causes increased urinary excretion zz Useful in patients intolerant to D-penicillamine zz It has fewer side effects compared to D-penicillamine zz Side effects—anaemia, fever, joint pain, skin rash, swollen glands. zz

Haemochromatosis It is a disorder in which there is excessive iron absorp­tion either alone or in combination with parenteral iron loading, leading to progressive increase in total body iron stores. Fig. 6.38  Clinical manifestations of Wilson’s disease

Classification zz zz

Nazer Criteria It is useful to decide the mode of treatment and it is based on serum bilirubin, AST, and prolongation of prothrombin time in seconds. Patients with score 9 by liver transplantation.

Management See management below. Management of Wilson’s Disease Disease status

1st choice

2nd choice

Hepatitis/cirrhosis without decompensation

Zinc

Trientine

Hepatic de-compensation  Mild

Trientine and zinc

 Moderate  Severe

Trientine and zinc Hepatic transplant

Penicillamine and zinc Hepatic transplant Trientine and zinc

Initial neurologic/ psychiatric

Tetrathiomolybdate Trientine and zinc and zinc

Maintenance

Zinc

Trientine

Presymptomatic

Zinc

Trientine

Paediatric

Zinc

Trientine

Pregnant

Zinc

Trientine

Zinc should not be ingested simultaneously with trientine as it chelates zinc.

Ch-6.indd 465

zz

Primary or idiopathic Secondary —— Refractory anaemia —— Chronic liver injury —— Dietary iron overload —— Porphyria cutanea tarda Parenteral iron overload —— Multiple blood transfusions —— Excessive parenteral iron —— Haemodialysis

Idiopathic Haemochromatosis It is an autosomal recessive disorder with the abnormal gene located in the HLA A6 locus on short arm of chromosome 6.

Clinical Features (Fig. 6.39) Lethargy, weight loss, change in skin color, loss of libido, abdominal pain, arthralgia, symptoms of diabe­ tes mellitus (65%) are common modes of presentation. Patients have hepatomegaly, skin pigmentation, testicular atrophy, loss of body hair, CCF (due to congestive cardiomyopathy) and arthritis (osteo­arthri­ tis, pseudogout). Hepatoma can occur in 30% of patients with cirrho­sis. Arrhythmias (atrial and ventricular tachyarrhyth­mias) and AV blocks are common.

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466

Manual of Practical Medicine Management zz

zz

zz

zz zz

Phlebotomy: There is 250 mg of iron in 500 mL of blood. The body burden of iron in IHC is more than 20 gm, a weekly phlebotomy of 500 mL of blood for 2–3 years may be needed to achieve a haemoglobin of 11 and serum ferritin of 10 Desferrioxamine: It is an iron chelating agent given in a dose of 40–80 mg/kg/day, subcutaneously. It removes 10–20 mg of iron/day Oral deferasirox is effective in thalassemia and secondary iron overload Avoid alcohol Plan liver transplantation for end stage liver disease.

Prognosis Hepatocellular carcinoma occurs in one-third of the patients with IHC and cirrhosis, despite iron removal. Causes of Death Death may be due to CCF, hepatocellular failure, portal hypertension or hepatoma.

Reye Syndrome (Fatty Liver with Encephalopathy) Fig. 6.39  Clinical manifestations—haemochromatosis

zz

zz

Investigations zz

zz

zz zz

zz

zz

Serum iron and total iron binding capacity. Serum iron more than 180–300 µg/dL and elevated TIBC suggest haemochromatosis Serum ferritin: It is the most specific screening test for increased iron stores. Serum ferritin level is between 600–900 µg/L (normal 10–200 µg/L) Transferrin saturation is 50 to 100% (normal 22–46%) Total iron binding capacity is between 200 and 300 µg/dL (normal 250–370 µg/dL) Liver biopsy: It is helpful in estimating tissue iron by histochemical staining. Hepatic iron concen­tration by dry weight can also be done and levels >1000 µg/100 mg of dry weight suggests IHC CT scan and MRI: Increased level of iron in liver is associated with an increased CT density or attenua­ tion coefficient. MRI is sensitive in the detection of moderate iron overload.

zz

zz

zz

zz

Budd-Chiari Syndrome It is characterised by thrombosis of larger hepatic veins and sometimes inferior vena cava.

Aetiology zz zz

Ch-6.indd 466

It is a rare and severe complication of influenza (usually B type and other viral infections (varicella), particularly in young children Rapidly progressive hepatic failure and encephalopathy with over 30% mortality It is associated with aspirin therapy in a variety of viral infections and exact pathogenesis is not known Elevated liver enzymes, blood ammonia, prolonged prothrombin time, hypoglycaemia and change in mental status—all occur within 2–3 weeks after the onset of viral infection Histology—Fatty infiltration in the periphery of liver lobules with glycogen depletion Treatment is supportive and directed towards the management of cerebral oedema.

Primary proliferative polycythaemia Paroxysmal nocturnal haemoglobinuria

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467

Abdomen zz zz zz

zz zz

Antithrombin III, protein C, S deficiency Pregnancy and oral contraceptive pills Obstruction due to tumours (CA of liver, kidney or adrenals) Congenital venous web Inferior venacaval stenosis.

Clinical Features (Fig. 6.39) zz zz zz zz

Upper abdominal pain Tender hepatomegaly Marked ascites Peripheral oedema

(only when IVC is occluded)

Investigations zz zz

zz

Doppler USG CT and MRI to demonstrate hepatic vein or IVC occlusion Liver biopsy—centrilobular congestion with fibrosis

Fig. 6.40  Acute pancreatitis zz

Treatment zz zz

zz zz zz

Treat the underlying cause Streptokinase followed by heparin and anticoagu­ lants in case of suspected thrombosis Angioplasty for hepatic vein stricture TIPS Liver transplantation.

Acute Pancreatitis

zz

zz

zz zz

The pathologic spectrum of acute pancreatitis varies from oedematous pancreatitis (mild and self-limiting) to necrotising pancreatitis. In haemorrhagic pancreatitis, there is interstitial haemor­rhage.

Causes (Fig. 6.40) zz zz zz zz zz zz

Ch-6.indd 467

Biliary disease (gallstones) Alcohol ingestion (acute and chronic alcoholism) Postoperative (abdominal, non-abdominal) Post-ERCP Trauma Metabolic —— Renal failure —— After renal transplantation —— Hypertriglyceridaemia —— Hypercalcaemia (hyperparathyroidism drugs) —— Acute fatty liver of pregnancy

zz

Infections (viral hepatitis, mumps, ascariasis, myco­plasma) Drug-induced —— Definite association: Sulfonamides, oestrogens, fruse­mide, thiazides, tetracycline, valproic acid. —— Probable association: Acetaminophen, etha­cryn­ic acid, procainamide, metronidazole, NSAIDs, ACE inhibitors. Connective tissue disorders: SLE, thrombotic thrombo­ cytopenic purpura Penetrating peptic ulcer Obstruction to ampulla of Vater (regional enteri­tis, duodenal diverticulum) Hereditary pancreatitis, pancreas divisum.

Clinical Features Abdominal pain (mild to severe and constant), nausea, vomiting, abdominal distension (gastric hypomotility) and chemical peritonitis, low grade fever, tachycardia, hypotension (due to exudation of blood and plasma proteins, vasodilatation due to release of kinin pep­ tides and systemic effects of proteolytic and lipolytic enzymes released into the circulation), jaundice (due to oedema of the head of the pancreas), erythematous skin nodules (due to subcutaneous fat necrosis), basal rales, pleural effusion, diminished bowel sounds, palpable pancreatic pseudocyst, bluish discolouration around the umbilicus (Cullen’s sign), bluish red or green brown discolouration of the flanks (Turner’s sign); latter two signs indicate severe necrotising pan­creatitis.

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468

Manual of Practical Medicine Investigations Serum amylase (no correlation between enzyme level and severity of pancreatitis): Levels increase up to 72 hours and return to normal in 1–2 weeks. Other causes of serum amylase elevation are: —— Pancreatic trauma, carcinoma —— Non-pancreatic disorders—mumps, calculus, macro­amylasaemia, DKA, burns, pregnancy, renal transplan­tation, cerebral trauma, mor­ phine, Ca lung, breast, oesophagus —— Other abdominal causes: Biliary tract diseases, per­forated or penetrating peptic ulcer, intestinal obstruc­tion, ectopic pregnancy, chronic liver disease. Serum amylase level has no prognostic value. zz Serum lipase measurement is preferable to serum amylase as it is equally sensitive and has greater specificity (normal serum lipase 0–160 U/L) Marked elevation of peritoneal or pleural fluid amylase >5000/dL also suggests pancreatitis. Persistently elevated amylase suggests pancreatic abscess, pseudocyst or non-pancreatic cause. zz Abdomen and chest X-ray: To rule out other causes, perforated viscus zz CT scan: It is helpful even when the amylase level is normal. CT may show phlegmon (solid mass of swollen inflamed pancreas), colon cut off sign pseudocysts (Figs 6.41 to 6.44) or even pancreatic fluid collection. zz USG and radionuclide scanning: These are useful in evaluating gallbladder and biliary tree (Fig. 6.45). zz

Fig. 6.42  Acute edematous pancreatitis

Fig. 6.43  CT scan—pseudocyst pancreas

Poor Prognostic Indicators zz zz zz zz

Ranson/Imrie criteria (scores 7–8) Haemorrhagic peritoneal fluid Organ failure Obesity

Ranson/Imrie Criteria zz

Fig. 6.41  CT-Acute pancreatitis with colon cut off sign

Ch-6.indd 468

At admission or diagnosis —— Age > 55 years 3 —— Leucocytosis >16,000/ mm

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469

Abdomen

A

B Fig. 6.44  Interventional radiology: Pseudopancreatic cyst pigtail drainage

5–6 Mortality 40% 7–8 Mortality 100%. Haemorrhagic Peritoneal Fluid Key indicators of poor prognosis: Hypotension—BP < 90 mmHg, tachycardia > 130/min, PO2 400 IU/L —— Serum AST >250 IU/L. During initial 48 hours —— Haematocrit fall >10% —— Fluid sequestration >4000 mL —— Hypocalcaemia 30) individuals. It is often associated with shock, respiratory failure (PaO 2 2 mg) and GI bleed. Multiorgan failure is common with Ranson criteria ≥ 3 and Apache II score > 8.

Differential Diagnosis Acute abdomen, myocardial infarct.

Complications Systemic Shock and renal failure zz Diabetes mellitus zz Hypocalcaemia (10 mL of 10% calcium gluconate IV slowly) zz Subcutaneous fat necrosis zz Respiratory failure zz DIC zz Transient hyperglycaemia. Pancreatic (after 1 week): Abscess, pseudocyst. Gastrointestinal: Haemorrhage, ileus, duodenal obstruction (mechani­cal), obstructive jaundice. zz

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Manual of Practical Medicine Management

Clinical Features

The basic principles of management are: Nil orally zz IV fluids and colloids to maintain normal intra­ vascular volume zz Pain relief using analgesic zz Nasogastric suction to decrease gastrin release from stomach zz Monitor pulse, BP, urine output, Serum amylase, Serum lipase, glucose, calcium and blood gases. zz Laparotomy and debridement in haemorrhagic pancreatitis zz Antibiotic therapy using agents that achieve high pan­ creatic tissue concentration decreases the mortality especially in necrotising pancreatitis. The agents include imipenem, ofloxacin and ciprofloxacin. zz Other drugs with variable efficacy include —— Glucagon —— H receptor blocker 2 —— Protease inhibitor—aprotinin —— Glucocorticoids —— Calcitonin —— NSAIDs —— Octreotide —— Lexipafant—platelet activating factor inhibitor —— Gabexate methylate—an antiprotease. zz Treatment of pseudopancreatic cyst–pigtail drainage (Fig. 6.44)

Pancreatitis pain is continuous or intermittent or even it may be absent. Referred pain may be felt over anterior chest or flank. Pain is often increased by alcohol or fat rich heavy meals. Weight loss, diarrhoea, steatorrhoea, minimal abdominal tenderness and mild fever also occur.

zz

Investigations zz zz

zz zz

Treatment zz

zz

Chronic Pancreatitis (Fig. 6.46) Chronic inflammation of pancreas may present as episodes of acute inflammation superimposed on a previously injured pancreas or as chronic damage with persistent pain or malabsorption. Prolonged consumption of socially acceptable levels of alcohol, i.e. 30 gm/day or less may result in pancreatitis. Cholelithiasis, stenosis of sphincter of Oddi, may cause pancreatitis or it may be familial.

Fig. 6.46  Chronic pancreatitis

Ch-6.indd 470

Plain abdomen X-ray shows calcification of pan­creas USG and CT show pancreatic atrophy, calcifications, dilata­­tions and stricture of CBD (Fig. 6.47). ERCP while planning surgery Pancreatic function tests —— N-benzoyl-L-tyrosyl-PABA test: Normal test excludes pancreatic insufficiency —— Secretin/CCK/stimulation test: To confirm pan­ creatic insufficiency —— GTT: It is done to demonstrate diabetes mellitus —— Fecal fat excretion after 5 days stool collection to demonstrate steatorrhoea —— LFT: Increased alkaline phosphatase indicates biliary obstruction.

zz

zz

Pancreatic extracts: 10,000–12,000 lipase units/meal. It causes reduction in faecal fat excretion H2 blockers and antacid to prevent inactivation of pancreatic extract by gastric acid Abstinence of alcohol, low fat diet (medium chain triglycerides do not require lipase for absorption and hence can be given) Operations for unremitting pain —— Pancreatectomy —— End to end or side to side pancreaticojejunos­tomy.

Fig. 6.47  CT scan—pancreatic calcification

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471

Abdomen

Tropical Pancreatitis

Cadaver Donor Selection

Tropical pancreatitis is a juvenile form of chronic calcific non-alcoholic pancreatitis found almost exclusively in the tropical world. It is characterised by recurrent abdomen pain, intraductal pancreatic calculi, exocrine pancreatic insuffi­ci­ency and diabetes. The unique features of this condition are: zz Affects younger people zz Relatively accelerated course zz Not associated with alcoholism.

Cadaver donor liver for transplantation is procured primarily from victims of head injury. Previously, liver transplant allocation was based upon Child Turcotte Pugh score which used five variables; namely, ascites, bilirubin, albumin, encephalopathy, and prothrombin time. Now the allocation is based upon Meld–score model for endstage liver disease that includes bilirubin, creatinine, and prothrombin time.

Indications

Aetiology This is not clearly established. The theories are: zz Under nutrition. zz Cassava diet which contains cyanogenic glycosides zz Familial and genetic predisposition zz Oxidant stress zz Infectious—Coxsackie and viral hepatitis.

In Children zz zz zz

Clinical Features Affects males mostly with a mean age of 20 years, usually with poor socioeconomic status. The usual findings include protein energy malnutrition, bilateral parotid enlargement, abdominal distension, growth retardation and a peculiar cyanotic hue of the lips. The abdominal pain is classically epigastric with radiation to back, persistent and precipitated by heavy fat rich diet or alcohol. Exocrine pancreatic deficiency manifests in the form of steatorrhoea and correlates directly with endocrine damage. Comparison between Alcoholic and Tropical Pancreatitis

zz zz zz

zz

Parameter

Alcoholic pancreatitis

Tropical pancreatitis

Age

35–45

20–40

Sex

Males

Males more than females

Diabetes

Less common

More common

zz

In Adults zz

Steatorrhoea

More common

Less common

zz

Calculi

Less common

More common

zz

Malignancy

Less common

More common zz

LIVER TRANSPLANTATION Liver transplantation has become an accepted lifesaving procedure when applied earlier in the natural history of end stage liver disease. Orthotopic liver transplan­tation means implantation of a donor organ, after removal of the native organ, in the same anatomic location.

Ch-6.indd 471

Biliary atresia Neonatal hepatitis Inherited disorders of metabolism —— Wilson’s disease —— Tyrosinaemia —— Glycogen storage diseases —— Lysosomal storage diseases —— Crigler-Najjar syndrome—type I —— Familial hypercholesterolaemia —— Haemophilia —— Protoporphyria —— Hereditary oxalosis α1-antitrypsin deficiency Congenital hepatic fibrosis Alagille’s disease (arteriohepatic dysplasia with paucity of bile ducts, congenital cardiac malfor­ mations like PS) Byler’s disease—Intrahepatic cholestasis, progres­sive liver failure, MR, growth retardation.

zz zz zz zz zz zz zz

Primary biliary cirrhosis Secondary biliary cirrhosis Primary sclerosing cholangitis Caroli’s disease (multiple cystic dilatations of biliary tree) Cryptogenic cirrhosis Chronic active hepatitis with cirrhosis Hepatic vein thrombosis Fulminant hepatitis Alcoholic cirrhosis* Chronic viral hepatitis* Primary hepatocellular carcinoma* Hepatic adenoma.

Note: *Controversial indications for liver transplant.

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Contraindications zz zz zz zz zz zz

Life-threatening systemic disease Uncontrolled extrahepatic bacterial or fungal infec­tion Preexisting cardiopulmonary disease HIV Active drug/alcohol abuse Multiple uncorrectable life-threatening congenital ano­malies.

Relative Contraindications zz zz zz zz

zz zz

zz zz

Age >60 years Highly replicative HBV infection Portal vein thrombosis Preexisting renal disease (not associated with liver disease) Intrahepatic or biliary sepsis Severe hypoxaemia (right to left intrapulmonary shunts) Previous extensive hepatobiliary surgery Uncontrolled serious psychiatric disorders.

Complications zz



zz

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Hepatic —— Primary graft failure (as a result of ischaemic injury to the organ) —— Vascular compromise (thrombosis/stenosis of portal vein or hepatic artery anastomoses) —— Failure or obstruction of biliary anastomosis —— Rejection. Postoperative jaundice —— Prehepatic: Transfusion (increased Hb pigment, due to haemo­lysis, haematomas, ecchymoses and other collections of blood). —— Intrahepatic „„ Early intraheptic: Drugs or anaesthesia, hypo­per­fusion injury due to shock, sepsis, benign postoperative cholestasis „„ Late intrahepatic: Post-transfusion hepatitis, recurrent pulmonary disease. —— Posthepatic: Biliary obstruction and decreased renal clearance of conjugated bilirubin. Nonhepatic —— Fluid overload in the postoperative period due to massive fluid losses and fluid shifts —— Continuous monitoring of cardiac and pulmonary function —— Renal dysfunction (hypoperfusion and ATN) —— Intraperitoneal bleeding

——

——

Anaemia (upper GI bleed or transient haemolytic anaemia, usually of autoimmune origin, transient thrombocytopenia, aplastic anaemia) Bacterial, fungal and viral infections.

In the immediate post-transplantation period Pneumonia zz Wound infections zz Infected intra-abdominal collections zz UTI zz IV line infections. zz

Beyond the Ist posttransplantation period: CMV, herpes, fungal infec­t ions (Aspergillus, Nocardia, Candida, Crypto­coccus), mycobacterial and parasitic infections (Pneumocystis carinii, Toxoplasma).

Immunosuppression Various combinations of cyclosporine, glucocorticoids, azathioprine, OKT3 have been tried.

Live Donor Transplantation Due to shortage of availability of cadaver organs, live donor transplantation comes into practice. Here, transplantation of the right lobe of the liver from a healthy adult into an adult recipient or left lobe of the liver into a child recipient is carried out.

Auxiliary Liver Transplantation Although orthotopic liver transplantation provides a means of rapidly restoring liver function in patients with acute liver failure, it carries with it two signi­ficant disadvantages: zz The need for life-long immunosuppression zz The elimination of the possibility that the native liver may spontaneously regenerate. These are circumvented by auxiliary liver trans­ plantation, in which an additional segment of liver is implanted to provide temporary support. Nowadays, a part of the native liver is replaced with an equivalent section of donor organ. This is called auxiliary partial orthotopic liver transplan­tation (APOLT). This technique has been found useful in Crigler-Najjar syndrome.

Split Liver Transplantation One cadaver organ can be split between two recipients– adult and one child. Adult receives right lobe and the child receives left lobe of cadaver liver.

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Abdomen

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Bioartificial Liver

Success Rate

This newly invented technique has been used in patients with acute liver failure as a bridge until the native liver regenerates or until a donor organ becomes available. Systems using cultured human hepatocytes, that would have the capacity to remove toxins and provide synthetic functions have been employed. Extracorporeal liver assist device (ELAD) uses cultured human hepatoblastoma cells grown in the extracapillary space of a hollow fibre dialyser. Venous blood is pumped through the fibres, leading to the ultrafiltration of plasma into the extracapillary space. Return of the ultrafiltrate to the patient allows the delivery of high molecular weight products including clotting factors.

Long-term survival is 60–80%.

Molecular Adsorbent Recirculating System (MARS) MARS is based upon the principle of albumin dialysis. It consists of three compartments—blood circuit, albumin circuit and renal circuit. Here the blood is dialysed against an albumin containing solution across a suitable membrane. The albumin bound toxins are potentially taken up by the binding sites of the dialysate albumin and thus removed from the blood.

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CHAPTER

7

Haematology

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HAEMATOPOIESIS AND HAEMATOPOIETIC GROWTH FACTORS Proliferation of the early haematopoietic cells occurs as the embryo grows and becomes a foetus (10–12 weeks). During early foetal life, after the sixth week of preg­nancy up to the second trimester, the liver and the spleen are the major sites for haematopoiesis. The sites of haemato­poiesis gradually shift from the liver and spleen to the medullary cavities of the bones. At birth, virtually medullary cavities of every bone contribute to this proliferative process. Pluripoten­ tial cells remain in other organs of the reti­culoendo­thelial system as haemato­poietic “rest cells.” These give rise to  extramedullary haematopoiesis when there is a demand.

Cell Divisions (Fig. 7.1) Stem cell gives rise to totipotent, pluripotent, multipotent and unipotent cells. zz Totipotent—ability to form the embryo and fertilized trophoblast of the placenta zz Pluripotent—ability to differentiate into almost all cells of the three germ layers zz Multipotent—ability to originate cell types of their original tissue site zz Unipotent—ability to generate one single cell type. zz Telomere is the region at the ends of a chromosome that prevents the loss of genetic material or the accidental fusion of two chromosomes together during cell division. Replicative senescence involves progressive shortening of telomeres, which ultimately results in

cell cycle arrest. Telomere length is maintained by telomerase enzyme.

Haematopoiesis Intrauterine Life (Fig. 7.2) zz

zz

zz

3 weeks to 3 months—intravascular haemopoiesis at yolk sac 3 months to 6 months—extramedullary haemopoiesis at liver and spleen Above 6 months—medullary haemopoiesis at bone marrow.

Postnatal Life (Fig. 7.3) zz

zz

High percentage of cellularity exists in flat bones even at the advanced age—vertebra, sternum, rib and pelvic bones As the age advances the percentage of cellularity decreases in long bones.

Fig. 7.2  Haemopatoiesis—Intrauterine life

Normal Haematopoiesis

Fig. 7.1  Physiology of cell division

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Fig. 7.3  Haematopoiesis—Postnatal life

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Haematology

Antigen Designation–Cellular Distribution Primarily T-Cell Associated CD1 Thymocytes and Langerhans cells CD3 Thymocytes, mature T cells CD4 Helper T cells, subset of thymocytes CD5 T cells and a small subset of B cells CD6 Cytotoxic T cells, subset of thymocytes, and some NK cells zz Primarily B-Cell Associated CD10 Pre-B cells and germinal- center B cells CD19 Pre-B cells and mature B cells but not plasma cells CD20 Pre-B cells after CD19 and mature B cells but not plasma cells CD21 EBV receptor, mature B cells, and follicular dendritic cells CD23 Activated mature B cells CD79a Marrow pre-B cells and mature B cells zz Primarily Monocyte or Macrophage Associated CD11c Granulocytes, monocytes, and macro­phages; also expressed by hairy cell leukaemias CD13  Immature and mature monocytes and granulocytes CD14 Monocytes zz



CD15  Granulocytes; Reed-Sternberg cells and variants CD33 Myeloid progenitors and monocytes CD64 Mature myeloid cells zz Primarily NK-Cell Associated CD16 NK cells and granulocytes CD56 NK cells and a subset of T cells zz Primarily Stem Cell and Progenitor Cell Associated CD34 Pluripotent haematopoietic stem cells and progenitor cells of many lineages zz Activation Markers CD30 Activated B cells, T cells, and monocytes; Reed-Sternberg cells and variants zz Present on All Leucocytes CD45 Leucocyte common antigen (LCA} MPO, CD117 and CD13 are myeloid markers. MPO is the most specific myeloid marker. CD13 is called as pan-myeloid marker.

Haematopoietic Stem Cells These are a unique clone of cells capable of differen­ tiating into the multiple cell lines of the haematopoietic system (Fig. 7.4). Stem cell proliferation is under direct influ­ence of haematopoietic growth factors present in the reticuloendothelial system.

Haematopoietic Stem Cell Differentiation

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Name of the cell

Function

Erythrocytes

Hb present in the erythrocytes helps in the O2 and CO2 transport mechanism of blood; it has a minor role in the acid-base balance.

Neutrophils

These are phagocytes capable of ingest­ing bacteria and fungi by chemotaxis and opsonisation. The bacteria are killed by O2 dependent (H2O2 production, myelo­peroxidase release) and O2 independent (lysozyme, lactoferrin release, and reduction of pH in the phagosome) mecha­ni­sms. They also produce trans­­cobalamin III, a vitamin B12 binding protein which increases in leukaemia. They liberate tissue damaging substances after inges­tion of uric acid crystals.

Eosinophils

These are weak phagocytes and are associated with allergic reactions. They ingest antigen-antibody complexes and can process foreign proteins. They also have a role in the containment of para­sitic infestation.

Basophils

These are poor phagocytes and can bind to IgE molecule. Degranulation of baso­phils can occur with release of histamine (type I hyper­ sensitivity). They also con­tain heparin which participates in the metabolism of lipids.

Monocytes

These are phagocytic and constitute the mono­cyte-macrophage system which removes debris as well as microorgan­isms by phagocytosis; they help in the collection and presentation of antigenic material to the lymphocytes. They help in the lysis of tumour cells. They also produce IL-I and TNF and other mediators of acute phase reaction. They produce platelet derived growth factor and helps in healing and tissue remodelling. Tissue thromboplastin is pro­duced in response to bacterial endo­toxin, thereby activating extrinsic coagu­lation pathway leading to intravascular coagulation.

Lymphocytes

These arise from committed stem cells of the marrow and migrate to thymus (T-cells). Others become B-cells (bursa of Fabricius in birds). A few become null cells. T-cells are involved in cell mediated immunity. B-cells are involved in humo­ral immunity by producing antibodies.

Thrombocytes (platelets)

They respond quickly to ADP, thrombin and collagen and adhere to vas­cular subendothelium by becoming spherical. There are three types of storage granules. α granules contain fibrinogen, vWF. Dense granules contain ADP and serotonin. They also have lysosomes which contain acid hydrolases. The release of contents causes platelet aggregation and fibrin deposition on the platelet surface. On activation, platelets release arachi­-donic acid which results in the formation of thromboxane A2 which in turn stimulates platelet aggre­gation.

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Fig. 7.4  Differentiation of haematopoietic cells

Nature of the Marrow Stem Cell zz zz zz zz

zz

Renewal capacity Great proliferative and differentiative potential Gives rise to all lymphohaematopoietic lineages Relatively quiescent but cycling population—easily induced into cell cycle Potential for giving rise to variety of non-haemato­ poietic cells.

Stem Cell Diseases zz zz zz zz zz zz zz

Acute myelocytic leukaemia Chronic myelogenous leukaemia Myelofibrosis and myeloid metaplasia Polycythaemia rubra vera Aplastic anaemia Cyclical neutropenia Paroxysmal nocturnal haemoglobinuria.

Therapeutic Application of Stem Cells zz

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Restoration of haematopoiesis after ablative chemoradiotherapy

zz zz zz zz

Treatment of marrow disorders like aplastic anaemia Treatment of immunodeficiency diseases Helps in the healing of chronic skin wounds Utilisation as a vehicle for gene therapy.

Haematopoietic Growth Factors These are heterogeneous group of cytokines that stimulate pro­genitor cells of haematopoietic system and induce proliferation and maturation. These hormones play a critical role in the regulation of all haemato­poietic cells in health and disease.

Major Growth Factors 1. Erythropoietin: This is synthesised by the peri­tubular cells of the kidney in response to hypoxaemia and is always present in minute amounts in human urine. About 10% of endogenous erythopoietin is secreted by the liver. The plasma half-life of erythopoietin in anaemic patients is 6–9 hours, and it shortens with continued therapy. The gene cod­ing for erytho­poietin is located on chromosome 7 (C7, q11-22).   Normal serum level is 10–25 IU/L.

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Haematology 2. Interleukin (IL-3): T-lymphocytes produce IL-3, and this factor is not lineage specific. IL-3 appears to stimulate production and renewal of the pluri­potent stem cell compartment, and for its differen­tiation into all myeloid cell lines and lymphocytes. The gene coding for IL-3 is located on chromosome 5 (C5, q23-31). 3. Granulocyte macrophage colony-stimulating factor (GM-CSF): GM-CSF is synthesised and secreted by bone marrow stromal cells, fibroblasts, T-cells, and endothelial cells. GM-CSF stimulates the growth of pro­genitors of granulocytes, monocytes, and ery­thro­cytes, and often causes eosinophilia as well. It activates granulocytes and monocytes/macrophages and enhances phagocytosis and other functions of these cells.

4. Granulocyte colony-stimulating factor (G-CSF): G-CSF is a potent, low-molecular-weight glycoprotein that stimu­lates proliferation and maturation of granu­locyte precursors. This factor is produced by stromal cells, monocytes, macrophages, and endo­thelial cells. Within 48 hours after administration, the number of circulating neutrophils dramatically increases. The effect is lineage specific and dose-dependent. The gene coding for G-CSF is located on chromosome 17 (C17, q11-21). 5. Macrophage colony-stimulating factor (M-CSF): M-CSF is secreted by stromal cells, macrophages and fibro­ blasts. It is a potent stimulator of macroph­age function and activation resulting in stimulation and elaboration of other cytokines resulting in increased expression of

Other Cytokines Affecting Haematopoiesis Cytokines IL-1 IL-2 IL-3 IL-4 IL-5 or B-cell stimulating factor-2 IL-6 IL-7 IL-8 IL-9 IL-10 IL-11 IL-12 IL-13 IL-14 IL-15 IL-16 IL-17 IL-18 Stem cell factor (SCF) IL-19 IL-20 IL-21 IL-22 IL-23 IL-24 IL-25 IL-26 to 29

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Gene locus

Function Endogenous pyrogen, induces production of other cytokines from other cells, co-stimulates stem cells, modulates immune response T-cell growth factor, inhibits myelopoiesis Stimulates multiple haematopoietic lineages Stimulates B-cells and modulates immune response Potent eosinophil-differentiation factor; causes a rise in peripheral eosinophils Major mediator of inflammation and immune response; important growth factor for myeloma cells Important growth and differentiation factor for T-cells; acts synergistically with IL-2 and IL-6

Long arm of chromosome-8 Long arm of A potent chemotactic activating factor for neutro­phils and also for T-cells and eosinophils chromosome-4 (C4q) Chromosome-5 (C5q31) Acts synergistically with IL-4 to potentiate antibody production by B-cells Chromosome-1 Potent immunosuppressant of macrophage function and down regulates MHC class II antigen expression on macrophages An inflammatory mediator stimulating the synthesis of hepatic acute phase reactants Produces gamma interferon (IFN-γ) from T-cells and NK cells and helps in the differentiation of helper T-cells — Similar in action to IL-4 on B-cells and monocytes, induces production of IFN-γ by large granular lymphocytes and stimulates T-cells — Induces B-cell proliferation and inhibits immunoglobulin synthesis — Shares activity with IL-2, facilitates IFN-γ and TNF-α production along with IL-12, stimulates proliferation of activated T-cells, NK cells and masT-cells — CD 4 + T-cell chemoattractant and growth factor stimulator — Stimulates adheren T-cell types like macrophages to secrete various cytokines, induces T-cell proliferation, stimulates granulopoiesis — Similar to IL-12, augments CMI, modulates T,B and NK cells function, induces IFN-γ in type 1 helper T and NK cells Promotes mas T-cell proliferation along with IL-3 and IL-4 Induces IL-6 and TNF-α and cellular apoptosis Keratinocyte proliferation Myeloma cell survival factor, T and NK cell regulation IL-10 homolog, acute phase production by hepatocytes Autoimmune inflammation of the brain, overlaps with IL-11 and 12 Tumour apoptosis Lymphoid cell proliferation, induces IL-4, IL-5, and IL-13 Identified and under evaluation

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Manual of Practical Medicine MHC class II antigen on macrophages and enhanced cytotoxicity. There is a slight to moderate rise in white blood cells after its administration. The gene for M-CSF is located on chromosome 5 (C5, q33). 6. Interleukin-2 (IL-2) or T-cell growth factor (T-CGF): IL-2 is synthesised and secreted by activated T-cells, primarily helper-T cells. IL-2 leads to clonal expansion of antigen-specific T-cells and the induc­tion of the expression of IL-2 receptors (CD25) on the surface membrane of T-cells. It induces non-MHC restricted cytotoxic lymphocytes. It also stimulates proliferation of NK cells and B-cells. 7. Interleukin-4 (IL-4) or B-cell stimulating factor (BSF-1): This is a potent growth factor derived from activated T-cells and mast cells. IL-4 induces the prolifer­ation and differentiation of B-cells and the expres­sion of MHC class II antigens on resting B-cells. IL-4 can also activate T-cells, monocytes/mac­ro­­phages, mast cells, fibroblasts, and endo­thelial cells.

8. Thrombopoietin: This is the major regulator of mega­ karyocyte proliferation, differentiation, and platelet production. It stimulates and supports the survival of primitive stem cells. These cytokines may be important in contributing to the delicate balance and regulation of haemato­poiesis. Through recombinant DNA technology, many of these cytokines have become available in sufficient quan­tities to allow clinical studies to be performed.

NORMAL REFERENCE VALUES IN HAEMATOLOGY zz

Age

Hb g/dL

Hct

Birth

17

52

Childhood

12

36

Adult

Commercially Available Haematopoietic Growth Factors and their Clinical Uses

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Haemoglobin and haematocrit

 Man

16 ± 2

47 ± 6

Factor

Clinical uses

 Woman

14 ± 2

42 ± 6

Recombinant human granulocytemacrophage colonystimulating factor

Acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma, ALL or Hodgkin’s disease who are undergoing autologous BMT

 Pregnant

12 ± 2

37 ± 6

Recombinant human granulocyte colonystimulating factor

Neutropenia in non-myeloid malignant disease in patients receiving myelosuppressive drugs or chemotherapy

Recombinant human erythropoietin Interleukin-2 IFN-α

Anaemia of chronic renal disease (in dialysisdependent patients) Advanced renal cell carcinoma Early stage CML, hairy cell leukaemia, mycosis fungoides, Sezary syndrome, malignant melanoma, multiple myeloma, HTLV 1 associated leukaemia or lymphoma

IFN-b

Relapsing remitting multiple sclerosis

IFN-g

Graft-versus-host disease Chronic granulomatous disease Idiopathic pulmonary fibrosis

IL-11

Chemotherapy-induced thrombocytopenia

Thrombopoietin

Thrombocytopenia

TNF-α

Used in isolated limb perfusion in sarcoma and melanoma

Keratinocyte growth factor (KGF)

Human recombinant KGF decreases gut GVHD by preserving graft versus leukaemia effect. May be used in wound healing and prostate cancer

Monocyte/ macrophage CSF

May be used in renal cell carcinoma, melanoma and severe fungal infections

Stem cell factor

Haematopoietic progenitor stimulation, mobilisation of stem cells when used along with G CSF and in aplastic anaemia

zz

zz

zz

Mean corpuscular volume (MCV) Hct × 10 = 90 ± 8 fL RBC count × 106 Mean corpuscular haemoglobin (MCH) Hb g/dL × 10 = 30 ± 3 pg RBC count × 106 Mean corpuscular haemoglobin concentration (MCHC)

MCH Hb g/dL × 10 = 33 ± 2% OR MCV Hct zz Mean corpuscular diameter Mean corpuscular diameter of 50 cells in smear = 7.5 µ (male and female) zz RBC count Male 4.5–5.5 millions/mm3 Female 4–4.5 millions/mm3 zz RBC life span 120 days (100–120) zz Red cell distribution width RDW = 11–16 zz Reticulocyte count Male 1.6 ± 0.5% Female 1.4 ± 0.5%

Absolute Reticulocyte Count Absolute reticulocyte count = % of reticulocytes × RBC count/mm3.

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Haematology An increase in reticulocytes to greater than 100,000/ mm3 suggests a hyperproliferative bone marrow associated with loss or destruction of RBCs. Anaemia with low reticulocyte count suggests impaired RBC production.

Peripheral Film Morphology (Fig. 7.5) zz

Reticulocyte Index* % of reticulocytes ×

account in anaemia there is premature release of reticulocytes and a correction will occur dividing the corrected reticulocyte per cent by 2 termed as reticulocyte index).

Observed Hct 1 × Normal Hct 2

(*Reticulocyte percentage can be corrected for the reduction in red cell counts in anaemia by multiplying the percentage with the ratio of observed Hct to normal Hct. This corrected reticulocyte percentage can further be adjusted by taking into

zz

zz

Acanthocytes/spur cells: RBC shows many irregular spicules, e.g. abetalipoproteinaemia. Anisocytosis: Variations in the size of RBCs, e.g. iron deficiency anaemia, megaloblastic anaemia, thalassaemia. Poikilocytosis: Variations in the shape of RBCs, e.g. iron deficiency anaemia, sideroblastic anaemia, thalassaemia.

Fig. 7.5  Morphology of RBCs in peripheral smear

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Manual of Practical Medicine zz

zz

zz

zz

zz zz

zz

zz

zz

zz

zz

zz

zz

zz

Hypochromia: Less stained RBCs, e.g. iron deficiency anaemia, sideroblastic anaemia. Microcytosis: Small sized RBCs 100 fL, e.g. B12 or folate deficiency anaemia. Dimorphic picture: Combination of microcytosis and macrocytosis, e.g. partially treated iron deficiency anaemia, mixed deficiency of Fe, folate or B12, posttransfusion, sideroblastic anaemia. Burr cells: Regularly placed spines in RBCs, e.g. uraemia. Schistiocytes: Fragmented RBCs, e.g. intravascular haemolysis. Basophilic stippling: Speckling of RBCs with fine dots on basic staining, e.g. lead poisoning, thalas­saemia, dyserythropoietic anaemias. Howell-Jolly bodies: Nuclear remnants seen in RBCs, e.g. post-splenectomy, hyposplenism, rarely in leukaemia, iron deficiency anaemia, megaloblastic anaemias. Heinz bodies: Precipitated haemoglobin in RBCs, e.g. unstable haemoglobins, oxidation stress. Spherocytes: Small densely stained RBCs with loss of central pallor, e.g. hereditary spherocytosis, immunohaemolytic anaemias. Target/Mexican hat cells: RBCs with a dark centre surrounded by a light band which is again encircled by a darker ring, e.g. thalassaemia, Hb S and C, liver disease. Pappenheimer bodies: Granules of siderocytes, e.g. lead poisoning, carcinomatosis, post-splenectomy. Reticulocytes: Young RBCs with a network of precipitated basophilic substance denoting active blood regeneration. Stomatocytes: Cup-shaped RBCs having a slit like central zone of pallor due to lack of RBC membrane protein 7.2 (stomatin) and Rh proteins.

WBC Count zz zz

Total count—4000–11000 cells/mm3 Differential count: 3 —— Polymorphs—40–75% (2.2–8.6 × 10 /µL = 2,200–8,600) 3 —— Lymphocytes—20–45% (0.8–3.5 × 10 /µL = 800–3,500) 3 —— Monocytes—2–10% (0.2–0.8 × 10 /µL = 200–800) 3 —— Eosinophils—4–5% (0.04–0.5 × 10 /µL = 40–500) 3 —— Basophils—0–1% (0.01–0.12 ×10 /µL = 10–120)

Automated Full Blood Analysis Causes of Spurious Results Result Increased haemoglobin Decreased haemoglobin Increased MCV Increased WBC count Decreased platelet count

ANAEMIA Anaemia may be defined as a state in which the blood haemoglobin level is below the normal range for the patient’s age and sex (Males 40% loss—hypovolemic shock, confusion, dyspnoea, diaphoresis, tachycardia, hypotension. zz Haemolytic anaemia: Acute back pain due to intra­ vascular haemolysis, haemoglobinuria, signs of renal failure.

Iron Deficiency Anaemia Haemoglobin is normally the largest iron compartment of the body. Hb is 0.34% iron by weight. In an adult, total iron content of Hb compartment is about 2 g.

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Manual of Practical Medicine Haemoglobin at birth is about 20 g/dL and it gets reduced to 10 g/dL at 3 months of age. In males, normal Hb level is about 14 g/dL and in females about 12 g/dL.

Iron Metabolism Iron taken in diet is absorbed at all parts of GI tract especially duodenal mucosa. Acid medium favours iron absorption. Acid medium favours formation of soluble macromolecular complexes of iron with vitamin C, sugar, amino acid or bile in the duodenum. Only 10% of the ingested iron is absorbed. Normal serum iron level is 50–150 mg/dL. Frank iron deficiency increases absorption by 30–40% and in iron overload, absorption decreases. Iron absorption is increased in: (i) ferrous state, (ii) increased erythropoiesis, (iii) iron deficiency. Iron absorption is decreased in: (i) ferric state, (ii) in the presence of phosphates and phytates, (iii) bone marrow hypoplasia. The absorbed iron is stored in the form of ferritin (water soluble form) and haemosiderin (water insoluble form). In men, storage compartment contains about 1000 mg of iron and in women, it ranges from 0 to 500 mg; in one-third of healthy women, there is no significant iron in storage compartment. The storage organs are liver, spleen, lymph nodes and bone marrow. Iron is transported after binding with transferrin, a cytoplasmic protein. Transport iron compartment contains 3 mg of iron. Transferrin concentration in plasma is measured by estimating total iron binding capacity or immunologically. Normally l mg of elemental iron is lost from shed­ding of senescent cells of gastrointestinal tract and genitourinary tract, and from desquamation of skin.

Causes of Iron Deficiency (Fig. 7.6) 1. Increased iron utilisation (increased demand) —— Postnatal growth spurt —— Adolescent growth spurt —— Erythropoietin therapy 2. Physiologic iron loss —— Menstruation —— Pregnancy 3. Pathologic iron loss —— Gastrointestinal bleeding. —— Genitourinary bleeding —— Pulmonary haemosiderosis —— Intravascular haemolysis —— Phlebotomy for polycythaemia rubra vera 4. Decreased iron intake —— Cereal rich diet —— Pica, food fads, malabsorption —— Acute or chronic inflammation. Physiological Causes In children, iron available during birth is adequate for erythropoiesis till 3–4 months and later weaning food rich in iron should be substituted. If weaning is delayed, anaemia develops. Prematurity and haemorrhage from the cord at birth deprive the infant of normal iron store. In adolescents, iron deficiency occurs during growth spurt and also occurs because of food fads. In Adults (Menstruating Women) Menstruation causes an average loss of 30 mg of iron per month. In pregnancy, there is no menstrual loss. However, additional iron is needed for the foetus, the placenta, and for the increased red cell mass and for the blood loss during delivery. 1. Iron requirement in males —1 mg per day 2. Iron requirement in females —2 mg per day 3. Iron requirement in pregnancy —3 mg per day In Postmenopausal Women and Adult Men Most common cause of iron deficiency in this group is gastrointestinal bleeding (drug-induced gastritis, gastrointestinal malignancy, pep­tic ulcers). At All Ages Hookworm infestation, schistosomiasis, diet deficient in iron are causes of iron deficiency at all ages, especially elderly. Stages in Iron Deficiency Anaemia

Fig. 7.6  GIT causes for iron deficiency anaemia

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There are three stages in the development of iron deficiency anaemia:

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485

Haematology 1. Negative iron balance 2. Iron deficient erythropoiesis 3. Iron deficiency anaemia.

Differential Diagnosis zz zz

Clinical Features Patients may have angular stomatitis, atrophic glossi­tis, koilonychia, brittle hair, pruritus, pica, Plummer-Vinson syn­drome (postcricoid web) or menorrhagia.

zz zz zz zz

zz

Investigations Haemoglobin level: When Hb is greater than 10 g/dL, symptoms of anaemia develop only on exertion or on exposure to hypoxia or high altitude. If Hb level is less than 7 g/dL, patient is symptomatic even at rest. There is also loss of pigmentation in palmar crease (Fig. 7.7). zz Microcytic, hypochromic (MCHC 80 mg/L, rules out iron deficiency anaemia (normal ferritin level—15–400 mg/L). zz *Iron absorption is increased and the total iron binding capacity rises. zz Chromium labelled red cells may be used to measure blood loss into the gut. zz RBC protoporphyrin is increased—> 200 µg/dL (normal value—30–50 µg/dL). zz Serum levels of transferrin receptor protein is increased—(normal 4–9 µg/dL). Note: *Serum iron, TIBC and transferrin saturation have a very limited diagnostic value since the results are variable during physiological conditions and during inflammatory diseases. zz

zz zz zz

Anaemia of chronic disease Thalassaemias Haemoglobinopathies (HbE) Chronic liver disease Chronic renal disease Myelodysplastic disorders (refractory anaemia with ringed sideroblasts) Myeloproliferative disorders Hereditary sideroblastic anaemia Myxoedema Congenital atransferrinaemia.

Management zz zz

zz



zz

Treat the underlying cause. Iron replacement by ferrous sulphate 200 mg tds orally. 200 mg of ferrous sulphate contains 60 mg of elemental iron. Oral therapy is safest and cheapest. Avoid enteric coated and sustained release tablets. Haemoglobin rises by 1 g/dL/week or by 1% per day (accompanied by a reticulocytosis). Continue until haemoglobin is normal and for 6–8 months to replenish stores. If there is no response to oral iron therapy, consider the following: —— Incorrect diagnosis —— Noncompliance —— Blood loss exceeding rate of replacement —— Marrow suppression by tumour, chronic inflammation —— Malabsorption: Other oral Fe preparations— ferrous fumarate, ferrous gluconate, polysac­ charide iron, carbonyl iron. Parenteral iron therapy: It is given for those who are unable to absorb iron from the GI tract or to those who have intolerance to oral iron. 100 mg of iron (IM) are required to increase the haemoglobin level by 4% but the total dose of iron should not exceed 2.5 g. Alternative parenteral Fe preparations: —— Sodium ferric gluconate: No test dose is needed. 125 mg in 100 mL of normal saline infused IV over 1 hour and not to exceed 250 mg/day. It is not given as single dose because of adverse reactions like hypotension. —— Iron sucrose: 100 mg in 100 mL of normal saline infused IV over 30 minutes and repeated 1–3 times/week.

Iron Dextran-IV (In IM Intolerance)

Fig. 7.7  Iron deficiency anaemia—hypochromic microcytes

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500 mg of the compound is given with 100 mL of sterile saline; and infused after a test dose of 1 mL and if there is no adverse reaction.

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Manual of Practical Medicine Differential Diagnosis of Microcytic, Hypochromic Anaemia Features

Iron-deficiency anaemia

β-thalassaemia trait

Anaemia of chronic disease

Serum iron

↓

Normal

↓

↑

TIBC

↑

Normal

↓

Normal

Serum ferritin

↓

Normal

↑

↑

Red cell protoporphyrin

↑

Normal

↑

↑ or Normal

Hb A2

↓

↑

Normal

↓

Side effects are fever, chills, arthralgia, lymphade­ nopathy, splenomegaly, aseptic meningitis, anaphy­ lactic shock, rarely sarcomas at the site of injection, and haemochromatosis. In conditions simulating iron deficiency anaemia (β-thalassaemia, sideroblastic anaemia, anaemia of chronic disease), a therapeutic trial of iron should be given. It is half corrected in 3 weeks and fully corrected in three months in case of iron deficiency anaemia and not in the other conditions. Oral iron therapy (200 mg tds) raises Hb by 1% 7 days of oral therapy raises Hb by l g% Parenteral iron (100 mg), raises Hb by 4%. If the Hb deficit is 7 g, oral iron replacement should be continued for at least 7 weeks; therapy should be continued for 6–8 months for replacing iron stores. Oral iron therapy is safest and cheapest. Avoid parenteral iron therapy unless it is strongly indicated. With iron therapy, the reticulocyte count peaks in 5–10 days, and the Hb rises over 1–2 months.

Megaloblastic Anaemia This term refers to abnormal haematomyelopoiesis charac­ terised by dyssynchronous nuclear and cyto­p lasmic maturation in all myeloid and erythroid cell lines due to aberrant DNA synthesis as a result of single or combined deficiency of either cobalamin (vit B12) or folate. Similar changes occur in other organs like uterine cervix, aerodigestive tract also and can be mistaken for carcinoma. A MCV of >100 fL should prompt the physician to go for further investigations.

Causes of Macrocytosis zz

zz

Ch-7.indd 486

MCV >110 fL Vitamin B12 or folate deficiency. MCV 100–110 fL —— Alcohol —— Liver disease —— Hypothyroidism —— Haemolysis —— Pregnancy

—— —— ——

Sideroblastic anaemia

Marrow infiltration Myelodysplastic states Drugs (zidovudine, azathioprine).

Causes of Vitamin B12 Deficiency zz

zz

Inadequate intake: Vegans (rare) pure vegetarians who do not consume milk and milk products. Malabsorption: —— Defective release of cobalamin from food „„ Drugs that block acid secretion „„ Gastric achlorhydria „„ Partial gastrectomy —— Inadequate production of intrinsic factor (IF) „„ Pernicious anaemia „„ Total gastrectomy „„ Congenital absence of IF „„ Functional abnormality of IF —— Disorders of terminal ileum „„ Tropical sprue „„ Non-tropical sprue „„ Regional enteritis „„ Intestinal resection „„ Neoplasms „„ Granulomatous lesions „„ Selective cobalamin malabsorption —— Competition for cobalamin „„ Fish tapeworm (diphyllobothrium latum) „„ Bacteria (blind loop syndrome) —— Drugs: PAS, neomycin, colchicine —— Other rare causes: „„ Nitrous oxide „„ Transcobalamin II deficiency „„ Congenital enzyme defects.

Metabolism of Vitamin B12 zz Sources of vitamin B 12 are bacteria and animal tissue. zz Serum level of vitamin B 12 is 200–600 pg/mL. zz Requirement of vitamin B 12 is 1 mg/day. zz Total body store of vitamin B 12 is 5 mg. The storage lasts for 5 years. More than 50% is stored in the liver. zz The ingested vitamin requires a gastric glyco­ protein called intrinsic factor facilitating intestinal absorption, in the terminal ileum (distal 3–4 feet).

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Haematology It is attached to a carrier protein (transcobalamin II) within the ileum and transported into the liver (major site of storage). Transcobalamin I binds most of serum cobalamin and it has no physiological role. Transcobalamin III is localised to specific neutro­phil granules and the level of this carrier protein is increased in myeloproliferative disorders especially CML. In pernicious anaemia, serum B12 level is 5 lobes are present) (Fig. 7.8). Increased ESR (malignancy) Thyroid function tests Serum B12 level Red cell folate level Bone marrow biopsy: —— Megaloblastic—B 12 or folate deficiency (Fig. 7.9) —— Normoblastic—liver damage, myxoedema —— Increased erythropoiesis—bleeding or haemo­lysis —— Abnormal erythropoiesis—sideroblastic anaemia, leukaemia, aplastic anaemia. Schilling test: It helps identify the cause of B 12 deficiency. This determines whether a low B12 is due to malabsorption or lack of intrinsic factor by comparing the proportion of an oral dose (1 mg) of radio­active B12 excreted in urine with and without the concurrent administration of intrinsic factor. The blood must be saturated prior by giving an IM dose of 1000 mg of B12. If intrinsic factor increases absorption, the lack of it is likely to be the cause. If not, look for other causes like blind loops, diver­ ticula and terminal ileal disease.

Beware of diagnosing pernicious anaemia before the age of 40 years and in younger age groups; most common cause would be GI malabsorption. Useful Clues for Diagnosis zz zz

Serum B12 level less than 200 pg/mL. Serum folate level less than 4 ng/mL.

Clinical Features Pallor (lemon colour), smooth tongue, cardiac “hemic” systolic murmur, hepatomegaly, rarely splenomegaly. Neurologic picture in vitamin B12 deficiency ranges from mental inatten­tiveness to severe mental con­fusion with or without dorsal and lateral column signs (subacute combined degeneration). However, some signs are not reversible with cobalamin therapy.

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Fig. 7.8  Pernicious anaemia—macrocytosis with multilobed neutrophil

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Fig. 7.9  Pernicious anaemia—megaloblasts in bone marrow zz

zz

RBC folate level is more diagnostic because it does not fluctuate frequently. Both homocysteine and methyl malonoic acid serum values are increased in B12 deficiency, but only homo­ cysteine level is increased in folic acid deficiency (MMA normal level).

The presence of antibodies to intrinsic factor is diagnostic of pernicious anaemia. Effects of B12 and Folate Deficiency Effects

B12 deficiency

Folate deficiency

Megaloblastic anaemia

Present

Present

Glossitis and cheilitis

Present

Present

Intestinal malabsorption

Present

Present

Neurologic complications

Present

Absent

Elevated serum homocysteine

Yes

Yes

Elevated serum methylmalonic acid

Yes

No

Management In B12 deficiency, hydroxocobalamin 1000 mg twice during the first week, then 1000 mg weekly for a further 6 doses. Bone marrow shows a striking change within 48 hours; within 2–3 days the reticulocyte count begins to rise (> 50% in 10 days); 1000 mg of cyanocobalamin per month for life-long should be given.   Rapid regeneration of the blood depletes the iron reserves of the body and hence ferrous sulphate 200 mg daily should be given soon after the commence­ ment of treatment and the picture will be dimorphic then.

zz

Ch-7.indd 488

In combined deficiency, folic acid replacement alone worsens B12 deficiency and hence it should not be given alone. zz In folate deficiency 5 mg of folic acid/day orally is given. 5 mg once a week is given as maintenance therapy.   Folate supplements 350 mg daily is given for all pregnant women. In methotrexate therapy, to over­ come the metabolic block, folinic acid 15 mg daily orally or as a IM/IV injection in a dose of 3 mg/mL are given. zz Treat the intercurrent infections (UTI or respi­ ratory infections). zz When Hb level is 900 pg/mL 8. Elevated neutrophil alkaline phosphatase score 9. Hyperuricaemia, pseudohyperkalaemia (due to release of potassium from platelets during in vitro coagulation).

Criteria for Diagnosis of Polycythaemia Vera Category A zz

zz zz

Total red cell mass: Male ≥ 36 mL/kg Female ≥ 32 mL/kg Arterial oxygen saturation ≥92% Splenomegaly.

Red cell mass can be normal in PV if there is massive splenomegaly or bleeding. Category B zz zz zz zz

Thrombocytosis (platelets >400 × 103/µL) Leukocytosis (white blood cells >12 × 103/µL) Increased leucocyte alkaline phosphatase (LAP) score Serum B12 >900 pg/mL or B12 binding capacity >2200 pg/mL.

PV is diagnosed when A1 + A2 + A3 or A1 + A2 and any 2 from category B are present. Over a period of time, these patients may progress to myelofibrosis or CML.

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Increased production of erythropoietin secondary to hypoxia —— High altitude —— Lung disorder —— Smoking —— Cyanotic congenital heart disease —— High affinity haemoglobins (Hb-M) —— Supine hypoventilation —— Carbon monoxide toxicity —— Sleep apnoea syndrome Inappropriate erythropoietin production: Tumours of kidney, liver, lung, uterus, and cerebellum. —— Renal cysts —— Hydronephrosis —— Hypernephroma —— Renal artery stenosis —— Renal transplantation —— Hepatoma —— Phaeochromocytoma —— Uterine fibromyoma —— Cerebellar haemangioblastoma —— Meningiomas —— Adrenal adenomas —— Bartter’s syndrome —— Androgen therapy —— Recombinant erythropoietin therapy.

Spurious or Low Plasma Volume Polycythaemia (Gaisbock Syndrome) This is due to reduced plasma volume. It often occurs with stress, hypertension, occlusive vascular disease. Erythropoietin Erythropoietin increase suggests hypoxia or autono­mous production of Epo as a cause for erythrocytosis. In PV, the Epo is normal or decreased but never increased. A normal Epo does not exclude hypoxia as a cause.

Management zz

Venesection (500 mL) of blood is removed in one sitting and it may be repeated within a day or two if necessary until hematocrit comes down to 50%. Iron removed in phlebotomy = Hematocrit/cc × volume of blood removed.

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Manual of Practical Medicine Chemotherapy with hydroxyurea is equally effec­tive. It is less leukaemogenic compared to radio­active phosphorus. zz Symptomatic thrombocytosis or splenomegaly can be treated with interferon alfa. zz Anagrelide—a quinazolin derivative and platelet anti-aggregant that also lowers platelet count and can also control thrombocytosis. zz Allopurinol may be given during chemotherapy to avoid hyperuricaemia. zz Intractable pruritus can be controlled with hydroxy­ urea or IFN-α or PUVA therapy. zz Allogenic bone marrow transplantation in young patients. Drug chemotherapy should be as short as possible to avoid leukaemic reaction. zz

Prognosis

zz

Clinical Features Thirty per cent of patients are asymptomatic; others present with GI bleed, arterial clotting, paraesthesias, erythromelal­gia (burning feet), vascular headaches. Splenomegaly is present in 75% and hepatomegaly is rare (20%). Some patients show Howel-Jolly bodies as an evidence of autosplenectomy.

Diagnostic Criteria zz zz zz

zz zz

Median lifespan in treated patients is more than 10 years. Acute leukaemia develops in those patients treated with radioactive phosphorus, chlorambucil. Overtime polycythaemia vera may progress to myelofibrosis or CML.

Essential Thrombocythaemia (Primary Thrombocytosis)

zz zz

zz zz zz zz zz

Causes of Thrombocytosis zz zz zz zz zz zz zz zz zz zz zz zz zz zz zz

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Iron deficiency anaemia Hyposplenism Post-splenectomy Malignancy Collagen vascular disease Inflammatory bowel disease Infections Haemolysis/haemorrhage Polycythaemia vera Idiopathic myelofibrosis Essential thrombocytosis Idiopathic sideroblastic anaemia Myelodysplasia (5q-syndrome) CML Post-surgery

Platelet count greater than 600,000/µL on two occasions. Palpable spleen (60–75% of cases). Haemoglobin and haematocrit in normal range (normal red cell mass: men 45 years Stage IV disease Hb 6 weeks duration and without abnormal clinical signs probably do not require investigations. zz Complete blood count including ESR is required to exclude temporal arteritis over the age of 50 years. zz X–ray —— Chest X–ray: To rule out bronchogenic carcinoma and pulmonary tuberculosis —— X-ray cervical spine: To rule out cervical spondylosis —— Skull X-ray „„ Reveal evidence of ICT „„ Midline shift (if the pineal gland is calcified) „„ Ca l c i f i cat i o n within the tumours (meningioma and craniopharyngioma) zz CT scan brain to localise tumours zz Lumbar puncture to rule out meningitis.

Treatment A. Treat possible underlying causes (sinusitis, trigeminal neuralgia, etc.) B. Migraine Triggers (Chocolate) —— Cheese

Ch-9C.indd 683



Focal neurological deficit (hemiparesis, aphasia)

Retinal haemorrhage

Oral-contraceptives Caffeine —— Alcohol —— Anxiety —— Travel —— Exercise. In 50% of cases, no trigger is found. ——

zz zz

Treat initiating factors (smoking, alcohol ingestion, lack of sleep, stress) Psychotherapy Avoid oral contraceptive pills Pharmacological treatment of acute migraine: —— NSAIDs—Acetaminophen, aspirin, caffeine —— 5 HT agonists Oral route: Ergotamine 2 mg (maximum 3 mg/day) Naratriptan 2.5 mg (repeat after 4 hours) Sumatriptan 50 to 100 mg (maximum 200 mg/day) Zolmitriptan 2.5 mg (maximum 10 mg/day) Almotriptan 6.25 to 12.5 mg PO every 2 hours (maximum 25 mg/day) Eletriptan 40 mg PO can be repeated in 2 hours (maximum 80 mg/day) Frovatriptan 2.5 mg PO every 2 hours (maximum 7.5 mg/day) Rizatriptan 5 to 10 mg PO every 2 hours (maximum 30 mg/day) Triptans should not be used in patients with coronary artery disease, cerebrovascular disease, uncontrolled hypertension, hemiplegic— migraine, or vertebrobasilar migraine. Triptans should not be taken within 24 hours of other triptans, isometheptene, or ergot derivatives. Ergotamine is a vasoconstrictive agent effective for aborting migraine headaches. Rectal preparations (2 mg) are better absorbed than oral agents. Dihydroergotamine (DHE) is a potent venoconstrictor with minimal peripheral arterial constriction. It should be used with caution in patients with CAD, PVD and elderly. Nasal route: Dihydro-ergotamine Sumatriptan Parenteral route: Dihydro-ergotamine 1 mg IV or IM or SC (maximum 3 mg/day) Sumatriptan 6 mg SC (maximum 2 doses)

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Manual of Practical Medicine ——

——

——

——

——

——

——

—— ——

——

Dopamine antagonists (adjuvant) Oral route: Metoclopropamide 5 to 10 mg/day Prochlorperazine 1 to 2 mg/day Parenteral route: Chlorpromazine 0.1 mg/kg IV Metoclopropamide 10 mg IV Prochlorperazine 10 mg IV Prophylactic treatment of migraine Propranolol 80 to 320 mg OD Timolol 20 to 60 mg OD Anticonvulsant Sodium valproate 250 mg BD Tricyclic antidepressants Amitriptyline 10 to 50 mg HS Nortriptyline 25 to 75 mg HS MAO inhibitors Phenelzine 15 mg TDS Serotinergic drugs Methylsergide 4 to 8 mg OD Cyproheptadine 4 to 10 mg OD Others Verapamil 80 to 480 mg OD Ketorolac tromethamine—30 to 60 mg IM or IV. Prochlorperazine 5 to 10 mg IV (caution— hypotension, dystonia) Opiate analgesics meperidine 50 mg or methadone 10 mg or fentanyl 0.1 mg or hydromorphone 2 mg IM or IV.

Abortive Therapy Ergotamine (3 mg orally), sumatriptan (100 mg orally or 6 mg subcutaneously).

zz

zz

D. Tension headache Aspirin 0.6 gm or acetaminophen 0.6 gm every 4 to 6 hours. E. Lumbar puncture headache Intravenous caffeine sodium benzoate given over a few minutes as a 500 mg dose will terminate headache in 75% of patients. A second dose relieves headache in another 10% of patients. If it fails, an epidural blood patch accomplished by injection of 15 ml homologous whole blood relieves headache in the rest (sealing of dural hole with blood clot). The effective strategies in reducing the incidence of post-LP headache are—to use small diameter (22-gauge or smaller), atraumatic needle and replace the stylet prior to removal of needle. Insert the LP needle with bevel oriented in cephalo-caudal direction. F. Giant cell arteritis Prednisone in a dose of 1 mg per kg body weight daily for first 4 to 6 weeks and tapered gradually.

Benign Intracranial Hypertension The patient presents with signs of increased intracranial hypertension. It mainly affects young woman. Causes zz

Prevention β blockers (60–240 mg), tricyclic antidepressants (amitriptyline—30–100 mg), anticonvulsants (valproate—500–2000 mg), verapamil (120–180 mg), phenelzine (45–90 mg), and methysergide (4–12 mg) are tried.

zz

zz

C. Cluster headache Prophylaxis It is given by prednisone, lithium, methysergide, ergotamine and verapamil. For chronic form, lithium 600 to 900 mg daily has been tried. Treatment zz

Ch-9C.indd 684

Oxygen inhalation for 15 minutes (9 L/min) is most effective during attacks.

Intranasal lidocaine to the most cadual aspect of inferior nasal turbinate can cause sphenopalatine ganglionic block which can terminate an attack. Sumatriptan 6 mg subcutaneously shortens an attack to 10 to 15 minutes.

zz

Obesity Endocrine causes: —— Cushing’s disease —— Hypoparathyroidism —— Amenorrhoea Drugs —— Oral contraceptives —— Excess vitamin A —— Nitrofurantoin —— Tetracycline —— Steroid withdrawal Severe anaemia.

Clinical Features zz zz zz zz

Headache and vomiting Significant papilledema VIth nerve palsy (false localising sign) Enlargement of blind spot.

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Nervous System Investigations zz

zz

zz

CT and MRI—small ventricles, no midline shift, no mass lesion Lumbar puncture—raised CSF pressure, CSF biochemistry normal.

Management zz

zz zz

Acetazolamide and diuretics to decrease the formation of CSF Regular LP to reduce the CSF pressure If vision is threatened, surgical decompression of optic nerves.

Classification Extramedullary (80%) —— Extradural (20%)—chordoma, sarcoma —— Intradural (60%)—meningiomas, neurofibromas Intramedullary (20%)—gliomas, ependymomas.

zz

zz zz zz zz

It arises from arachnoid covering of the roots or the cord. Almost always it lies in the dorsal region. It occurs more often in females than males. It accounts for 20% of brain tumours.

Clinical Features

Neurofibroma (NF) zz

Meningioma

It accounts for 2% of deaths; 50% of tumours are primary and remaining 50% brain tumours are metastases from other sites. Tumours of cerebral hemisphere are common in adult and of the brainstem in childhood. The most common primary tumours causing brain metastases are: lung (40%), breast (20%) and prostate (10%); leptomeningeal metastases are from CA breast (60 %), CA lung (20%) and lymphoma and melanoma (each 10%); epidural spinal cord metastases are from CA lung in case of males (20%) and in females from breast (15%) and from lymphoma and prostate (each 10%).

Spinal Cord Tumours (Excluding Secondaries)

zz

zz

Cerebral Tumours

NEOPLASTIC DISEASE OF THE CENTRAL NERVOUS SYSTEM

zz

zz

It rarely grows out through the intervertebral foramen, forming a dumb-bell shaped tumour and is palpable in the extraspinal portion. It develops at any level of the spinal canal and occurs equally in both sexes. It can also affect VIIIth cranial nerve (acoustic neuroma) in which papilloedema occurs late.

Neurofibroma usually arises from spinal roots (posterior more frequently than the anterior). It may be single or multiple.

zz

Signs of intracranial tension (headache, projectile vomiting, bradycardia, arterial hypertension and papilloedema).

Classification Types of the tumour

Common site

Age of occurrence

Incidence out of 50%

*1.

Meningioma

Cortical dural, parasagittal sphenoid ridge, suprasellar olfactory groove

Adults

20

 2.

Neurofibroma

Acoustic neuroma

Adult

1

 3.

Craniopharyngioma

Suprasellar

Childhood/adolescence

1

 4.

Pituitary adenoma

Pituitary fossa

Adult

2

*5.

Glioma (astrocytoma)

Cerebral hemisphere Cerebellum Brainstem

Adult Childhood/adult Adult/childhood

Benign

Malignant

 6.

Oligodendroglioma

Cerebral hemisphere

Adult

 7.

Medulloblastoma

Posterior fossa

Childhood

*8.

Ependymoma

Posterior fossa

Childhood/adolescence

10 1 5 10

Tumors of cerebral hemispheres are uncommon in child­hood. *Common tumours

Ch-9C.indd 685

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Manual of Practical Medicine zz

zz

zz

zz

Focal neurological deficit (depends upon involvement of anatomic site of the tumour). False localising signs. —— Unilateral/bilateral VI nerve involvement due to compression of the nerve trunks as they cross the apex of petrous part of temporal bone. —— Bilateral extensor plantar or grasp reflexes (due to ventricular dilatation in hydrocephalus). —— Unilateral III nerve palsy or facial pain/sensory loss (trigeminal neuralgia due to compression of gasserian ganglion as a result of tentorial herniation). —— Ipsilateral extensor plantar response due to compression of opposite cerebral peduncle against free tentorial edge in tentorial herniation (Kernohan’s sign). —— Cerebellar dysfunction resulting from a massive frontal lesion due to downward displacement of brainstem. —— Bilateral, fixed dilated pupils and defects of upward conjugate gaze due to central cerebellar lesion displacing the midbrain upwards. Focal/generalised seizures: The occurrence of seizures depends upon the area of the cortex involved. The development of focal motor or sensory seizures in adult may suggest the possibility of a tumour. Altered sensorium: It ranges from drowsiness to coma; it is also related to the level of intracranial pressure.

Fig. 9.116  CT brain—posterior fossa SOL with ring enhancement and hydrocephalus

Investigations zz

zz

zz

zz

zz

Ch-9C.indd 686

CT scan: It is a definite investigation for localisation and detection of cerebral tumours (Figs 9.116 to 9.120). Plain X-ray of the skull: It has the least diagnostic value with the exception of the pituitary tumours and calcified neoplasms (oligodendroglioma, craniopharyngioma and meningiomas). Chest X-ray: It is an important investigation and provides evidence of primary malignancy or metastases in the lung. Cerebral angiography: It is useful in identifying malignant tumours (presence of angiographic ‘blush’). It also helps in assessing the vascularity to aid in further management either by embolisation or by surgical means. MRI: Procedure of choice in evaluating neurologic dysfunction in patients with brain tumours. It deli­ neates metastatic and primary tumours of nervous system. Lesions of skull base, brainstem, cerebellum and spinal cord are well delineated. Flow void MRI images provide tumour vascularity and hence may obviate the need for preoperative angiography.

Fig. 9.117  CT brain—solitary metastasis

Fig. 9.118  CT brain with contrast—solitary metastasis shows enhancement

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Nervous System Management zz zz

zz

Fig. 9.119  CT brain—left parasagittal meningioma

Fig. 9.120  MRI–contrast–ring enhancing lesion



Haemorrhage in tumours (lipoma, epidermoid tumours, craniopharyngioma) and fat containing tumours are better recognised by MRI.

Surgical treatment is the only definite treatment. Medical management is useful for reducing the cerebral oedema. —— Dexamethasone 8 mg qid (or) methyl prednisolone 50 mg qid. —— Anticonvulsants (to control seizures). —— Bromocryptine for prolactinoma and growth hormone secreting tumours. Radiotherapy: Tumours sensitive are secondaries, glioblastoma, medulloblastoma, nasopharyngeal carcinoma, cerebellar astrocytoma, haemangio­ blastoma and pontine glioma. Shifts and Herniations in CNS

There are three types of herniations (Fig. 9.121). Type and contents

Effect—consequences

1.

Subfalcine (Cingulate) herniation: Part of one cerebral hemisphere is shifted under the falx towards the opposite side

Altered conscious level—focal signs may be absent—silent unless the anterior cerebral artery is compressed resulting in contralateral leg weakness with or without abulia

2.

Transtentorial (Uncal) herniation: Medial temporal structure pass through the tentorium and press upon the oculomotor nerve

Most common type—decreased level of consciousness—dilated pupil—ophthalmoplegia— Kernohan’s notch-herniated midbrain compresses the cerebral peduncle of the opposite side causing ipsilateral hemiparesis (hemiparesis contralateral to the original hemiparesis)

3.

Foramen magnum (Cerebellar tonsil) herniation: Increased pressure in the posterior fossa—cerebellar herniation

Severe occipital and neck pain with neck stiffness—head retraction, ataxia, VIth nerve palsies, loss of consciousness, irregular breathing, apnoea and positive Babinski’s sign

Ring Enhancing Lesion – Differential Diagnosis zz zz zz zz zz zz

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Brain abscess Tuberculoma Primary brain tumour Metastatic lesions Neurocysticercosis Toxoplasmosis.

Fig. 9.121  Types of brain herniations

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MOVEMENT DISORDERS

Spectrum of Parkinsonism

Depending on the amplitude, abnormal movements can be described as: zz Hyperkinesia (increased amplitude) zz Hypokinesia (decreased amplitude) zz Akinesia (total loss of movement).

Parkinson’s Disease

Atypical Parkinsonism

Secondary Parkinsonism

Genetic Sporadic Dementia with Lewy bodies

Multiple-system atrophy (MSA) Cerebellar type (MSA-C) Parkinson type (MSA-p) Progressive supranuclear palsy Corticobasal ganglionic degeneration Frontotemporal dementia

Drug induced tumour Vascular infection Trauma Liver failure Normal pressure hydrocephalus Toxins – CO, MPTP, cyanide, methanol, carbondisulfide, manganese, hexane

Classification Hypokinesia

Hyperkinesia

Miscellaneous

Characterised by poverty and slowness of movement, e.g. Parkinsonism

Characterised by abnormal involuntary movements, tremor, dystonia, chorea, athetosis, ballism, tics, myoclonus, stereotype movements, akathesia, restless legs, paroxysmal dyskinesia

Ataxic gait disorders, hyper-reflexia, hemifacial spasm, myokymia, stiffman syndrome, psychogenic

Parkinson’s Disease It is a movement disorder of unknown aetiology due to degeneration of the neurons in the nigrostriatal dopaminergic system (Fig. 9.122). There is an imbalance between dopamine and acetylcholine neurotransmitters (either an increase in acetylcholine or a decrease in dopamine level).

Clinical Features A. Motor General —— Expressionless face with staring look with infrequent blinking —— Greasy skin —— Soft, rapid, indistinct monotonous speech —— Flexed posture (universal flexion). zz Gait —— Patients walk with short steps, with a tendency to run (as though they catch their own centre of gravity) —— Slow to start walking —— Shortened stride —— Rapid small steps, tendency to run (festination) —— Reduced arm swinging zz

Fig. 9.122  Extrapyramidal system

Ch-9C.indd 688

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Nervous System Impaired balance on turning —— Propulsion and retropulsion and lateropulsion —— Kinesia paradox (patients can run fast during emergency). Tremor Resting tremor (4–6 Hertz) —— Usually first in fingers/thumb —— Coarse, complex movements, flexion/extension of fingers (pill rolling and drum-beating movements) —— Abduction/adduction of thumb —— Supination/pronation of forearm —— May affect arms, legs, feet, jaw, tongue —— Intermittent, present at rest and when distracted —— Diminishes on action and disappears during sleep. Rigidity —— It is seen predominantly in the limbs —— Cogwheel type, mostly appreciated in upper limbs especially in wrist joints (there is a phasic element to stiffness in all directions of movement) —— Plastic (lead pipe) type, mostly appreciated in the legs and trunk —— In the trunk, rigidity manifests itself by the presence of a flexed, and stooped posture. Hypokinesis —— Slowness in initiating movements —— Impaired fine movements, especially of fingers —— Poor precision of repetitive movements —— Handwriting—micrographia. ——

zz

zz

zz

zz zz zz zz zz

Difference between Idiopathic and Post-encephalitic Parkinsonism Features 1. Age 2. Mode of onset 3. Past history

——

—— ——

Neuropsychiatric symptoms—anxiety, depression, psychosis, dementia, impulse control disorder Autonomic failure Sensory symptoms.

Staging

4. Mainly tremor

6. Cranial nerves 7. Type of rigidity 8. Reflexes

6. Normal 7. Cogwheel 8. Normal

9. Autonomic features

9. None

10. L-dopa therapy 11. Lewy body

10. Good response 11. Present

zz

Unilateral involvement

Grade II

Bilateral involvement

Grade III

Bilateral with mild postural imbalance

Treatment

Grade IV

Bilateral with moderate postural imbalance and requires assistance

zz

zz zz zz

Ch-9C.indd 689

Decreased blink rate Hypometric saccades Impaired smooth pursuit

5. Normal 5. Impaired – mentally dull 6. Oculogyric crisis 7. Lead pipe 8. Brisk with extensor plantar 9. Sialorrhoea, flushing, hypotension 10. Poor response 11. Absent

Indications —— Patients under age 50 —— Signs entirely unilateral —— Atypical signs (e.g. pyramidal). zz Tests to exclude Wilson’s disease (in young patients (2nd to 4th decade) —— Serum ceruloplasmin —— Serum copper —— Urine copper —— Liver function tests. zz MRI brain (Figs 9.124 and 9.125).

Grade I

Eye Signs in Parkinsonism

2. Sudden 3. History of encephalitis 4. Mainly rigidity

Serological tests for syphilis (all patients) CT brain (Fig. 9.123)

Clinical features

Bedridden

Post-encephalitic 1. Relatively younger

Investigations

Grading

Grade V

Idiopathic 1. Late middle age or elderly 2. Insidious 3. Nil particular

4. Presenting complaint 5. Higher function

zz

B. Non-motor

Reflex blepharospasm (glabellar, Myerson’s sign) Blepharoclonus Spontaneous blepharospasm Oculogyric crises (postencephalitic parkinsonism) Reversed Argyll Robertson pupil (postencephalitic parkinsonism).

Treat the underlying disease Withdraw the drugs in drug-induced parkinsonism zz Drug therapy. I. Drugs —— Dopamine agonists —— Carbidopa/levodopa —— MAO-A inhibitors —— MAO-B inhibitors —— COMT inhibitors zz

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Manual of Practical Medicine Causes of Parkinsonism Mechanism Impaired release of dopamine Drugs depleting dopamine stores Toxins damaging dopaminergic neurones Viral infection Trauma Blockade of striatal dopamine receptors Damage to striatal neurones Miscellaneous

Example Idiopathic Parkinson’s disease Reserpine, tetrabenazine Methyl-phenyl-tetrahydropyridine (MPTP), manganese Encephalitis lethargica Japanese ‘B’ encephalitis Repeated head injury (punch drunk syndrome) Phenothiazines Butyrophenones Viral infection Multisystem atrophy Wilson’s disease Huntington’s disease Cerebral tumour Neurosyphilis

Fig. 9.125  Parkinsonism—smudging of pars compacta of substantia nigra between low signals of red nucleus and pars reticularis

Amantadine Anticholinergics II. Neuroprotective agents —— L-carnitine —— Co-Q —— Creatine monohydrate —— Dopamine agonists —— Seligiline III. Surgery —— Deep brain stimulation —— Substantia nigra ablation IV. Neurotransplantation —— Stem cell —— GDNF infusion (Glial cell derived neurotrophic factor) Non-motor symptoms: zz Anti-depressants—Tricyclic anti-depressants, SSRI zz Dementia—Donepezil, Rivantigmine zz Psychosis—Atypical antipsychotics Principles of drug therapy zz Avoid anticholinergics in old age (to avoid urinary retention and glaucoma) zz Selegiline and bromocriptine can be used in all ages zz Avoid early use of L-dopa zz Avoid intake of vitamin B along with L-dopa 6 zz Neuroprotective therapies. Neuroprotectives halt or delay the nigrostriatal degeneration. Neurorestorative therapies not only halt, but restore normal or near normal function in surviving neurons. —— Monoamine oxidase inhibitors: Selegiline blocks oxidative enzyme MAO-B, it induces secretion of neurotropic factors, increase formation of oxidative enzyme superoxidases dismutase, alter —— ——

Fig. 9.123  CT brain—basal ganglia calcification in hypoparathyroidism—causing parkinsonism

Fig. 9.124  MRI normal—Pars compacta and reticularis with red nucleus

Ch-9C.indd 690

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Nervous System glutamate receptor activity, and blocks apoptosis. Rasageline is a newer selective MAO-B inhibitor. —— Free radical scavengers: Vitamin E is a free radical scavenger which is tried. —— Neurotropic factor: Glial derived neurotropic factor can protect and rescue nigral neurons. —— Neuroimmunophilin: Immunophilins are proteins that serve as receptors to immunosuppressant drugs. Immunophilin ligands has been found to stimulate neurite growth —— Glutamate antagonist: Remacimide. Surgery—stereotactic thalamotomy and palidotomy. Supportive therapy (physiotherapy and speech therapy).

zz zz

Parkinsonism Plus Syndromes It refers to disorders in which the classical signs of parkinsonism are combined with other signs of neurological dysfunction, particularly autonomic, cerebellar, oculomotor or cortical. zz Progressive supranuclear palsy zz Multiple system atrophy —— Multisystem atrophy subtypes —— MSA-P (parkinsonism) —— MSA-C (cerebellar) zz Corticobasal degeneration

ALS/PD/dementia complex of Guam Alzheimer’s disease zz Pick’s disease zz Diffuse Lewy body disease. Parkinsonism plus sydromes may be suspected if there is: zz Prominent akinesia and rigidity without tremor at onset zz Rapid progression zz Development of neurologic signs indicating disease outside the basal ganglia. zz zz

Difference between Typical and Atypical Parkinsonism Typical Parkinsonism

Atypical Parkinsonism (Parkinson plus syndrome)

Late speech and gait impairment Presence of resting tremor Motor asymmetry Presence of Lewy body Good response to levodopa

Early speech and gait impairment Absence of resting tremor No motor asymmetry Absence of Lewy body Poor or no response to levodopa

Multisystem Atrophy Common name

Clinical features Early

Late

MSA with autonomic failure

Dysautonomia

Parkinsonism Cerebellar signs Motor neuron disease signs with amyotrophy and corticospinal signs Ocular palsies Dementia

MSA-C

Cerebellar dysfunction plus

Dysautonomia Corticospinal Parkinsonism signs

MSA-P

Parkinsonism

Dysautonomia Cerebellar signs

Treatment of Parkinsonism Stage

Features

Drugs

Early (stage I and II)

Tremor Rigidity

Under age 65 Anticholinergics Amantidine Over age 65 Avoid anticholinergics Amantidine All ages Deprenyl 5 mg bd (selegiline) (MAO–B inhibitor)

Moderate (Stage III)

Tremor Rigidity Hypokinesias

a.  *L–DOPA combinations b. Anticholinergics C. In younger patients consider low dose bromocriptine + L–DOPA combinations. Frequent small doses of L–DOPA combination are preferred.

Severe (Stage IV)

Tremor Rigidity Hypokinesias Dyskinesias Fluctuations

Frequent small doses of L–DOPA combination (1.5–3 hourly) ± selegiline 10 mg/d ± low dose bromocriptine 15–30 mg/d

* Carbidopa can be combined to prevent peripheral degradation of L–Dopa in the ratio of 1 : 4 or 1 : 10.

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MOTOR NEURON DISEASE Motor neuron disease is a disease of motor neurons and refers to progressive involvement of upper or lower motor neurons, without sensory system involvement. It is a disease of unknown origin which leads to degeneration of Betz cells, pyramidal fibres, cranial motor nerve nuclei and anterior horn cells.

Genetic Classification zz

Upper and lower motor neurons (familial ALS) —— Autosomal dominant —— Autosomal recessive (juvenile) —— Mitochondrial

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Manual of Practical Medicine Pathogenesis of ALS-MND Genetic

Familial ALS mapped to chromosome 21 (positive in 20% of families) Positive only in 1% of sporadic cases

Glutamate

Excitatory neurotransmitter that facilitates calcium entry into the neuronal cells inducing cell death. Glutamate antagonist Riluzole has only shown doubtful benefit.

Autoimmune

i. Possible higher instance of monoclonal paraprotein and lympho-proliferative disease ii. Association with anti-GM1 antibodies iii. Possible anti-calcium channel antibodies

Free radical accumulation

Trial with free radical scavenger, N-acetylcysteine, showed no significant benefit

Neurotrophic growth factors

No evidence of depletion of growth factors in ALS. Administration of neurotrophic factors may rescue nerve cells. BDNF and ILGF studies nearing completion.

Environmental factors

Cycas circinalis (Guamanian ALS phenotype) High iron levels

zz

zz

zz

Upper motor neurons —— Familial spastic paraplegia (FSP) „„ Autosomal dominant „„ Autosomal recessive „„ X-linked —— Adrenomyeloneuropathy Lower motor neurons —— Spinal muscular atrophies „„ Infantile: Werdnig-Hoffman disease „„ Childhood „„ Adolescent: Kugelberg-Welander disease —— X-linked spinobulbar muscular atrophy —— G M2 gangliosidosis „„ Adult Tay-Sach’s disease „„ Sandhoff disease „„ AB variant ALS-plus syndromes —— ALS with frontotemporal dementia —— Amyotrophy with behavioural disorder and parkinsonian features.

zz zz

zz

zz

zz

Differential Diagnosis zz

zz

zz

Amyotrophic Lateral Sclerosis It is the most common form of motor neuron disease. It occurs mostly as a sporadic form (90–95%) and rarely familial (autosomal dominant 5–10%).

Clinical Features zz

zz

zz

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It often starts unilaterally, later involves contralateral side, often symmetrically in a matter of a few weeks to months. There is progressive muscle wasting which usually begins in the small muscles of hand (first thenar group of muscles and then forearm muscles). It usually presents with UMN signs (spasticity, ↑ DTR and Babinski in the lower limbs) and LMN signs (fasciculation, wasting, weakness) in the upper limbs.

Foot and wrist drop may occur. The characteristic feature is the recent onset of cramping with volitional movement in the early morning (during stretching in bed). Ultimum moriens (serratus anterior, lower fibres of latissimus dorsi, upper fibres of trapezius and triceps are spared or involved very late). The ocular muscles and sphincters of the bowel and bladder are characteristically spared. The cause of death in motor neuron disease is respiratory paralysis.

zz zz

Compressive myelopathy at cervicomedullary junction or spinal cord especially at cervical region (root pains, segmental sensory loss are against the diagnosis of MND) Syringomyelia (dissociated sensory loss is against the diagnosis of MND) Subacute combined degeneration (posterior column and lateral column involvement) Chronic lead poisoning (only LMN signs) Poliomyelitis (flaccidity; no UMN signs).

Poor Prognostic Factors zz zz zz

Respiratory muscle involvement Increased CSF proteins Autonomic dysfunction.

Progressive Muscular Atrophy (Predominant LMN Involvement) zz

zz

It contributes to 10% of the cases of motor neuron disease. The male : female ratio is 5 : 1.

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Nervous System Clinical Classifications Disease

Features

Incidence (%)

1.

Amyotrophic lateral sclerosis (ALS)

UMN and LMN signs (pyramidal tracts and anterior horn cells)

50

5

2.

Progressive muscular atrophy (PMA)

LMN signs (anterior horn cells)

10

10

3.

Primary lateral sclerosis (PLS)

UMN signs (pyramidal tract)

5

3

4.

Progressive bulbar palsy (PBP)

LMN signs (cranial nerve nuclei)

25

2

5.

Pseudobulbar palsy

UMN signs (corticobulbar fibres)

10

2

zz

zz zz

It presents with diffuse wasting and weakness of hand muscles and gradually progresses to involve proximal part of limbs. Deep tendon reflex is diminished or absent. This has best prognosis of all motor neuron diseases.

Progressive Bulbar Palsy It comprises 20 to 30% of ALS, and may have initial bulbar symptoms (unilaterally or bilaterally). Other Causes of Bulbar Palsy Disease

Test

Motor neurone disease

ENMG

Thyrotoxicosis

FT4 and TSH

Polymyositis

CK and biopsy

Myasthenia gravis

Anti-Ach AB, Tensilon, ENMG

Exclude pseudobulbar palsy by MRI and Local obstruction by ENT exam and endoscopy

zz

Clinical Features Brisk DTR including jaw jerk and snout reflex and gag reflex zz Emotional instability zz Dysarthria and dysphagia zz Small spastic tongue. The dysarthria may ultimately lead on to mutism. zz

Other Causes of Pseudobulbar Palsy zz zz zz zz

zz

zz

zz

zz

Orbicularis oris muscle is the first muscle to be affected. Other muscles affected are muscles of the jaw, other facial muscles, tongue, pharyngeal and laryngeal muscles. Wasting and fibrillations of tongue, dysarthria and dysphagia and loss of palatal and gag reflexes are seen. Patient dies within 6 months to 2��₂ years due to respiratory infections, general weakness and debility.

Primary Lateral Sclerosis (Predominant UMN Involvement) zz

zz

zz zz

This is usually insidious in onset beginning with spastic paraparesis of the lower limbs. The age of onset is > 5th decade and there is no family history. It has a gradually progressive course. It is symmetrical in distribution.

Clinical features are limited to those with corticospinal dysfunction.

Pseudobulbar Palsy (UMN Fibres Corticobulbar Tracts) of Cranial Nerves

Clinical Features

Ch-9C.indd 693

Prognosis (years)

Multiple sclerosis Double hemiplegia at or above the internal capsule Multiple cerebral embolism (multiple infarctions) Diffuse atherosclerosis (cerebral atrophy).

Variants of Motor Neuron Disease 1. Madras Motor Neuron Disease The salient features are: The age of onset is between 10 to 30 years. zz It has male preponderance (2 : 1). zz It accounts for 10% of motor neuron disease in South India. zz There is gradual asymmetric involvement of limbs in > 50% cases, with the slowly progressive involvement of all four limbs over many years finally manifesting as a classical amyotrophic lateral sclerosis. zz There is a weakness of facial and bulbar muscles (in 60–70%). zz Sensorineural deafness is frequent (30%). zz There is decreased serum citrate and increased serum pyruvate levels. zz The patient may present with an abnormal glucose tolerance test. zz Longevity is prolonged. zz

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2.  Monomelic Amyotrophy (MMA) The clinical features are: Slow/nonprogressive wasting and weakness confined to one limb, usually in the upper limb. zz It is seen all over India and age of onset is between 15 and 25 years. zz It has male preponderance. zz The characteristic pattern of muscle wasting is seen in the upper limb muscles (commonest forearm flexors, followed by small hand muscles, arm muscles biceps/ triceps). zz The brachioradialis muscle is spared. zz

3.  The Wasted Leg Syndrome (WLS) (LMN Signs in Lower Limb) zz

zz

zz

It is a nonprogressive unilateral wasting disease of leg muscles. The characteristic features are gross wasting of lower limb muscles mainly posterior crural (calf muscle) followed by anterior crural and quadriceps. DTR are preserved.

5. Guamin ALS (Locally Called ‘Lytico’) zz zz zz zz

6.  Crural ALS (UMN and LMN in Lower Limb) It predominantly involves lower limbs.

7.  Hemiplegic Type (Mills Variant) It predominantly involves upper and lower limbs on the same side of the body.

8.  MND with Dementia The dementia is found in 5 to 10% of sporadic cases and 10 to 15% of familial cases.

9.  MND with Parkinsonism zz

4.  Juvenile MND of North India zz

zz

It is a nonfamilial disorder and the age of onset is between 10 and 30 years. Types —— Group I involves distal muscles of extremities „„ Slow progression „„ No cranial nerve involvement —— Group II resembles classical ALS „„ More rapid progression.

zz

zz

Differentiation between Bulbar and Pseudo-bulbar palsy

Ch-9C.indd 694

Pseudo-bulbar palsy

Type of lesion

LMN—from motor brain stem nuclei (V to XII)

UMN—bilateral corticobulbar lesions

Speech

Monotonous, nasal

Spastic dysarthria

Facial muscles

Lip and facial muscles are weak

Stiff spastic facial muscles

Chewing

Saliva pools and dribbles, occasionally nasal regurgitation

Chewing trouble, food may stay in mouth or spill over and may choke

Gag reflex

Depressed

Brisk

Tongue

Atrophy with fasciculations

Small and spastic

Emotion

No emotional incontinence

Emotional incontinence

It usually follows post encephalitic Parkinsonism. Parkinsonism can precede MND by months to decades. It runs a more benign course.

Secondary Causes of Motor Neuron Disease (Differential Diagnosis for MND)

zz

Bulbar palsy

The age of onset is between 10 and 30 years. It has a more marked UMN signs. Positive family history is present in 50% cases. It has a high incidence of associated parkinsonism dementia (PD) complex.

zz

zz

zz zz

Structural lesions —— Parasagittal or foramen magnum tumours —— Cervical spondylosis —— Syringomyelia —— Spinal cord AVM Infections —— Bacteria—tetanus, Lyme’s disease —— Viral—poliomyelitis, herpes-zoster Physical agents —— Toxins (lead, aluminium and other metals) —— Drugs (strychnine, phenytoin) —— Electric shock —— Irradiation Immunologic —— Autoimmune —— Polyradiculoneuropathy Paraneoplastic syndrome Metabolic —— Hypoglycaemia —— Hyperparathyroidism —— Hyperthyroidism —— Deficiency of folate, vitamin B 12 and vitamin E

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Nervous System zz

Hereditary biochemical disorders —— Hexosaminidase deficiency —— Superoxide dismutase deficiency —— Hyperlipidaemia.

Investigations zz

zz

zz

zz

Electrophysiological studies —— Fibrillation potentials —— Positive sharp waves —— Increased amplitude —— Increased duration of motor unit action potentials (in addition to fibrillations and fasciculations—polyphasic potentials) —— The electrophysiological dysfunction present in > 2 extremities is diagnostic of amyotrophic lateral sclerosis CSF in MND —— Cytology is normal —— Protein is increased in 20 to 30% of patients with ALS Serum CK levels: There is a mild to moderate rise occurring in 35 to 100% cases, secondary to muscle wasting. Cranial MRI in MND: Gyral atrophy, decrease in precentral gyrus width and increase in central sulcus width are seen in ALS.

Spinal muscular atrophies are a group of familial disorders associated with selective lower motor neuron involvement, with early age of onset of symptoms.

Investigations zz

zz

Creatine kinase is moderately increased only in chronic, slowly progressive forms of SMA. Electrophysiological studies —— Motor nerve conduction velocity is slow —— Sensory conduction studies are normal in all forms of SMA except type I in which sensory conduction is slowed and reduced in amplitude.

Management zz zz zz

There is no specific therapy for this disorder. Physiotherapy Genetic counselling.

ATAXIC DISORDERS (CEREBELLAR AND SPINOCEREBELLAR) Ataxia may be hereditary or acquired.

Hereditary Ataxia

Treatment There is no specific treatment zz Symptomatic treatment (supportive care and speech therapy). zz Treatment of secondary causes of motor neuron disease. zz However, insulin like growth factors, ciliary neurotrophic factors, thyroid releasing hormone are used to improve the muscle strength (they are under trial). zz Riluzole. Treatment of ALS Complications

Ch-9C.indd 695

Spinal Muscular Atrophy (SMA)

Hereditary ataxic disorder can be divided into four groups: Congenital zz Metabolic zz Unknown aetiology of early onset zz Unknown aetiology of late onset. zz

Differentiation between SMA and Motor Neuron Disease (Progressive Muscular Atrophy) Features

SMA

Progressive muscular atrophy

1.

Family history

Present

Absent

2.

Age of onset

2 to 20 years

Above 40 years

Dysphagia

Percutaneous gastrostomy, advice of dietician and speech therapist

3.

Symmetrical

Assess vital capacity—treat chest infection— continuous positive airway pressure especially at night

Pattern of involvement

Asymmetrical

Ventilation failure

4.

Bulbar muscle involvement

Not commonly

Usually involved

Dysarthria

Speech therapist and communication aids

5.

Anticholinergics or Amitryptyline

Deep tendon reflexes

Lost

Excessive salivation

Decreased (or) absent

Spasticity

Baclofen—Dantrolene–Benzodiazepine

6.

Progression

Slow

Rapid

Constipation

Increasing fluid intake

7.

Prognosis

Better

Worse

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I.  CONGENITAL ATAXIAS

Congenital Ataxia of Known Aetiology

Congenital Disorders of Unknown Aetiology

zz

zz

zz

zz

zz

zz

zz

Congenital ataxia with episodic hyperpnoea, abnormal eye movements and mental retardation (Joubert’s syndrome) Congenital ataxia with mental retardation and spasticity (includes pontoneocerebellar hypoplasia) Congenital ataxia ± mental retardation (includes granule cell hypoplasia) Congenital ataxia with mental retardation and partial aniridia (Gillespie syndrome) Dysequilibrium syndrome (mental retardation, autosomal recessive disorder, motor delay) X-linked recessive ataxia with spasticity and mental retardation (Paine syndrome).

It is due to: Cerebellar vermis or hemispherical degeneration zz Dysgenesis or agenesis of cerebellum zz Arnold-Chiari malformation zz Dandy-Walker syndrome. Common Symptoms of Congenital Ataxia zz Retarded motor development zz Hypotonia zz In coordination on reaching out for objects zz Nystagmus zz Truncal ataxia on sitting zz Often improves with age zz Fifty per cent AR inheritance zz Autopsy reveals pontoneocerebellar or granule cell hypoplasia.

Types of SMA Type

Onset

Inheritance

Clinical features

Type I (Werdnig-Hoffman)

Infancy

Autosomal recessive

Severe muscle wasting and weakness with associated hypotonia

Type II (Werdnig-Hoffman)

Childhood

Autosomal recessive

Slowly progressive form of SMA

Type III (Kugelberg-Welander)

Childhood and adolescence

Autosomal recessive

Proximal muscle wasting and weakness. Gradually progressive form of SMA

Distal form

Early adult life

Autosomal dominant

Distal weakness with wasting of small muscles of the hands and feet

Bulbospinal

Adult life. Affects males only

X-linked

Facial and bulbar weakness associated with proximal limb weakness

Differentiation between Primary Muscle Disease and SMA

Ch-9C.indd 696

Features

Myopathy

SMA

1.

Genetic

Familial

Familial

2.

Muscle bulk and power

Power grossly lost despite good bulk of muscle

Preservation of muscle power despite presence of gross muscle wasting

3.

Distribution of wasting

Always symmetrical and selective

Usually asymmetrical and sometimes symmetrical

4.

Group of muscles involved

Proximal group of muscles (except in myotonic distrophy and distal myopathy)

Proximal as well as distal group of muscles

5.

Predeliction of muscle involvement

Biceps, brachioradialis, serratus anterior, pectorals, supra and infraspinatus, quadriceps

Hamstring muscles

6.

Muscle hypertrophy

Common

Rare

7.

Deep tendon reflexes

Normal or sluggish

Absent

8.

Fasciculation

Absent

May be present

9.

Other system involvement

Bone and heart

Nil

10.

Contracture

May be present

Absent

11.

Enzymes (creatine kinase)

Markedly elevated

Mild elevation may be present in chronic cases

12.

EMG

Myopathic

Neurogenic

13.

Muscle biopsy

Evidence of muscle dystrophy

Evidence of muscle atrophy

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Nervous System Aetiology of Cerebellar Ataxia Symmetric and progressive signs Acute—hours to days

Subacute—days to weeks

Chronic—months to years

Intoxication:

Alcoholic

Hypothyroidism

Alcohol, lithium,

Nutritional deficiency

Phenytoin toxicity

phenytoin, barbiturates

(Vitamin B1 and B12)

Paraneoplastic syndrome

Acute viral cerebellitis

Cytotoxic drugs, Mercury,

Tertiary syphilis (Tabes-dorsalis)

Postinfection syndrome

Gasoline, Solvents, Glue, Lyme disease

Inherited diseases

Acute—hours to days

Subacute—days to weeks

Chronic—months to years

Vascular—Cerebellar infarction, haemorrhage, subdural haematoma, cerebellar abscess

Multiple sclerosis, AIDS—(Multifocal leukoencephalopathy) Cerebellar glioma/metastasis

Congenital lesion: Chiari or Dandy-Walker malformations Gliosis secondary to vascular lesion or demyelination

Focal and ipsilateral cerebellar signs

II. ATAXIC DISORDERS WITH KNOWN METABOLIC OR OTHER CAUSES A.  Metabolic Disorders 1.  Intermittent Ataxic Syndromes With hyperammonaemia Ornithine transcarbamoylase deficiency Arginosuccinate synthetase deficiency (citrullinaemia) Arginosuccinase deficiency (arginosuccinicaciduria) Arginase deficiency Hyperornithinaemia zz Aminoaciduria without hyperammonaemia Intermittent branched chain ketoaciduria Isovaline acidaemia Hartnup disease zz Disorders of pyruvate and lactate metabolism Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency Subacute necrotising encephalomyelopathy (Leigh’s disease) Multiple carboxylase deficiencies Mitochondrial myopathy. zz

2.  Progressive or Remitting Ataxic Syndromes zz zz zz zz zz zz

Ch-9C.indd 697

Abetalipoproteinaemia Hypobetalipoproteinaemia Hexosaminidase deficiency Cholestanolosis Mitochondrial myopathy Gamma glutamyl cysteine synthetase deficiency.

3. Metabolic Disorders in which Ataxia may Occur as a Minor Feature zz zz zz zz zz zz zz

Sphingomyelin storage disorders Metachromatic leukodystrophy Multiple sulphatase deficiency Late onset globoid cell leukodystrophy Adrenoleukodystrophy Ceroid lipofuscinosis Sialidosis.

Abetalipoproteinaemia zz zz zz zz

zz

zz

It is an autosomal recessive disorder The age of onset is from infancy to childhood Male to female ratio is 2 : 1 It has very low levels of lipids (especially cholesterol), low levels of fat soluble vitamins (vit A, D, E, K) The essential neurological features are: —— Progressive ataxia —— Loss of proprioceptive sensations —— Areflexia —— Ophthalmoplegia Secondary features are: —— Acanthocytosis —— Steatorrhoea —— Retinitis pigmentosa.

Pure Vitamin E Deficiency zz zz zz zz zz



Ataxia Areflexia Loss of proprioceptive sensations History of malabsorption Autosomal recessive disorder. Pure vitamin E deficiency is treatable.

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Cholestanolosis (Cerebrotendinous Xanthomatosis) zz zz zz

It is an autosomal recessive disorder The age of onset is in the second decade of life It is due to defect in bile salt absorption.

Clinical Features zz zz zz zz zz zz

Ataxia Dementia Spasticity Peripheral neuropathy Cataract Xanthomas on tendon.

Treatment It is treated with chenodeoxycholic acid.

zz zz zz zz zz

The autopsy findings are: Neuronal loss in cerebrum, cerebellum and brainstem.

Cockayne Syndrome It is an autosomal recessive disorder.

Clinical Features zz zz zz zz zz

Mitochondrial Encephalomyopathies It is a late onset ataxic disorder. It is characterised by: Ataxia zz Deafness zz Dementia zz Peripheral neuropathy. zz

B. Disorders Characterised by Defective DNA Repair zz zz zz

Ataxia telangiectasia Xeroderma pigmentosum Cockayne’s syndrome.

Ataxia Telangiectasia zz zz zz zz

zz

It is an autosomal recessive disorder The age of onset is in infancy The male female ratio is 1 : 1 The essential neurologic features are progressive cerebellar ataxia, nystagmus, choreoathetoid move­ ments, oculomotor apraxia The secondary features are oculocutaneous telangiectasia, immunoglobulin deficiency (lgA), pulmonary infection and malignancies.

Xeroderma Pigmentosum It is an autosomal recessive disorder.

Clinical Features zz zz

Ch-9C.indd 698

Skin photosensitivity and malignancies Mental retardation

Dementia Seizures Chorea Dystonia Ataxia.

zz

Skin photosensitivity Short stature Mental retardation Salt and pepper appearance in retina Ataxia Progeric facies (sunken eyes, prominent nose, large ears, and jutting chin).

C.  X-linked Ataxia 1. Cerebellar ataxia with lower limb spasticity and hyperreflexia 2. Skeletal and cardiac abnormalities are absent 3. X-linked ataxia should be considered during genetic counselling 4. Motor conduction velocity is reduced (whereas in other early onset ataxias with retained reflexes motor conduction velocity is normal).

III. ATAXIC DISORDERS OF UNKNOWN AETIOLOGY OF EARLY ONSET Early onset cerebellar ataxia (onset usually before 20 years) Friedreich’s ataxia zz Early onset cerebellar ataxia with retained tendon reflexes zz With hypogonadism and deafness and/or dementia zz With myoclonus (Ramsay-Hunt syndrome, Baltic myoclonus) zz With pigmentary retinal degeneration ± mental retardation and/or deafness zz With optic atrophy ± mental retardation zz With cataracts and mental retardation (Marinesco-Sjögren syndrome) zz With childhood onset deafness and mental retardation zz

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Nervous System zz zz zz

With congenital deafness With extrapyramidal features X-linked recessive spinocerebellar ataxia.

Friedreich’s Ataxia zz zz zz

It is an autosomal recessive disorder It is the most common type of hereditary ataxias The age of onset is between 2 and 16 years.

Autopsy Findings zz

zz zz

Differential Diagnosis zz zz

Signs and Symptoms Anita Harding’s criteria for diagnosis of Friedreich’s ataxia. Autosomal recessive inheritance zz Age of onset before 25 years. zz

Within 5 years from onset Limb and trunk ataxia zz Absent tendon reflexes in the legs zz Extensor plantar responses zz Motor NCV (Nerve conduction velocity) >40 m/s in upper limbs with small or absent SNAPs (Sensory nerve action potentials). zz

zz

zz zz

zz

Other features, present in 3 mm in diameter —— For patients > 50 years of age, two of the following criteria must be met—(a) Size of the lesion > 5 mm, (b) Lesions located adjacent to the bodies of the lateral ventricles, (c) Lesions located in the posterior fossa Lesions are dissociated in time and location—2 or more episodes involving different sites of CNS—each lasting at least 24 hours and occurring at least one month apart or gradual/stepwise progression over 6 months if accompanied by increased IgG synthesis or 2 or more oligoclonal bands— —— MRI may be used to document dissemination in time if a new T2 lesion or Gd enhancing lesion is seen 3 or more months after a clinically isolated syndrome Patient’s neurological condition could not be better attributed to another disorder.

Diagnostic Categories zz zz

zz

Ch-9C.indd 704

Definite multiple sclerosis—All 5 criteria fulfilled Probable multiple sclerosis—All criteria except —— Only one objective abnormality despite 2 symptomatic episodes 1; or —— Only one symptomatic episode with 2 or more objective abnormalities At risk for multiple sclerosis—Criteria 1, 2, 3 and 5 fulfilled

Patient has only one symptomatic episode and one objective abnormality.

zz

Onset before the age of 10 or after 60 Steady progression Early dementia Rigidity, sustained dystonia Deficits developing within minutes Cortical deficits – aphasia, apraxia, alexia, neglect. Difference between MS and Neuromyelitis Optica (Devic’s Disease)

Multiple sclerosis

Neuromyelitis optica

Worldwide common Progressive disease U/L optic neuritis Simultaneous involvement of brain and spinal cord –uncommon Involves 3 spinal segments Transverse myelitis – common CSF: Oligoclonal bands (OCB) negative Pleocytosis common Anti-aquaporin 4 channel antibody positive Treatment: Steroids useful and IFN β contraindicated

Features that Differentiate MS from other Demyelinating Disorders Acute Disseminated Encephalomyelitis (ADEM) zz zz zz zz zz zz zz

zz zz

Common in children Non-progressive monophasic course Viral trigger common Meningismus/coma/seizure – common B/L optic neuritis and transverse myelitis common CSF – OCB negative and pleocytosis MRI –Disseminated small foci of demyelination and basal ganglia involvement is unique Treatment—Steroids/IV Ig /plasmapheresis Almost full recovery

Progressive Multifocal Leukoencephalopathy (PML) zz

zz

Progressive disease caused by John Cunningham virus Common in immunocompromized states (MCC-AIDS)

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Nervous System zz zz

Optic nerve and spinal cord spared CSF – Normal and Positive for JCV DNA MRI – Multifocal asymmetric demyelinating lesions No specific therapy and prognosis is bad.

Treatment

No test is pathognomonic and diagnostic. CSF protein: < 100 mg/dl Cells < 75/microlitre—mononuclear pleocytosis. zz CSF electrophoresis: It reveals oligoclonal bands. zz The visual, auditory and somatosensory evoked potentials are prolonged. zz MRI: It is very sensitive for detecting lesions produced by multiple sclerosis (presence of periventricular plaque) (Figs 9.128 and 9.131).

Treatment may be divided into three categories. Disease modifying drugs. —— RRMS. „„ Interferon β1a—30 mcg IM once a week. „„ Interferon β1b—250 mcg SC on alternate days „„ Glatiramer acetate—20 mg S/C daily „„ Other drugs used are – Natalizumab, Alemtuzumab. Fingolimod, Dimethyl fumarate, Mitoxantrone, Teriflunomide, Daclizumab, Ocrelizumab. Treatment duration for 6 months —— Therapeutic decision—MS „„ In RRMS, delay initiating treatment in patients with a normal neurologic exams or

Fig. 9.128  MRI brain—periventricular plaque in multiple sclerosis

Fig. 9.130  MRI brain—periventricular plaque in multiple sclerosis

Fig. 9.129  MRI brain: Dawson finger (multiple sclerosis)

Fig. 9.131  Multiple sclerosis (MRI)—hyperintense signals in brainstem and corpus callosum with optic nerve involvement

zz zz

Investigations zz

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zz

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Manual of Practical Medicine a single attack or a low attack frequency or a low burden of disease as assessed by brain MRI. Till they remain stable, periodic clinical exam and MRI assessment (once in 6 months or as needed). „„ In case of acute exacerbation in RRMS—if there is no functional impairment, treat symptomatically. If there is functional impairment, treat with methylprednisolone or prednisone. „„ Unstable RRMS—treat them with interferon β1a or β1b or glatiramer acetate. If they do not tolerate the drug or if the response is poor, treat them with natalizumab—300 mg IV once a month. „„ In SPMS—treat them with β1a or β1b. If they do not tolerate the drug or the response is poor, consider treating them with one of the following drugs—mitoxantrone, azathioprine, methotrexate, pulse cyclophosphamide, IV Ig, pulse methylprednisolone. „„ In PPMS—treat them symptomatically. Acute exacerbation—Methyl prednisolone 1 gm IV OD × 3 days followed by oral prednisolone 60 mg OD × 5 days tapering doses—2 weeks. Symptomatic treatment —— Spasticity with Baclofen 15 to 18 mg/day divided doses Tisanidine 2 to 8 mg/d TDS Diazepam 1 to 2 mg TDS. —— Pain—Carbamazepine 100 to 1200 mg/day Gabapentine 300 to 3600 mg/day Phenytoin 300 to 400 mg/day Amitriptyline 25 to 150 mg/day. —— Paroxysmal symptoms—Carbamazepine, Gaba­ pentine or Acetazolamide may be given. —— Bladder hyperreflexia—treated with anti­ cholinergics like Oxybutinin 5 mg TDS, Tolterodine 1–2 mg BD or Propantheline 7.5–15 mg QID. „„

zz

zz

Clinical Variants zz

zz



Neuromyelitis Optica (Devics syndrome). Acute optic neuritis with myelitis. Acute MS (Marburg’s variant) It is a fulminant acute disease, usually fatal within one year.

Meningitis Meningitis is an infection of the pia-arachnoid and the CSF of the arachnoid space.

Causes Neonates: E. coli Children: (1 month to 15 years) —— Haemophilus influenzae —— Streptococcus pneumoniae —— Neisseria meningitidis. zz Adults —— Young—Meningococcus —— Older—Streptococcus pneumoniae. zz Elderly and immuno compromised persons —— Pneumococcus —— Listeria —— TB —— Gram-negative organisms —— Cryptococcus. zz Viral —— Enteroviruses —— Herpes simplex viruses —— Mumps virus —— Influenza virus —— Japanese encephalitis virus —— Arbo viruses —— Rabies virus —— HIV. zz Nosocomial and post-traumatic meningitis: —— Klebsiella pneumoniae —— E. coli —— Pseudomonas aeruginosa —— Staph. aureus zz Meningitis in special situations: —— CSF shunts—Staphylococcal —— Spinal procedures—Pseudomonas. TB Meningitis is common in extremes of age, in children and elderly. zz zz

Types of CNS TB Intracranial TB Meningeal zz

Prognosis zz zz zz

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Thirty-five per cent relapse in 5 years Sixty-five per cent relapse in 20 years Twenty per cent die of complications.

zz

Leptomeningitis Pachymeningitis

Parenchymal zz zz

Tuberculoma Tuberculous abscess

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Nervous System zz zz

Tuberculous cerebritis Tuberculous encephalopathy

Intraspinal TB zz zz zz zz

Spondylodiscitis Solitary vertebral body Intramedullary TB TB arachnoiditis.

Clinical Features (Figs 9.132 to 9.134) Clinical features are due to inflammatory mediators and not due to direct infection. zz Meningeal signs (positive Kernig’s sign, Brudzinski’s sign and opisthotonus) (Figs 9.114 and 9.115). zz Raised intracranial pressure signs. zz Septic signs (fever, arthritis, odd behaviour, rashes, petechiae (meningococcus), shock, DIC, tachycardia, tachypnoea). zz Focal or generalised seizures. The meningeal signs are invariably present in 50% of patients and their absence do not rule out bacterial meningitis. In 10 to 20% of cases cranial nerve palsy occurs (IV, VI and VII). Occasionally focal neurological deficits such as visual field defects, dysphasia and hemiparesis can occur.

Fig. 9.132  Method of examination for neck stiffness

Predisposing Factors zz zz zz

zz zz zz zz zz

Head injury (fractures of base of the skull) Sinusitis, mastoiditis and otitis media Immunosuppressed states (carcinoma, HIV, sple­ nectomy for sickle cell disease) Diabetes mellitus Pneumonia Alcoholism CSF shunts Iatrogenic (after LP).

Fig. 9.133  Stage 1—flex the hip to 90 degrees with the knee flexed

Investigations CSF Analysis zz

zz

zz

zz

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The only investigation that will confirm the diagnosis is lumbar puncture and CSF analysis. Lumbar puncture is contraindicated in the presence of gross papilloedema with or without neurological deficit or meningococcemia (risk of bleed). However, LP has to be planned after a preliminary CT scan. Early CSF analysis may be normal and the lumbar puncture should be repeated if the meningeal signs persist. Send 3 bottles of CSF (8 drops or ½ CC in each bottle) for urgent Gram stain and culture, virology study and biochemical study (especially glucose).

Fig. 9.134  Stage 2—extend the knee. Palpate for hamstring spasm

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Encephalitis

CSF Glucose Decreased Bacterial meningitis (markedly low in pyogenic meningitis than in TB meningitis) Carcinomatous meningitis Haematomyelia Epidural haemorrhage.

zz

zz zz zz

Empirical Treatment of Meningitis No.

Indication

Antibiotics

1.

Pre-term infants to infants < 1 month

Ampicillin + cefotaxime

2.

Infants 1–3 months

Ampicillin + cefotaxime/ ceftriaxone

3.

Immunocompetent children >3 months and adults < 55 years

Cefotaxime/ceftriaxone/ cefepime + vancomycin

4.

Adults > 55 years/adults of any age with alcoholism or other debilitating disorders

Ampicillin + cefotaxime/ ceftriaxone/cefepime + vancomycin

5.

Hospital acquired meningitis/ post-traumatic/postneurosurgery/ meningitis/ patients with neutropenia/ impaired cell mediated immunity

Ampicillin + ceftazidime or Meropenam + vancomycin

Complications of TB Meningitis zz zz zz

Hydrocephalus Tuberculous vasculitis Cranial nerve involvement.

Corticosteroids in CNS Tuberculosis Indications zz zz zz zz zz zz zz zz

Stage 2/3 disease Raised ICT Focal neurological deficit suggestive of vasculitis TB encephalopathy Cerebral oedema Hydrocephalus Optic arachnoiditis/infarcts Rising CSF protein suggesting spinal block.

Dose and Duration Adults – Prednisolone 1 mg/kg or 60 mg/day or dexamethasone 8–16 mg/day. Children – Dexamethasone 0.3 to 0.6 mg /kg/day. Duration – 3–6 weeks and then tapered slowly over 3 weeks.

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Encephalitis is an infection of the brain. The viruses causing encephalitis are herpes simplex (most common); measles, mumps, varicella, poliomyelitis, Japanese B encephalitis and arboviruses.

No Organisms Seen in CSF Ceftriaxone 2 gm IV q12h or Cefotaxime 2 gm IV q4h along with Vancomycin 500 to 750 mg IV q6h can be given. Add additionally ampicillin 2 gm IV q4h for immunocompromised and aged (>50 years). Vancomycin should not be used alone. Adjuvant Therapy—Dexamethasone Dexamethasone reduces inflammation. Dexamethasone exerts its beneficial effect by inhibiting the synthesis of IL-1 and TNF from inflammatory cells at the level of m-RNA, decreasing CSF outflow resistance and stabilising the blood brain barrier. Dexamethasone 10 mg IV should be given 20 minutes before the first dose of an antibiotic and continued 6th hourly for 4 days. The rationale for giving dexamethasone 20 minutes before the administration of antibiotic is that it inhibits the production of TNF by macrophages and microglia only if it is given before these cells are activated by endotoxin. Do not use dexamethasone when the patient is in shock.

Symptoms and Signs They are headache, fever, fits, altered sensorium with or without neurological deficit, signs of increased intracranial pressure, and meningeal signs.

Investigations zz

zz

zz

zz

zz

zz

CT scan: It is useful to differentiate encephalitis from cerebral abscess and CNS tumours (Fig. 9.135). Lumbar puncture: The CSF pressure is increased with increased protein and lymphocytic pleocytosis. EEG: It shows diffuse slowing with epileptiform discharge in herpetic encephalitis. Isotope scan: The increased temporal lobe isotope uptake on a brain scan is a feature of herpetic encephalitis. Brain biopsy: It is useful in potentially treatable herpetic encephalitis. The serology and immunological tests are useful in confirming the diagnosis.

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Nervous System Investigations zz

zz zz

CSF analysis: Lymphocytic pleocytosis or acellular, markedly elevated gamma globulin (antimeasles antibodies) EEG: Periodic burst of triphasic waves Brain tissue—culture positive for measles virus (immunocytochemical methods).

Management zz zz zz

Measles vaccination will prevent No specific treatment is available Isoprinosine and intrathecal INF-α may be tried.

Kuru Fig. 9.135  Herpes simplex encephalitis

Management zz zz zz

zz

zz

Skilled nursing care. Maintenance of fluid balance and nutritional status. The raised ICP is reduced by dexamethasone 4 mg 6th hourly. The herpes simplex virus encephalitis is treated with acyclovir 10 mg/kg IV 3 times daily for 10 days. Acyclovir 15 to 30 mg/kg 8th hourly for 10 to 14 days in viral meningitis.

Prognosis The highest mortality is seen in herpes-simplex (mortality rate of 15–20%).

Slow Virus Disease Slow virus diseases involving central nervous system mainly occur many months or even years after the infection with transmissible agents which have properties different from conventional viruses.

zz

zz zz

Creutzfeldt-Jakob Disease It mostly occurs as sporadic, although 5 to 15% are familial with an autosomal dominant inheritance.

Clinical Features The clinical manifestations are severe and progressive dementia, pyramidal and extrapyramidal motor disturbances and signs and symptoms of cerebellar dysfunction.

Investigations zz

zz

Subacute Sclerosing Pan Encephalitis (SSPE) It has a chronic progressive and eventually fatal course. It is caused by measles virus. It occurs in children and adolescents. It is more common between 5 and 15 years.

Clinical Features zz zz

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Intellectual deterioration, apathy and clumsiness Myoclonic jerks, rigidity and dementia.

The cardinal features are severe cerebellar ataxia with associated involuntary movements (choreo-athetosis, myoclonus and tremor) (Fig. 9.136). Mental impairment and frontal release signs. The source of transmission is due to ingestion of infected human brain material (cannibalistic practices).

zz

EEG: The typical pattern of periodic sharp wave complexes consists of a generalised slow, background interrupted by bilaterally synchronous sharp wave complexes occurring at intervals of 0.5 to 2.5 seconds and lasting for 200 to 600 milli seconds CT and MRI: This shows generalised cortical atrophy (The degree of clinical dementia is disproportionate to the amount of tissue lost) Brain biopsy: It is the gold standard for diagnosis of Creutzfeldt-Jakob disease. The pathologic hallmarks are spongiform changes (small round vacuoles) within the neuropia, neuronal loss, hypertrophy and proliferation of glial cells and absence of significant inflammation or white matter involvement. The above changes are predominantly seen in the basal ganglia, cerebellum and thalamus. The brainstem and spinal cord are usually spared.

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Fig. 9.136  Autonomic nervous system

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Nervous System Conditions

Appearance

Cells

Glucose

Protein

Organism

Normal

Clear

Lymphocyte 1 month (CIDP)] —— Relapsing (multiple episodes after acute and subacute onset). According to the types of nerve fibres involved —— Motor —— Sensory —— Autonomic —— Mixed According to the size of nerve fibres —— Large (posterior column) —— Small (pain and temperature) —— Mixed According to the distribution —— Proximal —— Distal —— Diffuse According to the clinical pattern of the involvement —— Mononeuropathy —— Mononeuritis multiplex —— Radiculopathy —— Symmetrical sensory motor neuropathy —— Symmetrical sensory neuropathy —— Autonomic neuropathy (DM) —— Secondary to systemic disorders

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Manual of Practical Medicine Craniometric Lines and Angles in Anteroposterior View Synonyms

Definition

Normal measurements

Implications

Fishgold’s digastric line (biventer line)

Joins the fossae for digastric muscles on undersurface of skull just medial to mastoid process

Dens tip should not project above this line; central axis of dens should be perpendicular to the line

Corresponds to McRae’s line on lateral view; may be oblique in unilateral condylar hypoplasia; oblique odontoid suggests paramedian abnormality

Fishgold’s bimastoid line

Line connecting tips of mastoid process

Runs across atlanto-occipital joints; line is 10 mm below digastric line

Odontoid tip may be 10 mm above the line

Schmidt-Fischer angle (angle of axes of atlanto- occipital joints)

Angle of axes of atlanto-occipital joints

124°–127°; should be measured in plane of dens on tomography

Angle is wider in condylar hypoplasia

zz

According to the pathology —— Axonal —— Demyelination —— Mixed.

Positive symptoms

Negative symptoms

Paraesthesia

Tingling; pins and needles

Numbness

Hyperpathia

Painful or unpleasant

Loss of specific sensory modalities (e.g. pain, touch and sensory ataxia associated with loss of position sense)

Allodynia

Sensation from non- noxious stimulation of skin

Dysaesthesia

Spontaneous painful sensation

Causalgia

Severe dysaesthetic pain usually associated with ANS disturbance

Neuralgia

Paroxysmal pain, e.g. trigeminal neuralgia

Sensory

Features

Axonal

Demyelination

Mode of onset

Insidious

Insidious or acute

Pattern of involvement

Glove and stocking distribution

Minimal sensory loss

Motor involvement

Preservation of proximal DTR except ankle jerk

Loss of all DTR

Recovery pattern

It takes months or years

Rapid recovery

Residual deformity

Common

Less

Central involvement

Due to toxic neuropathy

Rare

CSF protein

Normal

Raised

Nerve conduction study

Normal or slightly lowered

Very slow

Loss of sensory discrimination

Motor Fasciculation, myokymia and hemifacial spasm, muscle cramps neuromyotonia (continuous muscle fibres activity)

Symptoms

Weakness

It may be positive or negative symptoms. Predominantly Motor zz zz zz zz zz zz zz zz zz zz zz zz zz

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Guillian-Barré syndrome Infectious mononucleosis and polyneuritis Hepatitis and polyneuritis Diphtheritic polyneuropathy Porphyria Toxic (triorthocresyl PO4, thallium, lead and aluminium) Paraneoplastic Vaccinogenic/serogenic Systemic lupus erythematosus Acute panautonomic neuropathy Dapsone Organophosphorous poisoning Hereditary multifocal motor neuropathy with conduction block.

Sensory zz

zz

zz zz zz

zz

Toxin/drugs (cisplatinum, nitrofurantoin, pyridoxine toxicity, vitamin B12, vitamin E deficiency) Systemic —— Sjögren’s syndrome —— Paraneoplastic Idiopathic (acute and chronic) Hereditary Metabolic —— Amyloidosis —— Diabetes mellitus Infections —— Leprosy —— Lyme disease —— HIV.

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Nervous System Sensorimotor zz zz zz zz zz zz

zz

——

Hereditary motor sensory neuropathy I, II, III Metal poisoning (Gold, Ar, Pb, Hg, Thallium) Industrial chemicals Vitamins (Bl, B6, B12, E) Vasculopathic neuropathies Systemic —— Chronic renal failure —— Myopathy —— Acromegaly —— Primary biliary cirrhosis —— Hypereosinophilic syndrome Drugs: Alcohol, amiodarone, cisplatinum, dapsone, EMB, INH, lithium, phenytoin, thalidomide, vincristine.

Recurrent or Relapsing Polyneuropathy zz zz zz zz zz zz

GBS Porphyria CIDP Certain forms of mononeuritis multiplex Beriberi Refsum’s disease.

Subacute Sensorimotor Neuropathy Symmetrical

Asymmetrical (mononeuritis multiplex)

1. Deficiency states [Alcoholism (beriberi) Pellagra, vitamin B12, GI tract disorders]

1. Diabetes

2. Poisoning (Heavy metals: arsenic, lead and mercury)

2. Polyarteritis nodosa (angiopathic neuropathies)

3.  Drugs (INH, vincristine, dapsone, 3. Subacute idiopathic chloramphenicol, phenytoin) polyneuropathies 4. Uraemic (polyneuropathy)

4. Sarcoidosis 5. Ischaemic neuropathy 6. Vascular disease

Syndrome of Mononeuropathy or Plexopathy zz zz zz zz

Brachial plexus neuropathy Brachial mononeuropathy Lumbosacral plexopathies Entrapment neuropathies.

Neuropathies with Autonomic Involvement zz

zz

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Acute —— GBS —— Porphyria —— Toxic—vincristine —— Pan-autonomic neuropathy Chronic —— Diabetes

—— —— ——

Amyloidosis Paraneoplastic HIV neuropathy Hereditary sensory and autonomic neuropathies.

Small Fibre Neuropathies (Concerned with Pain and Temperature) zz zz zz zz zz zz

Amyloid neuropathy Diabetes Idiopathic Hereditary—sensory autonomic Fabry’s disease Tangier’s disease.

Neuropathy with Pain zz zz zz zz zz zz zz zz zz

Diabetic Vasculitic neuropathy Toxic arsenic, thallium Alcoholic HIV related Amyloid Paraneoplastic sensory neuropathy Small fibre neuropathy Fabry’s disease.

Entrapment Neuropathies Common sites: Median nerve in the carpal tunnel zz Ulnar nerve at the elbow zz Lateral cutaneous nerve of the thigh at the inguinal ligament zz Lateral popliteal nerve at the head of the fibula. Uncommon sites: zz Ulnar nerve at the wrist zz Radial nerve in the arm zz Posterior tibial nerve in the tarsal tunnel zz Lower cord of the brachial plexus by cervical rib or fibrous band. zz

Carpal Tunnel Syndrome Common causes: Premenstrual fluid retention zz Myxoedema zz Pregnancy zz Acromegaly zz Diabetes mellitus zz Rheumatoid arthritis zz Myeloma zz Previous trauma zz Amyloidosis zz Synovitis of flexor tendons zz Dislocated carpal bone—lunate. zz

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Manual of Practical Medicine Demyelinating Neuropathy Inflammatory—CIDP zz Paraproteinaemias —— Benign paraprotein (IgM, IgG, IgA) —— Myeloma (IgM, IgG, IgA) —— Waldenstrom’s macroglobulinaemia (IgM) —— POEMS syndrome (IgA or IgG) (Polyneuropathy, Organomegaly—liver, spleen, lymphnodes, endocrinopathies, M-protein, Skin changes) zz Hereditary —— HMSN (type 1a, 1b, 3 and X-linked) —— Refsum’s disease —— Globoid cell leukodystrophy —— Metachromatic leukodystrophy zz Toxic —— Amiodarone —— Suramin —— Diphtheria zz Acquired demyelinating neuropathies —— GBS —— CIDP —— Diphtheria —— Multifocal motor neuropathy with conduction block —— Paraproteinaemic neuropathy. zz

Investigations Blood: TC, DC, ESR, Urea, Electrolytes, LFT Blood sugar—If needed GTT, serum protein EPP (electrophoresis) Auto antibodies—ANA, Anti-ganglioside antibodies, Antineuronal antibodies Level of vitamin B12 DNA analysis—Chromosome 17 duplication (HMSN 1 and HMSN 1A) Chromosome 17 deletion—HLPP Urine: Bence Jones protein, porphyrins Nerve conduction studies: Slowing of motor and sensory conduction velocities zz Moderate in axonal neuropathies zz Severe in demyelinating neuropathies zz Reduced amplitude of sensory action potential— axonal neuropathy zz Conduction block in CIDP, GBS, MMN. Electromyography: Muscle denervation changes.

zz

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Sensory threshold: Thermal and vibration threshold.

zz

Imaging: X-ray chest for sarcoidosis and malignancy zz Skeletal survey for multiple myeloma zz Screening for malignancy. zz

Autonomic function tests: When there are symptoms and signs of autonomic neuropathy. Nerve biopsy: zz Progressive neuropathy when the cause is not known zz To consider long-term immunotherapy in vasculitis and inflammatory infiltration zz Most frequently biopsied sensory nerves: —— Sural nerve at the ankle —— Superficial peroneal nerve over the dorsum of the foot —— Superficial radial nerve at the wrist.

Guillain-Barré Syndrome Guillain-Barré syndrome (GBS) is an acute diffuse postinfective disease causing generalised paralysis involving spinal roots, peripheral nerves and occasionally cranial nerves, commonly involving VII nerve either unilaterally or bilaterally and lower cranial nerves. zz The incidence is 1 in 1 lakh populations. zz The age group is between 20 and 50 years in both sexes.

Aetiology/Predisposing Disorders zz

zz zz zz zz

Viral (CMV, HIV, EB, herpes virus, Mycoplasma pneumoniae) Bacterial (Yersinia, Campylobacter, Salmonella) Systemic lupus erythematosus Hodgkin’s disease Postvaccinial—rabies vaccine, influenza vaccine.

Clinical Features Patients have acute onset, ascending LMN type of paralysis of both lower limbs and upper limbs involving proximal group of muscle more than distal group. Later they may have respiratory, pharyngeal and laryngeal involvement and may need a ventilator. Autonomic dysfunction is also common. Patients may also have paresthesias of toes and finger tips. Weakness of lower limb is more than that of upper limb. 50% has facial diparesis. The muscles are floppy and the tendon reflexes are absent or sluggish. Bladder involvement is rare.

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Nervous System

Clinical Variants zz

zz zz zz

Miller Fisher’s syndrome: Ophthalmoplegia, ataxia and areflexia with little weakness in 5% of cases. Ophthalmoplegia with GQ 1b antibody Bulbar weakness with GM 2 antibody Acute dysautonomia.

Investigations CSF findings are: —— CSF protein (100–1000 mg/dl) —— Albuminocytologic dissociation. zz Abnormal electrophysiological findings (conduction delay). Diagnostic criteria (asbury criteria) of typical GBS zz Progressive weakness of two or more limbs due to neuropathy zz Areflexia zz Disease course < 4 weeks zz Exclusion of other causes (Vasculitis, diphtheria, toxin, porphyria, spinal cord syndrome). Supportive criteria: zz Relatively symmetric weakness zz Mild or absent sensory involvement zz Facial nerve or other cranial nerve involvement zz Absence of fever zz Typical CSF profile (Acellular with increased protein level) zz Electrophysiological evidence of demyelination. zz

Unusual Features in GBS zz

zz

zz zz zz

Normal CSF protein or numerous lymphocytes in CSF (more than 50/mm3) A band sensation or tightness around thorax— Transient sensory level Persistent but diminished DTR Early urinary retention. Babinski sign—without other signs of myelopathy. Persistence of any of two features or reduced sensation below a sharply defined level on the trunk indicates spinal cord disease—transverse myelitis.

Poor Prognostic Factors zz zz zz zz

Age more than 40 years Rapid progression to tetraplegia Delay in initiation of treatment Primary or secondary axonal variant.

Treatment of GBS Early: Frequent recording of vital capacity

zz

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Monitoring of O2 saturation Heparin 5,000 units SC bid zz Chest physiotherapy zz Ryles tube feeding if there is bulbar weakness zz IV immunoglobulin—0.4 g/kg/day for 5 days zz If there is no response to immunoglobulin—consider plasma exchange (Plasma exchange 40–50 mL/kg—4 times a week) zz Prevention of exposure keratitis, venous thrombosis, vigilance for hyponatraemia, and other electrolytes and prompt management of cardiac arrhythmias. Late: zz Ventilatory assistance if VC < 24 mL/kg zz Tracheostomy—for prolonged ventilatory assistance > 14 days zz Cardiac pacemaker for episodes of bradycardia/ cardiac asystole zz Physiotherapy zz Occupational therapy. zz zz

Chronic Inflammatory Demyelinating Polyneuropathy Chronic inflammatory demyelinating polyneuropathy (CIDP) is a slowly progressive, sometimes relapsing, steroid dependent, demyelinating sensorimotor polyneuropathy primarily affecting limbs.

Aetiology zz

zz zz

It may be preceded by viral infection, vaccination, injection and ingestion of foreign material It may follow cytomegalovirus infection It may be associated with GM1 antibodies.

Similarities between GBS and CIDP zz zz

zz

Symmetrical polyradiculoneuropathy Nerve conduction abnormalities of a demyelinating neuropathy —— Reduced conduction velocity —— Partial conduction block in motor nerves Pathologically both of them show inflammatory changes.

Features

GBS

CIDP

Mode of onset

Acute It evolves over period of days or weeks and stationary for several weeks

Insidious •  Slow and steady progression or stepwise manner •  Maximum severity after several months

Progression

Abbreviations: GBS, Guillian-Barré syndrome; CIDP, chronic inflammatory demyelinating polyneuropathy

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Pathology zz

zz

The demyelination is more pronounced in nerve roots, ganglia, and proximal nerve trunks and peripheral nerve throughout the length. The demyelination and remyelination are characteris­ tically seen as a “onion-bulb” appearance in nerve biopsy.

Clinical Features zz zz

zz

zz

It affects all age groups. Course: —— 65% chronic relapsing course —— 15% chronic progressive course —— 20% monophasic with subacute onset Patients have LMN type of weakness of both upper limbs and lower limbs (more of proximal than distal) with minimal sensory involvement affecting posterior column and spinothalamic tract. The other features are action tremor, nerve enlargement, papilloedema, impotence, incontinence and Horner’s syndrome.

Diagnostic Criteria for CIDP zz

zz

zz

zz

Ch-9C.indd 740

Mandatory clinical criteria —— Progressive or relapsing muscle weakness for 2 months or longer. —— Symmetrical proximal and distal weakness in upper and lower limbs. —— Hypo or areflexia Mandatory laboratory criteria —— Nerve conduction study with features of demyelination. —— CSF protein > 45 mg%, cell count < 10/µL —— Sural nerve biopsy with features of demyelination and remyelination including myelinated fibre loss and perivascular inflammation. Mandatory exclusion criteria —— Evidence of relevant systemic disease or toxic exposure. —— Family history of neuropathy. —— Nerve biopsy findings incompatible with diagnosis. Diagnostic categories —— Definitive: Mandatory inclusion and exclusion criteria and all laboratory criteria. —— Probable: Mandatory inclusion and exclusion criteria and 2 laboratory criteria. —— Possible: Mandatory inclusion and exclusion criteria and 1 laboratory criteria.

Investigations zz

zz

zz

In agarose gel electrophoresis, a single band is seen in the Ig region Electrophysiological study: Motor conduction velocity is reduced Nerve biopsy: It shows demyelination and remyelination (onion-bulb appearance).

Treatment Prednisolone 40 to 60 mg for 8 weeks or until improve­ment occurs and slowly tapered (10 mg/ month). If there is no improvement with steriods for 2 months, it can be discontinued. zz Plasma exchange: It is the first line of therapy in respiratory embarassment. zz High dose of intravenous human immunoglobulin. zz If no improvement with steriod or plasma exchange, try with immunosuppressive agents. Azathioprine, methotrexate, cyclosporine and cyclophosphamide have been used. zz

Hereditary Sensory Motor Neuropathy (Charcot-Marie Tooth Disease) The classical features of this polyneuropathy are genetic transmission, symmetric involvement, slow progression, degeneration of functionally related systems of fibres and axon-myelin fibre loss. It is one of the most commonly inherited peripheral neuropathy. These are 4 types.

HMSN Type 1 zz

zz zz zz zz zz zz zz

zz zz

zz

zz

zz zz

Autosomal dominant inheritance, recessive forms also occur. Most common type. Starts in first or second decade. Presenting symptoms is foot deformity and weakness. Pes cavus and hammer toes in 75%, kyphosis in 10%. Ankle jerk absent universally and total areflexia in 50% cases. All modalities of sensations impaired distally. Distal upper limb weakness and small muscle wasting follows lower limb. Palpable nerve thickening in 25%. Pupillary abnormality and extensor plantar occasionally occur. When associated with tremor or ataxia of limbs, it is called Roussy-Levy syndrome. Nerve conduction studies show absent or reduced sensory nerve action potential. Motor nerve conduction velocity is below 40 m/sec. Nerve biopsy shows hypertropic onion bulb changes. CSF is usually normal.

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HMSN Type 2 Usually autosomal dominant. Recessive and X-linked dominant forms are also present. zz Starts later than type 1-second decade or later. zz Presenting symptoms are same as type 1. zz Foot and spinal deformities are less frequent. zz Peripheral nerves not enlarged. zz Ankle jerks absent in most cases. zz Sensory symptoms are less prominent. zz Motor nerve conduction velocity is usually just within normal range. zz SNAPs are absent or reduced. zz Nerve biopsy shows axonal loss with little evidence of demyelination. Differential diagnosis zz Friedreich’s ataxia. zz CIDP. zz Paraproteinaemia. zz

HMSN Type 3 (Dejerine-Sottas Disease) zz zz zz zz zz zz zz zz zz zz

zz

Autosomal recessive disease usually. Begins in infancy or early childhood. Foot and skeletal abnormalities. Delayed motor development. Proximal weakness. Global areflexia. Enlarged peripheral nerves. All modalities of sensation impaired distally. CSF protein is persistently elevated. Motor conduction velocity markedly reduced to often less than 10 m/sec. Onion-bulb changes are seen in nerve biopsy.

HMSN Type 4 of Dyck (Refsum’s Disease) zz zz zz zz zz zz zz zz zz zz zz zz zz

Autosomal recessive disease. Begins in late childhood or adolescence. Progressive sensory motor demyelinating polyneuropathy. Cerebellar ataxia and retinitis pigmentosa. Cardiomyopathy. Nerve deafness. Cataract. Ichthyosis. All modalities of sensations reduced. DTR lost. CSF protein is increased markedly. Nerve biopsy shows hypertropic onion bulb formation. Diagnosis confirmed by increased phytanic acid in blood (normal < 0.3 mg%).

Causes of Nerve Thickening zz zz zz

Ch-9C.indd 741

Leprosy Neurofibromatosis HMSN type I and II

zz zz zz

Amyloidosis Acromegaly Refsum’s disease.

POLYMYOSITIS It is a condition of unknown aetiology in which the skeletal muscle is damaged by a nonsuppurative inflammatory process dominated by lymphocytic infiltration. Polymyositis is characterised by presence of muscle tenderness and oedema.

Classification Group I: Idiopathic polymyositis Group II: Idiopathic dermatomyositis Group III: Dermatomyositis (polymyositis) associated with neoplasia Group IV: Childhood dermatomyositis associated with vasculitis Group V: Polymyositis with collagen vascular disease

Clinical Features Idiopathic Polymyositis zz zz zz zz

zz

zz

It is insidiously progressive over weeks or months The female and male ratio is 2 : 1 The ocular muscles are spared The reflexes are disproportionately reduced (carcinoma with polymyositis and polyneuropathy or Eaton-Lambert syndrome should be considered) The other features are dysphagia (25%) and cardiac abnormalities (ECG changes, arrhythmias, CCF secondary to myocarditis) The respiratory symptom is dyspnoea (due to lymphocytic pneumonitis, pulmonary oedema and pulmonary fibrosis).

Idiopathic Dermatomyositis zz

zz

zz zz zz zz zz zz

The skin changes may precede or follow the muscle syndrome The localised or diffuse erythema; maculopapular eruption Scaling eczematoid dermatitis, exfoliative dermatitis “Heliotrope rash”—butterfly distribution Itching and periorbital oedema Subcutaneous calcification Erythematous rash over the anterior chest—V sign Erythematous rash over the back and shoulders— Shawl sign.

Dermatomyositis (Polymyositis) Associated with Neoplasia zz

The malignancy may antedate or postdate the onset of the myositis by up to 2 years.

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The most common malignancies (carcinoma lung, breast, ovary, Gastrointestinal tract and myeloproliferative disorders).

Childhood Dermatomyositis Associated with Vasculitis It is associated with vasculitis in skin and GIT. Polymyositis with Collagen Vascular Disease Dysphagia is a common symptom of this group (due to the involvement of the smooth muscle of the distal 1/3 of oesophagus in systemic sclerosis). It is associated with connective tissue disorder (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, malignancy, sarcoidosis). Extramuscular Manifestations zz

zz zz

zz

Systemic symptoms—fever, malaise, weight loss, arthralgia and Raynaud’s phenomenon. GI symptoms—dysphagia, GI ulcerations. Cardiac symptoms—AV conduction defects, tachyarrhythmias, dilated cardiomyopathy, congestive cardiac failure and myocarditis. Pulmonary symptoms—may result from interstitial lung disease and thoracic myopathy.

Investigations zz

zz zz

zz

Serum enzymes (CK, aldolase, AST, LDH and ALT) are increased Erythrocytesedimentation rate is raised Electromyography: It reveals a markedly increased insertional activity (muscle irritability) together with the typical myopathic triad of motor unit action potentials which are of low amplitude, polyphasic and have an abnormally early recruitment. Muscle biopsy: The muscle biopsy reveals inflam­ matory cell infiltrates, destruction of muscle fibres with a phagocytic reaction, and perivascular (perivenular) inflammatory cell infiltration (hallmark of polymyositis).

Step 3: IV 1 to 2 g/kg divided over 2 to 5 days per course repeated every 6 to 8 weeks. Step 4: Other drugs—Cyclophosphamide, chlorambucil, mycophenolate mofetil.

MUSCULAR DYSTROPHIES They are a group of hereditary disorders characterised by progressive degeneration of selective group of muscles without involvement of nervous system.

Classification The ‘pure’ muscular dystrophies: X-Linked muscular dystrophy —— Severe (Duchenne) —— Benign (Becker) —— Benign with acanthocytes (McLeod syndrome) —— Benign with early contractures (Emery-Dreifuss) —— Scapuloperoneal (rare) zz Autosomal recessive muscular dystrophy —— Limb-girdle (usually scapulohumeral, rarely pelvifemoral) —— Distal type —— Childhood type, resembling Duchenne —— Congenital muscular dystrophy zz Autosomal dominant muscular dystrophy —— Facioscapulohumeral —— Scapuloperoneal —— Late-onset proximal (limb-girdle) —— Benign early onset with contractures —— Distal —— Ocular —— Oculopharyngeal. zz

Duchenne Dystrophy (Fig. 9.155) zz zz zz

Treatment Step 1: Oral prednisolone 1 mg/kg/day for 3 to 4 weeks followed by tapering slowly over a period of 10 weeks to 1 mg/kg every alternate day. Step 2: Immunosuppressive drugs—usually started when the patient fails to respond to glucocorticoids after 3 months of treatment, glucocorticoid resistance, glucocorticoid related side effects, rapidly progressive disease with respiratory failure. A. Azathioprine 3 mg/kg/day. B. Methotrexate 7.5 mg weekly for 3 weeks followed by gradual increase up to 25 mg/week.

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zz

zz

Inheritance: X-linked recessive Age of onset: Between 3 and 10 years Proximal muscles of upper limbs and lower limbs are predominantly affected, later involving the diaphragm, neck muscles, extraocular muscles, and facial muscles. Patients may become bed bound within 1st decade of life. Pseudohypertrophy of the muscle is present (enlargement of calf muscle, quadriceps and deltoids) The associated features are macroglossia, absence of incisor teeth, low (less than 10% of normal) IQ, skeletal atrophy and deformity (long bones become pencil thin and fracture), and cardiac involvement (persistent tachycardia, tall R-waves in the right precordial leads and deep Q-waves in limb leads and left precordial leads).

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Limb Girdle Muscular Dystrophy zz

zz zz

zz

zz

zz

zz

Fig. 9.155  Lumbar lordosis in Duchenne dystrophy

Inheritance: Autosomal recessive and equally affects both sexes. The age of onset: Between 10 and 30 years. Pelvic and shoulder girdle muscles are predominantly affected. Patients notice disability only after 10 to 20 years of onset. The proximal tendon reflexes are absent except ankle jerk. The pseudomuscular hypertrophy is an associated feature (calves and deltoids). The cardiac involvement and mental deficiency are rare.

Investigations The serum enzymes are raised.

Investigations zz zz zz

The serum CK value is 20 to 100 times the normal EMG—myopathic pattern Muscle biopsy—the dystrophin deficiency is seen (Western blot analysis).

Prognosis Normal lifespan.

Facioscapulohumeral Dystrophy zz

Causes of Death zz zz

Respiratory insufficiency Aspiration pneumonia

Treatment Prednisolone 0.75 mg/kg/day significantly slows the progression of disease up to 3 years.

zz

zz zz

zz

zz

Becker’s Dystrophy zz zz zz

zz

zz

Inheritance: X-linked recessive Age of onset: Between 5 and 25 years The pelvic and pectoral muscles are predominantly affected The patients are unable to walk after about 25 years of onset (benign course) The associated features are cardiac involvement, contractures, skeletal deformity and hypertrophy of the muscles.

Investigations Same as in Duchenne dystrophy.

Prognosis The longevity is better than Duchenne dystrophy.

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Inheritance: Autosomal dominant and equally affects both sexes. The muscles predominantly affected are facial muscles, shoulder girdle muscles and serratus anterior. The biceps and triceps jerks are diminished. Patients may have absent pectoralis and biceps muscles. The progression is slow and disability is less (pseudohypertrophy is rare). Labile HTN, nerve deafness, coat’s eye disease (Telangiectasia, exudation, and retinal detachment).

Investigations The serum enzymes (CK) are raised.

Prognosis Normal lifespan.

Oculopharyngeal Dystrophy Clinical Features zz zz

zz zz

Inheritance: Autosomal dominant. Patients have external ophthalmoplegia. Ptosis and/ or dysphagia occur in the 4th to 6th decades. Mild neck and limb weakness can occur. Rarely diplopia but pupil is spared.

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Manual of Practical Medicine Investigations zz zz

The serum CK may be 2 to 3 times normal. Biopsy: The distinct feature is the presence of tubular filaments, of 8.5 nm in diameter within muscle nuclei.

Treatment zz

zz

Cricopharyngeal myotomy may improve swallowing (does not prevent aspiration) Eyelid crutches improve vision in patients with ptosis.

Mitochondrial Myopathy It can present in three forms. Chronic progressive external ophthalmoplegia (CPEO) zz Skeletal muscle CNS syndrome zz Pure myopathy zz

Skeletal Muscle CNS Syndrome zz zz

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, Stroke like episodes (MELAS).

Congenital Muscular Dystrophy It is mostly sporadic (without CNS involvement) and sometimes of autosomal recessive inheritance. It is due to α2 laminin deficiency.

Clinical Features zz zz

It is present at birth or within a few months of life. The signs and symptoms are hypotonia, proximal limb weakness, and joint contractures at the elbows, hips, knees and the ankles (contractures at birth is known as arthrogryposis).

Types zz

zz

zz

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Fukuyama congenital muscular dystrophy: The features are generalised tonic-clonic seizures and delayed development of both mental and verbal status, microcephaly and enlarged ventricles. Cerebro-ocular-dysplasia muscular dystrophy: The features are cataract, retinal dysplasia and hypoplasia of the optic nerve. Walker-Warburg syndrome.

Treatment Supportive care.

CONGENITAL MYOPATHIES Central Core Disease The features are: Inheritance: Autosomal dominant and may be sporadic also zz Decreased fetal movements and breech presentation zz Skeletal abnormalities (congenital hip dislocation, scoliosis, pes cavus, and clubbed feet) zz Hypotonia and delayed motor milestones. zz

Investigations zz zz zz

Serum CK is normal EMG: Myopathic pattern Muscle biopsy shows single or multiple central or eccentric discrete zones (cores) devoid of oxidative enzymes and diminished PAS staining.

Treatment It is essential because it predisposes to malignant hyperthermia during general anaesthesia.

Nemaline Myopathy Clinical Features zz

zz

zz

zz

zz

Inheritance: Autosomal dominant and may be sporadic Severe neonatal hypotonia with respiratory distress are present Patients may have delayed milestones and they have long, narrow facies or head, high arched palate and open mouth appearance due to prognathous jaw The other skeletal abnormalities are pectus excavatum, kyphoscoliosis, pes cavus, and clubbed foot Myocardial involvement is an unusual presentation.

Investigations zz zz zz

Serum CK is normal EMG: Myopathic pattern Muscle biopsy: The diagnostic features are clusters of small rods or nemaline bodies.

Investigation

Centronuclear Myopathy

Serum CK level ranges from normal to 20 times normal.

It is of X-linked recessive inheritance.

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Nervous System

Types Neonatal Form The clinical features are: Severe hypotonia and weakness at birth zz Respiratory distress zz Poor prognosis. zz

zz

zz

Late Infantile—Childhood Form The clinical features are: Delayed milestones (especially walking) zz Ptosis zz Ophthalmoplegia zz Marfanoid features. zz

Childhood—Adult Type The clinical features are: zz Onset: Second or third decade zz Sparing of ocular movements zz Mild nonprogressive limb weakness zz No skeletal abnormalities zz Predominantly distal weakness resembling CMT disease.

Investigations zz zz

zz

Normal or slightly elevated CK level EMG features are: —— Positive sharp waves —— Fibrillation potentials —— Complex and repetitive discharges Muscle biopsy: The features are rows of central nuclei often surrounded by a halo.

Treatment

Investigations zz zz zz

zz

Poor.

Myotonia Congenita (Thomson’s Disease) zz zz zz zz zz

Dystrophia Myotonica

zz

zz zz zz

zz

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Inheritance: Autosomal dominant Age of onset: Between 20 and 60 years The predominant muscles affected are temporalis, facial, masseter, sternomastoid (‘hatchet face’ and ‘swan neck’) and distal group of muscles (quadriceps and tibialis anterior). Sternomastoid is absent in some cases. Patients may have a transverse smile (due to delayed relaxation) The tendon reflexes are depressed Difficulty in releasing the hand after making ‘fist’ The patient is unable to walk within 15 to 20 years of onset of the disease The associated features are early frontal baldness, ptosis, gynaecomastia, cardiac involvement (cardiomyopathy and mitral valve prolapse), bronchiectasis, altered oesophageal, bowel and biliary

Phenytoin for myotonia (Other drugs which can be used for myotonia are quinine and procainamide. They should not be used in patients with heart block). Mexiletine is also useful for myotonia. Pacemaker for heart blocks.

Prognosis

zz

zz

Serum CK level—normal or mildly elevated EMG—myopathic pattern Muscle biopsy

Management zz

Supportive care.

zz

tree motility, testicular atrophy, bone changes, mental defect (dementia), hypersomnia, and abnormalities of serum immunoglobulin. Insulin resistance is not uncommon. Patients have ‘phenomenon of anticipation’, i.e. the disease occurs much earlier in successive generations Formation of dimple in thenar muscles or tongue or wrist extensors on percussion.

zz

Inheritance: Autosomal dominant Age of onset: From birth Muscular hypertrophy occurs in the second decade. Athletic ability is poor (due to slowness and stiffness) It is worse in the cold seasons (performance of winter games is not possible) The peculiar features are: —— Formation of dimple in the thenar muscles of the hand and tongue after percussion —— Demonstration of myotonia (difficulty in opening the hand after making ‘fist’) Patients have normal life expectancy.

Paramyotonia Congenita zz

zz zz

The myotonia (tonic spasm of muscle) and muscle paralysis occur on exposure to cold It is similar to hyperkalaemic periodic paralysis The responsible gene on chromosome 17q 13.1–13.3 causes a defect of the sodium channels a subunit.

Drugs and Myopathy zz

Drugs causing focal damage or fibrosis —— Intramuscular opiates

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Manual of Practical Medicine Antibiotics Paraldehyde Drugs causing necrosis —— Heroin —— Clofibrate —— Epsilon aminocaproic acid Drugs causing myoglobinuria/rhabdomyolysis —— Heroin —— Methadone —— Amphetamine —— Barbiturates —— Diazepam —— INH —— Carbenoxolone —— Amphotericin B Drugs causing hypokalaemia —— Diuretics —— Carbenoxalone —— Liquorice —— Purgatives Drugs causing inflammation —— Procainamide —— D-penicillamine —— L-dopa Drugs causing subacute or painless proximal myopathy —— Corticosteroid —— Chloroquine —— β-blocker Drugs causing myasthenic syndrome —— D-penicillamine —— Aminoglycoside antibiotic Drugs causing malignant hyperpyrexia —— Suxamethonium —— Halothane —— Cyclopropane —— Enflurane, ketamine. —— ——

zz

zz

zz

zz

zz

zz

zz

Inflammatory Muscle Disease zz

zz

zz

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Bacterial —— Clostridium welchii gas gangrene —— Diphtheria—extraocular myopathy Viral —— Influenza—mimics acute poliomyelitis —— Bornholm disease—general myalgia and inter costal tenderness Parasite —— Trichinella spiralis (trichinosis)—extraocular myopathy —— Taenia solium (cysticercosis)—muscle hypertrophy (thigh and deltoid region).

Myasthenia Gravis Myasthenia gravis is a neuromuscular disorder charac­ terised by weakness and fatiguability of skeletal muscles due to decrease in number of ACh receptors at neuro­ muscular junction due to antibody. It occurs at any age and is more common in young adults. This may be associated with other autoimmune disorders (thymic tumours, thyrotoxicosis, rheumatoid arthritis and disseminated lupus erythematosus). It is more common in females than males. It has a predilection for extraocular muscles and muscles of mastication, facial, pharyngeal and laryngeal muscles. The respiratory and limb muscles (proximal and asymmetric) may also be affected. zz Females—2nd to 3rd decade. zz Males—4th to 6th decade.

Myasthenia Gravis and Thymoma zz

zz

zz

zz

Thymus gland is the primary source of T-cells and it undergoes atrophy after the age of 12 years. It is hyperplastic and enlarged in 70% of cases of myasthenia gravis. The cells in the hyperplastic follicles are B-cells, plasma cells and T-helper cells. Myoid cells in the thymus sensitise the immune system to the ACh receptor protein.

Clinical Features zz zz

zz

zz

zz

zz

zz

zz

It is insidious in onset. The exacerbations occur in pregnancy or before menses. The cardinal symptom is abnormal fatigue of the muscle and intensification of symptoms towards the end of the day or following vigorous exercise. The first symptoms are intermittent ptosis or diplopia, but weakness of chewing, swallowing, speaking or of moving the limbs also occur. The muscle groups commonly involved in a decreasing order are bulbar, neck, limb girdle, distal limbs and trunk. The sustained activity of the muscles lead to temporary increase in weakness as evidenced by: —— Sustained upgaze for two minutes leads to increased ptosis. The power of the affected muscle improves after brief rest —— On counting aloud, the patients voice gradually weakens. The other features are normal DTR and normal pupillary response. Mild atrophy of the muscles occur in advanced stage.

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Nervous System

Modified Osserman Scale

Medical Treatment

Class I: Ocular only Class II: Ocular + generalised symptoms Class III: Generalised symptoms + myasthenic crisis Class IV: Acute myasthenic crisis.

Neostigmine 7.5 to 30 mg (average 15 mg) 4 to 8 times/day or Pyridostigmine 30 to 180 mg qid (average 60 mg)

Myasthenic Crisis It is defined as need for assisted ventilation because of  myasthenia induced weakness of the muscles of respiration (profound weakness of respiratory muscles demanding ventilatory support).

Adverse effects “Cholinergic crisis” Pallor Sweating Nausea, vomiting Salivation, colicky abdominal pain.

Diagnosis

Immunological Treatment

Antiacetylcholine receptor radioimmunoassay. Generalised: 90% positive Ocular myasthenia: 50% positive If positive: Definite diagnosis Negative results: Does not exclude MG. Mu SK (Muscle specific tyrosine kinase) is positive in 40% of negative cases. zz Tensilon test (Edrophonium): The edrophonium 2 mg is given initially IV and further 8 mg given a minute later if there are no undesirable side effects. The positivity of the test is indicated by improvement of the muscle power within 30 seconds and persists for 2 or 3 minutes. The alternative drug is neostigmine 1.5 mg and the effect lasts for 2 hours. (Atropine is used to counteract the muscarinic effect of neostigmine). zz Ice test: Ptosis improves by more than 2 mm when ice is applied to the (shut) affected eye lid for more than 2 minutes. This test is simple, sensitive, specific and non-invasive. Sensitivity is decreased in patients with complete ptosis. zz CT scan—chest: It detects thymic tumours. zz Electrophysiological study detects neuromuscular disorders. —— Repetitive nerve stimulation—Decremental pattern —— Single fibre EMG—increased variability of interpotential interval. zz MRI brain in ocular myasthenia gravis is essential to rule out sphenoid wing meningioma.

zz

zz

Treatment The principles of the treatment are: To maximise the activity of acetylcholine at the remaining receptors in the neuromuscular junction. zz To limit or abolish the immunological attack on motor end plates. zz

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zz



Thymectomy: The beneficial effects are not immediate but it gives symptomatic relief. It is done in patients under 60 years when the weakness is not restricted to extraocular muscles. Thymectomy is indicated from puberty to 55 years. Steroids: It is indicated when patients have a poor response to anticholine esterase drugs and who have already undergone thymectomy. The initial dose is 15 to 25 mg/day and then it is gradually raised to 50 to 60 mg/day. Later, it is slowly tapered due to early weakness.

Plasma Exchange It removes the antibody from the blood and provides a marked improvement but lasts for a brief period. It is usually reserved for myasthenic crisis or for preoperative preparation. IV Immunoglobulin It is an alternative to plasma exchange in the treatment of a severe myasthenia gravis. Azathioprine Indications Severe or progressive disease zz Patients showing poor response to anticholineesterase drugs, thymectomy and corticosteroid. Dose: 2 to 3 mg/kg/day. Cyclophosphamide and cyclosporine A have been shown to be effective in refractory cases. Mycophenolate and tacrolimus have also been used. Curariform medications are absolutely contraindicated in myasthenia gravis. zz

Prognosis If thymoma is present, the survival is five years in 30% of cases.

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Manual of Practical Medicine Congenital Myasthenia Gravis zz zz

zz

zz

zz

It is not due to autoimmune aetiology It is due to presynaptic nerve terminals or acetylcholine receptor or anticholinesterase Early onset in infancy or childhood without acetylcholine antibody confirms diagnosis EMG, edrophonium test, and genetic analysis are useful Treatment depends upon subtype.

Myasthenic Syndrome (Eaton-Lambert Syndrome) This syndrome is associated with bronchial small cell carcinoma or rarely with autoimmune disease (pernicious anaemia).

Clinical Features zz

zz

zz

zz

zz

The weakness is mostly in the proximal muscles of the limbs and trunk. The extraocular muscles and bulbar muscles are rarely affected. The power of the muscle is steadily increased if contraction is maintained. Tendon reflexes are reduced and show a slight response to edrophonium. Autonomic disturbances are present (dry mouth, constipation, impotence).

Investigation Electrophysiological study: An incremental pattern is seen to repetitive nerve stimulation (Fig. 9.156).

Aetiopathogenesis The antibody is directed against an antigen that crossreacts with voltage-gated calcium channels involved in ACh release (it is a presynaptic defect). Differences between Myasthenia Gravis and Eaton-Lambert Syndrome  

Features

1.  Male: Female 2.  Site of lesion 3. Associated tumour

Myasthenia Gravis 2:3 Postsynaptic Thymic tumour

4. Muscle power after exertion

Worsens

5. DTR 6. Repetitive nerve stimulation 7. Treatment with neostig­mine or pyridostigmine 8. Response to guanidine 9. Autonomic changes

Preserved Decremental

Eaton-Lambert syndrome 1:1 Presynaptic Oat cell carcinoma of the lung Muscle power may improve after first few contractions of muscle Diminished or absent Incremental

Marked improvement

Slight improvement

No effect No changes

Good response Present

A

B

Fig. 9.156  (A) Normal individual, (B) Myasthenia gravis patient

Treatment zz

zz zz zz

Treatment with neostigmine or pyridostigmine or combination with guanidine is variable 3 to 4 diaminopyridine (under trial) 25 mg/PO QID Plasmapheresis Immunosuppression (steroid and azathioprine).

Abbreviation: DTR, Deep tendon reflex

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CHAPTER

10

Endocrine and Metabolic Disorders

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HYPOTHALAMUS AND PITUITARY GLAND Anatomy The pituitary gland is enclosed in the sella turcica. The gland has two lobes, anterior and posterior and is connected to the hypothalamus by an infundibular stalk which has portal vessels carrying blood from hypothalamus to the anterior lobe and nerve fibres to the neurohypophysis.

Anterior Lobe Anterior lobe contains three types of cells which are identified by staining reaction. zz Chromophobe cells (non-secreting) zz Somatotrophs secrete growth hormone (GH) zz Mammosomatotrophs secrete prolactin (PRL) zz Corticotrophs secrete ACTH zz Thyrotrophs secrete TSH zz Gonadotrophs secrete FSH/LH. A group of growth hormone producing cell population is capable of producing PRL. These dual secretors are called mammosomatotrophs. These are transitional cells which can function as either somatotrophs or lactotrophs. The inhibitor hormones released by hypothalamus are somatostatin (inhibits growth hormone and thyroid stimulating hormone) and dopamine (inhibits prolactin secretion). Somatostatin is an endocrine cyanide.

Clinical Uses of Somatostatin zz

zz

zz

zz

It is useful therapeutically in pancreatic tumours like gastrinomas, insulinomas, glucagonomas, VIPomas and upper GI bleed. It decreases acid secretion in the stomach, gastrin secretion and mesenteric blood flow. It is therefore useful in the treatment of gastric ulcer and variceal bleed. It may also be used in treatment of acute pancreatitis as it decreases exocrine pancreatic secretion. It is used in the treatment of acromegaly as it decreases growth hormone level.

Feedback System The anterior pituitary hormones (TSH, ACTH, LH and FSH) stimulate the respective target glands to secrete hormones. These hormones in turn exert a negative feedback effect on their respective pituitary cells. In contrast, PRL and GH have no well-defined end organ hormone secretion that can exert a negative feedback.

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Hypothalamic hormones

Anterior pituitary hormones

Corticotrophin releasing factor (CRF)

Adrenocorticotrophic hormone (ACTH)

Arginine vasopressin (AVP)

*LPH

Gonadotrophin releasing hormone (GnRH)

Luteinising hormone (LH)

Growth hormone releasing hormone (GHRH)

Follicle stimulating hormone (FSH)

Growth hormone release inhibitory hormone (GHRIH)

Growth hormone (GH)

Thyroid releasing hormone (TRH)

Thyroid stimulating hormone (TSH) Prolactin (PRL)

(β-melanocyte stimulating hormone)

*β

melanocyte stimulating hormone (MSH) amino acid sequence is contained within β lipotrophin (LPH) which in turn is the C-terminal part of the ACTH precursor molecule, pro-opiocortin. The function of LPH is however not definitely known. MSH produces pigmentation of the skin. Of the MSH, LPH and ACTH hormones, ACTH is the most important hormone causing pigmentation.

Neurohypophysis The posterior pituitary lobe (neurohypophysis) contain neural fibres which arise from the supraoptic and paraventricular nuclei of the hypothalamus. The hormones secreted by posterior pituitary are vasopressin (ADH) and oxytocin.

HYPOPITUITARISM Aetiology This may be due to lesion in the hypothalamus or pituitary.

Hypothalamic Causes Congenital * —— Deficiency of GnRH ( Kallmann’s syndrome) —— Deficiency of TRH —— Deficiency of GHRH —— Deficiency of CRF zz Acquired —— Tumours (craniopharyngioma, glioma) —— Granulomas (sarcoidosis, histiocytosis-X and TB) —— Head injury, surgery (stalk section) —— Radiotherapy. Note: *Kallmann’s syndrome zz It is inherited as an autosomal dominant, autosomal recessive or sex-linked disorder zz Hypogonadotrophic hypogonadism is present zz Anosmia zz Midline anatomical defects are seen. zz

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Endocrine and Metabolic Disorders

Pituitary Causes zz zz zz zz zz

zz zz

zz

Infarction (Sheehan’s syndrome—postpartum) Infection (TB, syphilis, fungus, pyogenic, toxo­plasmosis) Granulomas (sarcoidosis, histiocytosis-X) Autoimmune lymphocytic hypophysitis Neoplasm (pituitary adenoma, craniopharyngioma and metastatic deposit) Haemochromatosis Idiopathic and genetic (deficient pituitary hormone production) Aneurysm of internal carotid artery.

Clinical Features This depends upon the underlying relation. If hypothalamus is affected, there may be isolated deficiency of the releasing hormone leading to clinical manifestation that reflects the deficiency. In lesions of the pituitary gland such as an expanding non-functioning pituitary tumour GH secretion is the earliest to be lost followed by LH, ACTH, and TSH. Loss of GH secretion does not produce obvious symptoms and signs in adults. Decreased LH secretion results in loss of secondary sexual character, loss of libido and impotence in males and amenorrhoea in females. ACTH deficiency causes secondary adrenal insufficiency. Hormone deficiency Clinical manifestation 1.

GnRH

2. 3. 4.

TRH GHRH CRF

Delayed puberty, obesity and associated anosmia Hypothyroidism Short stature Adrenal insufficiency

Clinical indications for detailed pituitary stimulation tests: To assist in diagnosis of pituitary/hypothalamic disease zz To assess the need for GH replacement zz To determine the feasibility of treating patients with hypothalamic-hypopituitarism with GnRH or GHRH. zz

Interpretation Glucose must fall below 40 mg/dl. Normal values are: GH > 20 mU/l, peak cortisol > 550 mmol/l, TSH at 20 min 3.9 to 30 mU/l, TSH at 60 min, 3.0 to 24 mU/l. Values lower than these indicate some pituitary deficiency. Contraindications Epilepsy, IHD and severe hypopituitarism.

Treatment The principle of management is to prevent and provide adequate substitution of the deficient hormone. zz Hypopituitarism is usually treated by measurement of end organ hormones thyroxine, cortisone, testosterone (male), oestrogen and progesterone (female). zz Pituitary hormones are replaced in only three conditions: —— GH replacement in short statured patients with unfused epiphysis —— Patients desiring fertility —— Prolactin therapy is rarely needed.

Deficiency

Hormone replacement

Dose

ACTH

Cortisol (hydrocortisone) Cortisone Prednisolone

20 mg 10 AM/ 10 mg 6 PM 25 mg AM/12.5 mg PM 5 mg AM/2.5 mg PM

TRH

L-thyroxine

0.1–0.15 mg/day (single dose orally)

LH, FSH In female (Premenopausal)

Cyclical oestrogen therapy with Ethinyl oestradiol Progestogen (medroxy Progesterone acetate)

20–30 µg for 3 weeks

Male

Human chorionic gonadotrophic hormone LH and FSH Testosterone (Pergonal)

3000 IU IM/week

GH

Biosynthetic

24 U/m2/week subcutaneously

Male

Testosterone transdermal patch

2.5–5 mg daily

Adult women

Dehydroepiandrosterone

50 mg in AM

Investigations Triple stimulation test Measure basal levels of serum T4, TSH, oestradiol, testosterone, FSH, LH, PRL, cortisol, glucose, GH. zz Triple stimulation test is performed by stimulation with injection of: —— Insulin: Inject insulin IV 0.15 U/kg (0.3 U/kg if acromegaly or Cushing’s syndrome is present or 0.05 U/kg if marked hypopituitarism is present). —— TRH: Inject 200 µg of TRH IV —— GnRH: Inject 50 µg of gonadotrophin-releasing hormone (GnRH) IV. Flush the syringe with citrate every time before injecting the other hormone. zz Collect blood samples as follows: FSH, LH, TSH at 20 min and 60 min. GH, cortisol, glucose at 30, 60, 90 and 120 mins. zz At the end of procedure, give the patient a good breakfast. zz

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5 mg/day from day 14–21 of menstrual cycle

75 IU 3 times/week 250–500 mg IM every 2–4 weeks

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HYPERSECRETORY DISORDERS OF ANTERIOR PITUITARY

zz zz zz zz

Acromegaly and Gigantism

zz

Excess of GH secretion, if occurs before fusion of epiphyses of long bones leads to gigantism and if it occurs after fusion of epiphyses leads to acromegaly.

Acral enlargement (Fig. 10.3) Large hands (difficult to remove rings) zz Large feet (increase in shoe size, increased width). zz

Other bone changes Growth of lower jaw-prognathism. Teeth are widely spaced zz Skull growth-prominent supraorbital ridges with large frontal sinuses zz Kyphosis.

Aetiology of Acromegaly

zz

Excess Growth Hormone Secretion zz

zz

zz

Pituitary—98% —— Granulated GH cell adenoma—60% —— Mixed GH and PRL cell adenoma—25% —— Mammosomatrope cell adenoma—10% —— Plurihormonal adenoma —— GH cell carcinoma/Metastasis —— MEN 1 (GH cell adenoma) —— McCune Albright syndrome —— Ectopic sphenoid/parapharyngeal sinus pituitary adenoma Extra-pituitary —— Pancreatic islet cell tumour —— Lymphoma Excess growth hormone-releasing hormone —— Central „„ Hypothalamic hamartoma „„ Choristoma „„ Ganglioneuroma —— Peripheral „„ Bronchial carcinoid „„ Pancreatic islet cell tumour „„ Adrenal adenoma „„ Small cell lung cancer „„ Pheochromocytoma.

Clinical Features (Fig. 10.1) Soft tissue changes zz Skin thickening zz Increased sweating (due to enlarged sweat glands or hypermetabolism) zz Enlargement of lips, nose and tongue zz Increased heel pad thickness (Fig. 10.2) zz Arthropathy (Due to bony overgrowth and deformity around large weight-bearing joints) zz Myopathy Carpal tunnel syndrome (compression of the median nerve by hypertrophied fibrocartilaginous tissue of the wrist) zz Visceromegaly (e.g. thyroid, heart, liver) zz Sleep apnoea (both central and obstructive)

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Galactorrhoea Hypertriglyceridemia Colonic polyps Deepened voice Abnormal PFT results.

Metabolic defects Glucose intolerance (25%) zz Clinical diabetes mellitus (10%) zz Hypertension (25% associated increase in total exchan­geable sodium). zz

CVS—Changes Hypertension zz LVH zz Cardiomyopathy zz Arrhythmias zz

Effects of tumour mass Headaches zz Visual disturbances—diplopia, field defect zz Hypopituitarism—decreased libido, erectile dys­ function, menstrual dysfunction. zz

Long-term complications Atheromatous disease zz Colonic cancer. zz

Lab Diagnosis zz

zz

zz

The most reliable test involves the assessment of GH responses to oral glucose. In acromegaly, glucose does not suppress growth hormone (GH) and in about 50% of patients there is paradoxical rise. (In normal subjects GH is suppressed to below 2 mU/litre). In 70% of acro­ megalics, there is a GH rise after TRH adminis­tration (this is not found in normal subjects). Failure of GH suppression to < 0.4 µg/L within 1 to 2 hours of an oral glucose load (75 gm). In the absence of serious concurrent illness, serum levels of IGF-I are uniformly elevated in patients with active acromegaly. Two or three random measurements of serum GH should also be obtained to provide an average pretreatment base line value.

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Fig. 10.1  Clinical features in acromegaly

Fig. 10.2  Acromegaly—increased heel pad thickness

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Fig. 10.3  Acromegaly—spade like fingers and toes

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Anatomic evaluation of the sellar contents by radiologic examination (CT or MRI scan) and a formal visual field examination (Figs 10.4 to 10.7).

Treatment Surgery: Transsphenoidal surgery is the preferred primary treatment. zz Drugs are adjuvants to surgery in preoperative reduction of tumour size. zz

Drugs: Octreotide: It is a synthetic analogue of somatostatin given in a dose of 50 µg tid and is increased upto 1500 µg/day. Sandostatin: LAR is a sustained release long acting formulation of octreotide incorporated into micro­ spheres that sustain drug level for several weeks after IM injection 30 mg IM every 6 weeks. Lanreotide: It is a slow release depot somatostatin preparation that suppresses GH and insulin like growth factor 1 hypersecretion for 10 to 14 days after 30 mg IM injection. —— It produces shrinkage of GH producing adenomas —— All symptoms improve except bone changes and osteoarthritis which do not increase but can be stabilised. zz Bromocriptine: The clinical effects of this drug are variable. It is used as an adjunctive therapy following radiation or surgery. zz Pegvisomant: A new GH antagonist that lowers IGF-1 to normal level in almost all patients. The dose is 10 to 30 mg SC daily. zz Radiation (External radiation therapy or high energy stereotactic techniques are used as adjuvant therapy for acromegaly). zz

Fig. 10.4  Widened sella turcica

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Fig. 10.5  CT-brain sagittal section—pituitary tumour

Fig. 10.6  MRI brain—pituitary tumour

Fig. 10.7  MRI brain sagittal section—pituitary tumour

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Hyperprolactinaemia It is the most common biochemical disturbance of pituitary function.

Causes zz

zz

zz

zz

Altered physiologic states: —— Sleep —— Stress —— Postprandial, especially in women —— Coitus —— Pregnancy, including pseudocyesis —— Nursing or nipple stimulation —— Chest wall or spinal cord lesions —— Hypoglycaemia —— Hypothyroidism —— Chronic renal failure. Drugs —— Phenothiazines —— Butyrophenones (e.g. haloperidol) —— Reserpine —— Alpha methyl dopa —— Opiates —— Cimetidine —— Oestrogens. Decreased delivery of prolactin-inhibiting factor to pituitary —— Stalk section —— Hypothalamic destruction. Prolactin-secreting pituitary tumours —— Prolactinoma.

Clinical Features zz

zz

zz

zz

In females, it produces amenorrhoea with or without galactorrhoea. In males, it produces decreased libido and impotence or symptoms due to intracranial mass lesion. Galactorrhoea is uncommon in men, because the male breast has not been “primed” with endogenous oestrogen. Some women with PRL-secreting tumours also manifest hirsutism and elevated serum androgens.

Lab Diagnosis zz

zz

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Since aetiological factor is multifactorial, careful history will avoid unnecessary investigations. Plasma prolactin levels greater than 30 to 40 ng/ml almost invariably indicate a diagnosis of prolactinoma (upper limit of normal for many assays is < 15 to 20 ng/ml).

Three important conditions to be excluded are renal failure, pregnancy and hypothyroidism before investigations. Plasma prolactin level correlates with the tumour mass size. Small lesions (microadenomas) can give rise to moderate elevation of plasma prolactin levels which can also occur in the other above-mentioned conditions causing hyperprolactinaemia. However, a large sized tumour (macroadenoma) can cause enormous elevation of plasma prolactin levels (> 200 ng/ml). zz Stimulation test is useful to differentiate PRL secreting tumours from other conditions causing hyperprolac­ tinaemia. TRH stimulation test will result in 100% elevation of serum prolactin level over the basal value in patients with hyper PRL due to other causes. The serum prolactin level does not show any significant increase, when hyper PRL is due to PRL secreting tumours. zz

Treatment Medical treatment is the treatment of choice. Dopamine agonist therapy. ——  Bromocriptine 2.5 to 15 mg/day 8 to 12 hourly orally. —— Cabergoline 250 to 1000 microgm twice weekly. —— Quinagolide 50 to 150 mg/day OD orally. —— Pergolide mesylate 3 mg daily —— Lisuride „„ It causes shrinkage of prolactin secreting tumours „„ It abolishes galactorrhoea and restores normal reproductive function. zz Surgery and radiotherapy are not usually necessary. Surgery is indicated in the following: —— Visual field defect persisting despite medical therapy —— Drug intolerance. zz Assess plasma prolactin level every 6 months while on therapy and every 2 years on cessation of bromocriptine therapy. zz Ninety per cent of cases of prolactin secreting macroadenomas respond to medical management. Women with prolactin secreting macroadenoma should not become pregnant unless the tumour has been resected (risk of tumour enlargement). zz Pituitary imaging should be repeated every 3 to 6 months in cases of prolactin secreting macro­ adenomas to assess the mass size. zz

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Pituitary Tumours

Clinical Features

Nearly all tumours are almost always benign. It contributes to 10% of all intracranial neoplasms. zz Chromophobes (70%): These usually produce hypopitui­tarism due to pressure effect. Sometimes it may secrete hormones like PRL, ACTH, or GH. zz Acidophilic (15%): It may secrete GH and PRL (10%). zz Basophil (15%): It secretes ACTH (pressure effect is rare).

The clinical features can be due to either pressure effect or hyper- or hyposecretion of pituitary hormones. The features are hydrocephalus, seizures, erosion of floor of sella leading to CSF rhinorrhoea, headache (dura stretching), bitemporal hemianopia initially starting in the upper field (optic chiasma, optic nerve tract), diplopia and strabismus and lesions of IIIrd, IVth and VIth cranial nerves (cavernous sinus involvement).

Pituitary adenomas: Microadenomas (< 10 mm in diameter): Clinical manifestation only when they secrete excess hormone. They do not cause mass effect or hypo­pituitarism. zz Macroadenoma (> 10 mm in diameter): Clinical mani­­ festations can be either hyperpituitarism or hypopituitarism or mass effect (headache, visual field loss) zz Secretory adenomas produce prolactin, GH or ACTH zz Non-secretory macroadenomas may cause hypo­ pituitarism or mass effects zz Non-secretory microadenomas are common incidental radiographic findings (10% of the normal population) and therapy is not needed. zz

Lab Diagnosis zz

zz

zz

Secretory Tumours zz zz zz zz zz zz

PRL 35% GH 20% GH + PRL 7% ACTH 7% FSH and LH 1% No hormone 30%

zz

Treatment zz

Familial Pituitary Tumour Syndromes

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Plain X-rays (X-ray skull to view the sella—cone view sella) —— It demonstrates the enlargement of sella turcica and erosion of the clinoid processes —— Suprasellar calcification (craniopharyngioma) —— A double floor of the sella. Computed tomography: It demonstrates the suprasellar and parasellar anatomy in patients with macroadenoma (more than 10 mm diameter) and microadenoma (less than 10 mm diameter). Cisternography: It is usually done in conjunction with CT scanning to demonstrate an empty sella, the superior aspect of a pituitary tumour or a hypo­ thalamic lesion. MRI (Fig. 10.8).

Category

Gene Mutated Clinical Features

Multiple endocrine neoplasia 1 (MEN 1)

MEN 1 (11q13)

Hyperparathyroidism Pancreatic neuroendocrine tumours Foregut carcinoids Adrenal adenomas Skin lesions Pituitary adenomas (40%)

Multiple endocrine neoplasia 4 (MEN 4)

CDKNIB (12p13)

Hyperparathyroidism Pituitary adenomas Other tumours

Carney complex PRKARIA (17q23-24)

Pituitary hyperplasia and adenomas (10%) Atrial myxomas Schwannomas Adrenal hyperplasia Lentigines

Familial pituitary AIP (11q13.3) adenomas

Acromegaly/gigantism

zz

In elderly and terminally ill patients, no active intervention is needed other than end organ hormone replacement or inhibition of hypersecreting tumours. Surgery can be done by the transsphenoidal or transfrontal approach.

Fig. 10.8: MRI pituitary microadenoma-anterior pituitary

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Endocrine and Metabolic Disorders Radiotherapy is useful for small and medium size tumours with pressure effect and also when surgery is contraindicated. It is a follow-up modality in invasive and incompletely removed tumours. It is contraindicated as a sole therapy in large tumours with major visual defect. Also contra­indicated in females with prolactinoma who wish to restore fertility. Radiotherapy is also contraindicated in acromegaly patients with serum GH levels >50 ng/ml prior to treatment. • – Medical management is the primary modality of treat­ment for prolactinoma. Pressure effect is also corrected with hormonal therapy. – Medical treatment is an adjunctive therapy in acromegaly and TSH secreting tumours. – There is no role for medical therapy in nonfunctioning tumours. zz Adjunctive treatment with octreotide in GH and TSH secreting tumours may be given. zz

Pituitary Hyperplasia It occurs in long-standing primary endocrine end organ failure, as a result of hypersecretion of appropriate trophic hormones. This condition should not be mistaken for pituitary neoplasm. Suppression test is useful to diagnose this condition. Replacement with specific end organ hormone therapy results in gradual regression of pituitary hyperplasia and sella size.

Empty Sella Syndrome Types

by surgery, radiotherapy, or following shrinkage after medical therapy.

Treatment zz zz

No treatment other than reassurance (primary) Hormone replacement may be useful in secondary empty sella syndrome of pituitary origin.

Craniopharyngioma It is a tumour of developmental origin arising from Rathke’s pouch. The peak incidence is in the second decade of life. Craniopharyngiomas are cystic in 60% of cases, solid in 15% of cases and combined cystic and solid in 25% of cases. zz It does not secrete any hormone zz Bimodal age of presentation—childhood and above 60 years zz Most common childhood intracranial tumour zz Most common cause of hypopituitarism in children zz 50% present as growth failure in childhood zz Adults may present with amenorrhoea, decreased libido, hypothalamic symptoms (central diabetes insipidus, hyperphagia, sleep disturbance) or tumour mass effect. The tumour originates above the sella. It causes pressure on the optic chiasma, hypothalamus and pituitary, resulting in increased intracranial pressure, visual defects, endocrine hypofunction (e.g. GH deficiency in children), hyperprolac­tinaemia and mental deficiency.

Investigations zz

X-ray skull—enlargement or erosion of sella with supra- or intrasellar calcification CT and MRI are useful.

Primary

zz

Empty sella syndrome is due to congenital incomplete diaphragma sella which allows CSF to enter into the sella as an extension of the subarachnoid space. Normal pulsatile CSF pressure then compresses the pituitary and gradually expands the sella turcica. Primary empty sella is most often found in obese, middle-aged women. This may result in compression of the pituitary stalk and thereby decreased transport of hypothalamic releasing hormones to the anterior pituitary (usual hormone deficiencies are those of gonadotrophic hormone and GH). There is no abnormality in function of the posterior pituitary gland.

Treatment

Secondary Empty sella syndrome is found in various pituitary tumours following infarction, ablation, destruction

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zz zz zz

Surgery Radiation therapy Hormone replacement therapy.

DISORDER OF THE NEUROHYPOPHYSIS Diabetes Insipidus Diabetes insipidus (DI) is the excretion of a large amount of dilute urine (hypotonic polyuria). The criteria to be satisfied in order to establish this diagnosis are:

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zz zz

Polyuria of more than 3 litre/day (more than 50 ml/kg/day) Urine osmolality less than 300 mOsm/kg Urine specific gravity less than 1.010.

Aetiology Diabetes insipidus may result from any one of the three defects: zz Inadequate secretion of arginine vasopressin (AVP) or antidiuretic hormone (ADH) known as central, or neuro­genic DI. zz Impaired renal responsiveness to AVP, known as nephrogenic DI. zz Increased water intake of primary polydipsia, known as dipsogenic DI.

Central DI Causes of Central DI zz zz

Familial (autosomal dominant) Acquired —— Idiopathic —— Trauma or surgery to the hypothalamus-posterior pituitary region —— Tumours (craniopharyngioma, meningioma, metastatic carcinoma, lymphoma, carcinoma of breast and lung) —— Infection (encephalitis, meningitis) —— Granulomatous disease (sarcoidosis, histio­cytosis, Wegener’s disease) —— Vascular disorders (aneurysm, Sheehan’s syndrome, aortocoronary bypass) —— Drugs-diphenyl hydantoin and alcohol —— Autoimmune-lymphocytic hypophysitis (rare).

Criteria to Diagnose Central DI zz

zz zz

Inappropriately dilute urine in the presence of strong osmotic or non-osmotic stimuli for AVP secretion. Absence of intrinsic renal disease. A rise in urine osmolality following the adminis­tration of AVP.

Clinical Features Central DI manifests itself clinically when AVP secretory capacity is reduced by more than 75%. The cardinal symptoms of DI are polyuria, thirst, and polydipsia. Urine volume varies between a few litres per day in partial DI to 20 litres per day in complete DI, and the onset being abrupt.

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The patient has intense thirst and has a preference for cold or iced drinks. If access to water is interrupted, hyperosmo­lality develops rapidly, and CNS symptoms such as irritability, mental dullness, ataxia, hyper­ thermia, and coma can develop. Lab Diagnosis zz

zz zz

zz

Large urine volume (usually greater than 3 litres per day) Urine osmolality less than 300 mOsm/kg Minimally elevated plasma osmolality of greater than 300 mOsm/kg Inappropriately low serum AVP levels despite slightly elevated plasma osmolality.

Water Deprivation Test Water intake is restricted until the patient loses 3–5% of body weight (avoid excessive dehydration) or until three consecutive hourly urinary osmolality values are within 10% of each other. 5 U of aqueous vasopressin is given subcutaneously and urinary osmolality is measured before and 60 minutes after injection. The inference is given in the following table. Condition

Urinary osmolality

Plasma vasopressin (pg/ml)

Increase in urinary osmolality with vasopressin SC

Normal

>800

>2

Little or no increase

Complete central DI

500

800 mOsm/kg (as urine is concentrated normally), whereas in patients with diabetes insipidus the urine osmolality remains low (due to failure to concentrate urine normally). The plasma osmolality rises in both conditions. Having detected the presence of DI, it is now possible to differentiate between central and nephrogenic DI. Exogenous desmopressin 2 µg IM or 20 µg intranasally is given and then urine is collected hourly for the next 4 hours. In patients with central DI, the urine osmolality will increase > 800 mOsm/kg. This does not occur in patients with nephrogenic DI, as the exogenous AVP has no action on the renal tubules. Hypertonic saline infusion test: A solution of 3% saline is infused to raise serum sodium to 145 to 150 mEq/L. Blood samples are obtained for measurements of serum osmolality and plasma AVP levels. Patients with dipsogenic DI and nephrogenic DI exhibit normal stimulation of AVP release in response to the hyper­ tonicity, whereas patients with central DI exhibit little or no rise in plasma AVP levels. MRI – T1W image of hypothalamus and pituitary. No bright spots – pituitary or nephrogenic DI. Presence of bright spots – Dipsogenic DI.

Syndrome of Inappropriate Antidiuretic Hormone Secretion Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterised by hyponatraemia and submaximal urinary dilution caused by a sustained release of AVP in the absence of osmotic and non-osmotic stimuli. SIADH usually results from a disease or an agent that enhances AVP release or action.

Causes of SIADH zz

zz

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Neoplastic diseases —— Carcinoma (lung, pancreas, duodenum, bladder, prostate) —— Lymphoma, leukaemia —— Ewing’s sarcoma, mesothelioma —— Thymoma (carcinoid). Pulmonary disorders —— Pneumonia —— Tuberculosis —— Asthma, pneumothorax

Cavitation, abscess Positive pressure breathing —— Empyema —— Cystic fibrosis. Central nervous system disorders —— Head injury —— Meningitis, encephalitis, abscess —— Guillain-Barré syndrome —— Cerebrovascular accident —— Brain tumours —— Epilepsy —— Porphyria —— Peripheral neuropathy —— Hydrocephalus —— Shy-Drager syndrome —— Cavernous sinus thrombosis —— Multiple sclerosis —— Psychosis, delirium tremens. Drugs —— Desmopressin, oxytocin —— Chlorpropamide —— Clofibrate —— Vincristine, vinblastine —— Cyclophosphamide —— Carbamazepine —— Phenothiazines —— Haloperidol —— Tricyclic antidepressants —— Monoamine oxidase inhibitors —— Nicotine —— Thiazide diuretics. —— ——

zz

zz

In patients with SIADH there is a persistent production of AVP or AVP-like peptide despite body fluid hypotonicity. As a result of the sustained release of AVP, patients retain ingested water and become hyponatraemic and mildly volume expanded.

Clinical Features The signs and symptoms of SIADH are those of water intoxication. In acute hyponatraemia, with serum sodium concen­ tration less than 120 mEq/L, the syndrome is manifest by somnolence, seizures, coma, and a high mortality rate. In chronic hyponatraemia, even though the serum sodium level may be less than 125 mEq/L, the patient may remain asymptomatic. When serum sodium is between 115 and 120 mEq/L, the common symptoms are anorexia, nausea, vomiting, head­ache, and abdominal cramps.

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Essential Diagnostic Criteria—SIADH zz zz

zz zz zz

zz

Treatment

Decreased plasma osmolality (100 mOsm/kg H2O) Clinical euvolemia Elevated urine Na+ concentration Absence of adrenal, thyroid, pituitary or renal insufficiency or diuretic use Abnormal water load test (Failure to excrete at least 90% of a 20 ml/kg water load in 4 hours and/or failure to dilute urine osmolality to 20

>1

Salt wasting •  Renal •  Extrarenal

Hypovolaemia Hypovolaemia

> 20 < 10

>1 diarrhoea —— Constitutional—Anorexia, weight loss Grading of eye signs NO SPECS —— No eye signs —— Only sign seen in upper eyelid —— Soft tissue involvement —— Proptosis —— Extraocular muscle affected —— Corneal involvement —— Sight loss—due to optic nerve involvement Cardiovascular symptoms are palpitations (due to AF, SVT). CCF may be precipitated in long-standing cases. Sleeping pulse rate is greater than 90 per minute. Isolated systolic hypertension can occur.

zz

zz

Metabolic symptoms are weight loss despite the increased appetite and intolerance to heat (due to increased BMR). GIT symptoms may be in the form of hyper­defaecation. It may exacerbate bronchial asthma CNS symptoms are nervousness and irritability (very common symptoms). There is fine tremor of out­s tret­c hed hands, insomnia, inability to relax and proximal muscle weakness. Acute psychosis may occur in about one-third of patients with hyper­thyroidism. Women may have amenorrhoea or oligomenor­rhoea and men may have impotence and loss of libido.

On examination, the thyroid gland may be diffusely enlarged and bruit may be heard over the gland due to increased blood flow.

Investigations zz zz

Serum free T3 and T4 levels are elevated Serum TSH level is not detectable —— Plasma TSH level > 0.1 microunits/ml excludes clinical hyperthyroidism —— Plasma level of TSH < 0.1 microunits/ml may indicate mild or subclinical hyperthyroidism and plasma free T4 is elevated —— Plasma level of TSH < 0.1 microunits/ml, but free T 4 is normal with clinical evidence of hyperthyroidism and is due to elevation of plasma T3

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TSH may also be suppressed in severe nonthyroidal illness. In this situation, a thirdgeneration TSH assay with a detection limit of 0.02 microunits/ml is helpful. Most patients with clinical hyperthyroidism have plasma TSH level < 0.02 microunits/ml. Non-thyroidal illness does not suppress TSH to this level.

High RAIU

Low RAIU

Graves’ disease

Subacute thyroiditis

Toxic multinodular goitre

Painless thyroiditis

Toxic adenoma

Graves’ disease with acute iodine load

Hashitoxicosis

Iodine induced hyperthyroidism

Choriocarcinoma

Thyroid hormone therapy

Hydatidiform mole

Metastatic functioning thyroid carcinoma

TSH secreting pituitary tumour

Struma ovarii

Thyroid uptake of radioiodine (131I) is increased The test is performed by administering I123 orally and measuring the percentage of radionuclide uptake after 4 to 24 hours. It is most useful for differentiating between high and low uptake types of hyperthyroidism and it should be performed when Graves’ disease is not evident. zz Test for presence of antibodies —— Thyroid stimulating immunoglobulin (TSI) is a marker for Graves’ disease —— TSH-receptor antibody is seen in 75% of patients with Graves’ disease —— Antimicrosomal (antiperoxidase) antibody is seen in Graves’ disease and also in Hashimoto’s thyroiditis. zz Thyroid scan with radioactive iodine is useful in patients with nodular goitre and hyperthyroidism to determine —— Whether there is an autonomous hyperfunc­ tioning nodule —— Whether multiple nodules are hyperfunctioning —— Whether the nodules are cold and the hyperfunctioning tissue is between the nodules. zz

Treatment zz

zz

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Immediate control of symptoms can be achieved with propranolol 40 mg/6 hr orally Long-term control of hyperthyroidism can be by use of antithyroid drugs, radioiodine, or surgery —— Antithyroid drugs: Carbimazole 15 mg tid initially and then reducing to 5 mg tid for 12 to 18 months, gives symp­tomatic relief. Relapse may occur in appro­ximately 70% of patients within

two years and is more common with large goitres and severe disease. Adverse reactions such as rashes and neutropenia are relatively common. There are two types of regimens for giving antithyroid drugs. i. Titration regimen: Titrate the dose every 3 to 4 weeks according to free T4 level. TSH often remains suppressed for several months and do not provide a sensitive index for treatment response. ii. Block-replacement regimen: Use high dose antithyroid drugs along with levothyroxine supplementation. 30 to 50% remission is achieved in 6 months. Among these titration regimen is preferred. —— Radioiodine ablation of the hyperfunctioning thyroid tissue may be adopted for post-meno­ pausal women and elderly men. Hypothyroidism is common after treatment, and may require replacement therapy. It can also be given in recurrent hyperthyroidism. When given for a fertile female, conception must be postponed for one year. —— Surgery should be undertaken only after the thyrotoxic crisis has been controlled. Hypothyroidism is common and relapse of thyrotoxicosis and hypo­p arathyroidism may occur. Surgery is indicated in presence of large goitres causing stridor or dysphagia or in patients not responding to adequate medical treatment. i. A thionamide is given until the patient is nearly euthyroid. ii. Supersaturated potassium iodide 40 to 80 mg (1–2 drops) bid 1 to 2 weeks before surgery.

Management Options for Hyperthyroidism of Graves’ Disease Management

Indications

Antithyroid drugs

First episode in patients less than 40 years

Subtotal thyroidectomy

i. Recurrent hyperthyroidism after course of antithyroid drugs in patients less than 40 years ii. Initial treatment in males with large goitres and in those with severe hyperthyroidism (total T3 > 9 nmol/litre) iii. Poor drug compliance

Radioiodine

i. Patients > 40 years ii. Recurrence following surgery irrespective of age iii. Other serious illness irrespective of age

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zz



iii. Atenolol 50 to 100 mg daily two weeks before surgery to reduce the heart rate < 90/min. iv. Both thionamide and iodide can be stopped postoperatively. Exophthalmos is best treated with high dose cortico­ steroids but may require tarsorrhaphy and/or orbital decompression. Cardiac arrhythmias especially AF may respond poorly to digoxin and β-blockers are often required. Once the patient is euthyroid, cardioversion may be considered. Warfarin should be added.

Thyrotoxic Crisis (Thyroid Storm) In this condition, there is rapid deterioration of thyrotoxicosis with hyperpyrexia, severe tachycardia, high output cardiac failure and extreme restlessness. It is usually precipitated by stress or infection in a patient with inadequate control of his thyrotoxic state or during thyroid surgery when the thyrotoxic state of the patient had not been adequately controlled in the preoperative state, or when patient with hyperthyroidism is treated with radioiodine. It is a medical emergency. Treatment is started imme­ diately with: zz Propranolol 80 mg/6 hrs orally (it may be given IV in a dose of 1–5 mg 6th hourly) zz Potassium iodide 60 mg daily, orally or sodium iopodate 500 mg per day orally may be given (reduces T3 level to normal in 48–72 hours) zz Carbimazole 60–120 mg daily (inhibits synthesis of new thyroid hormones) zz Injection dexamethasone 2 mg IV 6th hourly zz Fluid replacement zz Appropriate antibiotics for treatment of underlying infection, if present. RAI Therapy zz

zz

zz

zz

zz

zz zz

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A single dose permanently controls hyperthyroidism in 90% of cases. A 24-hour RAIU is usually measured to calculate the required dose. In fertile women, do a pregnancy test before RAI therapy. Thionamides interfere with RAI therapy and should be stopped 3 days before treatment. Iodine treatment should be stopped 2 weeks before treatment. Most patients require 10 mCi of radioactive iodine. If hypothyroidism develops, thyroxine therapy is initiated.

zz

zz zz

If symptomatic hyperthyroidism persists after 6 months, RAI therapy is repeated. It does not increase the risk of malignancy. Therapy is very safe in non-pregnant fertile women. Conception is permitted after an interval of 6 months. No increase in congenital abnormality in the offspring of women after RAI therapy. The radiation to the ovaries is meagre.

Hyperthyroidism in Pregnancy zz

zz

zz zz zz

If TSH is < 0.1 microunits/ml, confirm the diagnosis by measuring plasma T4. PTU should be used to treat hyperthyroidism in pregnancy. RAI therapy is contraindicated in pregnancy. Atenolol 25 to 50 mg PO can be used. Neonate should be monitored for hyperthyroidism.

Neonatal Hyperthyroidism (Neonatal Graves’ Disease) zz

zz

zz

Uncommon disorder in infants born to mother with Graves’ disease Their mothers with Graves’ disease have very high thyrotropin receptor stimulating antibody (TRS Ab) concentration It occurs as a result of trans-placental passage of TRS Ab.

In most infants, neonatal Graves’ disease resolves spontaneously in 3 to 12 weeks as the maternal TRS Ab disappears from infant’s blood. Sometimes thyrotoxi­ cosis can persist for years and have long-term sequelae. Many of these infants have an activating mutation of TSH receptor. Neonatal hyperthyroidism has also been reported in McCune-Albright syndrome caused by an activating mutation in α subunit of a protein.

Clinical Features zz zz zz zz zz zz zz zz zz zz zz

zz

Fetal tachycardia- >160/mt Intrauterine growth retardation Low birth weight Microcephaly and ventricular enlargement Exophthalmos Goitre can cause airway obstruction Hyperactive irritable infants Increased sweating Increased appetite Hepatosplenomegaly and jaundice Other symptoms and signs—vomiting, diarrhoea, jaundice, convulsions, coma, death. Mortality—30%

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Endocrine and Metabolic Disorders Investigations zz zz zz

„„

Maternal TRS Ab level > 500% of control values Abnormally elevated T4, T3 and decreased TSH X-ray—accelerated bony maturation.

Complications zz zz zz zz zz zz

Cardiac arrhythmias Cardiac failure Respiratory obstruction Craniosynostosis Intellectual impairment Pituitary hypothyroidism.

Management zz zz

zz

zz

Mild cases: Observation/propranolol Moderate/severe cases: Immediate vigorous treatment —— Propylthiouracil 5 to 10 mg/kg/day or Methimazole 0.5 to 1.0 mg/kg/day 8th hourly —— Propranolol 2 mg/kg/day and if no improve­ment in four days, double the dose can be used —— PTU 600 mg stratum followed by 200 to 300 mg qid PO. —— Adjunctive therapy—digoxin for heart failure Relief of airway obstruction due to goitre: Mild cases—simple neck extension Severe cases—ET intubation —— Nasal oxygen.

Clinical Features Congenital hypothyroidism Symptoms: Lethargy, somnolence, constipation, poor feeding/sucking, cold to touch, delayed dentition and mental retardation (Figs 10.14 and 10.15). Signs Dry, cool, mottled skin, hoarse cry, coarse face, broad flat nose, large protruding tongue, puffy face. zz Abdomen—protuberant, umbilical hernia, hypotonia zz Skull—large posterior fontanelle. zz

Improvement is often seen in 7 to 10 days with remission by 3 to 6 weeks.

Investigations

Hypothyroidism Hypothyroidism is the condition resulting from insufficient synthesis of thyroid hormones. Hypothyroidism dating from birth is termed cretinism. The term myxoedema indicates severe hypothyroidism in which there is accumulation of hydrophilic muco­ polysaccharides in the skin and other tissues. In children, the earlier the age of onset of hypo­ thyroidism, the greater the chance of brain damage especially before 3 years. Thyroxine is essential for growth and development of the CNS during the first 3 years. After 3 years, most of the effects of hypothyroi­dism are reversible.

Causes zz

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Primary thyroid diseases (accounts for 95% of cases): —— Thyroprivic „„ Congenital developmental defects „„ Primary idiopathic

Post-ablative (radioiodine or surgery) Post-radiation (e.g. lymphoma) —— Goitrous „„ Heritable biosynthetic defects maternal transmission „„ Iodine deficiency „„ Drug induced (PAS, iodide, phenylbutazone, lithium and amiodarone) „„ Chronic thyroiditis—(Hashimoto’s disease) —— Recurrent hypothyroidism Suprathyroidal (accounts for 5% of cases): —— Pituitary—postpartum pituitary necrosis (Sheehan’s syndrome) —— Hypothalamic. Drugs that cause hypothyroidism: —— Iodine containing drugs —— Lithium —— Interferon-α —— Interleukin-2 —— Thalidomide. „„

zz zz zz zz



Cord blood T4, TSH Serum T4 and TSH RAIU—optional X-ray—Knee—Lower femoral/upper tibial epiphyses absent Foot—Cuboidal epiphysis absent Skull—Sella size—supraseller calcification, wide sutures, large fontanelles.

Acquired Hypothyroidism Symptoms Juvenile

Short stature (upper segment more than the lower segment) Delayed dentition Poor performance at school Delayed sexual maturation

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Manual of Practical Medicine

Fig. 10.14  Congenital hypothyroidism

Fig. 10.15  A child with cretinism



Proximal myopathy (Hoffman’s syn­ drome adults) Kocher-Debre-Semalaigne syndrome (children) Adult (Figs 10.16 to 10.18) General Tiredness, lethargy, somnolence, weight gain, poor appetite, cold intolerance Skin Cool, coarse, dry and flaky Colour Pallor/yellowish due to carotenaemia Hair Sparse, brittle, loss of eyebrows Nails Brittle Skeletal Short stature Muscular Pain, stiffness, cramps, muscle weak­ ness, hypotonia, delayed relaxation

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phase of deep tendon reflexes (pseudomyotonic reflex) Neurological Higher functions show memory impair­ment and mental slowing and depression, 8th N deafness Carpal tunnel syndrome Sensory ataxia (if subacute combined degeneration is present) Cerebellar ataxia Acute encephalopathy Cardiovascular Bradycardia System Diastolic hypertension (increased peri­pheral vascular resistance) Cardiomegaly with pericardial effusion Gastrointestinal system Macroglossia, GIT hypomotility, Ascites, Achlorhydria Reproductive system   Female Menorrhagia, amenorrhoea, inferti­lity and abortion   Male Impotence, scrotal effusion Metabolic Hypothermia, hypercholes­terolae­mia, dec­rea­sed insulin requirement Eye Yellow sclera Respiratory Vocal cord oedema leads to low system pitched and hoarse voice (due to infiltration of mucopolysaccharides), pleural effusion, respiratory muscle weakness Haematology Normocytic normochromic anaemia, Iron deficiency anaemia (menor­rhagia), Megaloblastic anaemia (associated with pernicious anaemia)

Myxoedema Coma (Hypothermic Coma) It is a state of hypothermia (body temperature may drop to as low as 25° C), hypotension, convulsions, hypo­glycaemia, hyponatraemia, hypoventilation and coma. Precipitating factors Cold, stress, sepsis, surgery, CNS depressant drugs Increasing age Pneumonia, congestive cardiac failure, MI, GI bleeding, CVA, hypo­ glycaemia, hypoventilation and dilutional hyponatraemia. 100% mortality if untreated.

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769

Fig. 10.16  Clinical features of hypothyroidism

Fig. 10.17  Calf muscles hypertrophy— Hoffman’s syndrome

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Fig. 10.18  Face in hypothyroidism

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770

Manual of Practical Medicine Difference between Primary and Secondary Hypothyroidism

zz zz

Features

Primary hypothyroidism

Secondary hypothyroidism

1.

Skin

Coarse

Soft and silky

2.

Blood pressure

Hypertension or normal

Hypotension or normal

zz

3.

Menstrual cycle

Menorrhagia

Amenorrhoea

zz

4.

Trans cardiac diameter

Increased

Normal or decreased

5.

Serum TSH

Increased

Decreased

6.

Serum cholesterol

Increased

Not altered

7.

Evidence of deficiency of other pituitary hormones

Absent

Present

Subclinical Hypothyroidism zz zz zz

Investigations zz zz zz

zz zz zz zz zz

Serum thyroxine (T4) concentration Free T4 index Serum TSH concentration —— TSH elevation > 20 microunits/ml confirms the diagnosis of primary hypothyroidism. —— Mild elevation of TSH < 20 microunits/ml usually indicates mild or subclinical hypo­thyroidism. Mild elevation may also be due to nonthyroidal illness and measurement of plasma free T4 is helpful. —— In secondary hypothyroidism, TSH value is not helpful and measurement of plasma free T 4 confirms the diagnosis of hypothyroidism. —— In secondary hypothyroidism, plasma TSH cannot be used to adjust therapy, but plasma free T4 is useful to guide therapy. Serum cholesterol Serum sodium Serum CPK—MM, aldolase, LDH, SGOT ECG—Low voltage, bradycardia, T wave flattening. Echo—Pericardial effusion, ↓ pre-ejection time of LV.

Treatment zz

zz

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Replacement of the deficient hormone is the basis of therapy. The dose is 100 to 300 µg per day as single PO of thyroxine (1.6 mcg/kg/day) In elderly and those with heart disease, it is better to start with small dose 25 to 50 µg per day and then increase by 25 to 50 µg every 2 or 3 weeks until a full maintenance dose is reached. It is monitored clinically and biochemically. TSH should be maintained in lower half of normal limits.

The treatment is usually life long. In patients with pituitary hypothyroidism, thyroid hormone replacement should not be instituted until, replacement with hydrocortisone has been initiated (as it may result in adrenal crisis). If patients develop angina with thyroxine, β blocker should be added. Thyroxine dose increases by 50% in the first half of pregnancy. Periodic TSH estimation is essential to adjust the dose of thyroxine till the end of second trimester.

zz

Increased TSH but T4 and T3 remains normal Seen in 10% of those > 55 years Common after partial thyroidectomy or I131 therapy Risk of progression to frank hypothyroidism -2% and this risk doubles if thyroid autoantibodies are present.

Management zz zz

zz

Check thyroid antibodies Treat if TSH > 10 IU or with positive thyroid anti­bodies or history of previous Graves’ disease or presence of other organ specific autoimmunity In the absence of above criteria, monitor TSH annually.

Myxoedema Coma zz

zz

zz

zz zz zz

zz

L-thyroxine 400 to 500 µg IV should be given as a bolus injection, or orally through Ryle’s tube Triiodothyronine (T3) 20 µg IV every 8 hours till there is sustained clinical improvement Steroid (hydrocortisone hemisuccinate 100 mg IV 8th hourly) and IV fluids till results of serum T3, T4, TSH and cortisol are obtained. If serum cortisol level is normal, then steroid may be discontinued Subsequent parenteral maintenance dosage may be about 100 µg of L-thyroxine/day Treatment of underlying infection Rewarming the patient with electrical space blanket Ventilatory support is necessary especially in persistent hypoxaemia, hypercapnoea and respiratory acidosis. Other measures include correction of hypogly­caemia, electrolyte imbalance, broad spectrum antibiotics and high flow oxygen.

Thyroiditis These form a group of heterogeneous inflammatory disorders of varying aetiologies.

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771

Endocrine and Metabolic Disorders

Types zz zz

zz

Acute Subacute —— Granulomatous —— Lymphocytic Chronic —— Hashimoto’s thyroiditis —— Riedel’s struma.

Clinical Features zz

zz zz zz zz

zz

Acute Thyroiditis

zz

Suppurative Thyroiditis (Pyogenic or Bacterial Thyroiditis) It is a rare disorder caused by Staphylococcus aureus, streptococci, Streptococcus pneumoniae, Salmonella, E. coli. It occurs by direct introduction of infection, by trauma or by lymphatic or hematogenous spread.

Clinical Features Fever, chills, pain over the gland, anterior neck swelling and sometimes an abscess over the thyroid gland may be noticed. Lab diagnosis Leucocytosis with shift to left (immature leucocytes) zz Normal T , T 3 4 zz Radioactive iodine uptake is reduced zz Fine needle aspiration for smear and culture zz Elevated ESR. zz

Differential Diagnosis zz zz zz

zz

Subacute thyroiditis Cellulitis of anterior neck Acute haemorrhage into a thyroid cyst, adenoma or carcinoma Infected thyroglossal duct or cyst.

Treatment zz

zz

Appropriate parenteral antibiotics (according to results of culture and sensitivity) Incision and drainage if abscess is present.

Subacute Thyroiditis Granulomatous Thyroiditis (Viral or De Quervain’s Thyroiditis) This may be caused by a virus (coxsackie virus, adenovirus, mumps, ECHO, influenza, EBV) Genetic predisposition is associated with HLA BW35.

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Unilateral anterior neck pain with radiation to ear or mandible Low grade fever and malaise Sore throat Dysphagia is a common symptom Symptoms and signs of hyperthyroidism in 50% of patients Hard tender unilateral nodular enlargement of the gland There are three phases of presentation. —— Thyrotoxic phase —— Hypothyroid phase —— Recovery phase.

Lab diagnosis ESR is usually elevated > 50 mm/hr zz T and T are elevated 3 4 zz Antimicrosomal and antithyroglobulin antibodies are negative zz Radioactive iodine uptake is decreased in the acute phase due to disruption of iodine trapping mechanism. zz

Treatment zz

zz

zz

zz

In the initial phase, which lasts for 4 to 8 weeks, aspirin 600 mg 4th hourly, or other NSAIDs may be given (to decrease pain) Prednisolone 20 mg TID, and tapered by 2 mg every 2 to 3 days, after 1 week Symptoms of hyperthyroidism may be controlled with propranolol 20 to 40 mg 3 to 4 times daily orally. Antithyroid drugs are not indicated.

After the acute phase, usually patient becomes euthyroid. In severe cases, hypothyroidism may result which rarely lasts for > 2 to 3 months during which phase, 1-thyroxine 0.1 to 0.15 mg/day should be given which may be discontinued after patient attains the euthyroid state. A new syndrome of P. carinii thyroiditis has been reported which clinically simulates subacute thyroiditis, commonly seen in patients with AIDS. It is particularly common in those patients who are on aerosolized pentamidine prophylaxis for P. carinii pneumonia, as the infecting organism lodges at other sites like the thyroid instead of the lungs which are protected by the aerosolized pentamidine. Diagnosis is confirmed by fine needle aspiration and staining of P. carinii with Gomori silver methanamine.

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Manual of Practical Medicine Lymphocytic Thyroiditis (Painless Thyroiditis, Silent Thyroiditis, Lymphocytic Thyroiditis with Spontaneously Resolving Hyperthyroidism) It is a painless thyroiditis characterised by abrupt onset of hyperthyroid symptoms, elevated total and free T3 and T4 levels, and a low radioactive iodine uptake. There is a painless non-tender goitre. It is thought to be of autoimmune origin. Genetic predisposition is likely to be associated with presence of HLA-DRW3, HLA-DRW5.

Clinical Features zz zz

zz

zz

Signs and symptoms of hyperthyroidism are present. The hyperthyroid phase lasts for 6 weeks to 3 to 4 months and rarely longer. It may occur postpartum 6 weeks to 3 months after delivery. Physical examination may reveal mildly enlarged, diffuse firm, non-tender goitre.

The clinical features of painless thyroiditis is difficult to distinguish from that of Graves’ disease in the hyperthyroid phase. Clinical characteristics that are helpful in differentiating the two disorders are as follows:

Hashimoto’s Thyroiditis (Chronic Lymphocytic Thyroiditis, Chronic Thyroiditis Struma Lymphomatosa) It is an organ specific autoimmune disorder. A genetic predisposition is suggested owing to the presence of HLADR5 histocompatibility antigen. It may be associated with a variety of other organ specific autoimmune disorders as listed below: zz Endocrine disorders —— Graves’ disease —— Type 1 diabetes mellitus —— Idiopathic Addison’s disease —— Autoimmune orchitis or oophoritis —— Idiopathic hypoparathyroidism. zz Non-endocrine, organ-specific autoimmue disorders —— Pernicious anaemia —— Vitiligo —— Rheumatoid arthritis —— Idiopathic thrombocytopenic purpura —— Myasthenia gravis —— Sjögren’s syndrome —— Chronic active hepatitis —— Lupus erythematosus —— Primary biliary cirrhosis. zz Other disorders —— Renal tubular acidosis —— Down’s syndrome —— Turner’s syndrome.

Clinical features

Painless thyroiditis

Graves’ disease

1.

Onset

Abrupt

Gradual

2.

Severity of symptoms

Mild to moderate

Moderate to severe

3.

Duration of symptoms

< 3 months

> 3 months

Clinical Features

4.

Goitre

Very firm, diffuse, mildly enlarged

Soft to firm, diffuse, large

5.

Thyroid bruit

Absent

Often present

6.

Exophthalmos, dermopathy

Absent

May be present

7.

T3 and T4 ratio

< 20:1

> 20:1

8.

Radioactive iodine uptake

Suppressed

Elevated

This may present with clinical features of either hypothy­ roidism or hyperthyroidism (Hashitoxicosis) or the patient may be euthyroid, each of these manifestations presenting with or without a goitre. zz Hypothyroid phase—4 to 12 weeks zz Resolution phase zz Normal ESR zz TPO ab ( +ve)

Treatment In the initial hyperthyroid phase, patient may be treated with propranolol 20 to 40 mg 3 to 4 times/day. Carbimazole or propylthiouracil are not useful. Following hyperthyroid phase, there is a euthyroid phase lasting 3 to 6 weeks. This may be followed by a hypothyroid phase which may last for 2 to 3 months during which hormone replacement therapy with 1-thyroxine 0.10 to 0.15 mg/day may be required.

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Chronic Thyroiditis

Lab diagnosis T3, T4 and TSH may be normal zz Antithyroglobulin antibody, antimicrosomal antibody and antithyroperoxidase antibody may be detectable in 85% of patients zz Thyroid scan shows symmetrically enlarged thyroid with an irregular pattern of iodine uptake (cold nodule) zz Radioactive iodine uptake may be increased, decreased or normal zz Fine needle biopsy is done when there is a nodule or if there is growth of the gland, to rule out malignancy. zz

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Endocrine and Metabolic Disorders Treatment Thyroid hormone is given in full replacement doses (2–3 µg/kg/day) indefinitely in patients with hypothy­ roidism. This also corrects the enlargement of the gland if present and thereby relieves symptoms of compression by the enlarged gland. In patients who are euthyroid, with goitre, and who have normal serum T 4 and elevated TSH, thyroid hormone treatment is given as these patients subsequently become clinically hypothyroid. Glucocorticoids have been reported to be effective when there is rapidly enlarging goitre associated with pressure symptoms. They should be withdrawn once the symptoms have subsided. Surgery may be indicated if there is significant pressure symptoms not relieved medically.

Amiodarone Induced Toxicity

Aetiology

Clinical signs of thyroid disease Goitre Thyroid antibody Radioiodine uptake Thyroglobulin Late hypothyroidism Vascularity

AIT I

AIT II

Iodine toxicity (Jod-Basedow phenomenon) Yes

Thyroiditis

Frequent Positive Normal Normal/mildly elevated No Increased/Normal

Infrequent Negative Decreased Moderately elevated Possible Reduced

No

Treatment Type-I AIT: If possible stop amiodarone. zz Carbimazole 30 to 40 mg/day or propylthiouracil 300 to 400 mg/day and potassium perchlorate 1 gm/day for 2 to 6 weeks. zz Total thyroidectomy if stopping amiodarone is not possible. zz Radioiodine therapy. zz

Riedel’s Thyroiditis (Riedel’s Struma) It is a rare inflammatory disorder of uncertain aetiology. Clinically it presents with pressure symptoms. Physical examination reveals an extremely hard and immobile thyroid swelling. It may be associated with other focal sclerosing syndromes like retroperitoneal, mediastinal fibrosis and ascending cholecystitis. Thyroid function tests show hypothyroidism in 25% of patients. Thyroid antibodies are usually absent. Thyroid scan shows decreased iodine uptake in the involved areas. Treatment is surgical removal in those who present with pressure symptoms. Thyroid hormone replacement may be given for patients presenting with hypothyroidism, but this does not result in shrinkage of the enlarged thyroid gland. Amiodarone Effects on Thyroid Function zz zz

zz

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Acute and transient suppression of thyroid function Hypothyroidism—due to inhibitory effects of a high iodine load Amiodarone induced thyrotoxicosis (AIT)—JodBasedow effect in patients with multinodular goitre (MNG), thyroiditis like condition and incipient Graves).

Type-II AIT: zz zz

zz

Discontinue amiodarone. Prednisolone 40 mg/day along with carbimazole or propylthiouracil. Total thyroidectomy if stopping amiodarone is not possible.

In both the types follow-up for spontaneous progression to hypothyroidism is required. Amiodarone Induced Thyroid Dysfunction zz

zz

Thyrotoxicosis: Stop amiodarone and treat with antithyroid drugs. Hypothyroidism: Continue amiodarone and replace eltroxin.

Malignant Tumours of the Thyroid Primary thyroid malignancy is rare, accounting for less than 1% of all carcinomas. With the exception of medullary carcinoma, thyroid cancer is always more common in females. Thyroid malignancy can be classified according to the cell-type of origin.

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Manual of Practical Medicine Malignant Tumours of the Thyroid Cell type

Type of tumour

Frequency (%)

Age of presentation (yrs)

Approximate 10 years survival rate (%)

Spread

Therapy

Follicular cell

Papillary Follicular Anaplastic

70 10 5

20–30 30–40 > 60

95 80 40*

50

LN

Surgery

Lymphocytes

Lymphoma

5–10

> 60

10

Blood/LN

Chemo/Radio

*Patients

with medullary carcinoma as part of multiple endocrine neoplasia syndromes usually present in childhood

Medullary Carcinoma This tumour which arises from the parafollicular C-cells of the thyroid, secretes calcitonin, serotonin, ACTH and prostaglandins, as a consequence of which they may present with carcinoid syndrome and Cushing’s syndrome. Patients usually present with a firm thyroid mass. Spread is through lymphatics involving cervical lymph nodes. There is profuse diarrhoea. Serum calcitonin levels are raised and are useful in monitoring response to treatment. Despite the very high levels of calcitonin found in some patients, hypocalcaemia is extremely rare. Treatment is by total thyroidectomy with removal of affected cervical nodes.

DISORDERS OF PARATHYROID GLAND AND CALCIUM AND PHOSPHORUS METABOLISM Anatomy and Physiology Parathyroid glands are two pairs of glands situated in the posterior aspect of the thyroid gland. It secretes parathormone (PTH) by chief cells of the gland. This PTH regulates transtubular transport of calcium, phosphorus, magnesium and bicarbonate. The receptor for PTH is situated in the kidney and in osteoblasts. The metabolism of calcium and phosphorus are under the influence of three hormones: 1. Parathormone (PTH) 2. Calcitonin 3. Vitamin D. In addition to parathormone related peptides, cytokines and growth factors have a role in the metabolism.

Actions of Parathormone zz

Ch-10.indd 774

Causes tubular reabsorption of calcium, magnesium and facilitates excretion of phosphorus and bicarbonate.

zz

zz

Helps in the formation of 1, 25 (OH)2 cholecalciferol in kidney, this in turn helps in absorption of calcium from intestine. Mobilisation of calcium from bone along with vitamin D3.

Vitamin D3 (Cholecalciferol): Vitamin D is a prohormone present in skin as 7-dehydrocholesterol, which can be converted into cholecalciferol (Vitamin D3) by exposure to UV light. This is further converted to 25 OH cholecalciferol (calcidiol) by hydroxylation in the liver and finally to the active form of 1,25 (OH)2 cholecalciferol (calcitriol) by second hydroxylation in the kidney. Receptors for 1,25 (OH)2 vitamin D3 are present in number of tissues other than intestine and skeletal muscle (kidney, pancreas, vascular, smooth muscle, haematopoietic cellular elements). This indicates that vitamin D has a number of other functions which are unknown other than that of calcium phosphorus metabolism. Receptors for parathormone and vitamin D in the skeletal system are present only in osteoblasts and immature osteoclasts. Stimulation of immature osteoclasts by these hormones directly or of the mature osteoclasts indirectly through cytokine released by the osteoblasts results in bone resorption and increase in plasma calcium level. Calcitonin: This hormone is produced by parafollicular ‘C’ cells of thyroid gland. It is a hypocalcaemic hormone. Calci­ t onin secretion is stimulated by increased extracellular calcium level.

Actions of Calcitonin zz

zz

Decreased bone resorption by augmenting osteoblastic activity and inhibiting osteoclasts. Decreased tubular reabsorption of calcium resulting in increased excretion.

The measurement of plasma calcitonin has a limited clinical value except that it is a tumour marker for medullary carcinoma of thyroid.

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Endocrine and Metabolic Disorders

Parathormone Related Peptide (PTHrp) This is produced by malignant tumours and causes hyper­ calcaemia by increased osteoclastic activity and increased tubular reabsorption of calcium.

zz

zz

Causes of Hypercalcaemia Hyperparathyroidism and malignancy account for 90% of hypercalcaemia. zz Increased release of calcium from bone: —— Primary hyperparathyroidism —— Malignancies (humoral hypercalcaemia of malignancy, lytic bone metastasis, ectopic cytokine production) —— Immobilisation —— Thyrotoxicosis —— Vitamin A intoxication —— Paget’s disease of bone.

zz

zz

zz

Increased intestinal absorption of calcium: —— Vitamin D intoxication —— Chronic granulomatous diseases (e.g. sarcoidosis) —— Malignancy—ectopic 1, 25 (OH ), D production. 2 3 Decreased renal calcium excretion: —— Familial hypocalciuric hypercalcaemia —— Milk-alkali syndrome —— Acute renal failure. Decreased uptake of calcium by bone: —— Aluminium toxicity. Pseudohypercalcaemia: —— Macroglobulinaemia —— Myeloma —— Hyperalbuminaemia. Miscellaneous or uncertain pathogenesis: —— Thiazide diuretics, metolazone —— Adrenal insufficiency —— Lithium —— Oestrogen, tamoxifen

Treatment of Severe Hypercalcaemia Treatment

Onset of action

Duration of action

Advantages

Disadvantages

Hydration with saline

Hours

During infusion

Rehydration invariably needed

Forced diuresis; saline + loop diuretic

Hour

During treatment

Rapid action

Cardiac decompensation, (intensive monitoring needed) electrolyte disturbance, hypokalaemia, hypomagnesaemia

1st generation Etidronate

1–2 days

5–7 days in doses used

First available bisphosphonate; intermediate onset of action

Hyperphosphataemia; 3-day infusion

2nd generation Pamidronate*

1–2 days

10–14 days after high dose

High potency; intermediate onset; prolonged duration of action

Fever in 20%; hypophosphataemia, hypocalcaemia, hypomagnesaemia

3rd generation Zoledronate Calcitonin

Hours

2–3 days

Rapid onset of action; useful as an adjunct in severe hypercalcaemia

Often limited calcium lowering effect; rapid tachyphylaxis

Gallium nitrate

Day after 5 days

7–10 days

High potency

Length of IV administration; cannot be used in renal failure

Plicamycin (Mithramycin)

3–4 days

Days

Potent antiresorptive

Liver, kidney, and marrow toxicity; bleeding episodes

Oral

24 hours

During use

Low toxicity if p < 4 mg/dl

Limited use except as an adjuvant or chronic therapy

Intravenous

Hours

During use and 24–48 h afterwards

Rapid action, highly potent

Ectopic calcification; severe hypocalcaemia;

Glucocorticoid

Day

Days, weeks

Oral therapy, antitumour agent

Active only in certain malignancies; glucocorticoid side effects

Dialysis

Hours

During use and 24–48 h afterwards

Useful in renal failure; onset of effect in hours: can immediately reverse lifethreatening hypercalcaemia

Complex procedure, reserved for extreme or special circumstances

Bisphosphonates

Phosphate

*Dose is pamidronate depending on serum calcium level.

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776

Manual of Practical Medicine —— ——

Parenteral hyperalimentation Phaeochromocytoma.

——

Primary Hyperparathyroidism Familial primary hyperparathyroidism occur as part of MEN I and MEN II.

zz zz

Causes

zz

Single adenoma 80% Multiple adenoma 4% Carcinoma 1% Hyperplasia 15%

zz

Clinical Features

Parathormone level is increased Increased calcium (more than 12 mg%), and chloride —— Decreased phosphorus, potassium and bicarbonate —— Serum chloride/phosphorus ratio is diagnostic more than 75% (normal < 32%) Urinary calcium excretion is increased ECG—short QT interval Localisation by USG, CT, MRI, nuclear thallium technetium scan and parathyroid angiography (Figs 10.21 and 10.22). Radiological findings in hyperparathyroidism include osteitis fibrosa cystica, subperiosteal erosion especially along the radial aspect of middle phalanx, pepper pot skull (Fig. 10.20). ——

80% are asymptomatic. Central nervous system Fatigue Impaired memory Lassitude Psychosis Headache Dementia Depression Coma Neuromuscular and articular Myopathy Chondrocalcinosis Gout Erosive arthritis Pseudogout Ocular Cataracts

Band keratopathy

Cardiovascular Hypertension Vascular and cardiac Arrhythmia Calcification Gastrointestinal Peptic ulcer disease Reflux gastritis

Fig. 10.19  Hyperparathyroidism—osteolytic lesion

Cholelithiasis Constipation

Renal (Fig. 10.23) Polyuria (polydipsia) Nephrocalcinosis Urine concentrating defect Renal tubular acidosis Nephrolithiasis Skeletal (osteitis fibrosa cystica) Osteopenia and fractures Osteosclerosis Bone cysts Osteomalacia Brown tumours Miscellaneous Anaemia Fever

Lab Diagnosis (Figs 10.19 to 10.22) zz

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Biochemical —— Simultaneous parathormone and calcium level should be taken

Fig. 10.20  Hyperparathyroidism—pepper-pot appearance in lateral view of skull

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777

Endocrine and Metabolic Disorders Treatment zz



Fig. 10.21  CT neck—parathyroid adenoma

zz

zz

zz zz

zz

Fig. 10.22  Technetium-sestamibi scan—increased uptake by parathyroid zz

Surgery is the definitive treatment. Presence of coma in parathyroid storm or crisis is an indication for urgent medical management followed by surgery Indications for surgery are: —— Symptoms of hypercalcaemia ++ >12 mg% (1 mg increase over normal) —— Serum Ca —— Nephrolithiasis/24 hours urinary calcium excre­ tion > 400 mg. —— Reduced bone mass (Bone scan T-score < 2.5) —— Age < 50 years —— Inability for long-term follow-up —— Creatinine clearance reduced by 30%. Transcutaneous injection of parathyroid mass with alcohol under ultrasound guide Monitor hypocalcaemia postoperatively for more than 14 days Incidence of complication is high in alcohol ablation. In case of hyperplasia of parathyroid all the 4 glands are surgically removed and part of an excised gland is implanted into the forearm to maintain calcium and phosphorus metabolism Medical treatment is indicated in presence of dangerous hypercalcaemia (>15 mg/dl) or when surgical treatment is unsuccessful. Serum calcium (mg/dl)

Pamidronate (mg)

upto 12

20

14

40

16

60

> 16

80

The role for Raloxifene, a selective oestrogen response modulator with bone protective effect of oestrogen is under evaluation.

Familial Hypocalciuric Hypercalcaemia (Familial Benign Hypercalcaemia) zz zz

zz

zz

Fig. 10.23  CT: Nephrocalcinosis with multiple renal calculi with CT Neck-Parathyroid adenoma

Ch-10.indd 777

zz

Autosomal dominant disorder Renal tubules reabsorb calcium excessively leading to hypercalcaemia, hypermagnesaemia and hypo­calciuria The course of disease is benign in adults; but in neonates, symptoms of hypercalcaemia develop It is diagnosed by finding of hypocalciuria of less than 60 mg per 24 hours urine excretion with normal parathormone level Loss of calcium sensing receptor function mutation.

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Manual of Practical Medicine

Hypercalcaemic Crisis It may be the mode of presentation in primary hyper­ para­thyroidism especially in elderly. It presents with dehydration, hypotension, abdominal pain, vomiting, fever, altered sensorium. It is a medical emergency.

Management Medical management Rehydration until serum calcium level falls (4 to 6 litres of normal saline in first 24 hrs) zz Correct electrolyte imbalance and give frusemide 100 mg 1 to 2 hours zz Other methods to decrease serum calcium are: —— Salmon calcitonin 200 to 400 IU 8 hourly subcuta­neously —— Mithramycin 25 µg/kg IV —— Neutral phosphate IV (500 ml over 6–8 hrs) zz Avoid drugs like digoxin (hypercalcaemia and hypo­ cal­caemia may potentiate its toxicity), thiazides (decrease the calcium excretion), vitamin A, D (increase the bone turnover) oestrogen and antioestrogen.

zz zz

Secondary Hyperparathyroidism (Increased PTH and Calcium may be Normal or Low) Causes

zz

Hypercalcaemia in Malignancy Causes zz zz

zz

zz

zz zz zz

Dehydration, immobilisation Local infiltration with osteolysis (myeloma, carcinoma breast) Parathormone related peptides (pseudohyper­parathy­ roidism) in conditions like tumours of lung, kidney, squamous cell carcinoma Ectopic 1, 25 (OH)2 vitamin D3 (Hodgkin’s lymphoma, seminoma, renal cell carcinoma) Ectopic PTH Oestrogen and antioestrogens (tamoxifen) Prostaglandins, cytokines, TNF, transforming growth factor.

Treatment zz zz zz

zz

Adequate hydration Decrease dietary calcium intake Steroids may be tried (transient decrease in calcium level) Ketoconazole decreases calcitriol secretion.

Endocrine Causes of Hyperparathyroidism zz zz

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Hyperthyroidism Pheochromocytoma

Adrenal insufficiency MEN I and II.

zz zz zz

Renal failure Gastrointestinal malabsorption Vitamin D deficiency (dietary).

It is due to excessive calcium loss, and increased produc­ tion of parathormone as a compensatory mechanism.

Treatment Treat the underlying cause.

Tertiary Hyperparathyroidism In prolonged secondary hyperparathyroidism, the glands become autonomous and the serum calcium level rises secondary to increased parathormone secretion. Hyperparathyroidism Type

S calcium

PTH

Primary

Raised

Not suppressed

Secondary

Low

Raised

Tertiary

Raised

Not suppressed

Hypocalcaemic Disorder Disorder of Parathyroid Glands zz

PTH deficiency —— Surgical hypoparathyroidism —— Idiopathic hypoparathyroidism —— Agenesis of parathyroids (DiGeorge syndrome) —— Metastasis to parathyroid glands —— Granulomatous disease of parathyroids —— Haemochromatosis —— Wilson’s disease —— Aluminium toxicity 131I therapy —— Following —— Syndromes associated with PTH deficiency are poly­glan­dular autoimmune Type I deficiency, mitochon­d­r ial myo­pathies (Kearn-Sayre synd­ rome and MELAS— Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes)

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Endocrine and Metabolic Disorders zz

zz

zz

Suppressed PTH secretion —— Hypermagnesaemia —— WR-2712 (amifostine) PTH resistance —— Pseudohypoparathyroidism Type Ia, Ib, Ic and II —— PTH antibodies (iatrogenic) —— Magnesium depletion Accelerated bone remineralisation —— Following parathyroid surgery (Hungry Bone syn­drome) 131I therapy —— Following —— Vitamin D therapy of osteomalacia.

Clinical Features Symptoms and Signs Symptoms include muscle spasm, carpopedal spasm (Fig. 10.24), facial grimacing, laryngeal spasm, seizures, and respiratory arrest. Increased intracranial pressure and papilloedema may occur with long standing hypocal­ caemia and other manifestations include irritability, depression, psychosis, intestinal cramps, and chronic malabsorption. Chvostek’s sign (contraction of facial muscles on tapping the facial nerve) and Trousseau’s sign (carpopedal spasm on raising the BP above the systolic pressure) are frequently positive.

Fig. 10.24  Hypoparathyroidism—tetany

Treatment zz

zz

In children: A triad of carpopedal spasm, stridor, convulsions (grand mal, petit mal) are often present. ECG changes are increased QT-C interval, nonspecific. ‘T’ wave changes. Soft tissue calcification: Cataract, basal ganglia calcification (chorea, athetosis, parkinsonism), exostosis, chondrocal­ci­nosis, pseudogout. Haematological manifestation: Macrocytic, megaloblastic anaemia (calcium needed for B 12-intrinsic factor binding).

Pseudohypoparathyroidism (Target Organ Resistance) zz

Dental: Delayed dentition, enamel hypoplasia or dysplasia, caries or blunting of root of the teeth. Nail: Deformed, brittle with transverse grooves. Lab diagnosis zz Decreased PTH level zz Decreased serum calcium level zz Increased serum phosphorous level.

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Administration of oral calcium supplements or vitamin D analogues is the mainstay management of hypocalcaemic disorders. In general the therapeutic endpoint is to maintain serum calcium level in the range of 8.5 to 9.5 mg/ dl, with urinary calcium levels below approximately 400 mg/day. —— Oral calcium supplement administered alone (3–7 gm/day of elemental calcium) in multiple divided doses can be effective in correcting even moderately severe hypocalcaemia unless a malabsorption syndrome is present. —— Vitamin D analogues are required in special conditions. —— α-calcitriol (0.25–1 mcg/dl) with thiazide diuretic to decrease hypercalciuria.

zz zz

Signs are round face, short 4th and 5th metacarpal (knuckle-knuckle-dimple-dimple sign) and meta­ tarsals. Pachydactyly, obesity, pseudo webbing of neck, subcutaneous calcification and mental retardation (Fig. 10.25). PTH receptor is normal Other endocrine glands may be affected.

Lab Diagnosis Decreased serum calcium and phosphate level with normal parathormone level.

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Manual of Practical Medicine

Zinc Zinc Deficiency This may occur in parenteral nutrition or with inadequate dietary intake. Rarely it is due to a genetic defect.

Clinical Features Red, crusted skin lesions especially around nostrils and corners of mouth. Diagnosis Therapeutic trial of zinc (plasma levels are unreliable as they may be low, e.g. in infection or trauma, without deficiency). Fig. 10.25  Pseudohypoparathyroidism—short 4th and 5th metatarsals

Treatment Treatment is as for primary hypoparathyroidism.

Pseudopseudohypoparathyroidism The morphological features of pseudohypopara­thyroidism, but normal biochemistry.

Magnesium Magnesium is distributed 65% in bone and 35% in cells. Its level tends to follow those of calcium and potassium. Magnesium deficiency

Clinical Features Paraesthesiae, fits, tetany, arrhythmias. It can exacerbate digitalis toxicity.

Causes Severe diarrhoea; diabetic ketoacidosis; alcohol abuse, total parenteral nutrition (monitor level weekly); accompanying hypocalcaemia; accompanying hypokalaemia (especially with diuretics). Mechanism zz zz

Decreased PTH release Decreased PTH action.

Treatment Replace with magnesium salts.

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ADRENAL GLANDS Anatomy and Physiology Adrenal gland consists of an inner medulla and an outer cortex. The cortex is subdivided into three zones: zz Zona glomerulosa: Secreting aldosterone (mineralocorticoid) zz Zona fasciculata: Secreting cortisol (glucocorticoid) zz Zona reticularis: Secreting adrenal androgens.

Primary Hyperaldosteronism This is due to the excess production of aldosterone independent of renin-angiotensin system. This condition must be suspected when patient has evidence of hypertension, hypokalaemia and alkalosis, in the absence of diuretic administration.

Essential Criteria for Diagnosis zz zz

zz

Diastolic hypertension without oedema Hyposecretion of renin that fails to increase appropriately during volume depletion/upright position Hypersecretion of aldosterone that does not suppress appropriately in response to volume expansion.

Causes zz

zz zz zz

Aldosterone producing adrenal adenoma (Conn’s syn­drome)—60% Hyperplasia of adrenal glands—5% Idiopathic hyperaldosteronism—34% Aldosterone producing carcinoma—1%.

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Endocrine and Metabolic Disorders Clinical Features

Treatment

Patients have hypertension (diastolic BP > 110 mm Hg), features of hypokalaemia (potassium level 3). Adrenal Cushing’s syndrome —— CT scan of adrenal glands —— Abdominal ultrasonography —— MRI. Ectopic Cushing’s syndrome —— X-ray chest —— CT chest —— MRI —— Cytology.

Evaluation to Find out if the Patient has Cushing’s Syndrome or Not Test

Abnormality in Cushing’s syndrome

1.

Circadian rhythm of plasma cortisol (8.00 and 24.00 samples)

Loss of rhythm

2.

Low dose dexamethasone suppression: a.  1.5 mg at midnight and 9 am plasma cortisol next day b.  0.5 mg 6-hourly for 48 hours and plasma cortisol at 48 hours

> 180 nmol/l > 180 nmol/l

3.

Urinary free cortisol 24-hour excretion or overnight excretion

Elevated (value depends on method used); > 140 mmol/l diagnostic

4.

Insulin-induced hypoglycaemia

No rise in plasma cortisol

Evaluation to Find out the Cause of Cushing’s Syndrome

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Test

Pituitary dependent

Ectopic ACTH

Adrenal tumour

1.

Plasma ACTH 08.00

N (10–80 ng/l) or ↑ (80–300 ng/l)

↑ or ↑↑ (300 ng/l)

Undetectable

2.

Metyrapone 750 mg 4-hourly × 6 doses: measure 11-deoxycortisol at 24.00

↑↑

↑

→↑

3.

High dose dexamethasone 2 mg 6-hourly for 48 hours: Plasma cortisol 48 hours

↓

→

→

4.

Plasma K+

N

< 3.5 mmol/l

N

5.

Corticotrophin-releasing factor (1 µg/kg body weight) and measure plasma ACTH and cortisol over 3 hours

↑

→

→

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Endocrine and Metabolic Disorders

Fig. 10.26  Cushing’s syndrome

783

Fig. 10.27  Cushing’s syndrome— moon face, hirsutism, acne

Fig. 10.28  Clinical features in Cushing’s syndrome

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Manual of Practical Medicine Management zz



zz

zz

zz

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Pituitary Cushing’s syndrome —— Trans-sphenoidal adenomectomy or hypophysectomy —— Pituitary X-irradiation The therapeutic effect of X-irradiation is seen only after 12 to 18 months. During this period, mitotane in a dose of 3 gm/day is given to control hypercorti­ solism (medical adrenalectomy). Adrenal Cushing’s syndrome —— Unilateral adrenal adenoma—surgical removal; since the contralateral adrenal gland is suppressed, glucocorticoid replacement is necessary for several months until adrenal function returns. —— Adrenal carcinoma—surgery is the treatment of choice; in inoperable cases mitotane can be used in a dose of 250 mg qid upto 2 to 4 gm/day. MRI can be used for prognostic evaluation. Ectopic Cushing’s syndrome —— Surgery is the treatment of choice. Adrenalectomy can be considered in cases of indolent yet inoper­ able tumours such as medullary carcinomas of the thyroid. —— Adrenal enzyme inhibitors for reducing hyper­ cortisolism in ectopic ACTH syndrome. „„ Metyrapone (11-hydroxylase inhibitor) 250 to 500 mg tid. „„ Aminoglutethimide: This blocks the conversion of cholesterol to delta-5pregnenolone, in a dose of 250 mg qid upto 2 gm daily. „„ Adrenolytic agents: Mitotane (medical adre­ nalec­­tomy) can be used in addition to the enzyme inhibitors. It is contraindicated in pregnancy. Mitotane has a long half-life and can be detected in adipose tissue even after 2 years and hence it must be avoided in fertile females who desire pregnancy later in life. It is a teratogen and induces abortion. „„ Ketoconazole: This blocks steroidogenesis at several levels (esp. 20–22 desmolase catalysing the conversion of cholesterol to pregnenolone). The dose ranges from 400 to 2000 mg/day. Therapy can be combined with other agents mentioned above. „„ Mifepristone is another treatment option. Bilateral adrenal hyperplasia: ACTH/CRH —— Pituitary source—surgery —— Extra-pituitary source—surgery —— Inoperable—medical adrenelectomy —— Unknown source—bilateral adrenelectomy followed by life-long glucomineralocorticoid replacement.

Adrenal Insufficiency Adrenal insufficiency can be caused by: A primary disease at the, adrenal level, involving destruction of over 90% of the steroid-secreting cortex (Addison’s disease). zz A destructive process at the hypothalamic-pituitary level, leading to CRH or ACTH deficiency or both. zz Long-term suppression of the hypothalamo-pituitaryadrenal (HPA) axis by exogenous or endogenous gluco­ corticoids followed by inappropriate withdrawal. zz

Causes of Addison’s Disease Primary Anatomic destruction a. Idiopathic atrophy—65% (Autoimmune adrenalitis) Sporadic Type I polyglandular autoimmune syndrome Type II polyglandular autoimmune syndrome b. Surgical ablation c. Infection i. Bacterial Tuberculosis (20%) Meningococcemia (Waterhouse-Friderichsen syndrome) ii. Fungal Histoplasmosis Cryptococcosis Coccidioidomycosis iii. Viral HIV CMV d. Inflammation Sarcoidosis e. Haemorrhage Breech delivery Anticoagulant therapy f. Invasion Secondaries (breast/lung) zz Metabolic a. Congenital adrenal hyperplasia and hypoplasia b. Drugs Enzyme inhibitors (ketoconazole, aminoglutethimide) Metyrapone, Etomidate Cytotoxic (mitotane) c. Haemochromatosis zz ACTH blocking antibody (IgG) zz ACTH receptor gene mutation. zz

Secondary Adrenal Insufficiency zz

Tumours —— Pituitary tumour —— Craniopharyngioma —— Tumour of the third ventricle

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Endocrine and Metabolic Disorders zz

zz

zz zz zz zz

Pituitary infarction and haemorrhage —— Postpartum necrosis (Sheehan’s syndrome) —— Haemorrhage in tumours Granulomatous diseases —— Sarcoidosis Following hypophysectomy Steroid withdrawal Hypopituitarism Suppression of hypothalamo-pituitary axis by exogenous or endogenous steroids.

Clinical Features (Fig. 10.29) Due to glucocorticoid insufficiency Weight loss (100%) Malaise (100%)

zz

Weakness (100%) Anorexia (100%) Nausea (50%) Vomiting (50%) Gastrointestinal (diarrhoea or constipation in 50%) Postural hypotension (this is present in almost all patients and BP should be checked after standing for 1 minute. Systolic pressure should be < 100 mm Hg) Acute abdominal pain Hypoglycaemia zz Due to mineralocorticoid insufficiency Hypotension Hyperkalaemia

Fig. 10.29  Clinical features in Addison’s disease

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Manual of Practical Medicine zz



zz



Due to increased ACTH secretion Pigmentation is seen in —— Sun exposed areas —— Pressure areas, e.g. elbows, knees —— Palmar creases, knuckles —— Mucous membranes —— Conjunctiva —— Recent scars Due to loss of adrenal androgen Decreased body hair especially in females.

Hyperpigmentation, adrenal calcification and vitiligo are seen only in primary hypoadrenalism. Pigmentation is not seen in secondary hypoadrenalism.

Associated Other Autoimmune Diseases 1. Hashimoto’s thyroiditis 2. Primary atrophic hypothyroidism 3. Pernicious anaemia 4. Type 1 diabetes mellitus 5. Primary ovarian failure 6. Hypoparathyroidism 7. Mucocutaneous candidiasis 8. Vitiligo.

Lab Investigations zz

zz

zz

Plasma electrolytes—sodium is low, potassium is high, plasma urea is raised. Blood glucose—may be low in severe adrenal insuffi­ciency Eosinophilia, lymphocytosis and normocytic anaemia.

Special Tests ACTH Stimulation Test (Cosyntropin Test) Cosyntropin is a potent stimulator of cortisol and mineralocorticoids. Procedure Draw blood for baseline serum cortisol, aldosterone and ACTH at 8.00 am. zz 0.25 mg cosyntropin IV or IM should be given. zz Obtain blood samples for cortisol and aldosterone 30 min—60 mins following its administration. Normal Plasma cortisol > 495 nmol/lit Primary—No change Secondary—Subnormal ↑ zz

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Metyrapone Test This test is used to confirm diagnosis of adrenal insufficiency and useful especially when secondary causes are suspected. Metyrapone is an inhibitor of an enzyme required for cortisol synthesis and so its administration leads to a fall in the level of cortisol, rise in ACTH level and rise in 11-deoxycortisol (immediate precursor of cortisol). Procedure Metyrapone is given as a single dose of 2 to 3 gm (to be given at midnight with snack). ACTH, serum cortisol and 11-deoxycortisol are measured at 8.00 am the following day. Interpretation Type of adrenal insufficiency

ACTH*

Serum cortisol

11-deoxycortisol

Normal

↑

↓ < 5 µg/dl

↑ > 7 µg/dl

Primary

↑ < 5 µg/dl

Secondary

↑ < 5 µg/dl

*If

ACTH test is blunted, then the metyrapone test is unnecessary.

Plasma Renin Activity The values are always high in primary adrenal insufficiency since plasma aldosterone level is low. In secondary adrenal insufficiency plasma renin activity may be normal as serum aldosterone levels are normal.

Management Primary adrenal insufficiency requires replacement with both mineralocorticoids and glucocorticoids. —— Glucocorticoid replacement with either i. Prednisolone 5 mg in the morning and 2.5 mg in the evening. or ii. Hydrocortisone (cortisol) 20 mg in the morning and 10 mg in the evening. or iii. Cortisone acetate 25 mg in the morning and 12.5 mg in the evening. Increased doses are needed in patients who are obese, and also for patients who are on barbiturates, phenytoin or rifampicin as they enhance metabolism of steroids. Steroid doses should be lowered in patients with liver disease, diabetes mellitus, peptic ulcer or hypertension and also in old age. Appropriate weight gain and the regression of pigmen­tation are reliable indices for adequate steroid replacement.

zz

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Endocrine and Metabolic Disorders Mineralocorticoid replacement is done with fludro­cortisone, a synthetic product, in a dose of 0.05 to 0.3 mg with adequate salt intake. The dose can be adjusted according to the response. —— Patient should be educated regarding: i. Adjustment of steroid dose for mild illness (double dose in fever) ii. Carrying a card or wearing a bracelet with the name of the disease they are suffering from. iii. Administration of 100 mg of hydrocortisone 6th hourly for 24 hours prior and 50 mg IM 6th hourly thereafter. iv. In case of gastroenteritis, patients must have parenteral hydrocortisone if oral intake is not possible. —— Sex hormone replacement due to associated primary gonadal insufficiency is required in selected patients. Secondary adrenal insufficiency does not require mineralocorticoid replacement. Other tropic hormones of anterior pituitary should be replaced. HPA suppression can be minimised by giving single morning daily dose of short acting steroids like hydrocortisone and prednisolone or by doubling the total daily dose and giving it on alternate days. This does not hold true for long acting steroids like dexamethasone or betamethasone. Tapering of glucocorticoids: Once prednisolone is reduced to 5 mg/day, switch over to hydrocortisone 20 to 25 mg every morning. The short half-life of hydrocortisone gives time for HPA system to recover. 8 am plasma cortisol should be measured monthly and if it less than 10 µg/dl, it indicates continued HPA suppression. If it is more than 10 µg/dl, hydrocortisone can be withdrawn. ——







zz

zz

zz

a recovered HPA axis. If 8 am cortisol is greater than 10 µg/dl, but the response to ACTH is still blunted, steroid coverage for major illness will be necessary as long as the ACTH test yields a subnormal response.

Adrenal Crisis Causes zz zz zz zz zz

Idiopathic adrenal vein thrombosis Adrenal adenoma Adrenal infarction Pregnancy Anticoagulants.

It is a medical emergency and may be the first mani­ festation of hypoadrenalism. It occurs in patients with chronic adrenal insufficiency often precipitated by infection, trauma, surgery or bilateral adrenal haemorrhage (Waterhouse-Friderichsen syndrome).

Clinical Features Fever, dehydration, nausea, vomiting, hypotension with elec­tro­lyte imbalance (hyperkalaemia, hyponatraemia and hypercalcaemia occasionally).

Management zz

zz

zz zz zz

Similarly, an ACTH test can be performed. Following ACTH if plasma cortisol increases > 20 µg/dl, it indicates

IV fluids (2–3 litres of 5% dextrose saline) as quickly as possible and monitor fluid balance with central venous pressure recording. Hydrocortisone 100 mg IV is given initially and it should be repeated 100 mg 6th hourly till the patient stabilises. Treatment of underlying precipitating cause. Taper steroid to maintenance dose. Mineralocorticoid replacement with fludrocortisone 0.1 mg orally daily after stopping saline infusion. —— No need for mineralocorticoid if hydrocortisone > 100 mg/day is used.

Interpretation of the Test

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Cause of adrenal insufficiency

ACTH (Baseline level)

Serum cortisol

Aldosterone

1.

Primary

High

Baseline level ↓ and no ↑ after cosyntropin

Baseline aldosterone level ↓ and no ↑ with cosyntropin

2.

Secondary

Low or normal

Baseline level ↓ and increases after cosyntropin

Baseline level ↓ or normal and ↑ aldosterone level 30 mins after cosyntropin

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Manual of Practical Medicine Steroid Equivalents 1 mg of hydrocortisone is equivalent to 1.6 mg cortisone acetate or 0.2 mg of prednisolone or 0.25 mg of prednisone or 0.025 mg of dexamethasone. Steroids zz zz zz

zz zz zz

zz

Maximum glucorticoid activity – Dexamethasone. Maximum mineralocorticoid activity – Aldosterone. Glucocorticoid with maximum mineralocorticoid activity – Hydrocortisone. Most potent glucocorticoids – Beta/Dexamethasone. Selective mineralocorticoid – DOCA. Selective glucocorticoids – MPD, Para/Beta/Dexa methasone. Glucocorticoid with minimal side effects – Deflozacort.

Contributing Factors for HPA Suppression • Long-term use of steroids—> 2 weeks. • Abrupt withdrawal. • Long term small doses (20 mg × 6 months) is more harmful than large doses for short term (80 mg × 2 days) Mechanism Atrophy of adrenal cortex and stoppage of exogenous steroid precipitates withdrawal syndrome and results in acute adrenal insufficiency on stressful situations. Gradual Withdrawal by Tapering For doses > 20 to 25 mg/ day of hydrocortisone or equivalent doses of other steroids for longer than 2 to 3 weeks: zz Reduce the dose by 20 mg/day/week. zz Such patients need steroid supplementation at the time of stress. Preventive Measures Short acting steroids at the lowest possible dose. zz Use for short duration. zz Once daily dose in the morning. zz Alternate day therapy if possible (once in 48 hours) zz Use drugs with poor systemic effect—local delivery (beclomethasone, triamcinolone, fluticasone). zz

Phaeochromocytoma It is a relatively rare benign tumour arising from chromaffin cells of the sympathoadrenal system. It is a rare cause of hypertension accounting for < 0.1% of patients with sustained diastolic hypertension. The majority of pheochromocytoma arise from adrenal medulla (90%). Other sites of origin are organ of Zuckerkandl, aortic bifurcation (8%), rarely from extra

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adrenal sites in the abdomen, chest (< 2%), neck (< 0.1%) and left atrial region. It occurs at all ages with a peak incidence in the 3rd and 4th decade. There is equal frequency in both sexes (in adults). Ninety per cent of the tumours are benign and 90% are unilateral. Multiple tumours (adrenal and extra adrenal) are common in children than adults. It is called as 10% tumour because, 10% are bilateral, 10% malignant, 10% extra-adrenal, 10–30% familial, 10% multiple and 10% occur in children. Extra-adrenal phaeochromocytoma does not secrete epinephrine.

Pathophysiology They are encapsulated, vascular tumours of about 5 cm in diameter and weigh < 70 gm. There is no correlation between the size of the tumour and rise in plasma catecholamine levels or the clinical features. Most phaeochromocytomas secrete both epinephrine and norepinephrine (predominant). Some tumours secrete dopamine. Epinephrine is predominantly secreted in association with multiple endocrine neoplasia.

Clinical Features Symptomatic episodes may occur as often as 25 to 30 times/day or as infrequently as once every few months. The duration of attack is usually less than one hour but may extend to as long as one week.

Common Symptoms Headache (90%) Sweating (60%) Palpitations (70%) Nervousness (40%) Weight loss (40%) Nausea and vomiting (30%) Chest and abdominal pain (30%) Anxiety and fear of death (angor animi) occur in majority of the patients.

Signs Patient may present with paroxysmal or persistent hypertension or postural hypotension. Hyperglycaemia or impaired glucose tolerance is common. Pallor, tremor, Raynaud’s phenomenon and manifestations of coexist­ ing diseases (GIT ganglio­neuromatosis, neurofibromas, Cushing’s syndrome) can also be present.

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Endocrine and Metabolic Disorders Attacks are precipitated by pressure in the vicinity of the tumour, anxiety, exercise, micturition, alcohol ingestion, gene­ral anaesthetics, beta blockers, nicotine, phenothiazines, mor­phine, metoclopramide, hydrala­zine, droperidol and atropine.

Syndromes Associated with Phaeochromocytoma Multiple endocrine neoplasia (MEN) MEN-I Hyperparathyroidism Hyperpituitarism Zollinger-Ellison syndrome Hyperadrenalism (cortex) Hyperthyroidism Ectopic hyperinsulinism, hypergluca gonism and increased release of human pancreatic polypeptide Phaeochromocytoma (rarely) MEN-II Medullary carcinoma of thyroid Adenoma or hyperplasia of parathyroid Bilateral adrenal hyperplasia Phaeochromocytoma MEN-III or II B Medullary carcinoma of thyroid Mucosal neuromas Thickened corneal nerves (slit lamp examination) GIT ganglioneuromas Marfanoid habitus Phaeochromocytoma. Other Associated Syndromes • Neurofibroma (NF) with cafe-au-lait spots (von Reckling­hausen’s disease NF, phaeochromocytoma and somatostatin rich duodenal carcinoid tumour • von Hippel-Lindau disease (cerebroretinal hemangioblastoma) • Acromegaly.

zz



zz

zz

zz

zz zz

24 hours urinary free catecholamines (epinephrine, nor­epinephrine or dopamine). Normal values Total < 100 µg/24 hours Norepinephrine < 75 µg/24 hours Epinephrine < 25 µg/24 hours Plasma catecholamine levels before and after the attack. Normal value (Plasma) Diagnostic value Norepinephrine < 500 pg/ml > 1500 pg/ml Epinephrine < 100 pg/ml > 300 pg/ml Vanillylmandelic acid levels in urine: Normally present upto 1.5 to 6.5 mg/day; > 8 mg/day is diagnostic. It is the least reliable of all tests. Tumour localisation by CT scan, meta-131Iodobenzyl- guanidine (MIBG) scintigraphy or MRI. Central venous blood sampling can assist in localisation of tumour when all other measures fail (Figs 10.30 to 10.33). DOPA-PET scan. Somatostatin scintigraphy.

Management Acute medical therapy for severe hypertension. Bedrest with head end of the bed elevated. zz Alpha receptor blocker-phentolamine 2.5 mg IV every 5 minutes until BP is stabilised. zz Sodium nitroprusside (100 mg in 500 ml dextrose as IV infusion). zz Beta blocker to control arrhythmias (only after adminis­tration of alpha blocker). zz Intravascular volume replacement may be necessary. zz Avoid all precipitating agents to prevent tachy­­ arrhythmias. zz

Investigations zz

zz



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Single voided (spot) urinary metanephrine: This correlates with 24 hours urine test and is particularly useful when urine is collected following an attack. 24 hours urine test for total metanephrine: This is the most reliable screening test. However, false positive tests are common in patients taking chlorpromazine, benzodia­zepines or sympathomimetics. Normal metanephrine levels in urine Total < 1.3 mg/24 hours Normetanephrine < 0.9 Metanephrine < 0.4

Fig. 10.30  CT abdomen—right adrenal mass

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Manual of Practical Medicine Other Drugs for Control of Hypertension Prolonged control of hypertension can be advised with phenoxybenzamine (long acting alpha blocker) 10 mg bd upto a maximum of 200 mg/day. Prazosin can be used in a dose of 1 to 2 mg bd or tds. Beta blocker can be added only after adequate alpha blockade. Labetalol can also be tried.

Surgical Treatment

Fig. 10.31  CT abdomen—left extra-adrenal paraganglioma

This is the definitive treatment for phaeochromocytoma. However, preoperative stabilisation is done with phenoxybenzamine 10 to 20 mg 6th hourly for 6 weeks before surgery for restoration of intravascular volume. Preoperative and postoperative rise in BP can be controlled with phentolamine or nitroprusside. Postoperative hypotension and hypoglycaemia are common. This is managed by norepinephrine and IV dextrose. Failure of fall in BP after surgery indicates presence of additional tumour. Postoperative fall in BP is avoided by hydrating the patient well before operation along with adequate alpha blockade. Inoperable cases or those tumours with metastasis can be treated with metyrosine (tyrosine hydroxylase inhibitor).

Prognosis zz zz

zz

Fig. 10.32  MRI abdomen left extra-adrenal paraganglioma

5-year survival for benign tumours is 85% S eventy-five per cent become normotensive after surgery 5-year survival for malignant tumours is < 50%.

Sexual Disorders Ambiguous Genitalia

Fig. 10.33  MIGB scan-confirms the extra-adrenal paraganglioma

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The newborn with ambiguous genitalia should be considered a medical emergency as there may be immediate physiologic problems such as salt loss or shock and also since there is an urgent necessity to assign a sex to the child. Structural change into an early gonad begins in the fourth post-fertilisation week with the appearance of so-called sex cords. In the normal XY male, a specific gene on the Y chromo­ some, is believed to be the switch that turns on other genes in the indifferent gonad, directing the organisation of the sex cords into a testicular structure. In the XX female, the absence of the Y chromosome organises the sex cords into an ovarian structure.

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Endocrine and Metabolic Disorders In the male, testicular organogenesis is rapid and secretes testosterone and anti-Müllerian hormone. These hormones then allow development of the wolffian duct structures (epididymis, ductus deferens, seminal vesicle, and common ejaculatory duct) and the male external genitalia. In the female, the absence of anti-Müllerian hormone, and low circulating testosterone level allows the development of Müllerian duct structures (fallopian tubes and uterus) and the female external genitalia.

——

Contributing Factors Congenital adrenal hyperplasia: This is caused by various enzymatic defects in the steroid hormone pathway in the adrenal gland, inherited as an autosomal recessive trait. C-21 hydroxylase deficiency is the most common, resulting in virilisation of the female infants and cortisol deficiency, with or without associated salt-losing tendency. zz Iatrogenic virilisation: Virilisation of the female neonate may be seen in children of mothers who had ingested virilising agents such as progestogens (norethindrone) in the first trimester of antenatal period. zz True hermaphrodite: Embryonic events of gonadal differentiation are independent of one another and proceed independently in each gonad. Thus, gonadal histology can differ between sides, and even within a single gonadal ridge more than one type of gonad can develop as occurs in a hermaphrodite with one of bilateral ovotestes or one ovary and a contralateral testis. The karyotype may be 46XX, 46XY, or any mosaic (45X0/46XX/47 XXY). zz

Management zz

zz

Reconstructive surgery (between 18 and 24 months of age). Correction of underlying disorder (steroid replace­ ment in congenital adrenal hyperplasia).

zz

Principles of Management zz zz

zz

zz

Puberty is considered precocious if secondary sexual characteristics occur before the age of 9 years in boys. Causes of Precocious Puberty in Males zz

Precocious Puberty in Females zz

Causes of Precocious Puberty in Females zz

Ch-10.indd 791

Pituitary gonadotrophin secretion (true or central precocity)

Psychologic preparation and reassurance. Treatment of underlying cause (removal of CNS, ovarian, adrenal, or ectopic gonadotrophin-producing tumour). Replacement of thyroid hormones (in chronic primary hypothyroidism). In true sexual precocity, treatment is aimed at suppressing the underlying episodic release of gonadotrophins.

Precocious Puberty in Males

Premature Sexual Developmental Disorders This is said to occur when there is development of breasts, pubic hair and accelerated linear growth rate in a girl before age of 8 years.

Idiopathic (sporadic and familial) CNS abnormalities „„ Hypothalamic hamartomas „„ Space-occupying lesions (astrocytomas, pituitary adenomas and craniopharyngiomas) „„ Cerebral damage (irradiation, surgery, trauma, encephalitis, meningitis) „„ Hydrocephalus „„ Brain abscess „„ Granulomatous lesion. —— Occasional consequence of chronic primary hypo­thyroidism Ovarian steroid secretion (precocious pseudo­puberty) —— Ovarian tumours (granulosa cell, theca cell, or luteomas) —— Adrenal adenomas or carcinomas —— Exogenous sex steroids —— McCune-Albright syndrome (autonomous ovarian hormone secretion) —— Ovarian cysts. ——

zz

Central precocious puberty —— Idiopathic —— CNS disorders (tumours, hypothalamic hamar­ tomas, infections, hydrocephalus, trauma) —— Juvenile hypothyroidism. Incomplete precocious puberty —— Virilising congenital adrenal hyperplasia —— Adrenocortical carcinoma —— Interstitial cell tumours of the testes —— hCG-secreting tumours (hepatoblastomas, retroperi­toneal tumours, and germ cell tumours). Androgen therapy.

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792

Manual of Practical Medicine Treatment zz

zz

zz

Precocious puberty in males results in attenuation of adult stature depending on the age of onset. Administration of long acting gonadotrophin releasing hormone analogue suppresses the secretion of pituitary gonadotrophins and helps in the boy attaining normal stature. Treatment of underlying disorder (congenital adrenal hyperplasia with steroids).

Hirsutism and Virilism This implies increased hair growth in women, in a male pattern of distribution. It is seen in 10% of women and is usually benign. Causes of Hirsutism zz zz zz

Gynaecomastia It is the presence of an abnormal amount of breast tissue in males. This occurs due to an increase in the oestrogen/ androgen ratio. It is, therefore, seen in syndromes of androgen deficiency (Klinefelter’s, Kallmann’s) or from oestrogen excess (oestrogen secreting testicular tumours, decompensated liver disease). Causes zz zz

zz zz zz

zz zz zz

Physiologic (newborn or pubertal) Androgen deficiency —— Klinefelter’s syndrome —— Kallmann’s syndrome —— Congenital anorchia —— Androgen resistance —— Defects in testosterone biosynthesis —— Acquired testicular failure as in viral orchitis Oestrogen-secreting tumours hCG-secreting tumours Drugs (spironolactone, cimetidine, digitalis, phenothia­zines, antidepressants) Decompensated liver disease Trauma or recovery from severe illness Idiopathic.

Treatment zz

zz

zz

zz

Ch-10.indd 792

Patients with pubertal gynaecomastia must be reassured (condition may persist for 2 or 3 years). If it does not subside, then percutaneous dihydrotesto­sterone (125 mg twice daily for 1–4 months) or oral testosterone (150 mg tid for 2–6 months) may be tried. Alternatively surgical removal by liposuction of the glandular and adipose tissue may be done. Indications for surgery: —— Psychological and/or —— Cosmetic problems —— Continued growth or tenderness —— Suspected malignancy.

zz

Familial Idiopathic Ovarian —— Polycystic ovaries (hilus-cell hyperplasia) —— Tumour (arrhenoblastoma, hilus cell, adrenal rest cell) Adrenal —— Congenital adrenal hyperplasia —— Noncongenital adrenal hyperplasia (Cushing’s) —— Tumour (virilising carcinoma or adenoma).

In the presence of hirsutism, if menstruation is normal, there is almost certainly no increased testosterone production, but if menstruation is abnormal, the cause is usually polycystic ovary syndrome (Stein-Leventhal syndrome), which compri­ses of hirsutism, oligomenor­ rhoea, obesity and infertility.

Management zz

zz

If there is no underlying cause, treatment is by local removal of unwanted hair by depilation with wax or creams, or electrolysis, or with bleaching with 1:10 hydrogen peroxide, or by shaving. Treatment of the underlying cause if present (e.g. clomiphene therapy for polycystic ovary syndrome).

Virilism This is characterised by amenorrhoea, clitorimegaly, deep male voice, temporal hair recession and hirsutism. It is rare and needs investigation for presence of underlying androgen secreting adrenal or ovarian tumours.

DIABETES MELLITUS (DM) Diabetes mellitus is one of the most common endocrine disorders. It is a disorder of metabolism of carbohydrate, protein and fat due to absolute or relative deficiency of insulin secretion and with varying degrees of insulin resistance. This metabolic disorder results in long-term disease specific microangiopathy (nephropathy, retinopathy, neuropathy) and aggravation of macroangiopathy.

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793

Endocrine and Metabolic Disorders

Aetiologic Classification of Diabetes Mellitus I. Type 1 diabetes mellitus (β-cell destruction, usually leading to absolute insulin deficiency) A. Immune mediated B. Idiopathic. II. Type 2 diabetes mellitus (May range from predominantly insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance). III. Other specific types A. Genetic defects of β cell function 1. MODY 1—HNF* 4α mutation on chromosome 20. 2. M ODY 2—Glucokinase gene mutation on chromo­some 7 3. MODY 3—HNF 1α, mutation on chromosome 12 4. MODY 4—Insulin promoter factor 1 mutation on chromosome 13 5. MODY 5—HNF 1β, mutation on chromosome 17 6. Mitochondrial dysfunction—tRNA mutation. 7. Mutant insulin/proinsulin—Insulin gene mutation on chromosome 11 B. Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson-Mendenhall syndrome 4. Lipoatrophic diabetes 5. Others C. Diseases of exocrine pancreas 1. Pancreatitis Characteristics of Endocrine Cells of Islets of Langerhans Cell type β

Insulin Time Table Year of identification

Insulin products

1921

Pancreatic extracts showed blood sugar lowering effect (Banting and Best)

1922

Insulin was first used in human

1923

Production of insulin from animal sources

1925

First international insulin unit defined

1926

Crystallised amorphous insulin was made to give stability

1936

Protamine zinc insulin was identified

1939

Globin insulin with shorter action identified

1950

NPH (neutral protamine Hagedorn) was identified

1951

Lente insulins were developed

1955

Structure of insulin delineated

1960

Radioimmunoassay of insulin was made available

1967

Proinsulin discovered

1971

Insulin receptor defined

1972

U-100 insulin introduced to promote better accuracy in administration

1973

Small-dose IV insulin for DKA emerges

Percentage of islet cells

Hormonal content

60–80

Insulin

1976

C-peptide becomes a clinical tool Insulin gene cloned

α

15–20

Glucagon

1977

δ

5–10

Somatostatin

1978

PP

15–20

Pancreatic polypeptide

Purified single-peak pork insulins introduced (mono component insulin)

δ1

buttock.

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800

Manual of Practical Medicine

Diabetes and Exercise Exercise presents various problems for individuals with diabetes as they lack the normal glucoregulatory mechanisms. Those with Type 1 DM are prone to either hyper- or hypoglycaemia during exercise depending on the pre-exercise plasma glucose, circulating insulin level and exercise induced catecholamines. In the presence of low insulin levels, there is a high probability for hyperglycaemia due to exercise induced catecholamine release. In the presence of excessive circulating insulins, hypoglycaemia results. This can be avoided by taking the meal one to three hours before exercise and supplemental carbohydrate feeding every 30 mts. Other measures include, decreasing the insulin dose before exercise and injecting insulin into a non-exercising area. Exercise-induced hypoglycaemia is less common in those with type 2 DM, but can occur in patients taking insulin or sulfonylureas.

Complications of Insulin Therapy 1. Hypoglycaemia This is due to: Inaccurate self-monitoring zz Variability in timing and composition of meals and snacks zz Variability in timing and amount of exercise. zz Variability in insulin absorption. zz Acute illness—if nausea and vomiting are present. zz Critical illness—reducing insulin requirements (renal, liver, adrenal, pituitary failure) zz Weight loss zz Alcohol intake zz Hypoglycaemic unawareness due to drugs, tight glycaemic control, autonomic neuropathy, recurrent hypoglycaemic episodes zz Defective counter regulatory hormone response to hypoglycaemia zz Pregnancy zz Gastroparesis. zz

2.  Insulin Resistance It is arbitrarily defined as a situation in which the requirement of insulin exceeds 200 units per day to prevent hyperglycaemia and ketosis. Relative insulin resistance is present in most of the patients when carefully looked for, using the glucose clamp technique. In Type 1 DM it is due to near complete insulin defi­ ciency and in Type 2 DM, the major problem is due to obesity.

Ch-10.indd 800

Insulin receptor has two α and two β subunits. Insulin gets attached to a subunits and this activates β subunits (tyrosine kinase). Tyrosine kinase autophosphorylates the insulin receptor and initiates subsequent intracellular phosphory­lations that mediate multiple actions of insulin. Glucose transporters facilitate glucose entry into the cell (facilitated diffusion). Binding of insulin to the receptor initiates a rapid mobilisation of intracellular stores of the transporter to the plasma membrane while simultaneously activating those units already in place. In poorly controlled diabetes, the number of stored transporters appears to be deficient. Insulin resistance may be at: 1. Prereceptor level 2. Receptor level 3. Post-receptor level. 1. Prereceptor level resistance is due to the presence of abnormal insulin or insulin antibodies. 2. Receptor level resistance is due to decrease in number of receptors or decreased binding of insulin. 3. Post-receptor level resistance is due to abnormal signal transduction resulting in failure to activate the tyrosine kinase receptor. In diabetics with insulin requirements > 200 units/day, the resistance is mainly at prereceptor level due to insulin antibodies of IgG type (present in all patients within 2 months of initiation of insulin therapy). Onset may be abrupt or gradual leading to uncon­ trollable hyperglycaemia. 20 to 30% of patients have con­ comitant insulin allergy. Insulin Resistant States i. Prereceptor resistance (mutated insulins, anti-insulin antibodies) ii. Receptor and post-receptor resistance a. Obesity b. Type A syndrome (absent or dysfunctional recep­tor) c. Type B syndrome (antibody to insulin receptor) d. Lipodystrophic states (generalised or partial) e. Leprechaunism (elfin facies, hirsutism, thick skin, absence of subcutaneous fat) f. Ataxia telangiectasia (cerebellar ataxia, telan­ giectasia, immune system abnormality) g. Rabson-Mendenhall syndrome (dental dysplasia, dystrophic nails, premature puberty, acanthosis nigricans) h. Werner syndrome (autosomal recessive; growth retardation, alopecia, premature graying of hair, cataract, leg ulcer, atrophy of muscle, fat and bone, soft tissue calcification, sarcomas, menin­gio­mas)

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801

Endocrine and Metabolic Disorders

i. Alstrom syndrome (autosomal recessive; childhood blindness (retinal degeneration), nerve deaf­ness, vaso­pressin resistant diabetes insi­pidus, hypogonadism in males and end organ resistance to multiple hormones, baldness, hyperuricaemia, hypertriglyceri­ daemia and aminoacid­uria). j. Pineal hyperplasia syndrome (early dentition with malformed teeth, dry skin, thick nails, hirsutism, sexual precocity with enlargement of external genitalia). Other conditions of insulin resistance are already mentioned.

Treatment Prednisone should be given in a dose of 80 to 100 mg/ day. Response occurs in 2 to 3 days usually. If there is no response up to 3 to 4 weeks, steroids should be with­drawn. If there is response, and if insulin requirements begin to fall, prednisone can be gradually decreased to 10 to 20 mg even in 3 to 7 days until a maintenance level of 5 to 10 mg is reached. It can be continued for many months. When resistance is extreme, up to 500 units of regular insulin may be required; Addition of a protease inhibitor (aprotinin) to the insulin mixture can be useful. 3.  Insulin Lipoatrophy and Lipohypertrophy 4.  Insulin Allergy Local allergy at injection site: Redness, pruritus, swelling and heat occurs. It usually occurs within the first few weeks of therapy and is self-limiting. This is IgG mediated. Systemic allergy: Urticaria, angioneurotic oedema and ana­phylaxis can occur but rare, this is related to prior intermittent use of insulin. This reaction is IgE mediated. 5.  Insulin Oedema Patients who have been having poor glycaemic control in the past, may develop peripheral oedema when their glucose is rapidly brought down. CCF is also common. It is a self-limiting condition clearing in about one week unless the patient has a renal or cardiac problem. Home monitoring of glycaemic status can be done by: i. Double voided urine testing for sugar and ketones. Patient is asked to empty the bladder 15 minutes before the test. He is advised to consume water so that a fresh sample of urine is obtained. ii. a. Home blood glucose is monitored by using various reagent strips. Skin is punctured using automatic lancet injectors.

Ch-10.indd 801

b. Reflectance meters (Glucometer III, Accucheck III) are widely used with accuracy. c. Blood sugar monitoring from ear lobe or finger tip should be done for at least 3 conse­cutive days in a month, for a minimum of 4 times (prebreak­ fast, prelunch, presupper and at bedtime) and maximum of 8 times (post­prandial samples in addition) during each 24 hour period. In patients with early morning hyperglycaemia, an additional sample at 3 am should be taken. During sick days, monitoring should be done every 1 to 2 hours to identify subtle hypoglycaemia and/its after effects. Goal of therapy is to maintain euglycaemic level at all times. Any preprandial level should be maintained at 70 to 90 mg/dl and postprandial level lower than 160 to 180 mg/dl. In very young children, and in insulin sensitive individuals, insulin can be diluted using diluent given by the manufacturer. Glycated Haemoglobin Control

Hb A1 (%)

Hb A1c (%)

Good

8–10

6–8

Fair

10–12

8–10

Poor

12–14

10–12

Very poor

> 14

> 12

Hb A1 = Hb A1 (a, b, c) Hb A1c is preferred since the glycosylation is with glucose and not with other sugars. Hb A1c of 6% corresponds approximately to a mean plasma glucose level of 120 mg%. For every 1% rise in HbA1c, mean glucose rise by 30 mg%.

This test is an indicator of blood sugar control during the previous 2 to 3 months period; Blood is used after saline washing to detect the relative percentage of glycosylated haemoglobin present. a. Glucose attaches to Hb in an irreversible fashion throughout its lifespan. At any given point of time, a sample represents a collection of new­born, middle age and senescent RBCs. Hence glycohaemoglobin level obtained represents a glu­cose value that is reflective of the glucose environment confronting red cells over the pre­vious 3 months period. b. Methods used to detect glycated haemoglobin are high pressure liquid chromatography or gel electro­phoresis; the subfraction A1c is separated out. Values less than 10% of glycosylated haemoglobin are acceptable. This test tells about the previous glycaemic control also, so that insulin dose can be adjusted. Haemolytic anaemia, haemoglobinopathies and uraemia may interfere with estimation of glycated haemoglobin.

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802

Manual of Practical Medicine Glycosylated albumin, or total proteins (fructo­samine) can also be estimated to find out the previous status of glycaemic control. Since the half-life of serum protein is short (20 to 25 days), this estimation gives an idea about the glycaemic status in the previous 2 to 3 weeks only. Normal fructosamine level—0.9 to 1.5 ng/dl; > 1.5 ng/ dl—abnormal. Uncontrolled Diabetes Mellitus and Recurrent DKA Noncompliance is a major cause of recurrent keto­acidosis in children. Hypoglycaemia Most episodes are predictable and preventable. But children are usually unaware of hypoglycaemic symp­ toms. The combination of alcoholic beverages with insulin produces very severe hypoglycaemia. Abnormal counter regulatory response in diabetic patients may account for prolonged hypoglycaemia. Fasting Hyperglycaemia Somogyi phenomenon (Rebound effect): This is hypo­ glycaemia induced hyperglycaemia due to increased secretion of counter regulatory hormones. If the insulin dose is increased beyond the amount required for any given portion of the day, there is counter regulatory hormone response, resulting in hypergly­ caemia. Reduction of insulin is advised in such situations. Dawn phenomenon : Many patients with IDDM demonstrate early morning (4–8 AM) hyperglycaemia that is aggravated again by intake of food during breakfast (but not due to it). It may either be due to increased hepatic glucose production or decreased peripheral utilisation or both. In this condition, an excess of insulin is needed to control hyperglycaemia. Early morning blood sampling at 3 am is neces­sary to differentiate both the conditions.

Type 2 Diabetes Mellitus It is the most common type of diabetes accounting for 85 to 90% of the cases.

Risk Factors zz zz zz zz zz zz zz

Ch-10.indd 802

Family history of DM Obesity Physical inactivity Previously identified IGT History of gestational DM Delivery of large baby (> 4 kg) Hypertension

zz zz zz zz zz

HDL level < 35 mg/dl TGL level > 250 mg/dl Polycystic ovary syndrome Acanthosis nigricans History of vascular disease.

Pathophysiology The characteristic pathophysiologic abnormalities of Type 2 DM are: zz Impaired insulin secretion. zz Peripheral insulin resistance. zz Excessive hepatic glucose production. There are 3 phases of development: I phase (euglycaemia with increased insulin levels): Plasma glucose remains normal despite demonstrable insulin resistance because insulin levels are elevated. II phase (post-prandial hyperglycaemia with increased insulin levels): Insulin resistance tends to worsen so that despite elevated insulin concentrations, glucose intolerance becomes manifest by post-prandial hyper­glycaemia. III phase (overt diabetes with declining insulin levels): Insulin resistance does not change but insulin secre­tion declines resulting in fasting hyperglycaemia and overt diabetes. Resistance to insulin in Type 2 diabetes is at postreceptor level. The substance responsible for this is termed amylin.

Clinical Features Patients are usually obese; symptoms begin gradually (polyuria, polydipsia, polyphagia); patient may present with unhealed wounds, fungal infections, pruritus vulva or balanitis; patient can have frequent changes in refractory error and may have early develop­­ment of cataract; patient may be asymptomatic also. Rule out diabetes in tuberculous patients above 40 years and also in mothers who have babies born with a weight of more than 4 kg (macrosomia).

Diagnosis A. According to National Diabetes Data Group (NDDG), Type 2 DM is Diagnosed when a Patient: i. Is not ketosis prone under basal conditions does not require exogenous insulin for short-term survival ii. Random blood sugar > 200 mg/dl on two occasions iii. Has a fasting plasma glucose > 126 mg/dl or a sustained elevation of plasma glucose concen­tration ≥ 200 mg/ dl after an oral glucose load of 75 gm at two hours.

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803

Endocrine and Metabolic Disorders General Characteristics Type 1 and 2 DM Features

Type 1 DM

Type 2 DM

1.

Genetic locus

Chromosome 6

Multifactorial

2.

Age of onset

30 yrs

3.

Body weight

Lean

80% obese, 20% lean

4.

P. insulin

Low or absent

Normal or high

5.

P. glucose

High, suppressible

High, resistant

6.

Acute complications

DKA

NKHS

7.

Insulin therapy

Essential

Early may not require Late may require

8.

Sulphonylurea

Unresponsive

Responsive

9.

Autoantibodies

Present

Absent

10.

Early death without treatment

Yes

No

11.

Associated disorders

Autoimmune diseases

Insulin resistance Hypertension Hyperlipidaemia Polycystic ovary

1 day prior to the test. Test should not be done in patients with intercurrent illness. Fasting is advised for at least 10 hours to a maxi­mum period of 16 hours. Water alone is permitted. Smoking should be avoided. Time of start of test (glucose infusion): 7.30 to 10 A.M. Glucose dose: 0.5 gm/kg up to 35 gm 25% glucose diluted in normal saline and infused manually or by a pump in 3 minutes ± 15 seconds. Two baseline samples and samples at 1, 3, 5, and 10 minutes after the test are taken. It is done for patients who cannot take oral glucose. Glucose is present in urine and there is confusion with the diagnosis of diabetes in the following condi­tions: Renal Glycosuria The most common cause of glycosuria is a low renal threshold for glucose, which commonly occurs tempo­ rarily in pregnancy and is a much more frequent cause of glycosuria than diabetes in young people. Renal glycosuria is a benign condition and is not accom­panied by the classical symptoms of diabetes.

B.  Patients with Impaired GTT

Alimentary Glycosuria (Lag Storage)

Ten to fifty per cent of patients with impaired glucose tolerance develop Type 2 DM over a period of 10 years. Diagnostic criteria for impaired GTT are: Impaired glucose tolerance (IG) is defined by a 2-hour oral glucose tolerance test where the plasma glucose is >140 mg/dl but 140 mg% and post-prandial glucose > 250 mg/ dl) persists even after 1 month of drug therapy while the patient is on strict diet therapy and exercise, primary failure is diagnosed and insulin may have to be started. Secondary failure: Some patients (5–10%) show initial satisfactory response followed by recurrence of hyper­ glycaemia. This is called secondary failure. The causes for secondary failure are: 1. Non-adherence to either diet or sulfonylurea therapy. 2. Disease progression. 3. Loss of efficiency of the drug. 4. Intercurrent illness. 5. Physical or mental stress.

Ch-10.indd 806

Side effects of sulfonylurea therapy • Hypoglycaemia: This is prolonged and recurrent. Treatment and intense monitoring should be conti­ nued for at least a week. • Several drugs may potentiate the action of sulfonyl­ ureas sulfonamides, coumarin, phenylbutazone, phenytoin, etc. • Sulfonylureas should not be used in patients with liver disease, renal disease, allergic reactions to sulfonylureas or during pregnancy. • Chlorpropamide induces fluid retention by exerting ADH effect on distal tubules. • Patients may experience flushing after alcohol intake. Selection of sulfonylureas 1. Second generation drugs are advantageous. 2. For elderly, glipizide is preferred since there is less incidence of hypoglycaemia with this drug. Gly­buride (Glibenclamide) is preferred when there is fasting hyperglycaemia. 3. In renal insufficiency, drugs having dual route of excretion (liver and biliary) like glyburide or drugs with inactive liver metabolites like glipizide should be used.

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807

Endocrine and Metabolic Disorders 4. Drugs should be started in small dosage and should be increased gradually based on self-monitoring of blood glucose. (ii) Meglitinide These are a new class of insulin secretogogues which modulates β cell insulin release by regulating potassium channels. The first member of the group is Repaglanide —0.25 to 4 mg before each meal. It has very fast onset of action with peak effect within 1 hr of ingestion. Duration of action is 4 to 5 hrs. Because of the rapid onset and short duration it is indicated for postparandial glucose control. Contraindication includes hepatic impairment. Since there is no sulphur in the structure, it can be used in patients with sulfonylurea allergy. (iii) Nateglinide It is a D phenyalanine derivative which acts directly on β cells to stimulate early insulin secretion. Dose: 120 mg orally taken 10 mts before each meal. Leads to insulin secretion within 15 mts and return to baseline in 3 to 4 hrs. It is effective in control of postprandial hyper­glycaemia. II. Insulin sensitisers: (i) Biguanides The drugs under this group are phenformin and met­ formin. These are drugs of choice for obese type II diabetes. They have no effect on insulin secretion. They improve peripheral tissue sensitivity to insu­lin thereby enhancing peripheral utilisation of glu­cose. They suppress hepatic production of glucose by reduc­ing gluconeogenesis. They do not cause weight gain and rather facilitate weight loss (due to anorexic effect). The drug also decreases triglyce­ rides, espe­cially when they are elevated. It also increases glucose transporters in insulin sensitive cells. Biguanides can be given orally alone or with insulin. Primary failure is 5 to 20% and secondary fail­ure is 5 to 10%, Starting dose of metformin is 500 mg/day with meals up to 3 gm/day in 2 to 3 doses. They should be avoided in patients with renal or hepatic insufficiency, in alcoholics, in cardiopulmonary insuffi­ ciency and in other known risks for lactic acidosis. They should not be used in pregnancy. Absorp­tion is decreased by guargum. Cimetidine delays its renal clearance. Biguanide can be used along with sulfonyl­ureas and the combination has an additive glucose lowering effect. Metformin should be withheld for one day prior to contrast studies with iodinated dyes and it can be restarted 48 hours after the contrast study (If renal function is normal).

Ch-10.indd 807

(ii) Thiazolidinediones They improve insulin sensitivity in muscle, liver and adipose tissue. There is reduced hepatic glucose production also. It seems to reduce plasma triglyceride levels and increases HDL cholesterol levels. There is no hypoglycaemia, as they do not affect pancreatic insulin secretion. Patients with little pancreatic insulin reserve do not respond adequately. Hence, it is used in type 2 DM it also prevents the progression from IGT to type 2 DM. They can be combined with other oral hypo­glycemic agents or insulin. Pioglitazone 15 to 45 mg OD Rosiglitazone 2 to 8 mg OD There should be frequent hepatic monitoring for idiosyncratic hepatic injury. Contraindications: Liver disease CCF—class III and IV B.  Alpha-Glucosidase Inhibitors (Acarbose) Delaying digestion and absorption of sucrose and complex carbohydrates may be advantageous. They require action of an intestinal brush border enzyme glucosidase for absorption. Inhibitors of this enzyme, when taken before a meal causes a slower rise and lower peak in blood glucose in both Type 1 DM and Type 2 DM; 30 to 50 mg/dl reduction of blood glucose and 0.5 to 1% reduction in HbAlc has been reported with these drugs. Acarbose is the most popular drug in this group and it is given in a dose of 50 to 100 mg TDS/day before meals. Miglitol is the newer agent. It defers structurally from acarbose and is 6 times more potent in inhibiting sucrase. Dosage: 25 to 100 mg Adverse effects: Flatulence, diarrhoea, abdominal pain. The drugs are contraindicated in those with hepatic or renal disease and in patients with inflammatory bowel disease or gastroparesis. C.  Fatty Acid Oxidation Inhibitors (Acipiomox) In Type 2 DM, due to decreased insulin action on adipocytes, excess fatty acids are released. These may stimulate hepatic gluconeogenesis and lead to fasting hyperglycaemia. Acipiomox, a nicotinic acid derivative (20 times more potent than nicotinic acid), decreases free fatty acid levels. It also lowers fasting hyper­glycaemia and triglyceride levels. D. Insulinotropins a. Glucagon-like peptide-1 (GLP-1): This is under evaluation. GLP-1 is a fragment of proglucagon molecule. It seems to stimulate insulin release. b. Insulin-like growth factor-1 (IGF-1) or somatomedin.

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808

Manual of Practical Medicine Pharmacology of Sulfonylurea Drugs Drugs

Duration of action

Dosage

Protein binding

Hepatic metabolites

Route of excretion

First generation

a. Tolbutamide

6–12

500–3000 mg in 2–3 doses

Ionic

Inactive

Liver



b. Chlorpropamide

24–72

100–500 mg in a single dose

Ionic

Inactive; Weakly active

Kidney



c. Acetohexamide

12–18

250–1500 mg/day up to 750 mg BD

Active

Kidney



d. Tolazamide

16–24

100–1000 mg (up to 500 mg BD)

Weakly active

Kidney

Second generation

a. Glipizide

12–24

2.5 to 40 mg in 1–2 doses

Non-ionic

Inactive

Liver/kidney



b. Glyburide/glibenclamide

16–24

1.25–20 mg in 1–2 doses

Non-ionic

Inactive and moderately active

Liver/kidney



c. Micronized glyburide

16–24

0.75–12 mg in 1–2 doses

Non-ionic

Inactive, moderately active

Liver/kidney



d. Gliclazide

10–12

80–240 mg in 1–3 doses

Probably inactive

Liver (30%) kidney (70%)



e. Glimepiride

12–24

1–8 mg od

Inactive

Liver

—

Pharmacology of Other Oral Antidiabetic Agents Drugs

Dosage/day

Interval

Duration of action

Adverse effects

Meglitinide Repaglinide Nateglinide

Rapid acting 1–16 mg 180–360 mg

Before Meals TID

1–2 hours

Hypoglycaemia and weight gain

Biguanide Metformin

1–3 gm

BID/TID

6–12 hours

Lactic acidosis and GI intolerance

75–300 mg 75–300 mg 0.2–0.6 mg

TID TID TID

Alpha-glucosidase inhibitors* Acarbose Miglitol Voglibose

GI intolerance and flatulence Minimal GI tolerance

(Poorly absorbed and renal excretion is negligible) Thiazolidinediones Rosiglitazone Pioglitazone

2–8 mg 15–45 mg

OD/BID OD

12–24 hours 24 hours

Fluid retention, CHF, weight gain, hepatotoxicity

*Patients on alpha-glucosidase inhibitors when they develop hypoglycaemia should be treated with glucose and not sucrose.

Incretins

Excretins

Incretins are enteroendocrine derived gut peptides. They act on endocrine pancreas. The predominant incretins are glucose-dependent insulinotropic polypeptide (GIP), which is secreted by the intestinal ‘k’ cells located in the duodenum and proximal small bowel and glucagons-like peptide-1 (GLP-1) which is secreted from the enteroendocrine ‘L’ cells located in the ileum and colon. The GLP-1 stimula­tes both insulin secretion and production whereas sulfonylureas stimulate insulin secretion but not biosynthesis.

The hormones such as secretin that stimulate the exocrine pancreas are called excretins.

Ch-10.indd 808

GLP-1 Analog (Exendin 4) The original peptide was identified from the oral secretion of the Gila monster. The newer analog improves insulin resistant state and decreases fasting, postprandial glucose level. It suppresses appetite and leads to weight loss. It also lowers triglyceride level.

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809

Endocrine and Metabolic Disorders Exenatide It is a synthetic preparation of exendin 4 with prolonged duration of action. It is given parenterally in a dose of 5 to 10 µg twice daily. It can be given either with metformin or with sulfonylurea or with both. It helps in achieving good control of DM. Adverse effects are nausea and hypoglycaemia. Amylin Analog (Pramlintide) It delays absorption of carbohydrate from the GIT and suppresses postprandial glucagon levels and also induces weight loss. Dipeptidyl Peptidase IV (DPP IV) Inhibitors zz zz

zz zz zz

An enzyme that degrades GLP-1 DPP IV inhibitor inhibits the degradation of GLP-1 and thus enhances incretin effect It enhances glucose mediated insulin secretion It inhibits glucagons secretion These drugs are contraindicated in type 1 DM, pregnancy and DKA.

Sitagliptin zz An inhibitor of dipeptidyl peptidase IV zz It increases insulin secretion. zz It lowers glucagon secretion. zz It can be combined with metformin and thiazolidinediones zz It is contraindicated in ketoacidosis, pregnancy and breastfeeding. zz Dose—100 mg once daily PO. Vildagliptin zz It is the second molecule of the DPP-IV inhibitor zz It can be combined with other OHAs and insulin zz It is weight neutral and has favourable effect on lipids zz Not recommended for paediatric patients zz Avoid in moderate renal failure, pregnancy and hepatic impairment zz Dose—50 mg bid along with metformin, TZD or insulin or 50 mg qd along with sulphonylurea. Linagliptin zz Dose—5 mg PO per day zz No dose adjustment is required in renal and hepatic impairment zz Adverse effects: Rashes, acute pancreatitis, nasopharyngitis and hyperlipidaemia. Alogliptin zz 25 mg PO per day zz Dose adjustment required in hepatic and renal impairment

Ch-10.indd 809

zz

Adverse effects: Rashes (Stevens Johnson’s syndrome), headache, pancreatitis, nasopharyngitis, hepatic failure.

Saxagliptin zz zz

zz

zz zz

2.5 to 5 mg PO per day Decrease the dose if combined with CYP 450, 3 A4/5 inhibitors Incidence of hypoglycaemia is more when combined with insulin/sulfonylureas It is mainly excreted by the kidneys Increased risk of pancreatitis and hypoglycaemia in alcoholics.

E. SGLT—Inhibitors zz

zz

zz zz

zz

By inhibiting sodium glucose cotransporter 2, renal glucose reabsorption is prevented, urinary loss of glucose is promoted and this decreases glucose level in type 2 DM SGLT 2 is a sodium dependent glucose transport protein Approved drugs—Dapagliflozin and canagliflozin Drugs under trial—Phase III trial—Ipragliflozin, tofogliflozin, empagliflozin Phase II trial—Sergliflozin etabonate, remogliflozin etabonate.

F. Glitazar zz zz

zz

Saroglitazar (Lipaglyn) is the first glitazar approved. It has dual action on both lipid and glycaemic parameters. PPAR (Peroxisome proliferator-activated receptor) agonist at subtypes α and γ. PPAR α-agonist lowers high triglycerides and PPAR γ-agonist improves insulin resistance and lowers blood sugar.

Insulin Indications in Type 2 DM: 1. In primary or secondary sulfonylurea failure 2. Major trauma, surgery 3. Stress 4. Pregnancy 5. DKA 6. Myocardial infarction, CVA 7. Liver failure, renal failure and respiratory failure 8. Infections. Principles of Insulin Therapy a. Start with a low dose; Gradually increase the dose to find out the optimum level. It can be given as a single prebreakfast injection of intermediate acting insulin or twice daily as prebreakfast and predinner doses (0.3–0.4 U/kg/day).

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810

Manual of Practical Medicine b. Blood glucose level should be monitored at home. When facilities are not available for blood sugar estimation, second voided urine samples are utilized. c. Insulin dosage and pattern of administration are adjusted until reasonable control of blood glucose is achieved. Then the frequency of blood glucose monitoring is decreased to 3 to 4 times a day, later once or twice weekly sugar estimation is sufficient. Insulin is Maximally Tolerated in the Following Conditions zz zz zz

Pregnancy Neuropathy Skin lesions.

Diabetic Complications (Fig. 10.38) Acute complications Diabetic ketoacidosis zz Hyperosmolar coma zz Hypoglycaemia. zz

Chronic complications zz Microvascular —— Eye disease i. Retinopathy (proliferative/nonproliferative) ii. Macular oedema iii. Cataract iv. Glaucoma. —— Neuropathy i. Sensory and motor (mono and polyneuro­pathy) ii. Autonomic. —— Nephropathy zz Macrovascular —— Coronary artery disease (CAD) —— Peripheral vascular disease (PVD) —— Cerebrovascular diseases (CVD). zz Others —— Gastrointestinal —— Genitourinary —— Dermatologic —— Cardiomyopathy.

Acute Complications of Diabetes Diabetic Ketoacidosis (DKA) DKA is characterised by a plasma glucose > 250 mg/ dl, arterial pH < 7.30 or serum bicarbonate level < 15 mEq/l and moderate ketonaemia with ketonuria.

Ch-10.indd 810

This is the most frequent endocrine emergency; it has a mortality of 6 to 10%. All the abnormalities can be traced to an absolute or relative insulin lack, which develops over a period of several hours or days. It is more common in type I diabetes. In newly diagnosed patients, there is failure of endogenous insulin secretion whereas in a known NIDDM patient, it is due to the insulin deficiency occurring as a result of either inadequate administration of exogenous insulin or a stressful condition. Stresses can be: 1. Infection (pneumonia, UTI, URI, meningitis, chole­ cystitis or pancreatitis) 2. Vascular disorder (MI, CVD) 3. Endocrine disorder (hyperthyroidism, Cushing’s syn­­ drome, acromegaly, pheochromocytoma) 4. Trauma 5. Pregnancy 6. Emotional stress (especially in adolescence) 7. Drugs—cocaine. Pregnancy and alcohol ingestion are associated with “euglycemic DKA.” In these situations, there is increase in production of counter-regulatory hormones namely, epinephrine, cor­ti­ sol, glucagon and growth hormone and hence, the dose of insulin has to be increased. In 25% of patients, there is no precipitating cause. Pathophysiology of DKA 1. Role of Insulin a. Insulin deficiency leads to hyperglycaemia, osmotic diuresis resulting in dehydration and electrolyte depletion. b. Activation of glycogenolysis and gluconeogenesis and lipolysis by insulin lack, all resulting in new glucose production. c. There is also decreased peripheral utilisation of glucose (secondary to insulin lack and resistance) and volume depletion (secondary to osmotic diuresis) that decreases renal blood flow and there­ fore the amount of glucose filtered and excreted by the kidney. d. Free fatty acids are delivered to the liver, where ketone bodies are produced resulting in ketonaemia, which is intensified by decreased peripheral utilisation. The resultant ketonuria further depletes the electrolytes. e. Acidosis occurs as a result of exhaustion of body bases in the process of buffering ketone bodies which are produced uncontrollably.

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Endocrine and Metabolic Disorders

811

Fig. 10.38  Diabetes mellitus—complications

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812

Manual of Practical Medicine 2. Role of Counter Regulatory Hormones Hypersecretion of epinephrine (EN), glucagon, cortisol and growth hormone (GH) results in DKA by: a. Inhibiting insulin mediated glucose uptake by muscleperipheral utilisation (EN, cortisol, GH). b. Activating glycogenolysis and gluconeogenesis (EN, glucagon, cortisol). c. Activating lipolysis (EN, GH). d. Inhibiting residual insulin secretion (EN, GH).

Clinical Features Patients present with polydipsia, polyuria and weak­ ness; anorexia, nausea, vomiting, and abdominal pain (especially in children) may be there due to ketonaemia. Ileus and gastric dilatation may cause aspiration. A characteristic type of breathing called Kussmaul’s breath­­ ing (deep, sighing) occurs as a respiratory compen­­sation for metabolic acidosis especially when pH < 7.2. Patients may have altered sensorium and 10% of them are comatose. Clinical examination shows: a. Fruity or musty odour in breath b. Loss of skin turgor, dry tongue and decreased intra­ ocular pressure resulting in sunken eyes c. Hypothermia (presence of fever is a strong evidence of infection) d. Tachycardia e. Hyperpnoea or Kussmaul’s breathing depending on degree of acidosis. f. Hyporeflexia (decreased potassium) g. Signs simulating surgical abdomen h. Hypotonia, stupor or coma i. Evidence of precipitating illness.

Investigations zz

zz



Ch-10.indd 812

Serum glucose is > 300 mg/dl (may vary from high normal to very high levels). Severe fluid and electro­lyte loss and the presence of glucose contribute to increased osmolality in DKA (up to 340 mOsm/kg). Ketones (acetone, acetoacetic acid (AAA), β hydroxy butyric acid). Total ketone concentration is usually > 3 mM/L and can go up to 30 mM/L (Normal value—0.15 mM/L) —— Acetone does not contribute to acidosis.

Ratio of β hydroxy butyrate to acetoacetate is 3 : 1 in mild DKA and 15 : 1 in severe DKA. —— Ketostix, acetest, chemstrip (UKG) are the strips available to detect ketone bodies. Standard nitro­ prus­side reagents in them react with acetoace­ tate and not with β hydroxy butyrate and the test can be false negative. zz  As DKA is getting corrected, β hydroxy butyrate is converted to acetoacetate and the test is high positive; This does not mean that there is worsening of DKA state. False positivity for ketones: Drugs like captopril and penicillamine may cause false positive reaction. zz Acidosis (due to accumulation of β hydroxy butyrate and acetoacetic acid) a. Serum HCO3– level is < 15 mEq/L b. Arterial pH is < 7.3 Some degree of lactic acidosis (due to hypoper­ fusion) and hyperchloremic acidosis (after IV ther­ apy and during recovery phase) may also contribute to acidosis. zz Electrolytes + —— Serum Na is low, high or normal. Presence of elevated serum glucose results in obligatory movement of water from intracellular to extracellular space causing apparent hypo­ natraemia despite dehydration and hyperosmo­ lality. Hypertrigly­ceridaemia causes artefactual fall in serum Na+. + —— Serum K level can be low, normal or high due to: 1. Egress of K+ from cells secondary to acidosis. 2. Intravascular contraction. Actual K + deficiency cannot be estimated because of the above reasons. An initial low K + level, attests to severe depletion and should be managed aggres­sively. —— Serum PO level may be normal and does not 4 reflect actual body deficits as intracellular PO4 shifts to extracellular space as a part of catabolic state. zz Other tests —— BUN: 20 to 30 mg/dl due to volume depletion —— WBCs: 15,000 to 20,000/µl in infections —— Serum amylase level is increased (may be due to increase in pancreatic or salivary amylase) —— Increased transaminases (unknown signifi­cance) —— In the presence of DKA, thyroid function tests are unreliable. ——

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813

Endocrine and Metabolic Disorders Management zz

zz

zz

General —— Monitor vital signs and neurologic status —— Monitor a flow sheet including data on glucose (hourly), serum ketones, electrolytes, BUN, creatinine, calcium, phosphorous, arterial gases, urine glucose and ketones. —— Maintain intake and output chart. ——  A nasogastric tube should be used in patients with shock, stupor or coma. Bladder should be catheterised ——  C ontinuous ECG monitoring to find out K + toxicity. Fluids ——  Replacement of intravascular volume is the mainstay of treatment of DKA. Isotonic saline (0.9%) or Ringer lactate solution should be used. —— The average fluid deficit in diabetic ketoacidosis is 6 litres, 3 litres from the extracellular compart­ ment and 3 litres from intracellular compartment. In patients with normal cardiac function, initial fluid replacement is at a rate of 5 to 10 ml/kg/hr over the first 1 to 3 hrs. —— In later stages when serum sodium is > 155 mEq/ litre, ½ normal saline may be substituted. —— Rate of infusion is reduced to 150 to 250 ml/hour depending on clinical status and ongoing fluid losses. ——  Add 5% dextrose to IV solution when blood glucose ≤ 250 mg/dl. Potassium + —— Wait for serum K level before adding KCl to the drip. ——  If clinical signs of hypokalaemia exist (ileus, hypo­reflexia, abnormal ECG), infuse 20 to 40 mEq KCl/hour. Close ECG monitoring and frequent serum K+ level are necessary. If K + level is < 2.5 mEq/l, 60 to 80 mEq/l/hour of KCl may be needed. Care should be taken in anuric patients. Serum K+ > 5.5 mmol/l

zz

Ch-10.indd 813

Monitor for hypocalcemia. Do not give in presence of renal failure. Bicarbonate —— Routine use of bicarbonate is controversial. —— Indications are: i. Life-threatening hyperkalaemia ii. Lactic acidosis complicating DKA iii. Severe acidosis (pH < 6.9) or shock or coma which is unresponsive to fluid therapy. iv. P. HCO¯3< 5 mEq/litre v. Acidosis induced cardiac and respiratory dys­function. + —— If used, subtract amount of Na given as sodium bicarbonate from Na+ in replacement fluids. —— 88 mEq (2 amp) in a litre of ½ NS can be given over 1 to 2 hours and it should never be given as IV bolus. Insulin —— Insulin given in a dose of 10 to 15 units as a bolus or 0.15 U/kg IV as an infusion is the treatment of choice in DKA. —— Continuous infusion is given in a dose of 125 units regular insulin/250 ml NS at a rate of 0.1 unit/kg/hr (for a 60 kg individual, 6 units/ hour, i.e. 5 drops/minute). —— Insulin infusion should be given until DKA is resolved (usually 8–24 hours). —— If no suitable veins are obtainable, IM injection can be given. 10 to 20 units regular insulin IM in deltoid as a loading dose and then 5 to 10 units/ hr q1h until adequate glucose response is noted. Later insulin can be given every 2 to 4 hours. —— When serum glucose lowers to 250 mg/dl, add 5% dextrose to IV solution. —— A decrease in blood glucose of 50 to 75 mg/dl/ hour is appropriate. Lesser decrease indicates insulin resistance or problem with insulin delivery. In case of insulin resistance the dose of hourly insulin can be increased by 50 to 100% to achieve proper glycemic control. —— Excessively rapid correction of hyperglycaemia (> 100 mg/dl/hr) has a risk of inducing osmotic encephalopathy (especially in children). —— Reduce the dose of insulin to 1 to 2 units/hour when the serum bicarbonate rises to 15 mEq/l. Magnesium 1 to 2 gm IV over one hour is indicated in patients with ventricular arrhythmia. Treat infections with IV antimicrobials. —— ——

zz



zz

Dose of KCl (mmol/l of infused fluid) No KCI

3.5–5.5 mmol/l

20

< 3.5 mmol/l

40

Phosphate ——  Replacement of phosphate is controversial. Phosphate can be given as K+ salt.

zz

zz

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814

Manual of Practical Medicine Distinguishing Features between DKA and Non-ketotic Hyperosmolar State Features A.

B.

DKA

NKHS Type 2 DM

Clinical 1.

Type

Type 1 DM

2.

Age

Younger

Older

3.

Consciousness

Altered

Comatose

4.

Seizures

Usually absent

May be present

5.

Respiration

Kussmaul

Normal or shallow

6.

GI symptoms

Usually present

Usually absent

7.

Temperature

Normal or low

May be raised 600–1200 mg%

Biochemistry 1.

B. sugar

300–600 mg%

2.

Fluid deficit

3–5 litres

9–10 litres

3.

Osmolality

300–320 milli osm/kg

330–380 milli osm/kg

4.

Plasma ketones

4+

±

5.

Anion gap

↑

Normal or slightly ↑

6.

Arterial pH

6.8–7.3

>7.3

7.

Na+

S. (mEq/litre)

125–135

135–145

8.

S.

HCO3–

600 mg/dl Markedly elevated serum osmolality > 320 mOsm/l.



Osmolality = 2 (Na) +

zz

zz

zz zz zz zz zz

Blood glucose BUN + 2.8 18 BUN is usually high (30–40 mg/dl) or blood urea is 60 to 80 mg/dl Serum ketones are not detectable Serum sodium may be high, normal or low Potassium levels may be high, normal or low Serum bicarbonate > 20 mEq/L and pH > 7.3 Lactic acidosis may develop from underlying infection or other causes.

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815

Endocrine and Metabolic Disorders Difference in Coma due to Hypoglycaemia and Ketoacidosis Hypoglycaemic coma

Coma with ketosis

History

No food intake; unaccustomed exercise

Too little or no insulin; or an infection or digestive disturbances

Onset

In good previous health; related to last insulin injection

Ill health for several days

Symptoms

Hypoglycaemia; occasional vomiting from depot insulins

Of glycosuria and dehydration; abdominal pain and vomiting

Signs

Moist skin and tongue Full pulse Normal or raised BP Intraocular pressure—normal Shallow or normal breathing Brisk reflexes

Dry skin and tongue Weak pulse Low blood pressure Decreased Air hunger Diminished reflexes

Urine

No ketonuria No glycosuria, if bladder recently emptied

Ketonuria Glycosuria

Blood

Hypoglycaemia (< 60 mg/dl) Normal plasma bicarbonate

Hyperglycaemia (> 300 mg/dl) Reduced plasma bicarbonate

Management zz

zz

zz

zz

zz zz



Supportive measures (treatment of shock and nursing for coma). Hourly blood glucose, electrolyte levels should be monitored. Fluid replacement —— Initially fluid replacement is done to correct volume deficit. —— Normal saline is given at a rate of 1 litre/hour and switched over to 0.45% saline once intravascular volume is corrected. It is given with caution in elderly and in patients with MI, heart failure and renal insufficiency. —— After volume is restored and hyperglycaemia has come down, 5% dextrose should be given to patients with persistent hyperosmolarity and hypernatrae­mia. Fluid is maintained at a rate of 100 to 250 ml/hour. Potassium should be replaced especially in patients on diuretics. Bicarbonate may be needed when pH is < 7.2. Insulin treatment: Regular insulin 5 to 10 units IV, should be given when glucose is > 600 mg/dl and smaller doses are given later. Insulin can also be given as an infusion or intra­ muscular injection. Insulin requirement is less when compared to DKA.

Lactic Acidosis Patients with DM are vulnerable for disease like MI, sepsis, etc. Lactic acidosis is common in them and also during treatment with biguanides.

Ch-10.indd 815

This is differentiated from DKA by plasma ketone levels and enzyme assays for lactate, acetoacetic acid, β hydroxy butyrate. Lactic acidosis occurs in 2 general settings. Type A—Vascular collapse + tissue hypoxia. Type B—No vascular collapse + No tissue hypoxia Placenta is the only site where there can be lactic acidosis even in the presence of increased oxygen supply. Lactic acidosis: Metabolic acidosis (pH < 7.2) with serum lactate > 5 mmol/l. Causes Group A (With Tissue Hypoxia) —— Shock from any cause (septic shock, myocardial infarction, haemorrhage) —— Respiratory failure —— Cardiac failure —— Poisoning with cyanide or carbon monoxide —— Vigorous exercise (benign) —— Convulsions. zz Group B (Without Tissue Hypoxia) —— Diabetes mellitus —— Hepatic failure —— Severe infection —— Pancreatitis. Drugs Phenformin Sorbitol Metformin Fructose Salicylates Sodium nitroprusside INH Epinephrine and norepinephrine. zz

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816

Manual of Practical Medicine Toxins Ethanol Methanol. Congenital enzyme defects Glucose-6-phosphatase Fructose 1, 6 biphosphatase Pyruvate carboxylase Pyruvate dehydrogenase Leukaemia, lymphoma, solid tissue tumours (malig­nant).

Treatment zz zz zz

Treat the cause Dichloroacetate has been tried Bicarbonate is given for severe acidosis.

Long-term Complications of Diabetes Diabetic Retinopathy This is the most common cause for blindness in adults between 30 and 65 years. The lesions can be broadly divided into: 1. Simple/background retinopathy 2. Preproliferative retinopathy 3. Proliferative retinopathy. Earliest change is increase in permeability of the capillaries which progresses to the formation of saccular and fusiform aneurysms. Hypertension in Diabetes Mellitus The prevalence and time of development of hypertension in patients with diabetes mellitus varies with the type of diabetes. zz The incidence of hypertension in type 1 diabetes rises from 5% at 10 years’ duration, to 30% at 20 years, and 70% at 40 years. The blood pressure begins to rise within a few years after the onset of albuminuria and increases progressively as the renal disease progresses. Albuminuria typically precedes hypertrension. zz In type 2 diabetes, 40% are hypertensive at the time of diagnosis, in approximately one-half of these patients, hypertension existed before the onset of albuminuria. zz ACE inhibitors and ARBs are useful agents to treat diabetic hypertensives since they slow renal disease progression. zz Among beta-blockers, carvedilol may be the drug of choice because of potential benefits on glycaemic control and lower rate of development of albuminuria when compared with metoprolol. zz A loop diuretic is necessary for patients with moderate renal failure or heart failure.

Ch-10.indd 816

zz

zz

Hypertension can accelerate other complications of DM, particularly CVD, nephropathy, and retinopathy. In type 2 DM, the possibility of renovascular hypertension should be considered when the blood pressure is not readily controlled.

Background Retinopathy without Maculopathy It constitutes: a. Venous dilatation b. Peripheral microaneurysms, small blot haemo­rrhages, small hard exudates. Lesions in Background Retinopathy 1. 2. 3. 4. 5. 6.

Increased capillary permeability Capillary closure and dilatation Microaneurysm (outpouching of capillaries) Arteriovenous shunts Dilated veins Haemorrhages (dot and blot): It occurs in deeper layers of the retina and hence are round and regular; flame shaped haemorrhage is common in patients with hypertension. 7. Cotton wool spots: These are microinfarcts, i.e. non-perfused areas surrounded by a ring of dilated capillaries; a sudden increase in number is a bad prognostic sign. 8. Hard exudates: These are due to leakage of protein and lipids from damaged capillaries (Fig. 10.39). Macular oedema should be suspected when loss of visual acuity is not corrected by glasses. There is no immediate threat to vision. Hyper­tension, DM, should be controlled. Smoking and alcohol should be avoided. Regular fundus exami­nation every 6 to 12 months is recommended.

Fig. 10.39  Flame shaped haemorrhages and hard exudates— hypertension with diabetes

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Endocrine and Metabolic Disorders

817

Preproliferative Retinopathy It constitutes: Venous loops and beading zz Clusters/sheets of microaneurysms zz Small blot haemorrhages and large retinal haemorrhages. zz Intraretinal microvascular abnormalities zz Multiple small exudates zz Macular oedema and decreased visual acuity zz Perimacular exudates ± retinal haemorrhages of any size. zz

This stage imposes mild threat to loss of vision. Rapid reduction of blood sugar results in development of soft exudates and haemorrhages and hence sugar has to be reduced gradually.

Fig. 10.40  Diabetic proliferative retinopathy—peripheral

Proliferative Retinopathy It constitutes: Preretinal haemorrhage zz Neovascularisation zz Fibrosis zz Exudative maculopathy. zz

This stage is an emergency and urgent ophthalmo­ logical review is mandatory. Proliferative retinopathy is more common in insulin treated patients than in those not treated with insulin. The lesions are (Figs 10.40 to 10.42): New vessel formation (due to retinal hypoxia secondary to capillary or arteriolar occlusion; new vessels form from mature vessels on the optic disc or the retina in response to areas of ischaemic retina) zz Formation of retinal scar (retinitis proliferans) zz Vitreal haemorrhage zz Retinal detachment. zz

Fig. 10.41  Diabetic proliferative retinopathy well seen over the optic disc

The last two are serious complications of proliferative retinopathy causing sudden loss of vision in one eye. Risk Factors for Diabetic Retinopathy Common in young males; uncommon < 10 years regard­­ less of the duration of Type 1 DM; frequency of retinopathy increases after 13 years. Changes occur­ring in puberty (like increase in insulin like growth factor I, growth hormone and sex hormones) BP and poor glycaemic control are thought to be responsible for  increase in incidence of retinopathy. Increased insulin  resistance, inadequate insulin dosage, poor compliance are the reasons for poor glycaemic control in post-pubertal teenagers. Patients develop cataract at an early age.

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Fig. 10.42  Proliferative retinopathy— photocoagulation with laser

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818

Manual of Practical Medicine Rubeosis Iridis

zz

There is development of new vessels on the anterior surface of iris and it may obstruct anterior angle of eye leading to glaucoma. Other Ocular Manifestations • • • • • • •

zz

Cataract formation Dyskinetic pupils Glaucoma Optic neuropathy Extraocular muscle paresis Floaters (pre-retinal or vitreous haemorrhage) Fluctuating visual acuity (Changing blood sugar level).

zz

Treatment Photocoagulation is the mainstay of treatment of diabetic retinopathy. It can be of two types namely xenon arc-white light, and laser beam (monochro­ matic blue or green light). It decreases the incidence of haemorrhage and scarring and is always indicated for neovascularisation. It is also used in the treatment of microaneu­ rysms, haemorrhages and macular oedema even if the proli­ferative stage has not begun. Over a 2-week period, thousands of lesions (photocoagu­lation) are produc­ed to diminish retinal demands for oxygen, thus decreasing the stimulus for neo­vascular­isation.

zz

Pars plana vitrectomy is utilized for treatment of nonresolving vitreal haemorrhage and retinal detach­ment (retinal tears, detachment, cataract, recurrent vitreal haemorrhage, glaucoma, infection, loss of the eye are complications of the surgery). Duration and degree of glycaemic control of diabetes are the most important risk factors for retinopathy. Patients usually have no visual sym­ptoms ­­­­ until serious late complications develop, which have no effective treatment. Hence, regular screening for retinopathy is mandatory in all diabetics. Extracapsular extraction of lens with intraocular lens implantation is done for cataract. This surgery is also indicated when adequate assessment of fundus is precluded or when laser therapy to retina is prevented by presence of the cataract.

Recent Drugs for Diabetic Retinopathy VEGF inhibitors—Vascular endothelial growth factor (VEGF) such as bevacizumab, ranibizumab and aflibercept are useful adjunct therapy to panretinal photocoagulation and/or vitrectomy for selected cases of proliferative diabetic retinopathy. Bevacizumab and ranibizumab are humanized antibodies that recognize all forms of the VEGF proteins. Aflibercept is a recombinant fusion protein consisting of VEGF binding portions from the extracellular domains of human VEGF receptors 1 and 2 that are fused to the Fc portion of human IgG1 immunoglobulin.

Anatomical Classification of Neuropathy Structure

Disorder

Aetiology

Signs and symptoms

A.

Nerve root

Radiculopathy

Probably vascular

Pain and sensory loss along a dermatome

B.

Mixed spinal or cranial nerve

Mononeuropathy

Probably vascular

Pain, weakness, loss of reflexes, sensory loss

C.

Nerve terminals

Polyneuropathy

Metabolic

Glove and stocking sensory loss; minimal weakness, absent reflexes

D.

Nerve terminal? Muscle?

Diabetic amyotrophy

Unknown

Anterior thigh pain; proximal muscle weakness

E.

Sympathetic ganglion

Autonomic neuropathy

Unknown

Postural hypotension, anhidrosis, impotence gastropathy, bladder atony, nocturnal diarrhoea

Different Types of Diabetic Neuropathy

Ch-10.indd 818

Features

Large fibre

Small fibre

Proximal motor

Acute mononeuropathy

Pressure palsies

Sensory loss

0 - +++

0-±

0-±

0-±

++

Pain

+ - ++

+ - +++

+ - +++

+ - +++

±

Tendon reflex

N - ↓↓↓

N-↓

↓↓

Normal

Normal

Motor deficit

0 - +++

0

+++

++

++

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819

Endocrine and Metabolic Disorders

Limited Joint Mobility (LJM, Diabetic Hand Syndrome)

Diabetic Neuropathy

This is common in 15 to 30% of adolescents with Type 1 DM; a subset of those are 400 to 600% at greater risk of developing complications associated with hyper­glycaemia. Patient keeps the hands together in prayer position; there is sclerodermatous, tight, waxy skin; fifth finger is involved early (cannot extend fully).

This is the most frequently encountered chronic compli­ cation of diabetes. The neuropathic disorder includes manifestation of the somatic and/or auto­nomic parts of the nervous system (Fig. 10.43). Classification (Fig. 10.44) 1. Anatomical classification

Fig. 10.43  Neuropathies in diabetes

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820

Manual of Practical Medicine

Fig. 10.44  Diabetic neuropathy

2. Clinical classification a. Bilaterally symmetrical peripheral polyneuro­pathy i. Sensory polyneuropathy ii. Mixed sensory motor polyneuropathy iii. Motor polyneuropathy. b. Symmetrical or asymmetrical proximal motor neuro­pathy c. Mononeuropathy (simplex or multiplex) i. Cranial nerves ii. Peripheral nerves. d. Abdominal polyradiculopathy e. Autonomic neuropathy. Factors Involved in the Aetiology and Pathogenesis of Diabetic Neuropathy A. Metabolic 1. Hyperglycaemia a. Sorbitol accumulation b. Myo-inositol depletion c. Sodium-potassium ATPase deficiency d. Protein glycosylation 2. Lipid disturbances B. Vascular C. Others 1. Mechanical factors 2. Stress 3. Autoimmunity 4. Hereditary 5. Hypoglycaemia.

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Differentiating features between neuropathic and vascular pain Characteristic

Neuropathy pain

Vascular pain

Site of pain

Feet more than calves

Calves, thighs, buttocks than feet

Quality of pain

Superficial, sharp, burning, tingling

Deep ache

Present at rest

Common

Rare

Effect of walking

Pain improves

Pain made worse

Pain worse in bed

Yes

No

Effect due to glycaemic changes

Sometimes

No

Small Fibre Neuropathy (C–fibre) • Neuropathy of symptoms • Pain and paraesthesias—burning, lancinating, pins and needles, tingling, numbness, coldness • Feet more affected than hands • Acute < 6 months, Chronic > 6 months to years • Decreased autonomic function—decreased sweating and dry skin • Impaired blood flow—cold feet • Motor power and deep reflexes are intact • Risk of foot ulceration and gangrene • Early detection of impairment of touch and pricking sensation by monofilament and Waardenburg wheel tests • Topical application of capsaicin and clonidine are useful.

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821

Endocrine and Metabolic Disorders Large Fibre Neuropathy • Neuropathy signs • Impairment of vibration and position sense • Delta type deep seated gnawing pain similar to toothache • Sensory ataxia (Waddling like duck) • Wasting of small muscles of hands and feet • Shortening of Achilles tendon—pes equinus • Increased blood flow—hot foot • Charcot’s neuroarthropathy of different joints. Classification of Autonomic Neuropathy in Diabetic Patients According to Systems Involved Gastrointestinal disorders Esophageal dysfunction Stomach atony Gallbladder atony Small intestinal dysfunction Large intestinal atony Anorectal dysfunction zz Genitourinary disorders Bladder atony Impotence Retrograde ejaculation of semen into the bladder Loss of testicular sensation zz Cardiovascular disorders Orthostatic hypotension Heart rate abnormalities Painless myocardial infarction zz Respiratory control and airway tone disturbances zz Peripheral autonomic disorders Sudomotor and piloerector dysfunction Vasomotor disturbances Peripheral oedema Orthostatic hypotension zz Endocrine disorders Hypoglycaemia Defective epinephrine and glucagon   counterregulatory response Defective central perception Norepinephrine (vascular) deficiency Pancreatic polypeptide disturbances Renin disturbances zz Lacrimal gland disorders zz Pupillary disorders zz Special complications related to neuropathy Diabetic foot disease Neuropathic arthropathy (Charcot’s joint) Pseudotabes and pseudosyringomyelia Entrapment neuropathies Loss of visceral pain sense zz



Ch-10.indd 821



Increased mortality (associated with autonomic neuro­pathy).

Tip-Therm Test Tip-Therm is an early diagnostic testing device for symmetrical polyneuropathy which measures temperature sensitivity of the skin. Tip-Therm is made of special polymer and metal alloys. The polymer side feels warmer and the metal alloy side cooler due to the thermal conductivity property of the materials. Diabetic neuropathy can lead to the diabetic foot syndrome, resulting in ulceration. This distal sym­metrical polyneuropathy involves both large and small nerve fibres. The large myelinated (Aα, Aβ) fibres detect vibration and sensation. The small myelinated (Aδ) and unmyelinated C fibres can detect thermal sensation. Studies show abnormal small fibre function is usually affected before large fiber function While temperature discrimination can be tested anywhere, it is best tested on the dorsal foot (Fig. 10.45). If sensation is not felt on the foot dorsum, try the test on the inside of the forearm. The patient should not watch the procedure so that objective results are obtained. It was shown to have 100% specificity and 97.3% sensitivity in diagnosing diabetic neuropathy compared to biothesiometer testing. Note: Testing vibratory sensation using 128 MHZ tuning fork at the base of the great toe and also the ability to sense touch with a monofilament (size of the mono­filament- S 07/10 gm) are useful tests to detect moderately advanced diabetic neuropathy. Monofilament Test Early loss of protective sensation can be detected in the foot of the diabetic patients by using the 10 gm mono­filament (Fig. 10.46A).

Fig. 10.45  Tip-Therm test

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822

Manual of Practical Medicine

A

B Figs 10.46A and B  Monofilament test

Ten sites are chosen and the monofilament is applied with enough pressure to bend the filament for the duration of not less than 2 seconds (Fig. 10.46B). It is tested for three times at each site and it is enough if he answers correctly in 2 out of 3 applications. Failure to feel the mono­ filament in more than 4 sites denotes loss of protective sensation. The risk of ulcer formation is greater. This test is 95% sensitive and 80% specific.

Management of the Diabetic Neuropathies General measures a. Improvement in diabetic control b. Aldose reductase inhibitors: Sorbitol accumulation has a role in the pathogene­sis of diabetic neuropathy and cataract; this sorbitol pathway can be shutdown by aldose reductase inhib­itors. Epalrestat is a reversible aldose reductase inhibitor approved for treatment of diabetic neuropathy. c. Relief of contributory factors like alcohol, ischaemia, hyperlipidaemia, malnutrition, uraemia, neurotoxic drugs. d. Relief of nerve entrapment: Constricting apparel, anti-inflam­matory agents, surgical decompression, sympto­matic drug treat­ment. e. Treatment of painful neuropathy: i. Ibuprofen, sulindac are used; narcotic anal­gesics are not useful. ii. Tricyclic antidepressants, phenothiazines (imi­ pra­mine or amitriptyline 50 to 150 mg/day + fluphe­nazine 1 mg every 8 hours is used in the treatment of various neuropathic cach­ exia. Nortriptyline or doxepin—25–100 mg at night.

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Others—Duloxetine 60–120 mg/day or venlafaxine 75–225 mg/day. iii. Carbamazepine—up to 200 mg every 8 hours (prevents generation of action potentials) Sodium valproate—500–1200 mg daily. iv. Capsaicin—topical application works by deplet­ ing the nociceptive neurotransmitter substance ‘P’ in unmyelinated sensory nerve terminals. v. Gabapentin—300 mg tid (maximum 1800 mg/ day) or Pregabalin—75 to 150 mg bid (maximum 600 mg/day). vi. Alpha lipoic acid 600 mg/day IV for three weeks. vii. Pancreatic transplantation. viii. Isosorbide dinitrate spray. ix. Transcutaneous electrical nerve stimulation (TENS). f. Autonomic neuropathy i. Gastroparesis—metoclopramide, cholinester­ase inhibitors, domperidone, erythromycin. ii. Diabetic diarrhoea—clonidine, codeine, lopera­ mide, diphenoxylate, kaopectate, cholestyra­ mine, broad spectrum antibiotics, octreotide 50 to 75 µgm tid S/C. iii. Constipation—laxatives, metoclopramide. iv. Orthostatic hypotension—fludrocortisone, salt loading, sympathomimetics. v. Diabetic cystopathy—cholinergics. vi. Retrograde ejaculation—brompheniramine mal­­eate. vii. Gustatory sweating—anticholinergics, cloni­dine. Supportive measures, prosthesis, surgery Foot care, foot wear Foot and leg braces Elastic stockings

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Endocrine and Metabolic Disorders Physical therapy Small meals, gastroenterostomy Bladder massage (crede), self-catheterisation, bladder neck resection Orthopaedic surgical measures Penile prosthesis Anaesthetic precautions. Treatment for diabetic erectile dysfunction Non-hormonal Therapy Sildenafil citrate, a Phosphodiesterase 5 inhibitor is used at a dose of 50 to 100 mg (25 mg for men over 55 yrs) 1 hr before intercourse. It is contraindicated in patients with coronary artery disease and those taking nitrates. α2 blockers (yohimbine) Tadalafil: It is very similar to sildenafil. It is a selective inhibitor of cyclic guanosine monophosphate (CGMP) and a specific phosphodiesterase 5 inhibitor (PDE 5). It is used in the dose of 10 to 20 mg one hour prior to sexual activity and the effect persists for 24 hours. Patients on nitrates or alpha blockers should avoid taking this drug. Vardenafil: Similar to tadalafil and the dose is 10 to 20 mg one hour before sexual activity. Alprostadil (Prostaglandin E1): 2.5 to 10 mcg is given by intracavernosal injection or intraurethral application for the management of erectile dysfunction. Painful erection lasting for more than 4 hours (priapism) and penile fibrosis are complications. Hormonal Therapy Hypogonadotrophic hypogonadism—parenteral testo­ sterone 200 mg IM. Hyperprolactinaemia or pituitary tumour—cessation of causative medications, bromocriptine, extirpative surgery. Non-invasive Therapy Vacuum erection devices Intracavernosal injection of vasoactive agents (papa­ verine, phentolamine, PG-E). Invasive Therap Penile prosthesis Microvascular arterial bypass surgery.

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Diabetic Foot It is a complication of diabetes due to an interplay of a number of disturbances like large vessel disease, neuro­­ pathy, infection, poor wound healing and possibly small vessel disease also (microangiopathy). • Sensory loss results in unrecognised trauma from poorly fitting shoes, thermal or hot water burns, penetrating objects, toe nail cutting, etc. • Motor defects causing foot deformities, produce abnormal pressure points on weight-bearing areas. Autonomic neuropathy results in poor arteriolar constriction and dilatation. • Poor vasodilatation in response to heat or infection in combination with impaired sweating may compromise the local tissue microenvironment. • Anhidrosis causes dry skin with fissures and cracks, predisposing to secondary infection. • Denervation hypersensitivity (vasoconstriction in response to cold) may contribute to the development of diabetic foot ulcers. • Hence, peripheral neuropathy is viewed as a primary underlying disturbance of diabetic foot lesions and vascular insufficiency is an important secondary factor. • The ulcers are painless, with a punched out appearance. Foot is characteristically warm and pulses are easily felt. Secondary infection is common and may lead to wet gangrene. X-ray may show underlying osteomyelitis with sequestra and destruction of bone. • Repetitive stress of walking results in interosseous atrophy causing cocked up toes and thinning of fat pad over metatarsal head. Foot infections in diabetic patients are classified into two categories: 1. Non-limb-threatening infections (superficial, lack systemic toxicity, minimal cellulitis less than 2 cm, ulceration not extending fully through the skin, lack of significant ischemia). S. aureus is the major pathogen involved. 2. Limb-threatening infections (extensive cellulitis, lymphangitis, ulcers penetrating through the skin into the subcutaneous tissues, prominent isch­emia). Polymicrobial infections are common. Staphylococ­cus aureus, group B streptococci, Enterococcus, and facultative gram-negative bacilli along with anaerobes are commonly implicated.

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Manual of Practical Medicine Clinical Features of Diabetic Foot Primarily neuropathic

Primarily ischaemic

Warm

Cold

Bounding pulses

Absent pulses

Diminished sensation

Sensation intact

Pink skin

Skin blanches on elevation

Anhidrosis

-

Callous formation

-

Cracks and fissures

-

Painless ulceration

Painful ulceration

Digital ulceration

Digital gangrene

Charcot’s joints

-

Wasting of interosseous muscles

-

Clawed toes

-

Neuropathic oedema

Oedema associated with cardiac decompensation

Management zz

zz

zz

zz

General instructions: Patients are advised not to smoke. They should not walk on hard surfaces or  sandy beaches especially with barefeet. They should not use adhesive tapes or chemicals for removing corns/callosities. They should wear pro­ perly fitting stockings. Shoes should be comfortable at the time of purchase. Leather shoes are preferred and they are best tried in the afternoon when feet are largest. Shoes with pointed tips should be avoided. They should cut their nails straight across using a nail cutter. Regular chiropody should be done every week to debride the lesion. Relieve high pressure area with bed rest and special footwear. If there is cellulitis, admit the patient and start on IV antibiotics (benzylpenicillin 600 mg/6 h IV and flucloxacillin 500 mg/6 h IV ± metronidazole 500 mg/8 h IV or cefazolin IV). For mild infections, oral clindamycin or cephalexin or cloxacillin for 2 weeks can be given. IV antimicrobial therapy is recommended for 10 to 12 weeks in the presence of osteomyelitis.

Absolute indications for surgery Abscess or deep infection zz Spreading anaerobic infection zz Osteomyelitis zz Severe ischaemia-gangrene/rest pain zz Suppurative arthritis. zz

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Newer treatment Platelet derived growth factor topical application for diabetic ulcer. zz Living human skin equivalents—by tissue engineering technique. zz

Diabetic Nephropathy (DN) About 50% of end stage renal disease are due to diabetic nephropathy. About 35% of patients with IDDM develop this complication. In NIDDM, pre­valence varies from 15 to 50%. There are 2 distinct pathologic patterns: 1. Diffuse glomerulosclerosis: This consists of widen­ing of glomerular basement membrane and mesan­gial thicken­ing. 2. Nodular glomerulosclerosis: There is deposition of PAS positive material in the periphery of glomer­ ular tufts, (the Kimmelstiel-Wilson lesion). In addi­ tion, there is hyalini­sation of afferent and efferent arterioles, ‘capsular drops’ in Bowman’s capsule, fibrin caps and occlusion of glo­meruli. Kimmelsteil-Wilson nodular glomerulosclerosis and capsular drops are pathognomonic of diabetic nephropathy.

Stages in Diabetic Nephropathy

Time curve of diabetic nephropathy

Stage I Stage II

Glomerular hyperfiltration and renomegaly Early glomerular lesions (expansion of mes­ an­gial matrix and thickening of glomer­ular basement membrane). Occurs 18 to 36 months after onset of IDDM. Stage III Microalbuminuria stage (incipient DN) with persistent hypertension of > 140 to 160/90 mm Hg. Albumin excretion is in the range of 30 to 300 mg/day. Albumin excretion rate (AER)—20 to 200 µg/min. Microalbuminuria is due to ↓ concentration of anionic heparan sulfate-proteoglycan in the glomerular basement membrane. Diagnosis is by finding an AER > 15 µg/min (30 mg/day) in 2 to 3 samples collected in a 6 month period.

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Endocrine and Metabolic Disorders Persistent leakage of protein greater than 500 mg/day is predictive of subsequent macroproteinuria. Stage IV Clinical nephropathy (macroproteinuria) Once macroproteinuria begins, there is a steady decline in GFR of about 1 ml/min/month. Stage V End stage renal disease Azotemia develops usually after 10 years progres­ sing to nephrotic syndrome and ESRD later.

Treatment Angiotensin—converting enzyme inhibitors are use­ ful in slowing progression of diabetic nephro­pathy, especially in microalbuminuric stage. They are useful in hypertensive patients with diabetes. If proteinuria persists after 3 months of therapy, the drug dose is increased until either the albuminuria disappears or the maximum tolerable dosage is reached. If ACE inhibitors are contraindicated, then calcium channel blockers (non-dihydropyridine class—verapamil, diltiazem) can be used. zz Low protein diet. zz Hyporeninemic hypoaldosteronism associated with renal tubular acidosis, may require alkalinizing solution (Shohl’s solution); external K + should be avoided. Rarely fludrocortisone may be needed for treating hyperkalaemia. zz Plan for dialysis or renal transplantation in patients with end stage renal failure. zz

Pregnancy and Diabetes In pregnancy, hormonal and metabolic effects increase the tendency to both ketoacidosis and hypoglycaemia (due to aggressive insulin therapy).

Effect of Diabetes on Pregnancy The risk of congenital malformations is increased in infants born to diabetic mothers who have poor control of diabetes during the first trimester of pregnancy. Polyhydramnios is common in poorly controlled diabetic women and can lead to preterm delivery. Maternal or fetal hyperglycaemia causes fetal hypoxia or asphyxia in the 3rd trimester. If preprandial blood glucose exceeds 150 mg/dl, careful foetal monitoring should be done. Foetal macrosomia is also common (birth weight > 90th percentile for gestational age or more than 4 kg); intrauterine growth retardation can occur in diabetic women with vascular disease or persistent hypoglycaemia. Other neonatal risks are respiratory distress syndrome, hypoglycaemia, hyperbilirubinaemia, hypo­calcaemia and poor feeding.

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Foetal Development Incidence of congenital anomalies in infants of diabetic mothers is 6 to 12% whereas it is only 2% in non-diabetic populations. The congenital malformations found in children of diabetic mother are: 1. Caudal regression 2. Anencephaly 3. Spina bifida, hydrocephalus and CNS defects 4. Cardiac anomalies (TGV, VSD, ASD) 5. Anorectal atresia 6. Renal anomalies (agenesis, cystic kidney, ureter duplex) 7. Situs inversus. Any intervention to reduce the incidence of major congenital anomalies should be done very early in pregnancy, i.e. between 5th and 8th week of gestation. This implies that PPBG should be maintained < 160 mg/dl prior to conception in diabetic women who plan pregnancy. Effective contra­ceptive counselling should also be given to them. At 16 to 18 weeks, maternal serum alpha-fetoprotein should be measured and ultrasound study of the foetus should be performed at 20 weeks to rule out neural tube defects. Echocardiography should be done at 22nd week in patients who have increased glycosylated haemoglobin early in pregnancy. Ultrasound is also useful for finding out foetal growth and the length of gestation. Maternal hyperglycaemia > 130 mg/dl is associated with excessive birth weight in infants of diabetic mothers (MACROSOMIA). This excess growth and fat deposition is due to foetal hyperglycaemia. In contrast to macrosomia, the foetus of a woman with diabetes may have intrauterine growth retard­ation due to decreased uteroplacental perfusion; oligohydramnios is common.

Screening and Diagnostic Criteria for Gestational DM (O’ Sullivan-Mahan Criteria) Screening is done by plasma glucose measurement in the following way: 1. 50 gm oral glucose administration between 24th and 28th weeks without regard to time of day or time of last meal to all pregnant women who have not been identified as having glucose intolerance before 24th week. 2. Venous plasma glucose is measured l hr later. 3. A value of ≥ 140 mg/dl indicates the need for a full diagnostic GTT.

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Manual of Practical Medicine

Diagnosis of Gestational DM zz

zz

zz



100 gm of oral glucose is given after overnight fasting of at least 8 hours, but not more than 14 hours, and after at least 3 days of unrestricted diet (≥ 150 gm of carbohydrate) and physical activity. Venous plasma glucose is measured fasting and at 1, 2, and 3 hours after oral glucose (no smoking is allowed during test and patient should not under­take any physical activity). Two or more of the following venous plasma glucose concentrations must be met or exceeded for a posi­tive diagnosis. Fasting 105 mg/dl (5.8 mmol/l) l hour 190 mg/dl (10.6 mmol/l) 2 hours 165 mg/dl (9.2 mmol/l) 3 hours 145 mg/dl (8.l mmol/l) Classification of Carbohydrate Intolerance in Pregnancy

Class

Classification criteria

Gestational DM (GDM)

Carbohydrate intolerance of varying severity with onset during present pregnancy.

  GDM-Class A1

Fasting glucose normal for preg­nancy; venous plasma < 105 mg/dl.

  GDM-Class A2

Fasting glucose exceeds normal for pregnancy; venous plasma > 105 mg/dl on at least 2 occasions. Postpartum reclassification after 75 gm of oral glucose (can be normal, impaired glucose tolerance or dia­betes mellitus).

Previous GDM   * (Class A1 and A2)

Abnormality of glucose tolerance in a previous pregnancy, without DM having been diagnosed postpartum (Post­partum GTT having been normal, impaired or not perform­ed).

* Criteria for Class A1 and A2 in previous GDM is similar to that of GDM

Pregestation Diabetes Mellitus DM-type I zz

zz

Uncomplicated Absence of retinopathy, nephro­ pathy, neuropathy, coronary artery disease or hypertension. Complicated Presence of one or more of the above complications.

DM-type II zz zz

Uncomplicated Complicated.

Stages of Care in Diabetic Pregnancy before Conception Establish preprandial blood glucose level (PPBG).

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I trimester (PPBG > 9 mmol per litre) or (160 mg/dl): Abortion risk and risk of congenital anomalies should be taken care of monitor for ketonaemia. II trimester (PPBG > 7 mmol per litre) or (130 mg/dl): Macro­somia is common; monitor for leucine, threonine, free fatty acid and total glucose values. III trimester (PPBG > 7 mmol per litre) or (130 mg/dl): Respi­ratory distress syndrome and stillbirths are common; monitor for ketonaemia. Postpartum (PPBG > 10 mmol per litre) or (180 mg/dl): Counsel­ling on lactation, contraception and child development are recommended. Aim of therapy is to maintain a fasting plasma glucose of 60 to 100 mg/dl and a postprandial level of 100 to 130 mg/dl. I.  Dietary Management of Diabetic Women • The key stone of management is the diet. • Caloric intake should be less to prevent weight gain (> 4 pounds/month during first trimester and > 4 pounds during II and III trimester) • Hypoglycaemic reactions should not be overtreated to minimise rebound hyperglycaemia. • For moderate hypoglycaemic symptoms—8 ounces of milk • If blood glucose is < 60 mg/dl, 10 gm of fast acting carbohydrate (dextrosols or 4 ounces orange juice) should be given. • For severe hypoglycaemia, patient must keep glucagon on hand and it should be given subcuta­neously. II.  Insulin Therapy in Pregnancy Most pregnant diabetics require at least 2 injections of a mixture of regular and intermediate insulin each day to prevent fasting and postprandial hypergly­caemia. A 2/3rd of insulin can be given before breakfast and 1/3rd before supper. Fasting blood glucose is better controlled by delaying evening dose of inter­mediate insulin to bed time, which prevents nocturnal hypoglycaemia. III.  Obstetric Management 1. a. Antepartum foetal surveillance is necessary during the 3rd trimester (26–34 weeks) to reduce the chance of stillbirth. Foetus is monitored by foetal activity determination recorded by preg­nant woman. b. Foetal heart rate monitoring (stress and non-stress tests) c. Ultrasound. 2. The goal for delivery should be 38 weeks or later to reduce neonatal morbidity arising from a preterm labour.

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Endocrine and Metabolic Disorders Foetal pulmonary maturity should be assessed by amniotic fluid analysis for lecithin sphingomyelin ratio (L/S) or phosphatidyl glycerol (PG).   L/S ratio >3.5 or the presence of PG predicts the lowest risk for respiratory distress syndrome. 3. If the foetus is large (> 4200 gm), primary caesarean section should be done to avoid shoulder dystocia and birth trauma. Otherwise, labour can be induced with continuous fetal heart rate monitoring. During labour, mater­nal blood sugar should be kept within 80 to 100 mg/dl by IV insulin (0.5–2 units/hour) along with Ringer lactate or normal saline as infusion. 4. Diabetic mothers should be encouraged to breastfeed. If breastfeeding is abruptly terminated, there may be a transient increase in insulin sensitivity. Intrauterine contraceptive devices are effective in diabetic women and low dose sequential birth control pills do not harm glycemic and lipid profiles in diabetic women < 35 years of age.

Surgery and Diabetes Surgery is a stressful condition either when performed electively or as an emergency. It results in the pro­duction of catabolic hormones cortisol, catechola­mines, glucagon and growth hormone in normal persons as well as in diabetics. Careful monitoring of blood glucose is necessary to: a. Avoid hyperglycaemia and acute complications (DKA, hypoglycaemia) b. Allow a normal inflammatory response and wound healing.

Modification of Chronic Therapy It is guided by patients usual treatment and by the nature of the surgery. i. Patients who are managed on diet alone often require no additional measures. For patients with fasting or postprandial hyperglycaemia >200 mg/dl, human insulin is advised. ii. Patients using oral hypoglycaemic drugs should discontinue them on the day before the major surgery. They may need insulin whereas patients undergoing minor surgery, can be main­tained on oral hypoglycaemic drugs. However, oral drugs should be stopped on the morning of surgery and restarted when the patients start taking feeds adequately.

Ch-10.indd 827

iii. Patients who are treated with insulin require dosage adjustments. Hypoglycaemia is antici­p at­e d and dextrose solution should be available. In Type 1 DM Uninterrupted insulin administration is essential to prevent DKA. At least half the daily dose of insulin should be given on the day of surgery. Adminis­tration of 5% dextrose is helpful to limit lipolysis and keto­ genesis in patients with restricted oral intake. Periodic monitoring of glucose, electrolytes and urinary ketones should be done. For patients using conventional therapy, a dose of intermediate acting insulin should be given in the morning before minor surgery and then can be given twice daily. Hyper­ glycaemia is managed with supplements of regular insulin given every 4 to 6 hours till oral intake is resumed. In patients using MDII or CSII, basal insulin given preoperatively, is continued during peri­operative period. In Type 2 DM Patients requiring large dose of exogenous insulin (> 50 units/day), are given insulin in preoperative and immediate postoperative period. 2/3rds of the dose is given as intermediate acting insulin and the rest is given as short-acting insulin. iv. IV insulin infusion therapy: Very stressful proce­ dures like coronary artery bypass, renal transplant, etc. may require insulin infusion, during pre (0.5–1 unit/hour), intra and post-operative periods till the oral drugs are replaced, or when insulin can be given subcutaneously. Emergency surgery may be needed despite severe hyperglycaemia, DKA, or NKHS; IV insulin infusion is preferred along with replacement of intravascular volume. In the perioperative period, assess for chronic com­ pli­cations of diabetes, i.e. patients with cardiovascular disease and autonomic neuropathy are susceptible for asymptomatic MI. Decubitus ulcer is common in patients with neuropathy especially when they are immobilized for a longer period. Enteropathy can alter GI responses to surgery and anaesthesia. Guidelines for Perioperative Diabetes Management with IV Insulin Infusion Twenty-five units of regular human insulin in 250 ml of normal saline is connected to a perioperative main­tenance fluid line (5% dextrose at a rate of 100 ml/hr).

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828

Manual of Practical Medicine Blood glucose mg%

Criteria for Exclusion

Insulin units/hr

ml/hr

zz

0

0

zz

81–100

0.5

5

zz

101–140

1

10

141–180

1.5

15

181–220

2

20

221–260

2.5

25

261–300

3

30

301–340

4

40

>341

5

50

80 restart insulin infusion. • Insulin needs are decreased in patients on treatment with diet or oral agents or those requiring < 50 units/ day and in those with endocrine deficiencies. • Insulin needs are increased in patients with obesity, sepsis, steroid therapy, renal transplant, coronary artery bypass. Preoperative Assessment Assess cardiovascular function and renal function. Check for signs of neuropathy (particularly auto­nomic). zz Assess diabetic control (Estimation of Hb A , monitor 1 preprandial blood glucose 4 times daily). zz Review treatment of diabetes. Replace long-acting with intermediate insulin. Stop sulfonylureas (long acting) or biguanides (metformin) and replace with insulin if necessary. zz zz

Criteria for Simultaneous PancreasKidney Transplantation Criteria for Inclusion zz zz zz

Insulin-dependent diabetes mellitus Age 18 to 55 years Established diabetic nephropathy (serum creati­nine ≥ 2 mg/dl).

Hormone

Ch-10.indd 828

Onset of

zz zz zz

Insufficient cardiac reserve (by ECHO, perfusion scan) Peripheral vascular disease Major psychiatric illness Substance abuse (drugs, alcohol) Cancer Active infection.

Hypoglycaemia in Adults Hypoglycaemia is a biochemical abnormality, not a disease. Criteria for Diagnosis Glucose level

Fasting state

Fed state

Plasma glucose

< 60 mg/dl

< 50 mg/dl

Whole blood

< 50 mg/dl

< 40 mg/dl

Whipple’s triad for the diagnosis of hypoglycaemia: 1. Symptoms of hypoglycaemia. 2. Low plasma level of glucose. 3. Relief of symptoms after raising the level of plasma glucose. Random blood glucose level of < 50 mg/dl suggests hypoglycaemia.

Glucose Homeostasis Most important organ which consumes glucose is the brain (requirement 100 gm/day). Other organs which use glucose as the major fuel are RBCs (35 gm/day) and muscle (30 gm/ day). Other tissues use predominantly free fatty acids or ketone bodies. Glucose production is mainly by the liver during short fasts. Glucose is produced by two separate pathways: 1. Glycogenolysis: Seventy-five per cent of glucose produc­tion is by this pathway especially during an overnight fast. 2. Gluconeogenesis: It is the synthesis of new glucose from noncarbohydrate sources. The three major sub­strates are lactate, derived from peripheral tissues, amino acids released by muscle and glycerol derived from the breakdown of triglycerides in adipose tissue. Only 25%

Effects

Secretion

Action

Epinephrine, Norepinephrine

Rapid

Rapid

Inhibits glucose utilisation by muscle; increases hepatic gluconeogenesis; stimulates glucagon secretion; inhibits insulin secretion; stimulates hepatic glycogenolysis

Glucagon

Rapid

Rapid

Increases hepatic glycogenolysis; increases hepatic gluconeogenesis

Cortisol

Delayed

Probably immediate

Increases hepatic gluconeogenesis; inhibits glucose utilisation by muscle

Growth hormone

Delayed

Delayed

Inhibits glucose utilisation by muscle; increases hepatic gluconeogenesis

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829

Endocrine and Metabolic Disorders of hepatic glucose production derives from gluconeo­ genesis after an overnight fast. When the contribution from glycogenolysis ceases, gluconeo­genesis becomes dominant as the period of fasting lengthens. Obligate glucose consumers continue to function normally even after prolonged fasting because of powerful defense mechanisms. During fasting the glucose level decreases (by 15–20 mg/dl) and the insulin levels decrease and get stabilised at a lower level. After a feed there is an increase in blood glucose concentration closely followed by a rise in blood insulin concentration. This response is exag­gerated in obese than in lean subjects. Fifty per cent of the insulin undergoes degradation in the liver and the rest, circulate and act on 3 specific receptors on liver, muscle and adipose tissue. Hypoglycaemia is better tolerated by females. They do not develop symptoms till the blood glucose falls to 35 to 40 mg/dl. Ten per cent of glucose is converted to glycogen and stored in the liver.

Hormonal Response to Hypoglycaemia zz

zz

zz

In normal persons: Levels of epinephrine, norepinephrine and glucagon increase quickly whereas levels of cortisol and growth hormone increase slowly during hypo­glycaemia. This response is brought about by sensitising glucose receptors in hypothalamus and it continues for 8 to 10 hours. In type I diabetes: First 5 years after the onset of Type 1 DM, glucagon response to hypoglycaemia is lost. After 10 years, the epinephrine response is also lost even in the absence of autonomic neuropathy. The other counter regulatory hormones continue to act. This results in absence of recognition of hypo­glycemic symptoms produced by epinephrine and they become more prone for hypoglycaemia when on insulin ther­ apy. Because of this, patients suffer from “hypoglycae­ mia unawareness” due to impaired, glucagon, epinephrine and autonomic nervous sys­tem response. In type 2 diabetes: Levels of counter regulatory hormones remain normal.

Signs and Symptoms of Hypoglycaemia zz

zz

Ch-10.indd 829

Adrenergic symptoms (increased activity of the autonomic nervous system, triggered by a rapid fall in glucose level): Weakness, sweating, tachycardia, palpitations, tre­­mor, nervousness, irritability, tingling of mouth and fingers, hunger, nausea, vomiting. Neuroglucopenic symptoms (due to decreased activity of CNS, requires an absolutely low level of glucose):

zz



Headache, hypothermia, visual disturbances, men­tal dullness, confusion, amnesia, seizures, coma. Relationship between plasma glucose and signs of hypoglycaemia. 90 to 75 mg% Inhibition of insulin secretion 75 to 60 mg% Glucagon, epinephrine and GH secretion 60 to 45 mg% Cortisol secretion, cognitive dysfunc­tion 45 to 30 mg% Lethargy 30 to 15 mg% Coma, convulsions 20% of insulin. Ratio of insulin to proinsulin in normal individuals is 6 : 1. In insulinoma, the ratio is 1 : 1 whereas in sulfonylurea induced hypogly­caemia, the ratio is 10 : 1. zz

Ch-10.indd 831

zz

zz

zz

C-peptide level: It increases in equimolar concen­tration as that of insulin. Glucagon test: After an overnight fast, give gluca­gon 1 mg IV and if the peak insulin response is more than 130 µu/ml, the test is positive. Localisation of tumour by CT, MRI, radionuclear scan is done if the tumour is more than 2 cm in size. If the tumour is less than 2 cm in size, pancreatic arterio­ g raphy and CT with contrast can be used.

Treatment Medical: Acute treatment is by giving IV glucose infusion till plasma levels of glucose reach normal range. Drugs which act by increasing blood glucose level. zz Oral diazoxide 300 to 1200 mg/day along with a diuretic (thiazide) to compensate for salt retaining property of diazoxide zz Phenytoin zz Chlorpromazine zz Propranolol zz Verapamil zz Octreotide (100–600 mg/day subcutaneously). Drug of choice for metastatic islet cell carcinoma is strep­tozotocin and doxorubicin or L-asparaginase or mithramycin. Surgical: Surgery is the definitive treatment. Detect­ able tumours can be resected. If there is no detectable tumour, stepwise distal pancreatectomy is done until frozen section or blood glucose shows that all the tumour is removed.

8. Renal Failure Poor dietary intake, decreased gluconeogenesis, and increased peripheral utilisation of glucose are the reasons for hypoglycaemia.

Treatment Frequent feeding and glucocorticoids (15–20 mg predni­ solone) sometimes. In patients with end stage renal disease, hypoglycaemia is a poor prognostic sign and the patients may die within 1 year.

9. Insulin Autoantibodies Occasionally a patient may spontaneously develop antibodies to insulin even though he has never recei­ ved insulin which leads to hypoglycaemia. This is due to binding of large amounts of endogenous insulin with subsequent release of free insulin at inappropriate time.

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Manual of Practical Medicine Unusual cause for hypoglycaemia may be as a part of endocrine syndrome as occurs in rheumatoid arthritis, systemic lupus erythematosus, or Graves’ disease.

10. Insulin Receptor Autoantibodies This occurs usually in females. Patients have a syn­drome of insulin resistance and acanthosis nigricans. Patients have raised ESR, anti-DNA antibodies, increased gamma globulin and decreased complement levels.

11. Sepsis Hypoglycaemia is occasionally seen in both gram-positive and gram-negative sepsis.

12. Falciparum Malaria In malaria, hypoglycaemia is due to increased glucose utili­ sation by parasitised RBCs. It occurs commonly in severely ill, fasting patients especially children.

13. Congestive Heart Failure Patients have weight loss, anorexia, decreased cardiac output, and mild hepatic dysfunction. In CCF, hypo­ glycaemia is due to decreased delivery of gluconeogenic substrates to the liver as a result of poor appetite and diminished hepatic blood flow.

Fed (Reactive) Hypoglycaemias In fed hypoglycaemia, symptoms are mainly adrener­ gic. The onset is rapid and transient. It is usually reversed by the normal hormonal responses. Adminis­tration of adrenergic antagonists results in dis­appearance of signs and symptoms but is usually not necessary.

Causes of Fed Hypoglycaemias zz zz zz zz zz zz zz zz

Hyperalimentation Impaired glucose tolerance Idiopathic reactive hypoglycaemia Adrenal insufficiency* Beta-cell tumours (insulinomas)* Insulin autoantibodies* Hereditary fructose intolerance Galactosemia.

*Also cause fasting hypoglycaemias.

Oral Glucose Tolerance Test Alimentary hyperglycaemia is now called hyperalimen­ t­­ation. Early diabetes is now called impaired glucose

Ch-10.indd 832

tolerance; functional hypoglycaemia is now called idiopathic reactive hypoglycaemia. Abnormally high glucose levels in the early part of oral GTT indicates impaired glucose tolerance and a normal early levels of glucose indicates idiopathic reactive hypoglycaemia. Hyperalimentation It is common in patients who have undergone gastric surgery. The normal relationship between the stomach and the small intestine is altered. The entry of the stomach contents into the duodenum is rapid and the rate of absorption of glucose is also increased causing hyperglycaemia. In response to this, there is an increased insulin secretion which causes hypoglycaemia. Impaired GTT The explanation for late hypoglycaemia occurring several hours after food, is due to the high insulin level. This is because of lack of influx of enough carbo­hydrate from the intestinal tract at this time to buffer the effect of the hormone. Idiopathic Reactive Hypoglycaemia The GTT shows the normal early concentration and later low levels of glucose. Diagnostic Criteria zz

zz

zz

zz

Decreased glucose concentration must be docu-­­ mented. Signs and symptoms must occur at the time of hypoglycaemia. Signs and symptoms must improve shortly after a meal. This pattern should occur regularly.

Treatment of Reactive Hypoglycaemia zz



zz

Diet: Diet is the mainstay of treatment in the fed hypo­ glycaemics. Avoid simple or refined carbohydrates. For obese patients weight reduction is advised and carbohydrate is reduced to 35 to 40% of the total calories. Multiple small feedings are advised for patients with hyperalimentation. Drugs: —— Propantheline bromide—7.5 mg half an hour before food —— Phenytoin—100 to 200 mg tid; it acts by inhibiting insulin secretion —— Propranolol—10 mg half an hour before food

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Endocrine and Metabolic Disorders Calcium channel blockers —— Acarbose (Glucosidase inhibitor). Surgery: In patients with hyperalimentation, a reversed jejunal segment near the gastric outlet prevents the rapid release of glucose into the circulation. ——

zz

Neuroendocrine Tumours of GIT Gastrinoma • It occurs in duodenum (50–70%) and pancreas (20–40%). • It secretes gastrin. • It is associated with MEN 1 syndrome. • The clinical manifestation is due to hypergastrinaemia with gastric acid hypersecretion—Zollinger-Ellison syndrome. • Peptic ulcer with unusual features—persistent multiple ulcers in unusual locations, refractory to treatment and associated with diarrhoea. • Fasting gastrin > 1000 pg/ml, gastric pH ≤ 2.0 and basal gastric acid output (BAO) > 15 mEq/hour. • Treatment: Long term proton pump inhibitor (PPI) therapy and surgical resection if the medical management fails. Glucagonomas • Endocrine tumour of pancreas secreting glucagon. • Clinical features: Necrolytic migratory erythema, glucose intolerance, weight loss, thromboemboli, anaemia, diarrhoea. • Plasma glucagon levels > 1000 pg/ml (normal < 150 pg/ ml) • Medical management: Somatostatin analogues— octreotide and lanreotide. • Surgical debulking of tumour mass. VIP-omas • Endocrine tumour of pancreas secreting vasoactive intestinal peptide. • Pancreatic cholera—Verner-Morrison syndrome. • WDHA—W = watery, D = diarrhoea, H = hypokalaemia, A = achlorhydria. • Large volume secretion—>1 liter/day and persisting during fasting. • Diagnose by elevated VIP level and large volume diarrhoea. • Medical management by octreotide/lanreotide, prednisone, clonidine, loperamide, metacloproamide, and propronolol.

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• Chemoembolisation and radiofrequency ablation in advanced cases. Somatostatinoma • Neuroendocrine tumour of pancreas. • It secretes somatostatin. • Clinical features: Diabetes mellitus, gallbladder disease, steatorrhoea and diarrhoea. • Elevated somatostatin levels and psammoma bodies in duodenal tumour should raise the suspicion. • Octreotide and surgery for patients without widespread metastasis. Carcinoid Syndrome (Refer to chapter on Abdomen)

HYPERLIPOPROTEINAEMIAS Hyperlipoproteinaemias are due to disturbances of lipid transport that result from accelerated synthesis or reduced degradation of lipo­proteins that transport cholesterol and triglycerides.

Structure Lipoproteins are globular proteins with an inner lipid core and an outer protein coat. The inner hydrophobic core consists of varying amounts of: 1. Cholesterol esters 2. Triglycerides. The outer hydrophilic coat is made up of varying amounts of: 1. Phospholipids 2. Unesterified cholesterol 3. Apoproteins.

Classification of Lipoproteins and their Composition A.  Chylomicrons and their Remnants 1. Major lipid: Exogenous (dietary) triglycerides 2. Apoproteins: AI, All, B48, CI, CII, CIII, E 3. Electrophoretic mobility: Remains at the origin.

B.  VLDL (Very Low Density Lipoprotein) 1. Major lipid: Endogenous triglycerides 2. Apoproteins: B48, CI, CII, CIII, E 3. Electrophoretic mobility: Slow pre-beta.

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C.  IDL (Intermediate Density Lipoprotein) 1. Major lipid: Cholesterol esters and triglycerides 2. Apoproteins: B100, CIII, E 3. Electrophoretic mobility: Slow pre-beta.

cardiovascular disease. Moderate reduction is possible only with niacin and the primary approach to therapy is reduction of LDL-C. Fredrickson’s Classification of Hyperlipoproteinaemias

D.  LDL (Low Density Lipoprotein)

Types Lipoprotein

Lipid

1. Major lipid: Cholesterol esters 2. Apoproteins: B100 3. Electrophoretic mobility: Beta.

Type I

Chylomicrons

TGL

Type 2a

LDL

Cholesterol

Type 2b

LDL+ VLDL

TGL + Cholesterol

E.  HDL (High Density Lipoprotein)

Type 3

Chylomicron remnants + IDL

TGL + Cholesterol

1. Major lipid: Cholesterol esters 2. Apoproteins: AI, AII 3. Electrophoretic mobility: Alpha.

Type 4

VLDL

TGL

Type 5

Chylomicrons + VLDL

TGL + Cholesterol

Low HDL-C (< 40 mg/dl) may be due to a genetic disorder or to secondary causes. Primary disorders: • Familial hypoalphalipoproteinaemia • Primary hypertriglyceridaemias • Fish-eye disease • Tangier disease • Lecithin-cholesterol–acyl transferase (LCAT) deficiency. Secondary disorders: • Cigarette smoking • Obesity • Lack of exercise • Androgens and progestational agents • Anabolic steroids • Beta-blockers • Hypertriglyceridaemia. Low HDL levels are associated with increased risk of cardiovascular disease. Correct the precipitating factors. Niacin is the most effective agent for increasing HDL. 10 to 20% increase can occur with fibrates only in patients with elevated TGL.

F.  Lp (a) [Lipoprotein Little a] It consists of an apoprotein (a) molecule bound by sulfhydryl link to the apolipoprotein B moiety of LDL particle. Apo­ protein (a) has homology with plasminogen and may inhibit fibrinolysis by competing with plasminogen. Thus, it provides an important link between haemostasis and blood lipids and plays a major role in atherogenesis. Normal serum level is 0 to 3 mg/dl. Elevated levels of lipoprotein (a) above 30 mg/dl are associated with increased risk for atherosclerotic

Ch-10.indd 834

Major elevation in plasma

Primary Hyperlipoproteinaemias Resulting from Single Gene Mutations A.  Familial Lipoprotein Lipase Deficiency • It is an autosomal recessive disorder. • The conversion of chylomicron to chylomicron remnants is defective. The disease presents in infancy or childhood with recurrent attacks of abdominal pain. The pain is due to pancreatitis. • Eruptive xanthomas occurs as yellowish papules with an erythematous base in the buttocks and other pressure sensitive areas. • As TGL is deposited in the RE system, there is hepatomegaly, splenomegaly and foam cell infil­tration of the bone marrow. • Lipemia retinalis is due to excess of chylomicrons in the serum of the retinal vessels. There is no acceleration of atherosclerosis in this condition. Pathogenesis of pancreatitis: The circulating chylo­ microns cause inflammation of the pancreas as they pass through its capillaries. There is release of pancreatic lipase, which splits the TGL into toxic products like lysolecithin, etc. which sets the stage for the onset of the pancreatitis. B.  Familial Apoprotein CII Deficiency • A rare autosomal recessive disorder • This disorder resembles familial lipoprotein lipase deficiency • The lack of apoprotein CII results in ineffective action of lipo­­protein lipase, because CII is the cofactor for this enzyme • Type-I or Type-V hyperlipoproteinaemia may occur.

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Endocrine and Metabolic Disorders The differences between this disorder and familial lipoprotein lipase deficiency include: a. Later onset of symptoms b. Greater elevation of VLDL c. Rare incidence of eruptive xanthomas. C. Familial Type-3 Hyperlipoproteinaemia (Dysbetalipopro­teinaemia) Inherited as an autosomal recessive disorder, charac­ terised by the presence of a defective apoprotein-E. There is elevation of chylomicron remnants and IDL. They do not manifest before 20 years of age. Two unique xanthomas seen in this disease are: a. Xanthoma striae palmaris b. Tuberous/tuberoeruptive xanthomas over knees and elbows. Severe fulminant atherosclerosis involves the coro­ nary, carotid arteries and the abdominal aorta. Patients often develop myocardial infarction, strok­es and/or peripheral vascular disease. Patients often have hypothyroidism, diabetes melli­­tus and/or obesity complicating this disorder. Broad beta band (type-3 pattern) is seen in electro­phoresis. D.  Familial Hypercholesterolemia • Inherited as an autosomal dominant disorder • A very common genetic disorder affecting 1 in 500 persons • This is due to deficiency of LDL receptors • Heterozygotes show a 2 to 3-fold rise in LDLcholesterol while homozygotes have a 7 to 8-fold rise in LDL-cholesterol • Symptoms in heterozygotes develop after the 3rd decade while homozygotes usually die within 20 years of age • Premature atherosclerosis occurs. Tendon xanthomas are diagnostic but occurs only in 75% of the patients. In homozygotes a unique type of xanthoma, planar cutaneous xanthomas, are seen at birth. Arcus senilis and xanthelasma also occur but are not unique to this disorder. Slender body habitus is the rule in this disorder. Differential diagnosis include: a. Polygenic hypercholesterolaemia and b. Multiple lipoprotein-type hyperlipidaemia. E. Polygenic Hypercholesterolaemia • Five per cent of general population have serum cholesterol exceeding the 95th percentile.

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• If we consider 20 persons having hypercholestero­ laemia, 17 will have this disorder while 2 will have familial hypercholesterolaemia. This disorder can be differentiated from the latter by the following: a. Only 10% have a positive family history in contrast to 50% with the latter two disorders b. Tendon xanthomas occur only with familial hyper­­cholesterolaemia. F.  Multiple Lipoprotein-Type Hyperlipidaemia • Inherited as an autosomal dominant disorder. • Manifests as premature atherosclerosis. • The affected may have type-2a, type-2b or type 4 hyperlipidaemias • Tendon xanthomas do not occur. • The serum cholesterol levels seldom exceed 400 mg per dl. G.  Familial Hypertriglyceridaemia • Inherited as an autosomal dominant disorder. • VLDL levels are raised. • The affected individuals usually manifest with hyper­triglyceridaemia during late puberty or early adulthood. • The incidence of atherosclerosis is increased, but it is not definitely known whether this is due to hyper­ triglyceridaemia per se. • Xanthomas are not a characteristic feature of this disorder. • This disease is associated with acute exacerbations, during which period the patient may have serum TGL levels exceeding 1000 mg/dl. During these exacerbations the patient may lapse into Type-5 hyperlipidaemia and develop pancreatitis and/or eruptive xanthomas. The following conditions predispose to the develop­ ment of these exacerbations: a. Poorly controlled diabetes mellitus b. Alcoholism c. Oestrogen containing contraceptive pills d. Hypothyroidism. There is an increased prevalence of obesity and dia­ betes in these people. H.  Familial Hyperalphalipoproteinaemia • This is inherited as an autosomal dominant trait and also as a multifactorial disorder in some cases • Increased levels of HDL are seen • The longevity of these cases is greater than the longevity of the general population.

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Secondary Hyperlipoproteinaemias A.  Endocrine and Metabolic Causes zz

zz

zz

Type-4 hyperlipoproteinaemia is seen in: —— Diabetes mellitus —— Von-Gierke’s disease —— Acromegaly. Type-2a hyperlipoproteinaemia is seen in: —— Cushing’s syndrome —— Hypothyroidism —— Anorexia nervosa —— Acute intermittent porphyria. Type-2b hyperlipoproteinaemia is seen in: —— Cushing’s syndrome —— Isolated GH deficiency.

zz

Type-2a hyperlipoproteinaemia is seen with: —— Corticosteroid use —— Thiazide diuretics —— Beta blockers. Type-2b hyperlipoproteinaemia is seen with: —— Alcohol abuse —— Oral contraceptives.

C. Renal zz

zz

Type-2a or 2b hyperlipoproteinaemia is seen in nephrotic syndrome Type-4 hyperlipoproteinaemia is seen in uraemia.

D. Hepatic zz

zz

zz zz

zz zz

Type-1 hyperlipoproteinaemia is seen in SLE Type-3 hyperlipoproteinaemia is seen in multiple myeloma.

Type-2a or 2b hyperlipoproteinaemia is seen in hepa­tomas Type-4 hyperlipoproteinaemia is seen in acute hepa­titis.

LDL cholesterol (mg%) 190

Optimal Near optimal/above optimal Border line high High Very high

Total cholesterol (mg%) < 200 200–239 > 240

Desirable Borderline high High

HDL (mg%) < 40 > 60

Low Borderline high

Triglycerides (mg%) 500

Normal Borderline high High Very high

Cholestyramine Colestipol.

Mechanism of Action 1. Both act by binding bile acids in the intestinal lumen 2. Receptor mediated removal of LDL from plasma. Dose zz zz

Cholestyramine 24 gm/day Colestipol 30 gm/day.

Side Effects zz

NCEP Guidelines (National Cholesterol Education Programme)

Ch-10.indd 836

E. Immunologic

Bile Acid Sequestrants

B.  Drug Induced zz

Risk categories modify LDL-C goals: High risk categories are those with CAD and CAD risk equivalents. CAD risk equivalents include clinical CAD, carotid artery disease, peripheral vascular disease and abdominal aortic aneurysm. Other CAD equivalents include DM, HTN, smoking and metabolic syndrome (abdominal obesity, HTN, DM, low HDL-C and elevated TGL). In these patients the LDL-C must be lowered < 70 mg/dl by aggressive therapy.

zz

Constipation and bloating Exacerbation of pre-existing haemorrhoids.

Drug Interaction Decreases the absorption of digitalis, β blockers, thyroxine, thiazides and warfarin.

Nicotinic Acid Mechanism of Action zz zz

zz

Reduces lipolysis in adipose tissue Direct inhibition of the synthesis and secretion of apo B-containing particles by the liver. Reduction in synthesis of lipoproteins.

Dose 3 to 6 gm/day. Indications Heterozygous familial hypercholesterolaemia zz Familial combined hyperlipidaemia. zz

Side Effects Cutaneous flushing zz Nausea, abdominal discomfort zz

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Endocrine and Metabolic Disorders Diet Therapy of High Blood Cholesterol Nutrient

Recommended intake Step I Diet

Step II Diet

Total fat

30% of total calories

20% of total calories

Saturated fatty acids

10% of total calories

7% of total calories

Polyunsaturated fatty acids

10% of total calories

7% of total calories

Monounsaturated fatty acids

10% of total calories

7% of total calories

Carbohydrates

55% of total calories

55% of total calories

Protein

15% of total calories

15% of total calories

Cholesterol

300 mg/dl

< 200 mg/dl

Dryness of the skin Blurred vision. Flushing can be prevented by concurrent intake of small dose of aspirin or NSAID.

zz zz

Laboratory Abnormalities zz zz zz zz

Hyperglycaemia Hyperuricaemia Increased plasma amino transferase Increased plasma alkaline phosphatase.

Contraindications Gouty arthritis zz Active liver disease zz Peptic ulcer. zz

HMG CoA Reductase Inhibitors The specific competitive inhibitors of the rate-limiting enzymes in cholesterol synthesis are lovastatin, pravastatin, simvastatin, ganavastatin, cerivastatin, fluvastatin and atorvastatin. Mechanism of Action zz Reduction of rate of hepatic cholesterol synthesis zz Reduction in the cellular pool of cholesterol zz Compensatory increase in affinity for LDL recep­tors. Effects Decreases LDL concentration in patients with hetero­zygous familial hypercholesterolaemia and familial combined hyperlipidaemia. Dose Lovastatin Simvastatin Pravastatin Atorvastatin Fluvastatin

Ch-10.indd 837

10 to 80 mg/day 10 to 40 mg/day 10 to 40 mg/day 10 to 80 mg/day 20 to 40 mg/day

Cerivastatin Rosuvastatin

0.3 to 0.4 mg/day 5 to 20 mg/day

Benefits with statin therapy: Prevents as well as arrests the process of atherosclerosis zz Stabilises the unstable atherosclerotic plaque zz Improves endothelial function zz Exhibits anti-thrombotic and anti-inflammatory effects zz Reduces CHD events such as angina, myocardial infarction zz Reduces the risk of cerebrovascular events such as stroke zz Reduces the need for angioplasty/bypass surgery zz Reduces risk of restenosis in patients who have undergone angioplasty or bypass surgery zz Reduces the number of hospitalisations/duration of hospital stay. zz

Side Effects Nausea, fatigue, insomnia, myalgias, headaches, changes in bowel function, skin rashes and myopathy.

Ezetimibe It is a cholesterol absorption inhibitor at the level of the enterocyte. The dose is 10 mg OD and the absorption is not affected by food. It lowers LDL level. It can be given alone or in combination with statins. The action of statin is potentiated. It can cause diarrhoea. 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline for Statin Therapy for Atherosclerotic Cardiovascular Disease (ASCVD) There are four major statin benefit groups: 1. Individuals with clinical ASCVD (Acute coronary syndrome, history of MI, stable or unstable angina, coronary or other arterial revascularisation, stroke, TIA, peripheral arterial atherosclerotic disease). 2. Primary elevation of LDL-C ≥ 190 mg/dl. 3. Diabetic patients aged 40 to 75 years with LDL-C 70 to 189 mg/dl and without clinical ASCVD. 4. Individuals aged 40 to 75 years without ASCVD or diabetes with LDL-C 70 to 189 mg/dl and with estimated ASCVD risk ≥ 7.5%. There are three modalities of statin therapy—high, moderate and low intensity. High intensity therapy is initiated for group 1 and 2. Moderate intensity therapy is advised for group 3 and 4. Diabetic patients with ASCVD risk ≥ 7.5% is advised high intensity therapy. Age > 75 years and those who do not tolerate high intensity therapy due to conditions or drug interactions can be put on moderate intensity therapy.

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Manual of Practical Medicine LDL Cholesterol Goals and Cutpoints for Therapeutics Lifestyles Changes (TLC) and Drug Therapy in Different Risk Categories Risk category

LDL goal

LDL level at which to initiate therapeutic lifestyle changes (TLC)

LDL level at which to consider drug therapy

CHD or CHD risk equivalents (10-year risk > 20%)

< 100 mg/dl

>100 mg dl

> 130 mg/dl (100–129 mg/dl-drug optional)*

2 + Risk factors (10-year risk ≤ 20%)

< 130 mg/dl

> 130 mg/dl

0-1 risk factors

< 160 mg/dl

> 160 mg/dl

10-year risk 10–20%: ≥ 130 mg/dl —————————————— 10-year risk < 10%: ≥ 160 mg/dl ≥ 190 mg/dl (160–189 mg/dl: LDL-lowering drug optional)

*CHD risk equivalent means diabetes mellitus or peripheral vascular disease or carotid stenosis or multiple risk factors

High intensity

Moderate intensity

Low intensity

Daily dose lowers LDL-C on average by ≥ 50%

Daily dose lowers LDL-C on average by > 30 to 500 mg/dl 2. Secondary causes for elevated LDL-C 3. Unexplained ALT > 3 times upper limit of normal zz ASCVD risk is calculated by using the new Pooled Cohort Equations for ASCVD risk prevention developed by the Risk Assessment Work Group. The following factors are taken into account for calculating the ASCVD risk—age, sex, race, total cholesterol, HDL, systolic BP, treatment for high BP, DM and smoking status.

Secretion of cholesterol into bile. Inhibition of biosynthesis of cholesterol.

zz

Vitamin D Deficiency —— Dietary deficiency —— Lack of synthesis in skin —— Decreased absorption „„ Coeliac disease „„ Hepatobiliary disorders „„ Pancreatic disease „„ Gastric and intestinal surgery. Defective Metabolism —— Drugs (anticonvulsants, sedatives, rifampicin)

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839

Endocrine and Metabolic Disorders Chronic renal failure Renal osteodystrophy —— Dialysis bone disease —— Vitamin D dependent rickets. Hypophosphataemia with Normal Vitamin D —— Familial hypophosphataemic rickets —— Inherited and acquired renal tubular defects (e.g. Fanconi syndrome, cadmium poisoning, multiple myelomatosis). Osteomalacia with Normal Calcium, Phosphate and Vitamin D —— Hypophosphatasia —— Osteogenesis imperfecta —— Aluminium bone disease. —— ——

zz

zz

Clinical Features zz zz zz zz

Severe bony pain and tenderness on pressure Muscular weakness (waddling gait) Spontaneous fracture of neck of femur Features of tetany (carpopedal spasm and facial twitching).

zz zz zz

zz

zz

zz zz

zz

zz

Dietary vitamin D deficiency: Vitamin D 50,000 IU PO weekly for several weeks to replace bone stores, follo­ wed by long-term therapy with 400 to 1000 IU/day. Malabsorption of vitamin D: Vitamin D 50,000 IU PO per day to 50,000 IU PO per week Calcium supplementation If it is due to malabsorption, give parenteral calci­ferol 7.5 mg monthly. If it is vitamin D resistant, give calciferol 10,000 units/24 hr PO. If it is due to renal disease, give alphacalcidol 1 mg/24 hr PO and adjust the dose according to the plasma calcium.

OSTEOPOROSIS It refers to reduction of bone mass per unit volume (loss of matrix and defective mineralisation) (Figs 10.48A and B).

Aetiology

Investigations zz

Treatment

The serum calcium and phosphate are low Alkaline phosphatase level is raised There is loss of cortical bone The apparent partial fracture without displace­ment (pseudofracture or looser zones) is seen in lateral border of the scapula, inferior femoral neck, the pubic rami and the medial cortex of the upper femur. (X-ray shoulder girdle for scapula, pelvic girdle for pubic rami and neck of femur and chest X-ray for ribs) (Fig. 10.47).

zz

zz

zz

Involutional —— Type I (postmenopausal) and Type II (senile) Endocrinological —— Hyperthyroidism —— Hyperparathyroidism —— Diabetes mellitus —— Hypogonadism —— Cushing’s syndrome Gastrointestinal —— Malnutrition

A Fig. 10.47  Osteomalacia

Ch-10.indd 839

B

Figs 10.48A and B  (A) Normal bone; (B) Osteoporosis

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Manual of Practical Medicine Malabsorption Anorexia nervosa Haematological —— Multiple myeloma —— Mastocytosis Rheumatological —— Rheumatoid arthritis Collagen vascular —— Marfan’s syndrome —— Ehler-Danlos syndrome —— Osteogenesis imperfecta Drugs —— Anticonvulsants —— Steroids —— Vitamin A —— Alcohol —— Heparin —— Furosemide —— Thyroid hormone in excessive doses —— Lithium —— GnRH agonist —— Cyclosporin —— Cytotoxic drugs Cigarette smoking Glucocorticoid therapy Hypogonadism Alcoholism Renal disease GI/Hepatic disorders —— ——

zz

zz

zz

zz

zz zz zz zz zz zz

Types Features Age

Type-I 50–70 years

Type-II (senile) > 70 years

Sex F : M Bone Fractures

6:1 Trabecular Forearm, crush vertebra

2:1 Trabecular and cortical Hip, wedge vertebra

WHO Criteria for Osteoporosis Diagnosis

T Score

Normal

> 1.0 SD

Osteopaenia

1.0 to 2.5 SD

Osteoporosis

< 2.5 SD

Severe osteoporosis

< 2.5 SD with fragility fractures

Investigations Radiological X-ray thoracolumbar region, radius and neck of femur —— Decrease in mineral density in bone. —— Fracture (mostly seen in middle, lower thoracic and upper lumbar vertebral bodies). Upper dorsal spine fracture (above D 4 ) suggests malignancy rather than osteoporosis. —— Collapse —— The microfracture, expansion of intervertebral disc leading to biconcave (cod fish) vertebra (Fig. 10.49). Other causes cod fish vertebra: 1. Sickle cell disease; 2. Hereditary spherocytosis; 3. Homocystinuria; 4. Renal osteodystrophy; 5. Thalassemia major zz Biochemical —— Serum calcium or phosphate and alkaline phosphatase are normal (increase in alkaline phosphatase after fracture). —— Urine hydroxy proline (24 hour) is relatively high in a case associated with the endocrino­pathy. zz

Clinical Features The clinical features depend upon the major clinical sequelae (fracture of the vertebra, wrist, hip, humerus and tibia). zz Pain is usually of acute onset in the dorsal and lumbar regions and often radiating to flanks and abdomen.   Pain is often aggravated by bending, lifting weights or while jumping. zz Loss of appetite and muscular weakness are also present. zz The collapse fractures of vertebral bodies (anterior) usually produce wedge shaped deformity with loss in height and results in dorsal kyphosis and exaggerat­ed, cervical lordosis (dowager or widows hump). zz Scoliosis is also common. zz

Ch-10.indd 840

Fig. 10.49  Osteoporosis—spine “cod fish vertebra”

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Endocrine and Metabolic Disorders zz

Measurement of bone mass: The techniques available include: —— Dual energy X-ray absorptiometry (DXA) —— Single energy X-ray absorptiometry —— Quantitative CT —— US.

Indications for measurement of bone mass: Oestrogen deficient women at clinical risk of osteoporosis zz Vertebral anomalies on X-ray suggestive of osteo­porosis zz Glucocorticoid treatment equal to >7.5 mg predni­ solone or duration of therapy more than 3 months zz Primary hyperparathyroidism zz Monitoring response to therapy for osteoporosis. zz

Differential Diagnosis zz zz zz zz zz zz

Hyperparathyroidism Osteomalacia Lymphoma Leukaemia Metastatic carcinoma Multiple myeloma.

Treatment General —— Bedrest —— Local heat —— Analgesics —— Exercise: Regular walking or other weight-bearing exercise for 1 hour 3 times a week protects bone mass —— Prevention of injury (most hip and wrist fractures are caused by falls). —— Excessive thyroid hormone replacement therapy should be avoided. zz Antiresorptive agents —— Oestrogen: Oestrogen 0.625 mg + Medroxypro­ ges­­terone (cyclic progestin) 5 to 10 mg per day 10 to 14 days/month. Progesterone to be added to prevent endometrial carcinoma.   Transdermal oestrogen patch­es are used to avoid deep vein thrombosis and pulmonary embolism.   Oestrogen therapy is important in women with premature or surgical menopause. Contraindica­ tions of oestrogen therapy are carcinoma breast or endometrial cancer, recurrent thromboembolic disease, acute liver disease and unexplained vagi­nal bleeding. —— Calcium: The recommended daily calcium intake for postmenopausal women is 1,500 mg, and 1,000 mg for premenopausal women. zz

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Calcitonin: Salmon calcitonin for 1 to 2 years increas­es vertebral bone density and decreases the risk of vertebral fracture. The usual dose is 50 IU SC per day 3 times a week (salmon calcitonin 200 units/day as nasal spray). The side effects are nausea, flushing, and rarely allergic reactions. —— Bisphosphonates: They specifically impair osteoclast function and reduce osteoclast number partly by induction of apoptosis. a. Alendronate 5 to 10 mg/day b. Risedronate 5 mg/day The prominent adverse effect is esophageal irritation and hence both should be taken with a full glass of water and the patient should remain upright for 30 min after taking the drug. c. Etidronate is given as an intermittent cyclical regimen, 400 mg orally for 2 weeks, has some efficacy against vertebral fractures. —— Selective oestrogen receptor modulators (SERMs) a. Raloxifene 60 mg/day b. Tamoxifen Both reduce bone turnover and bone loss in postmeno­pausal women. In addition Tamoxifen is beneficial in women at increased risk of breast cancer and Raloxifene reduces serum total and LDL cholesterol, Lp (a), and fibrinogen. zz Bone forming agents —— Fluoride—75 mg/day —— Anabolic steroids: Testosterone is used in the treat­ment of osteoporotic man with gonadal deficiency. zz Supplementation of vitamin D metabolites and thiazide diuretics. ——

Male Osteoporosis The incidence of osteoporosis in men is increasing due to the increased longevity of the population. The late onset of osteoporosis in men (10 years behind that of women) is due to higher initial bone mass in early life and absence of sudden loss of gonadal hormones as occurs in menopause in women.

Management zz zz zz zz zz

zz

Good calcium and vitamin D intake Regular physical exercise Avoid smoking and excessive alcohol Testosterone replacement for hypogonadism Bisphosphonates like alendronate has been shown to increase bone mass and reduce incidence of fractures Management of concurrent medical disorders.

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Paget’s Disease zz

zz zz zz zz zz

zz

Focal skeletal disorder—rapid disorganized bone remodeling affecting one or more bones—charac­ terised by increased bone turn over (osteoclastic activity) and increased but disorganised osteoid formation (osteoblastic activity) Incidence—3% of population older than 50 years Family history—15 to 30% Often affects pelvis, femur, spine and skull Bone pain, deformity and degenerative arthritis Sometimes extensive multifocal involvement of many bones can occur Enormously elevated serum alkaline phosphatase value as a result of increased bone turn over. Fig. 10.50  Paget’s disease—tibia

Clinical Features zz zz zz zz zz zz

zz zz zz

zz

zz

zz zz zz zz

zz

Bone pain due to micro-fractures Muscular strain and accelerated osteoarthritis Joint deformity due to periarticular bone involvement Enlargement of head—due to involvement of skull Reduction in height Narrowing of cranial ostia and compression of cranial nerves Nerve root compression due to vertebral involvement Otosclerosis—hearing loss Hypercalcaemia and hypercalciuria with nephro­ lithiasis—due to prolonged immobilisation High output cardiac failure—increased blood flow to the affected bones Osteogenic sarcoma—late complication and sudden accentuation of bone pain at a specific site denotes the possibility. Investigations Elevated serum alkaline phosphatase Increased 99mTc bone scanning activity Characteristic X-ray finding—local radiolucency— more commonly affecting one region of skull ‘Osteoporosis Circumscripta’ X-ray tibia of lower limb (Fig. 10.50).

Indications for Therapy zz zz zz zz

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Bone pain due to Paget’s disease. Nerve compression syndromes Pathologic fracture Progressive skeletal deformity

zz zz

Immobilisation hypercalcaemia Asymptomatic involvement of weight-bearing bones and skull.

Management zz

zz zz

zz



Adequate hydration and mobilisation to avoid hypercalcaemia Pain relief—ibuprofen, COX-2 inhibitors Mild disease (serum alkaline phosphatase < 3 times) Tiludronate 400 mg/day for 3 months or Etidronate 400 mg/day for 6 months Moderate to severe disease Risedronate 30 mg/day for 2 to 3 months Alendronate 40 mg/day for 6 months.

The effectiveness of therapy is monitored by measurement of serum alkaline phosphatase (SAP) and it must be monitored every 3 months. Therapy can be repeated when the SAP level increases above normal by 25%. In very severe disease Pamidronate single dose 60 mg IV in 500 ml normal saline or dextrose over 4 hours for rapid response. Repeat the course weekly once for 1 month if the response is not adequate. Calcitonin: Reserved for patients who cannot tolerate bisphosphonates. Injection salmon calcitonin 100 U/day SC followed by 50 U SC three times/week for maintenance. It causes suppression of SAP. Use nasal form for milder disease.

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CHAPTER

11

Connective Tissue Disorders

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ARTHRITIS Approach to Musculoskeletal Pain zz zz

zz

It can be either articular or non-articular. Articular involvement is either inflammatory or noninflammatory as in osteoarthritis or hypothyroidism. Inflammatory arthritis can involve single joint or a few joints or many joints: —— Monoarthritis—(1 joint involved) —— Oligoarthritis—(2–4 joint involved) —— Polyarthritis—(≥5 joint involved).

zz zz zz

Tuberculosis Brucellosis Cervical or lumbar spondylosis. Differentiating Features between Inflammatory and Non-inflammatory Rheumatic Diseases

Features

Inflammatory rheumatic diseases

Non-inflammatory rheumatic diseases

Examples

RA/SpA/SLE

OA/Trauma/Hypothyroidism

Morning stiffness

< 30 minutes

< 30 minutes

Pain aggravation

On resting the joint

On moving the joint

Spontaneous flares

Common

Uncommon

Classification

Acute phase reactants (CRP/ESR)

Increased

Normal

Monoarthritis

Synovial fluid inflammatory cells

More in number

Less in number

zz

zz

zz

Acute —— Septic arthritis —— Gout —— Pseudogout —— Traumatic arthritis Chronic —— Psoriasis —— Ankylosing spondylitis —— Rheumatoid arthritis —— Tuberculosis —— Sarcoidosis —— Osteoarthritis Oligoarthritic causes: —— JIA (Juvenile idiopathic arthritis ) —— Chronic Gout —— SpA (Spondyloarthropathy).

Polyarthritis zz

zz

Asymmetric —— Acute „„ Rheumatic fever „„ Reactive arthritis —— Chronic „„ Psoriatic arthritis Symmetric —— Acute „„ Hepatitis B, serum sickness —— Chronic „„ Rheumatoid arthritis „„ Systemic lupus erythematosus „„ Osteoarthritis

Rheumatoid Arthritis It is a chronic inflammatory, destructive and deforming sym­m etrical polyarthritis associated with systemic involvement. The individuals with HLA-D4 and HLA-DR4 are more prone to rheumatoid arthritis. The female : male ratio is 3:1. Common in 20 to 50 years of age.

Criteria for the Diagnosis zz

zz

zz

zz

zz zz zz

Diagnosis of rheumatoid arthritis is made when four or more criteria are present.

Pathogenesis zz

zz zz

Axial Arthritis zz zz

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Ankylosing spondylitis Reiter’s syndrome

Morning stiffness (more than one hour for more than six weeks) Arthritis involving three or more joint areas (with or without soft tissue involvement lasting more than six weeks) Arthritis of hand joints (wrist, MCP or PIP joints more than six weeks) Symmetrical arthritis (at least one area lasting for six weeks) Rheumatoid nodules Rheumatoid factor Radiographic changes.

zz zz zz zz

Synovitis (synovial cell hyperplasia, hypertrophy with CD4 lymphocytic infiltration and synovial effusion) Pannus formation Cartilage loss Fibrosis Bony erosion, deformity, fibrous and bony ankylosis Muscle wasting Periarticular osteoporosis.

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Connective Tissue Disorders The other joint manifestations are swelling, warmth, tenderness, and synovial thickening without ery­thema.

Revised Classification as per American College of Rheuma­tology (ACR) and European League Against Rheumatism (EULAR)-2010 Joint involvement •  One large joint (shoulder, elbow, hip, knee, ankle) •  Two to ten large joints •  One to three small joints (MCP, PIP, thumb IP, MTP, wrists) •  Four to ten small joints •  > Ten joints (At least one small joint)

Score 0 1 2 3 5

Serology •  Negative RF and anti-CCP Cyclic citrullinated peptides-antibodies •  Low positive RF or anti-CCP (Antibodies ≤ 3 times upper limit of normal) •  High positive RF or anti-CCP antibodies (>3 times upper limit of normal)

0

2 3

Acute phase reactants •  Normal CRP and ESR •  Abnormal CRP and ESR

0 1

Duration of symptoms •  < Six weeks •  ≥ Six weeks

0 1

Total score ≥6 is indicative of definite rheumatoid arthritis

Triggering Factors zz zz zz zz zz

Infection Vaccinations Physical trauma Psychological stress. Smoking – The risk is more in women than men and the risk persists for many years even after smoking cessation. Smoking related risk is more in RF and antiCCP antibody positive disease.

Clinical Features Constitutional symptoms Fatigue zz Weakness Articular symptoms zz Vague arthralgias zz Myalgias zz Joint stiffness zz Low grade fever zz Weight loss zz Excessive sweating zz Lymphadenopathy. zz

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The joints most commonly involved are: Finger joint (40%)—MCP and PIP joints zz Shoulder joint (20%) zz Foot joint (20%) zz Wrist joint (15%). zz

Other joints involved in chronic rheumatoid arthritis are: zz Temporomandibular joint (malalignment of teeth with mal occlusion) zz Cervical joints C C 1 2 (atlantoaxial dislocation— quadriplegia) zz Cricoarytenoid (sensation of foreign body, hoarse­ness, weak voice and stridor) zz Sternoclavicular zz Acromioclavicular zz Glenohumeral zz Elbow (extension defects, epicondylitis and olecra­non bursitis-ulnar deviation), hand (swan neck deformity, boutonniére deformity) zz Hip and knee (Morant-Baker’s cyst) zz Talocalcaneal, midtarsal, metatarsophalangeal. Course It is variable. It can be slowly progressive with oligoarthritis or rapidly progressive erosive arthritis with marked deformity with downhill course. The following features, exclude rheumatoid arthritis: Butterfly rash—SLE zz High concentration of LE cells zz Polyarteritis nodosa zz Dermatomyositis zz Scleroderma zz Chorea    —— Rheumatic fever —— Erythema marginatum zz Tophi-gout zz Arthritis associated with bacterial or viral infec­tions zz Positive AFB zz Reiter’s syndrome zz Shoulder hand syndrome zz Hypertrophic pulmonary osteoarthropathy zz Neuroarthropathy zz Homogentisic acid in urine zz Sarcoidosis zz Multiple myeloma zz Erythema nodosum zz Leukaemia and lymphoma zz Agammaglobulinaemia zz Distal interphalangeal joint of hand and feet (Fig. 11.1). zz

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Extra-articular Manifestations of Rheumatoid Arthritis (Fig. 11.2) Respiratory System zz zz zz zz zz zz zz zz

Fig. 11.1  Rheumatoid arthritis—sparing of distal IP joints

Pleurisy with or without effusion Pneumothorax Rheumatoid nodule (Caplan’s) Interstitial fibrosis Pneumonia Chronic bronchitis or bronchiectasis Pulmonary hypertension. Caplan’s syndrome—pulmonary nodulosis with pneumoconiosis following silica exposure in rheumatoid arthritis patients.

Fig. 11.2  Extra-articular manifestations—rheumatoid arthritis

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Connective Tissue Disorders Cardiovascular System zz zz zz zz zz zz

zz

Pericarditis Endocarditis Cardiomyopathy Conduction defects Cardiac arrhythmias Infiltration of valves (mitral incompetence and aortic incompetence) Myocardial infarction (due to coronary vasculitis).

Gastrointestinal System zz zz zz zz

Xerostomia Parotid enlargement Dysphagia Mesenteric artery occlusion.

Renal System zz zz zz

Pyelonephritis Analgesic nephropathy Amyloidosis.

Lymph Nodes

zz zz

Skin zz zz zz zz zz

zz zz zz

Dermal atrophy Leg ulcers Nail dystrophy Nodules Pyoderma gangrenosum.

Subcutaneous nodules occur in 30–40% of cases and are more common in those with highest level of disease activity as evidenced by positive RF and radiographic evidence of joint erosions. Nodules are usually benign, although they can be associated with infection, ulceration and gangrene. Bones Periarticular osteoporosis. Central Nervous System zz zz zz

Local and generalised lymphadenopathy. zz

Ocular

Myopathy (steroid, chloroquine) Tenosynovitis.

Episcleritis, scleritis (Fig. 11.3) Keratoconjunctivitis sicca Scleromalacia perforans.

Cervical dislocation (quadriplegia) Peripheral neuropathy (sensory and motor) Autonomic neuropathy (reduced sweating, cold hands, and palmar erythema) Entrapment neuropathy. —— Elbow—ulnar —— Carpal tunnel—median —— Knee—lateral popliteal —— Tarsal tunnel—posterior tibial.

Ear

Haematological

Defective hearing (involvement of ossicular chain).

zz

Muscle zz

Weakness and atrophy

Fig. 11.3  Rheumatoid arthritis—scleritis

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Anaemia —— Normocytic hypochromic —— Megaloblastic ( ↓ folic acid) zz Haemolytic anaemia zz Serum Fe—low zz Iron-binding capacity—normal zz Raised ESR zz Neutropenia Pancytopenia: Felty’s syndrome: Splenomegaly zz Eosinophilia (vasculitis, nodules) zz Hyperviscosity syndrome: It is due to increased rheumatoid factor. The mani­fest­ations are dizziness, diplopia, dyspnoea and bleeding tendency. zz Vasculitis —— Dermal infarction —— Cranial-cerebrovascular accidents —— Coronary-myocardial infarction —— Mesenteric-gut gangrene —— Peripheral-digital gangrene —— Vasa nervosum-neuropathy.

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Manual of Practical Medicine Lymphoma—RA patients have 2–4-fold increased risk for developing lymphoma when compared with general population. Diffuse large B cell lymphoma is more common in severe RA or Felty’s syndrome patients.

zz

Rheumatoid arthritis nodules

Rheumatic fever nodules

Adherent to periosteum, tendons, bursae

Lies beneath the skin overlying bony prominences

Sites of repeated trauma— forearm, sacral prominences, Achilles tendon, lungs, pleura, pericardium, peritoneum

Sites—hands, feet, elbow, occiput, occasionally vertebra

Firm and non-tender

Painless, small (0.5–2 cm), mobile

Felty’s syndrome: It occurs in late stages of severe RA and the incidence is less than 1%. It is defined by the clinical triad of neutropenia, splenomegaly and nodular RA. Comparison of Rheumatoid Arthritis and Osteoarthritis Characteristics

Rheumatoid arthritis

Osteoarthritis

Age

Any age group

Middle/old age

Inflammation

Prominent

Mild

Disease cause

Autoimmunity

Trauma

Onset

Rapid with swelling

Gradual

Bone density

Decreased (osteoporosis)

Increased

Stiffness

Morning stiffness

Due to joint damage

Synovial space

Thickened and Increased

Decreased

DIP-joint

Never involved

Involved

Investigations Complete blood count (anaemia, thrombocytosis, ↑ ESR) zz Increased acute phase proteins (C-reactive protein) zz Increased plasma viscosity zz Serum proteins —— Albumin ↓ —— Gammaglobulins ↑ —— α globulin ↑ 2 —— IgG, IgM, IgA ↑ zz Serological tests Rheumatoid factor: Rheumatoid factors are immuno­globulins of the IgG or IgM class, which react with the Fc portion of IgG. It is produced by plasma cells and lymphocytes in subsynovial tissue and draining lymph nodes. It is detected by: —— Rose Waaler test: It is more specific and is said to be positive when more than 1 : 32 zz

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Latex test: It is sensitive, but less specific and said to be positive when more than 1 : 20. The above two tests are used to detect IgM rheumatoid factor. Radiological features of rheumatoid arthritis —— Early: „„ Soft tissue swelling „„ Periarticular osteoporosis „„ Periosteitis „„ Erosions—periarticular and subarticular cysts —— Late: „„ Narrowed joint spaces „„ Articular surface irregularity „„ Osteoporosis „„ Subluxation „„ Ankylosis „„ Secondary osteoarthritis Antinuclear antibody is positive in 20 to 50%. LE cell is positive in 10 to 20%. Pleural fluid analysis —— Low glucose —— Increased LDH —— Low complement Synovial fluid analysis Antibodies to CCP (Cyclic citrullinated polypep­tide). This test has similar sensitivity and better specificity for RA than RF. Presence of anti-CCP is most common in person with aggressive disease with a tendency for developing bone erosion. ——

zz

zz zz zz

zz zz

Synovial Fluid Colour

Viscosity Clarity

Normal Colourless Very high Clear Osteoarthritis Colourless High Clear

Cell count/ Other tests mm3 0–200 400–4000

Rheumatoid Yellow arthritis* Seronegative Yellow inflammatory arthritis Gout/ Variable Pseudo-gout

Low

Cloudy

Low

Cloudy

Low

Variable 2000– 40000

Septic arthritis

Low

Very turbid

Yellow

4000– 40000 4000– 40000

> 50000

Low complement Normal complement Crystals— monosodium urate, calcium pyrophosphate dihydrate under polarising microscope Gram stain, culture and GLC (gas liquid chromatography)

* Poor mucin precipitation

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849

Connective Tissue Disorders Management zz

zz

zz

Goals —— Education and motivation. —— Disease modification through the suppression of inflammation and the immunologic process which is active systemically and in the joints and other tissues. —— Maintenance of joint function and prevention of deformities. —— Repair of joint damage if it will relieve pain or facilitate function. Systemic and articular rest —— Short bedrest is recommended for about an hour in the midmorning and midafternoon. —— Splints: The wrist splints are particularly useful during bouts of acute wrist synovitis and for manage­ment of carpal tunnel syndrome. Physiotherapy —— Regular exercise „„ Exercise is most successful after heat appli­cation. „„ A fifteen minute early morning shower or a bath at 98 to 100°F will help decrease morning stif­fness. „„ Static quadriceps exercises should be performed to strengthen the muscular, ligamentous, and tendinous support of the knees. —— Joint protection: The principles of joint protection are mainte­nance of muscle strength and range of motion, avoidance of positions of deformity, the use of the strongest joints possible for a given task, and the utilization of joints in the most stable anatomic planes.

Choice of NSAIDs The general approach is to choose an NSAID and treat for 2 to 4 weeks, the usual time period needed to define the drug’s efficacy and side effect profile. Salicylates Aspirin (acetylsalicylic acid): Aspirin is the initial treatment of choice of rheumatoid arthritis. Dose: 3 to 4 grams per day. Preparations zz

zz

zz

zz

zz

zz

zz

Toxicities zz

zz

zz

zz

Drug Therapy Group I: Nonsteroidal Anti-inflammatory Drugs (NSAIDs) zz zz zz zz zz zz zz zz zz

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Aspirin Indomethacin Fenamides Propionic acid compounds Sulindac (clinoryl) Tolmetin Piroxicam Diclofenac COX-2 inhibitors.

Plain tablets (inexpensive, cause gastritis, standard tablet dose 325 mg) Buffered tablets (formulated with the insoluble calcium and magnesium antacids) Enteric-coated tablets (the coating remains intact until tablet reaches small intestine) Timed-release tablets (encapsulated aspirin parti­cles, delayed absorption, more sustained plasma levels) Sodium salicylate (enteric-coated) preparations prefer­red, less potent analgesic than aspirin) Choline salicylate (very soluble, liquid form, negligi­ble gastric bleeding) Choline magnesium trisalicylate (trilisate).

zz

Common: Dyspepsia, gastrointestinal bleeding, and peptic ulceration. Tinnitus or deafness: It is the earliest indication of salicylate toxicity in adults and is reversible with a small (i.e. 1 or 2 tablets) decrease in daily dosage. Central nervous system symptoms: Headache, verti­go, nausea, vomiting, irritability, and psychosis (elderly). At high serum levels (25–35 mg/dL), especially in juvenile patients, salicylates may cause mild, acute, reversible hepatocellular injury, as demonstrated by a rise in serum enzymes. Platelet adenosine diphosphate (ADP) release, adhesive­ness, and aggregation are inhibited for as long as 72 hours after a single 300 mg dose of aspirin, probably as a result of irreversible acetyl­ation of platelet membrane proteins.

Other Nonsteroidal Anti-inflammatory Drugs (NSAIDs) These agents are equipotent to aspirin and exert antiinflam­ m atory action by modifying prostaglandin meta­bolism.

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Manual of Practical Medicine Indomethacin Dose: 25 to 50 mg tid. Drug interactions Probenecid prolongs action zz Furosemide decreases action zz Antacids delay absorption. zz

It is teratogenic. Minor side effects—GI intolerance, stomatitis, rash, headache, and alopecia zz Bone marrow suppression (periodic blood count) zz Cirrhosis liver (periodic LFT) zz Hypersensitivity pneumonitis zz Rheumatoid nodule may develop or worsen (Paradoxical). Methotrexate can be combined with sulfasalazine 500 mg bid and hydroxychloroquine 200 mg bid in the treatment regimen for RA. zz

Group II

Propionic Acid and Other Compounds zz zz zz zz

Disease Modifying Agents (DMARDs) This group of drugs take a long time (6–12 weeks) for their actions to commence and so in the induction phase, NSAIDs must be given to reduce pain and their dose should be tapered subsequently. zz Chloroquine zz Sulphasalazine.

Ibuprofen (brufen) Ketoprofen Fenoprofen Flurbiprofen Naproxen.

Brufen Dose: 200 to 400 mg tid. • It is less toxic and less effective than aspirin and well tolerated. • Piroxicam: 10 to 20 mg dose once daily. Cyclo-oxygenase-2 inhibitors They have selectivity for COX 2 enzyme. GI symptoms and ulcerations are reduced. Platelet function is not impaired. The anti-inflammatory and analgesic efficacy is same as that of traditional NSAIDs. Partially selective Aceclofenac Meloxicam Nabumetone

100 to 200 mg /day 7.5 to 15 mg/day 500 to 1500 mg/day

Highly selective Celecoxib Roficoxib

100 to 200 mg BD 12.5 to 50 mg/day

Methotrexate Methotrexate is the first choice in the management of moderate and severe rheumatoid arthritis. It is non-oncogenic and it acts rapidly in 4 to 6 weeks and is comparatively less toxic. It can be used along with NSAIDs. It is given in

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Toxicities zz

Toxicity zz Dyspepsia zz GI bleeding zz Gastric and ileal ulcer zz Drowsiness zz Depression zz Seizures zz Neuropathy zz Interstitial nephritis zz Hepatitis zz Retinopathy zz Blood dyscrasias.

zz

a dose of 7.5 mg PO weekly once along with breakfast. The dose can be increased up to 15 mg once a week. Folic acid supplementation at a dosage of 1 to 2 mg daily may reduce methotrexate toxicity without impeding its efficacy.

Indications zz

zz

Failure of conservative management (even after 3 months with NSAIDs and general measures) Rapidly progressive erosive arthritis.

Contraindications: It is contraindicated in patients with a history of previous severe skin, bone marrow, or renal reactions to gold. Dose: Start with 10 mg per week and then increase up to 50 mg per week. Maintain with 50 mg once in 2 weeks. It can be given orally or intramuscularly. Toxicities Bone marrow depression zz Renal failure zz Stomatitis and oral ulcer zz Skin rash zz Neuropathy zz Hepatotoxicity zz Ocular toxicity. zz

Chloroquine Indications: Failure to respond to conservative regimen of rest, salicylates, other NSAIDs or gold.

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Connective Tissue Disorders Contraindications: Patients with significant visual, hepatic, or renal impairment or with porphyria, in pregnant women, and in children. Dose: zz Chloroquine 250 mg OD; zz Hydroxy chloroquine 200 mg BD. Toxicity zz Keratopathy zz Retinopathy zz Neuropathy zz Myopathy. Sulphasalazine It is metabolized by the colonic bacteria into 5 amino salycilic acid and sulpha pyridine of which sulpha pyridine has more important anti-inflammatory role in rheumatoid arthritis. Dose: Started at 500 mg/day and slowly increased to 1 gm BD over a period of 4 weeks. Toxicity Rash zz Depression zz Megaloblastic anaemia zz Leukopenia. zz

Group III (Highly Toxic) zz zz

——

zz

zz

zz

zz

zz

zz

zz

Corticosteroids, *ACTH Leflunomide

Corticosteroids Indications Along with DMARDs in the initial phase, if NSAIDs are not adequate to relieve the distressing symptoms, a short course of 7.5 mg of prednisolone can be added and tapered subsequently. zz Failure to control the disabling symptoms. zz Elderly patients in acute conditions. zz Life-threatening conditions (severe pericarditis, poly­ arteritis or scleritis). zz

Dose: Prednisolone 10 to 15 mg per day. Toxicities Endocrine —— Moon face —— Truncal obesity —— Hirsutism —— Impotence

zz

Menstrual irregularity Suppression of HPA axis —— Growth suppression. Metabolic —— Negative Ca, K, N balance —— Sodium and fluid retention —— Hyperglycaemia —— Hyperlipoproteinaemia. Musculoskeletal —— Myopathy —— Osteoporosis —— Avascular necrosis. Skin —— Acne, striae —— Skin atrophy —— Bruising —— Impaired wound healing. Immunological —— Suppression of delayed hypersensitivity —— Reactivation of TB —— Susceptibility to infection. Gastrointestinal —— Peptic ulceration —— Pancreatitis. Cardiovascular —— Hypertension —— Congestive cardiac failure. Ocular —— Glaucoma —— Posterior subcapsular cataracts. CNS —— Changes in mood and personality —— Psychosis —— Benign intracranial hypertension. ——

zz

Leflunomide It inhibits autoimmune T cell proliferation and production of antibodies by T cells. It also blocks TNF dependent nuclear factor kappa B activation. Dose: 20 mg/day. A loading dose of 100 mg for three days can be used. Clinical response is seen within 4 to 8 weeks. The drug is teratogenic. Contraindications: Hypersensitivity, pregnancy, lactation, concurrent vaccination with live vaccines, uncontrolled infection, children < 18 years. Toxicity: Elevation of liver enzymes, diarrhoea.

Group IV (Cytokine Antagonist) TNF α Antagonist

*Preferable in children since it does not interfere with growth. The drug of choice is prednisolone.

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Anti-TNF α drugs produce a very good response when combined with methotrexate.

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Manual of Practical Medicine zz

zz

zz

zz

zz

Infliximab: It is a chimeric monoclonal antibody that binds with high affinity and specificity to human TNF α. Dose: 3 mg/kg at 0, 2 and 6 weeks and thereafter at intervals of 4 or 8 weeks intravenously. Toxicity: Nausea, headache, rash, cough, upper respiratory infection, formation of human antichimeric antibodies, antinuclear antibodies and anti-dsDNA antibodies. Etanercept: It is a recombinant fusion protein capable of binding to two TNF α molecules. It has an earlier onset of action than methotrexate. Dose: 25 mg subcutaneously twice weekly. Toxicity: Injection site reactions and development of anti-nuclear and antidsDNA antibody. Adalimumab: It is a fully human monoclonal antibody against TNF α. Dose: 20 to 80 mg SC every 2 weeks Golimumab: It is a humanized monoclonal antibody against TNF a. Dose: 50 mg SC monthly. Certolizumab pegol: It is a pegylated Fc free fragment of a humanised monoclonal antibody with binding specificity for TNF a.

IL 1 Receptor Antagonist Anakinra It is a recombinant form of naturally occurring IL-1 receptor antagonist that is approved for use in RA. Dose: 100 mg SC daily. Toxicities zz Increased incidence of bacterial infections zz Injection site reactions zz Anakinra should not be combined with TNF blocker because of enhanced risk of serious infection and neutropenia. Abatacept It is a soluble fusion protein consisting of extracellular domain of human cytotoxic T lymphocyte associated antigen-4 (CTLA-4) linked to the modified portion of human IgG. Action: It inhibits co-stimulation of T cells by blocking CD 28 to CD 80/86 interactions and inhibit the function of antigen presenting cells.

Tocilizumab It is a humanized monoclonal antibody against IL–6 receptor. Dose: 4 to 8 mg/kg IV monthly. Tofacitinib Tofacitinib inhibits JAK1 and JAK3, which mediate signalling of the receptors for many cytokines. These cytokines promote T and B cell activation as well as inflammation. Dose: 5 mg bid PO. It can be used as monotherapy or in combination with methotrexate. Adverse effects: Liver injury as evidenced by elevated transaminases, neutropenia, elevates cholesterol and creatinine levels. There is increased risk for infections.

Drugs in Pregnancy Safest: Hydroxychloroquine and Sulfasalazine. Flare ups: Use low dose prednisone.

Medical Synovectomy Yttrium (90) silicate is used for larger joints (knee) and Erbium (159) acetate for smaller joints. Joints should be immobilized for 72 hours to prevent the spread to adjacent lymph nodes. It is contraindicated in patients below 45 years.

Surgical zz zz zz zz

Surgical fusion of joints usually results in freedom from pain but also in total loss of motion and this procedure is well tolerated in the wrist and thumb. Cervical spine fusion of C1 and C2 is indicated for cervical subluxation (> 5 mm) with associated neurological deficits.

Rehabilitations zz

Dose: Body weight < 60 kg to 500 mg/60 to 100 kg to 750 mg/ > 100 kg to 1000 mg IV at 0, 2, 4 weeks and then every 4 weeks. Rituximab It is a chimeric monoclonal antibody against CD 20. Dose: 1000 mg IV 2 doses at 0 and 14 days and then repeated every 24 weeks.

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Synovectomy Arthroplasty Osteotomy Arthrodesis.

zz

Physical —— Bath aid —— Toilet aid —— Dressing aid —— Walking aid —— Household aid —— Wheel chair —— Beds —— Reading, writing aids. Occupational.

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Connective Tissue Disorders

Causes of Death Coronary artery disease is the most common cause of death in rheumatoid arthritis. CAD and carotid atherosclerosis in RA is two-fold higher than in general population. zz Intercurrent infection zz Cervical cord lesion zz Arteritis zz Cardiac failure zz Renal failure zz Amyloidosis zz Iatrogenic: —— Peptic ulcer —— Pyelonephritis —— Steroid toxicity.

Poor Prognostic Factors zz zz zz zz zz zz zz

zz zz zz

Increased duration of morning stiffness High titre of rheumatoid factor ↑ ESR Mode of onset (insidious onset of disease) Weak hand grip ↑ed feet-walking time Systemic involvement—active more than one year without remission Associated vasculitis, rheumatoid nodules Involvement of cervical joints Protracted anaemia.

Osteoarthritis (OA) It is a degenerative joint disease. It is characterized by deterioration of articular cartilage with new bone formation—osteophytes at the articular surface. The common joints affected are distal and proximal inter­ phalangeal joints of the hands, first carpometacarpo­ phalangeal joint at the base of thumb, hips, knees, and cervical and lumbar spine. The wrists, elbows, and shoulders are typically spared. The disease is more common in the elderly but may occur at any age. The precipitating factors may be trauma, congenital malformation, or chronic inflam­m ation. Osteoarthritis (OA) of the spine may lead to spinal stenosis with root pain either in the arms or in the lower limbs. The X-ray of the affected joints reveal narrowing of the joint space, osteophyte formation, and the hands might show Heberden’s and Bouchard’s nodes in the distal and proximal interphalangeal joints respectively. CT/MRI are useful to assess the spinal involvement. Serum biochemistry and complete haemogram are normal.

Ch-11.indd 853

Management zz zz

zz

zz

zz zz zz

zz

zz

Acetaminophen in a dosage of 1,000 mg bid or tid. Low dose NSAIDs or COX-2 inhibitors (caution—GI bleeding, heart failure) Glucosamine sulphate—1,500 mg PO daily reduces the symptoms as well as the rate of cartilage deterioration. Intra-articular glucocorticoid injection is beneficial (avoid frequent doses) Tramadol is an alternative analgesic agent Topical capsaicin and NSAID creams for external use. Brief periods of rest to the affected joints followed by exercise programs. OA-spine—cervical collar, lumbar corset, exercises to strengthen muscles. Epidural steroid injection may reduce radicular symptoms.

Spondyloarthropathy These are a group of diseases in which an inflamma­ tory arthritis, characterised by persistently negative tests for IgM rheumatoid factor is variably associated with a number of other common articular, extra-articular and genetic features. These disorders include: Ankylosing spondylitis zz Reactive arthritis zz Psoriatic arthritis and spondylitis zz Juvenile onset spondyloarthritis zz Enteropathic artyhritis and spondylitis zz Undifferentiated spondyloarthritis. zz

Differentiation between Inflammatory and Mechanical low Back Pain (LBP) Factors

Inflammatory LBP

Mechanical LBP

Age of onset

< 40 years

Any age (usually later)

Type of onset

Insidious

Acute

Duration of symptoms

> 3 months

< 4 weeks

Morning stiffness

> 30 minutes

< 30 minutes

Nocturnal pain

Common

Absent

Effect of exercise

Improvement

Exacerbation

Sacroiliac joint tenderness

Frequent

Absent

Back mobility

Loss in all planes

Abnormal flexion

Chest expansion

Often decreased

Normal

Neurologic deficits

Unusual

Possible

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Ankylosing Spondylitis zz

zz

zz

zz

zz

Ankylosing spondylitis (AS) is an inflammatory disorder of unknown cause that primarily affects the axial skeleton. The disease usually begins in the second or third decade of life. Onset of the disease in adolescence correlates with a worse prognosis and more severe hip involve­ment. Men are affected approximately 3 times more than women. The disease in women tends to progress less frequently to total spinal ankylosis. Ankylosing spondylitis shows a striking correlation with the histocompatibility antigen HLA-B27.

Clinical Features zz

zz

zz

zz zz zz

zz

zz zz

Sacroiliitis is usually one of the earliest manifes­tation of AS. The initial symptom is usually a dull pain, insidious in onset, felt deep in the lower lumbar or gluteal region, accompanied by low-back morning stiffness of up to a few hours’ duration that improves with activity and returns following prolonged periods of inactivity. In some patients, bony tenderness over costosternal junctions, spinous processes, iliac crests, greater trochan­ters, ischial tuberosities, tibial tubercles, and heels may be present. Arthritis in the hips and shoulders may occur. Peripheral arthritis, if present, is usually asym­metric. Constitutional symptoms such as fatigue, anorexia, fever, weight loss, or night sweats may occur. Acute anterior uveitis, can antedate the spondylitis (Fig. 11.4). Attacks are typically unilateral and tend to recur. Loss of spinal mobility, with limitation of anterior flexion, lateral flexion, and extension of the lumbar spine, is seen (Fig. 11.5).

zz zz zz zz zz zz

Psoriasis Crohn’s disase or ulcerative colitis Good response to NSAIDs Family history of SpA HLA – B27 Elevated CRP.

Schober Test It is a useful measure of forward flexion of the lumbar spine. The patient stands erect, with heels together, and marks are made directly over the spine 5 cm below and 10 cm above the lumbosacral junction. The patient then bends forward maximally, and the distance between the two marks is measured. The distance between the two marks increases 5 cm or more in the case of normal lumbar mobility and less than 4 cm in the case of decreased lumbar mobility.

Fig. 11.4  Ankylosing spondylitis—anterior uveitis with hypopyon

ASAS Criteria for Diagnosis of Axial Spondyloarthritis (ASAS—Assessment of Spondyloarthritis International Society) Sacroiliitis on imaging plus ≥ 1 SpA feature or HLA – B27 plus ≥ 2 other SpA features. Spondyloarthritis (SpA) Features zz zz zz zz zz

Ch-11.indd 854

Inflammatory back pain Arthritis Enthesitis (heel) Anterior uveitis Dactylitis

Fig. 11.5  Ankylosing spondylitis—limitation of spinal forward flexion

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855

Connective Tissue Disorders There is limitation of chest expansion (Normal chest expansion is 5 cm or greater). As the disease progresses, the lumbar lordosis is obliterated with accompanying atrophy of the buttocks. The thoracic kyphosis is accentuated. If the cervical spine is involved, there may be a forward stoop of the neck. Hip involvement with ankylosis may lead to flexion contractures. The progression of the disease may be followed by: zz Measuring the patient’s height (the patient’s height decrea­s es with progression of the disease due to exaggerated thoracic kyphosis and forward stoop­ing of the neck). zz Chest expansion (chest expansion decreases with disease progression, and produces a restrictive lung disease, culminating in type 1 respiratory failure). zz Schober test. zz Occiput-to-wall distance when the patient stands erect with the heels and back flat against the wall (this distance increases with increasing involve­ment of the cervical spine by the disease due to increasing forward stoop of the neck). Complications that can arise are spinal fracture, which can occur with even minor trauma to the rigid, osteoporotic spine. Involvement of the cervical spine can lead to quadriplegia. Cauda equina syndrome is another complication of long-standing spinal disease. Pulmonary involvement, is characterized by slowly progressive upper lobe fibrosis. Cardiovascular involvement may manifest as aortic insufficiency or cardiac conduction disturbances (includ­ ing third degree heart block). Prostatitis occurs with increased frequency in men.

Investigations zz zz zz zz

Elevated ESR and C-reactive protein. Mild normochromic, normocytic anaemia. Elevated serum alkaline phosphatase. Elevated IgA levels.

Radiographic Findings The earliest changes in the sacroiliac joints demon­stra­ ble by plain X-ray show blurring of the cortical margins of the subchondral bone, followed by erosions and sclerosis. Progression of the erosions leads to ‘pseudo­widening’ of the joint space and later the joints may become obliterated with onset of bony ankylosis. X-ray of the spine shows a characteristic appear­ance of a ‘bamboo spine’ (ossification of interspinous ligaments).

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There is diffuse osteoporosis of the verte­bral column. Erosion of vertebral bodies at the disc margin leads to ‘squaring’ of the vertebra. Dynamic MRI is highly sensitive and specific for identifying intra-articular inflammation, cartilage changes, and bone marrow oedema in sacroiliitis. Modified New York criteria for diagnosis of anky­losing spondylitis: zz A history of back pain. zz Limitation of motion of the lumbar spine. zz Limited chest expansion. zz Definite radiographic sacroiliitis. Under these criteria, the presence of radiographic sacroiliitis plus any one of the other three criteria is sufficient for a diagnosis of definite ankylosing spondylitis. The detection of HLA B27 is useful only as a diag­nostic adjunct, since the presence of B27 is neither necessary nor sufficient for the diagnosis, but it can be helpful in patients who have not yet developed radio­graphic sacroiliitis.

Treatment zz

zz

zz

zz

zz

zz

zz

There is no definite treatment for ankylosing spondy­­­ litis. An exercise programme may be designed in order to maintain functional mobility. Anti-inflam­ matory agents may be given to achieve sufficient relief of symptoms Indication for surgery in patients with ankylosing spondylitis is severe hip joint arthritis, when total hip arthroplasty may be done Attacks of acute anterior uveitis are usually effective­ly managed with local glucocorticoid adminis­tration in conjunction with mydriatic agents Methotrexate and sulphasalazine may be beneficial in some cases Infliximab (Chimeric Human/Mouse Anti-TNF-2 monoclonal antibody). It is given in a dose of 5 mg/ kg IV infusion, repeated at 2 weeks, 6 weeks and then at 8 weeks interval. Etanercept (Soluble P75 TNF-α receptor-IgG fusion protein): —— It is given in a dose of 25 mg SC bid. —— Both the above drugs have shown rapid, profound and sustained reductions in all clinical and lab measures of disease activity. Human anti-TNF a monoclonal antibody: —— Adalimumab—40 mg SC biweekly . —— Golimumab—50 to 100 mg SC every 4 weeks.

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Diffuse Idiopathic Skeletal Hyperostosis (DISH) zz zz zz zz

zz zz

DISH occurs in the middle age and elderly Usually asymptomatic and may have stiffness Ligamentous calcification and ossification ‘Flowing Wax’-appearance on the anterior bodies of the vertebra as a result of anterior spinal ligament calcification Intervertebral disc spaces are preserved Sacroiliac and apophyseal joints appear normal.

Axial Spondyloarthritis Consider this diagnosis for patients with back pain ≥3 months duration and the age of onset 55 years especially in females. There is evidence of familial occurrence.

Pathology Panarteritis with inflammatory mononuclear cell infil­ trates with frequent giant cell formation occurs. There is proliferation of intima and fragmentation of internal elastic lamina.

Clinical Features It is characterised clinically by fever, anaemia, raised ESR and headaches in an elderly patient. Patients may also have loss of appetite, loss of weight, sweats, malaise, arthralgias, polymyalgia rheumatica syn­drome (stiffness, aching and pain in the muscles of neck, shoulders, hips and thighs). They may present with scalp pain and jaw claudication. On examination patients have tender, thickened, nodular arteries which may become cord like and pulseless and later get occluded. Another dreaded complication is chronic ischaemic optic neuritis causing visual impairment and sudden blindness. Strokes, MI, aortic aneurysms, dissections and infarctions of visceral organs also occur.

Investigations Elevated ESR Normochromic or hypochromic anaemia zz Abnormal­ities in liver function test (↑ SAP) zz Increased IgG and complement. zz Temporal artery biopsy is done to confirm the diagnosis. A therapeutic trial of glucocorticoid therapy results in dramatic response. zz zz

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Manual of Practical Medicine Treatment Prednisone is given in a dose of 40 to 50 mg/day and gradually tapered to 7.5 to 10 mg/day and later changed to alternate day therapy for 1 to 2 years to prevent relapse. Aspirin is used to reduce the cranial ischaemic complication. ESR is a useful indicator of inflammatory activity and is useful in monitoring therapy.

Prognosis

(American College of Rheumatology) Onset before the age of 40 years zz Limb claudication zz Decreased brachial artery pulse zz Unequal arm blood pressure (> 10 mm Hg) zz Subclavian or aortic bruit zz Angiographic evidence of narrowing or occlusion of aorta or its primary branches or large limb arteries. zz

The presence of three or more of the six criteria is 91% sensitive and 98% specific for the diagnosis.

Prognosis is good.

Takayasu’s Arteritis (Aortic Arch Syndrome) It is an inflammatory stenotic disease of medium and large sized arteries characterised by a strong predilection for arch of aorta and its branches, ascending aorta and femorals especially at their origin. It is common in adolescent girls and young women associated with HLA-DR 2, MB1, HLADR4 and MB3. The disease involves medium and large sized arteries with a predilection for aortic arch and its branches and also pul­monary arteries. Renal artery occlusion leads to hypertension. There is marked intimal proliferation, fibrosis, scarring and vascularization of the media and disruption and degeneration of elastic lamina.

Clinical Features It is a systemic disease with generalised as well as local symptoms. Generalised symptoms include malaise, fever, night sweats, arthralgias, anorexia, weight loss, and syncopal episodes. Strokes can occur. There is pain over involved arteries and pulses are absent. AR, cardiomegaly, CCF due to hypertension (systemic or pulmonary) may also occur. Clinical course can be fulminant and death is usually due to CCF or CVA. Artery

Clinical manifestations

Subclavian

Arm claudication, Raynaud’s phenomenon

Common carotid

Visual changes, TIA, syncope, stuttering hemiplegia

Abdominal aorta

Abdominal pain, nausea, vomiting

Aortic arch or root

Aortic insufficiency or CCF

Vertebral

Visual changes, dizziness, diplopia, dysarthria, dysphagia

Coeliac axis

Abdominal pain, nausea, vomiting

Superior mesenteric Abdominal pain, nausea, vomiting

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Classification Criteria for Takayasu’s Arteritis (Pulseless Disease)

Iliac

Leg claudication

Pulmonary

Atypical chest pain, dyspnoea

Coronary

Chest pain–myocardial infarction

Investigations zz zz zz zz

Elevated ESR Mild anaemia Elevated immunoglobulin Aortogram.

Diagnosis The diagnosis of Takayasu’s arteritis should be suspected in a young woman who develops a decrease or absence of peripheral pulse, discrepancies in blood pressure and arterial bruits.

Treatment Spontaneous remission is common. Glucocorticoids in a dose of 40 to 60 mg/day can be tried. Angioplasty can be done for stenosed vessels. In refractory cases metho­ trexate up to 25 mg/week can be given.

Kawasaki Disease (Mucocutaneous Lymph Node Syndrome) It is an acute, febrile, multisystem disease of children characterised by unresponsiveness to antibiotics, nonsuppura­tive cervical adenitis and changes in skin and mucous membrane such as oedema, congested con­junctivae, erythema of oral cavity, lips, palms and desquamation of skin of the fingertips. There is typical intimal proliferation with infiltration of mononuclear cells. Complications are common between 3rd and 4th weeks of illness. Vasculitis and aneurysms of coronary arteries are com­ mon. Other manifestations include pericarditis, myocarditis, myocardial ischaemia, infarction and cardiomegaly.

Treatment High dose IV gammaglobulin in a dose of 2 gm/kg as a single infusion over 10 hours together with aspirin 100 mg/kg/day for 2 weeks followed by 3 to 5 mg/kg/day for several weeks.

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Prognosis

Diagnostic Criteria

Three per cent develop fatal complications. Prognosis for unevent­ful recovery is excellent.

In addition to recurrent oral ulcers if the patient has any two of the following criteria, the diagnosis is confirmed: zz Genital ulcers zz Skin lesions zz Eye lesions zz Pathergy test.

Behçet’s Syndrome It is a multisystem disorder presenting with recurrent oral or genital ulcers as well as ocular involvement.

Incidence

Treatment zz

1 in 10,000 to 1 in 500,000. zz

Pathology Autoimmune vasculitis, linked to HLA B51 and HLA-DR5.

zz zz zz

Clinical Features zz



zz

zz

zz

zz

zz

zz

Patients have recurrent aphthous ulcers which are 2 to 10 mm in size, painful, shallow or deep with central necrotic material, occurring singly or in crops which can be located any where in the oral cavity. Genital ulcers resemble oral ones. Vaginal ulcers are painless. Genital ulcer does not affect glans-penis and urethra. Skin involvement is in the form of folliculitis, erythema nodosum, acne like exanthem, and vasculitis. Involvement of eyes may be in the form of posterior uveitis, iritis, retinal vessel occlusion and optic neuritis. Patients can have superficial and deep vein thrombosis, and SVC obstruction. CNS involvement causes benign ICT, multiple sclero­ sis like picture, pyramidal signs and psy­chiatric disturbances. Pulmonary artery vasculitis presents with dysponea, cough, chest pain, haemoptysis and infiltrates on chest X-rays The arthritis is not deforming and affects the knees and ankles.

Sjogren’s Syndrome (SS) (Autoimmune Exocrinopathy/ Autoimmune Epithelitis) It is a chronic slowly progressive autoimmune disease, characterized by lymphocytic infiltration of the exocrine glands. It is the second most common autoimmune disease. The common age of onset is between 15 and 65 years. This disorder is more common in females, F : M ratio 9 : 1.

Aetiology zz zz zz

zz zz zz zz

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Elevated ESR Elevated C reactive protein Antibodies to oral mucosa. Pathergy test: This is an abnormal inflammatory response to scratch or intradermal saline adminis­ tration, which is not seen in normal individuals.

Defective immune tolerance Infectious causes—EBV, CMV, HHV 6 Genetic factor—HLA DR3.

Pathogenesis zz

zz

zz zz

Investigations

For mouth ulcers, topical steroids as paste or mouth wash. Analgesics for arthritis Aspirin 150 mg/day for thrombophlebitis Prednisone 1 mg/kg/day for uveitis In refractory cases, azathioprine in a dose of 2 to 3 mg/kg/day or cyclosporine A in a dose of 5 to 10 mg/ kg/day can be tried.

zz

Periductal and perivascular lymphocytic infiltration of the exocrine glands by CD4+ T cells predominantly B cells produce autoantibodies against α fodrin and M3 receptor. This finally results in duct obstruction and dilatation. Acinar injury It ends up with interstitial fibrosis.

Types zz

zz

Primary SS—Sicca complex in the absence of another connective tissue disorder. Secondary SS—Sicca complex secondary to autoimmune disorder.

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Glandular Manifestations zz zz zz zz zz

zz

zz

Management

Sicca complex Skin—Dry skin, dry hair, pruritus Keratoconjunctivitis sicca Salivary gland swelling—Xerostomia Airway glands (upper and lower)—Dry nose, xerotrachea GIT—Exocrine glands—GERD, subclinical pancreatitis, malabsorption, constipation Vaginal glands—Dyspareunia.

Extraglandular Manifestations Arthralgia/Nonerosive arthritis

(60%)

Raynaud’s phenomenon (It may precede sicca manifestations)

(37%)

zz

Lymphadenopathy (Exclude lymphoma)

(14%)

zz

Lungs—small airway disease

(14%)

Vasculitis—commonly cutaneous palpable purpura

(11%)

zz zz

zz

Glomerulonephritis—usually associated with cryoglobulinemia

(9%)

zz

Primary biliary cirrhosis

(6%)

zz

Lymphoma—glandular MALTa lymphoma

(6%)

zz

Polyneuropathy—Sensory/sensorimotor

(2%)

Myositis—inclusion body myositis

(1%).

zz

zz

Difference between Primary and Secondary Sjogren’s Syndrome Characteristics

Primary

Secondary

Aetiology

Idiopathic origin

Secondary to other autoimmune disorders

Sicca symptoms

Severe

Less

Parotid enlargement

More common

Less common

Glomerulonephritis

Rare

Can occur

Anti Ro/La antibody

Positive

Negative

Investigations zz zz

zz zz

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Examination of the eyes Examination of Salivary glands —— Sialography —— Sialometry —— Salivary scintigraphy ANA assay LIP biopsy (Gold standard).

Glandular Manifestations: Care of the dry eyes: —— Avoid windy, low humidity environment, anticholinergics and diuretics. —— Lubrication with artificial tears —— L o c a l stimulation—cyclic adenosine monophosphate, cyclosporine 2% olive solution —— Systemic stimulation—pilocarpine 5 mg PO tid; cevimeline 30 mg PO tid —— Severe dry eyes—Nasolacrimal duct occlusion (temporary/permanent), soft contact lenses; corneal transplantation if needed zz Care of the dry mouth: —— Oral hygiene after each meal and topical application of fluoride —— Frequent lubrication with water —— Local stimulation—Sugar-free flavored lozenges or gum —— Systemic stimulation—As for dry eyes —— Oral candidiasis—Topical nystatin or clotrimazole lozenges zz Parotid gland enlargement: —— Apply local wet hot fomentation —— Treat infections with antibiotics and analgesics —— Persistent hard/firm gland—Rule out lymphoma zz

Extraglandular manifestations: Arthritis—Hydroxychloroquine 200–400 mg/ day or methotrexate 0.2–0.3 mg/kg weekly plus prednisolone < 10 mg PO daily zz Raynaud’s phenomenon—Gloves for cold protection, stop smoking, nifedipine 5–10 mg PO tid, or sildenafil or endothelin-1 receptor antagonist bosentan or sympathetic ganglion blockade zz Renal tubular acidosis—Bicarbonate replacement zz Vasculitis—Prednisone 60-80 mg/day or Cyclophosphamide 1-2 mg/kg/day zz Lymphoma—CHOP + anti-CD20 zz

Antiphospholipid Antibody Syndrome (APS) Antiphospholipid antibody syndrome (APS) is an acquired systemic autoimmune disease, characterized by recurrent arterial or venous thrombosis, pregnancy morbidity because of antiphospholipid antibodies. zz APS is primarily a coagulation disorder, resulting in hypercoagulable state. zz Antiphospholipid antibodies are directed against phospholipid-binding proteins rather than phospholipids alone.

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Connective Tissue Disorders

Antiphospholipid Antibodies zz zz zz

Anti- β2 glycoprotein-1 antibody Anticardiolipin antibody Lupus anticoagulant.

zz

zz

Types zz zz

Primary APS—Idiopathic type Secondary APS—Secondary to autoimmune disorders—SLE (MC)

Triad of APS zz zz zz

Recurrent vascular thrombosis Recurrent pregnancy loss Thrombocytopenia.

Pregnancy Morbidity zz zz zz zz

Pregnancy-induced hypertension (PIH) Placental abruption Intrauterine growth retardation (IUGR) Recurrent foetal loss.

Clinical Features of APS zz

zz

zz

zz

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Related to venous thrombosis: —— Livedo reticularis —— Pulmonary embolism —— Superficial thrombophlebitis —— Venous thrombosis at various sites Related to arterial thrombosis: —— Cerebrovascular disorder—transient ischaemic attack, stroke, multi-infarct dementia —— Coronary artery disease—angina, infarction —— Coronary bypass thrombosis —— Cardiac valve thickening or dysfunction/ Libman-Sacks vegetations —— Arterial thrombosis in extremities—leg ulcers, digital gangrene —— Retinal artery thrombosis—amaurosis fugax —— Ischaemia of visceral organs —— Avascular necrosis of bones Neurological manifestations of uncertain aetiology: —— Migraine —— Seizure disorder —— Chorea —— Cerebellar ataxia —— Transverse myelopathy Renal manifestations due to: —— Arteial /venous/glomerular thrombosis/fibrous intimal hyperplasia

Articular manifestations: —— Arthralgia/arthritis Pregnancy morbidity: —— Preeclampsia —— Eclampsia —— Recurrent abortions/foetal loss.

Diagnosis Clinical Criteria —— Arteial/venous/small vessel thrombosis—≥1 episode in any organ zz Pregnancy morbidity —— ≥3 unexplained consecutive spontaneous abortions before the 10th week of gestation with no other obvious causes ‘or’ —— ≥1 unexplained death of a normal foetus beyond the 10th week gestation ‘or’ —— ≥1 premature birth of normal neonate before the 34th week of gestation due to preeclampsia/ eclampsia/placental insufficiency zz Laboratory criteria —— Presence of lupus anticoagulant in plasma on ≥2 occasions (clotting assay) —— Anticardiolipin antibody—Immunoglobulin (IgG/ IgM) isotype in plasma on ≥2 occasions (ELISA) —— Anti-β2 glycoprotein 1 antibody of (IgG/IgM) isotype in plasma on ≥ 2 occasions (ELISA) —— All above tests to be repeated at least 12 weeks apart. Definite APS is present if at least one clinical and one laboratory criteria are met. zz

Management zz

zz

zz

zz

zz

zz

zz

No treatment is required in asymptomatic cases, thrombocytopenia (>50,000 cells/cu mm), first pregnancy, and single pregnancy loss at < 10 weeks. Give warfarin to keep INR at 2.5 indefinitely in both arterial and venous thrombosis. Give prophylactic heparin and low dose aspirin throughout pregnancy in cases of ≥1 foetal or ≥3 embryonic losses with no thrombosis and discontinue 6–12 weeks postpartum. In cases of thrombosis regardless of pregnancy history, give either therapeutic heparin or low dose aspirin throughout pregnancy and warfarin postpartum. In cases of thrombocytopenia (50 years—40% risk —— >70 years—70% risk Obesity Long standing diabetes mellitus Chronic pancreatitis Cigarette smoking.

Germ line mutation—BRCA 1 and BRCA 2 Strong family history Nulliparous women Early menarche Late menopause Longer length of menstrual life before first full-term pregnancy Oral contraceptives and postmenopausal HRT Radiation.

Renal Cell Carcinoma zz zz zz zz zz

Pancreatic Cancer

Leading cause of cancer death Age incidence is 55 to 65 years Tobacco smoking is the main cause (except adenocarcinoma).

Breast Cancer

zz

Hepatocellular Carcinoma

Alcohol Tobacco—smoking, chewing or snuffing Exposure to nickel Exposure to wood working Exposure to textile fibres HPV—oral and tonsil cancers EBV—nasopharyngeal cancer Decreased consumption of fruits and vegetables Consumption of salted fish.

Cigarette smoking Obesity Acquired cystic disease of kidney Family history Von Hippel-Lindau syndrome.

Bladder Cancer zz

zz

zz zz

Cigarette smoking (risk persist for 10 years after stopping smoking) Exposure to aniline dyes, drugs—phenacetin, cyclophos­phamide Radiation Schistosoma haematobium infection.

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Testicular Cancer zz zz

zz zz

Age incidence 20–40 years Cryptorchidism (abdominal cryptorchid testis > inguinal cryptorchid testis) Testicular feminizing syndrome Klinefelter syndrome.

Ovarian Cancer zz zz

zz zz

zz zz

Increasing frequency with aging Disordered ovarian function—infertility, nulliparity, frequent miscarriages Ovulation inducing drugs like clomiphine Pregnancy, breastfeeding, tubal ligation reduces the risk Family history of ovarian cancer Hereditary breast—ovarian cancer, BRCA1 and BRCA 2.

Cervical Cancer zz

zz

zz zz

This is the major gynaecological cancer seen in the lower socioeconomic groups in the under-developed countries Women with early sexual activity or multiple sexual partners Cigarette smoking Human papilloma virus—Venerally transmitted (types 16, 18, 31, 45, 51, 52 and 53).

Skin Cancer Persistently changing mole zz Family history of melanoma zz Personal history of prior melanoma zz More than 50 nevi of 2 mm diameter or larger size zz Excess exposure to sun or sun sensitivity zz Immunosuppression either due to diseases or therapy. Atypical moles: They have increased risk for malignant transfor­mation. Features of atypical mole 1. Various colours like black, brown, red, pink, within a single nevus 2. Irregular ill-defined borders 3. Larger size more than 6 mm in diameter 4. Number more than 100 (normal—10 to 40 or nil in 15% of individuals). Nonmelanoma skin cancer (basal cell ca and squamous cell carcinoma) zz Cumulative exposure to sunlight UV B spectrum zz Male sex zz Older age zz Outdoor occupation zz

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zz zz zz zz zz zz

Exposure to arsenic—well water or industrial source Exposure to tar soot or shale Cigarette smoking—lip cancer Human papilloma viruses UV radiations Immunosuppression induced by disease or drugs.

CLINICAL FEATURES OF CANCER General Features Cachexia General ill health due to altered metabolism, anorexia, weight loss, is seen as a common manifestation of gastrointestinal cancers, cancers of lung, ovaries, testes and uncommonly in breast cancers, intracranial tumours, leukaemia and lymphoma. It is due to malnutrition, maldigestion, malabsorption, either as a result of GI cancers or pancreatic cancers or biliary tract involvement.

Cancer Anorexia and Cachexia This syndrome consists of anorexia, distortion of taste perception, and loss of muscle mass. Tumour type is related to asthenia rather than tumour burden. Megestrol acetate 160 mg PO daily improves appetite and results in weight gain in some patients. Cortico­steroids, cannabinoids and metoclopramide also improve the appetite.

Pain It is due to: Nerve compression zz Distension of an organ zz Brachial plexus involvement—Ca lung or breast zz Lumbosacral plexus involvement—Ca rectum or cervix zz Paraspinal nerves—Ca pancreas zz Distension and stretching of capsule—hepatoma and secondaries liver zz Primary and metastatic lesions of bone zz Soft tissue involvement zz Pleural involvement zz Muscle spasm zz Colicky pain can be due to visceral involvement zz Periarthritis. zz

Nausea and Vomiting zz zz zz zz

Gastric irritation Delayed gastric emptying Oesophageal reflux Intestinal obstruction

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Oncology zz zz zz zz

Raised intracranial pressure Chemotherapy Radiotherapy Metabolic—uraemia and hypercalcaemia.

Pruritus zz zz zz zz zz

Drug reaction Cholestatic jaundice Renal failure—uraemia Malignant disease—lymphoma, leukaemia Coexisting diabetes mellitus or skin disease.

Breathlessness zz zz zz

Malignant pleural effusion, pericardial effusion Massive ascites Extensive lung involvement.

Extreme Anaemia zz zz zz

Bleeding Malnutrition Myelosuppression.

Metabolic Syndromes Uraemia.

Glomerular Injury This type of paraneoplastic syndrome consist of minimal change disease (Lymphoma especially Hodgkin’s) and membranous glomerulonephritis (solid tumours) results in renal failure. Treatment of underlying cancer can revert the renal disease.

Hypertrophic Osteoarthropathy It is an advanced stage of clubbing associated with poly­ arthritis and periostitis involving the long bones, most often seen in non-small cell lung cancer and metastatic mediastinal nodes due to other cancers. Treat the under­lying cause.

Fever It can accompany lymphoma, renal carcinoma, and hepatic metastasis. NSAIDs are useful and carefully rule out infectious cause for fever.

Other Manifestations zz zz

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Prolonged fever Malaise

zz zz

Fatigue Hiccough.

Specific Clinical Features Oesophageal Cancer zz zz

zz zz

Dysphagia for solid foods and later for semisolids Dysphagia denotes more than 60% of oesophageal circumference involvement Odynophagia—pain on swallowing Retrosternal pain, pain radiating to back, etc.

Gastric Cancer Small superficial and surgically removable lesion is usually asymptomatic. zz Anorexia and weight loss zz Upper abdominal discomfort zz Dysphagia in lesions of cardia zz Nausea and vomiting—in lesions of pylorus zz Palpable abdominal mass indicates long standing growth zz Metastasis to intra-abdominal and supraclavicular nodes zz Metastatic nodule to ovary (Krukenberg’s tumour) and periumbilical region (Sister Mary Joseph nodule) zz Malignant ascites and metastases to liver zz Occult blood in stools zz Iron deficiency anaemia zz Migratory thrombophlebitis zz Haemolytic anaemia zz Acanthosis nigricans denotes gastric adenocarci­noma.

Colorectal Cancer zz

zz

zz

zz

zz

Unexplained iron deficiency anaemia leading to fatigue, palpitation, and at times angina Occult blood in stools—positive or negative owing to intermittent bleed Altered bowel habits (transverse and descending colon growth) Abdominal cramping, tenesmus (rectosigmoid region) and occasional obstruction Haematochezia.

Small Bowel Cancer zz zz zz

Periumbilical pain made worse by eating Weight loss Vomiting due to intestinal obstruction (occasional).

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Anal Cancer zz zz zz zz

Sensation of perianal mass Pruritus Pain Bleeding.

Lung Cancer zz zz zz zz zz

Hepatocellular Carcinoma zz zz zz zz zz

zz

Right upper quadrant mass with pain Friction rub or bruit over the mass Haemorrhagic ascites 20% of cases Jaundice is not common Elevated alkaline phosphatase, serum α fetoprotein (AFP) >500 µg/litre Paraneoplastic syndromes consisting of erythro­ cytosis, hypercalcaemia, hypercholesterolaemia, hypoglycaemia, dys­fibrinogenaemia.

zz

zz zz zz zz

zz zz zz zz

Pancreatic Cancer zz zz zz zz zz zz zz zz zz zz zz

zz

zz

Head—70% Body—20% Tail—10% Ductal adenocarcinoma 90% Islet cell tumour 10% Epigastric pain radiating to back Weight loss (pain and weight loss in 75% cases) Jaundice is seen in lesions of pancreatic head only Painless jaundice is a feature of carcinoma of bile duct Enlarged palpable gallbladder—Courvoisier’s sign Venous thrombosis and migratory thrombo­phlebitis— Trousseau’s syndrome Tumour compressing portal venous system leading to splenomegaly and GIT bleeding Glucose intolerance is infrequent.

zz zz zz zz zz zz zz zz

Breast Cancer zz

zz zz zz zz

Head and Neck Cancer zz zz

zz zz

zz zz zz zz zz zz zz

Ch-12.indd 882

Nonhealing ulcers of oral cavity Alterations in speech—tumours of tongue and oropharynx Persistent hoarseness of voice—laryngeal cancer Serous otitis media due to obstruction of Eustachian tube—cancer of nasopharynx Nasal obstruction or epistaxis Local pain, otalgia, trismus Dysphagia/odynophagia Airway obstruction Neuropathies of cranial nerves Unilateral/bilateral cervical lymphadenopathy Leukoplakia/erythroplakia are premalignant lesions.

Persistent cough/haemoptysis Localised monophonic wheeze/stridor/dyspnoea Unresolved/recurrent pneumonia of the same segment Lung abscess Tracheal/oesophageal obstruction due to metastatic lymph nodes Involvement of recurrent laryngeal nerve—hoarseness of voice Phrenic nerve—elevated hemidiaphragm Cervical sympathetic chain—Horner’s syndrome C8T1 and T2 spinal nerve—Pancoast tumour Pleural involvement with pain or haemorrhagic pleural effusion Superior vena cavae syndrome Pericarditis/effusion Cardiac arrhythmias, failure Brain metastasis with neurological deficits Liver metastasis with jaundice, altered liver functions Bone metastasis with pain and fracture Paraneoplastic syndromes Clubbing/hypertrophic pulmonary osteoarthropathy Neurologic/myopathic syndromes Migratory thrombophlebitis Nonbacterial thrombotic (marantic) endocarditis Rare manifestations include dermatomyositis, acan­ thosis nigricans, glomerulonephritis.

Palpable mass—hard, irregular, painless, tethered, or fixed Retraction of skin over the breast or the nipple Nipple discharge Enlargement of regional lymph nodes One per cent risk of false negativity (triple negati­vity— benign feeling lump, negative mammogram, negative fine needle aspiration).

Renal Cell Carcinoma Classical triad – Haematuria – Flank pain – Palpable flank mass zz Anaemia, fever, weight loss zz Raised ESR zz Abnormal liver function zz Hypercalcaemia zz Erythrocytosis (3%) zz Neuromyopathy zz Amyloidosis. zz

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Oncology

Bladder Cancer zz zz

Gross haematuria Irritative symptoms—increased frequency, dysuria, urgency.

zz zz

Gastric Cancer zz

Prostate Cancer Symptoms of outlet obstruction: zz Hesitancy zz Diminished stream zz Intermittent voiding zz Incomplete emptying zz Post-void leakage. Other symptoms: Symptoms of increased frequency nocturia, dysuria and urgency zz Urinary retention zz Microscopic haematuria zz Haematospermia zz Erectile dysfunction zz Pain secondary to bone metastasis zz Spinal cord compression. zz

Testicular Cancer zz zz zz zz

Painless testicular mass Persistent painful testicular swelling Back pain due to retroperitoneal metastasis Dyspnoea due to pulmonary metastasis.

Ovarian Cancer zz zz zz zz zz

Mostly asymptomatic Increased urinary frequency Constipation Acute abdominal pain due to torsion mass Solid irregular and fixed adnexal mass.

Cervix Cancer zz zz zz zz zz zz

Post-coital spotting Abnormal menstrual bleeding Intermenstrual bleeding Yellowish vaginal discharge Lumbosacral back pain Urinary symptoms.

zz zz

zz zz zz

zz

zz zz

zz

Barium study by infusing barium through a nasogastric tube placed in the duodenum Endoscopy and biopsy For lymphomas —— Peripheral blood smear —— Bone marrow aspiration —— Chest X-ray —— CT thorax and abdomen Surgical exploration and resection.

Anal Cancer zz zz

Digital rectal examination Proctoscopy.

Hepatocellular Carcinoma zz

zz zz zz zz zz zz zz zz

AFP levels more than 500 µg/litre (in the absence of obvious GIT tumour). Elevated serum alkaline phosphatase USG abdomen CT/MRI abdomen Hepatic artery angiography Technetium scan USG/CT-guided liver biopsy Ascitic fluid cytology Laparoscopy/minilaparotomy.

Pancreatic Cancer zz

Oesophageal Cancer

zz

Ch-12.indd 883

Fecal haemoccult test Sigmoidoscopy/colonoscopy Double contrast—air barium enema.

Small Bowel Cancer

Investigations Contrast radiographs—Barium swallow with screening

Double contrast radiographic examination Gastroscopy and biopsy Brush cytology.

Colorectal Cancer

zz

zz

Oesophagoscopy and biopsy Cytologic examination of tumour brushings.

zz

zz zz

Carcinoembryonic antigen and CA-19-9 USG CT abdomen (detection rate 85%) Endoscopic retrograde cholangiopancreatography (ERCP) Endoscopic USG (EUS) MRI and PET—no better than CT

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Manual of Practical Medicine zz zz

Spiral CT with contrast Selective angiography.

zz

zz

Head and Neck Cancer zz zz zz zz zz

Laryngoscopy, oesophagoscopy, bronchoscopy Biopsy of all visible lesions CT head and neck Chest X-ray and bone scan for distant metastasis Lymph node biopsy.

zz

Testicular Cancer zz zz zz zz

Lung Cancer zz zz zz zz zz zz zz zz

Sputum cytology Chest X-ray PA and lateral view CT thorax Spiral CT Bronchoscopy—brush cytology and biopsy Fine needle aspiration under CT guidance Biopsy of enlarged lymph nodes Pleural fluid cytology.

zz zz zz zz zz zz zz

Diagnostic mammography Fine needle aspiration USG MRI Sestamibi imaging Excision biopsy Stereotactic core biopsy for nonpalpable lesions.

Renal Cell Carcinoma zz zz zz zz zz

Urine analysis and urine cytology CT abdomen and pelvis Chest X-ray USG MRI for lesions involving IVC.

Bladder Cancer zz zz zz zz zz zz zz

Urine cytology Cystoscopy and biopsy Intravenous pyelogram (IVP) CT and MRI USG Chest X-ray Radionuclide scan for skeletal metastasis.

Prostate Cancer zz

Ch-12.indd 884

Abnormal per rectal examination

Serum tumour markers—AFP and hCG USG testis Chest X-ray CT abdomen and pelvis.

Ovarian Cancer zz zz zz zz

Serum level of tumour marker—CA 125 Transvaginal USG Doppler flow imaging coupled with transvaginal USG Chest X-ray, CT pelvis and abdomen for staging.

Cervix Cancer zz zz

Breast Cancer

Prostate specific antigen >10 ng/mL (5–10 ng/mL is borderline positive) Transrectal USG and biopsy CT and MRI.

zz zz

PAP smear Colposcopy and biopsy Cone biopsy for endocervical tumour Chest X-ray, IVP.

Diagnosis Tumour tissue biopsy is essential to confirm the diagnosis. Tumours may be heterogeneous in appearance and in such cases more tissue is required for making the correct diagnosis. The biopsy technique that involves cutting into the tumour carry with them the risk of facilitating spread of tumour. There are several types of biopsy procedures. 1. Excisional biopsy 2. Incisional biopsy 3. Endoscopic core needle biopsy 4. Fine needle aspiration. Immunological detection of proteins is more effec­tive in fresh frozen tissue rather than in formalin fixed tissues.

Staging Staging defines the extent of dissemination of tumour by extensive radiographic and other imaging procedures and at times by surgical procedures. It is very essential to select the correct mode of management and also to assess the prognosis.

TNM Classification TNM classification is the internationally recognised staging system.

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Oncology Karnofsky Performance Index

Investigations to Define TNM Status Tumour: � Palpation �

I nspection including endoscopy �  Cytology/aspiration/ biopsy. � 

Radiology

Node: � Palpation � Biopsy

� �

Metastasis: � Biochemical screening � USG liver � Laparoscopy

Aspiration Radiology.

Radionuclide scan Radiology � Laparotomy. � �

TNM Classification

Performance Functional capability of the patients status 100 Normal 90 Able to carry on normal activity; Minor signs and symptoms of disease 80 Normal activity with effort; Some signs or symptoms of disease 70 Cares for self; Unable to carry on normal activity 60 Requires occasional assistance for care of self; 50 Requires considerable assistance and frequent medical care 40 Disabled; Requires special care and assistance 30 Severely disabled; Hospitalisation is indicated 20 Very sick; Active supportive treatment is necessary 10 Moribund; Fatal processes progressing rapidly 0 Dead

Eastern Cooperative Oncology Group Performance Status Scale

T - Extent of primary tumour N - Extent of regional lymph node involvement M - Presence or absence of metastasis

Per­formance status 0

Extent of disease: T0 Excised tumour zz T1 zz T2 Increasing primary tumour size zz T3 zz

1

}

2

Extent of involvement of nodes: N1 zz N2 Increasing involvement zz N3 zz

3

}

4

Presence of metastasis: M0 not present zz M1 present.

Functional capability of the patients Fully active, able to carry on all usual activity with­out restriction and without the aid of analgesics Restricted in strenuous activity, but ambulatory or fully active but only with the aid of analgesics Ambulatory and capable of all self-care but unable to work, moving about for more than 50% of the waking hours Capable of only limited self-care, confined to bed or chair for more than 50% of waking hours Completely disabled, unable to carry out any self-care and totally confined

Cancer Screening

zz

Screening recommendations for asymptomatic normal risk subjects.

Site of Metastatic Involvement—% Primary site Lung Breast Thyroid Liver Pancreas Stomach Colorectal Renal Ovary Prostate

Liver 30–50 60 60 NA 50–70 35–50 70 35–40 10–15 10–15

Lungs 30 60 65 20 25–40 20–30 25–40 50–75 10 10–50

Bone 30–50 50–85 40 10 5–10 5–10 5–10 30–50 5 50–75

Brain 15–30 15–25 1 0 1–5 1–5 1 5–10 1 2

Performance Status Various scales are used to assess the functional capability of the patient. They are useful in assessing the prognosis and also the efficacy and toxicity of management. Fully active patients are likely to fare well and the bed-ridden patients are likely to fare worse.

Ch-12.indd 885

Cancer Screening Test of procedure

American cancer society recommendations

Sigmoidoscopy

>50 years, every 3–5 years

Fecal occult blood

>50 years, every year

Digital rectal examination

>40 years, every year

Prostate specific antigen

>50 years, every year

PAP test

From age 18 yearly thrice, and then at physicians discretion

Pelvic examination

18–40 years, every 1–3 years with PAP test >40 years, every year

Endometrial tissue sampling

At menopause, if obese or a history of unopposed oestrogen use

Breast self-examination

>20 years, monthly

Breast clinical examination

20–40 years, every 3 years >40 years, yearly

Mammography

>40 years, every year

Complete skin examination 20–40 years every 3 months

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Complications

zz

Infections in Cancer Patients

zz

Infections in cancer patients increase morbidity and mortality. Alterations in the immune system either as a result of the disease per se or as a result of chemo/radiotherapy predisposes the individual to intercurrent infections.

Progressive multifocal leucoencephalopathy.

Gastrointestinal Tract Infection

Cardiovascular Infections

Mouth ulcerations

zz

zz

zz

Streptococcus viridans —— Virus—HSV (Acyclovir) —— Fungal thrush—Candida albicans (Fluconazole). Oesophageal infections —— HSV and candidiasis.

Hepatosplenic involvement

Alterations in Normal Barriers of Infection in Malignancy Disease

Head and neck, squamous cell ca Renal, ovarian, biliary, metastatic ca Breast cancer surgery Hodgkin’s disease, ITP, leukaemia Hairy cell leukaemia, AML, ALL CLL

Cellulitis

Hodgkin’s disease T cell lymphoma, leukaemia

Bacteraemia UTI Cellulitis Overwhelming sepsis

Underlying defence/ immune abnormality Disruption of physical barrier (skin) Occlusion of normal patent orifices Disruption of lymphatic Splenectomy

Bacteraemia

Phagocytic abnormality of granulocytes Infection with encapsulat- Humoral immunity ed organism, pneumonia sinusitis Infections with Intracellular bacteria, Cellular immunity fungi, parasites

Typhlitis Neutropaenic necrotising colitis, ileocaecal syndrome; all due to aerobic gram-negative bacilli (broad spectrum bactericidal agent). Clostridium difficile-induced diarrhoeas.

Central Nervous System Infections zz

Ch-12.indd 886

Meningitis —— S. pneumoniae —— H. influenzae —— N. meningitidis —— Cryptococcal and —— Listerial infections

Intravenous catheters —— Bacterial endocarditis —— Valve damage Severe bacteraemia —— Nonbacterial thrombotic endocarditis.

Endocrine Infections zz

Chronic disseminated candidiasis (Amphotericin B and Fluconazole). Type of cancer

zz

Encephalitis —— Varicella zoster virus Brain abscess —— Cryptococcus —— Nocardia —— Aspergillus.

zz

Candida infection of thyroid CMV adrenalitis with/without adrenal insufficiency.

Renal and Ureteral Infections Fungal balls/candiduria or persistent funguria—Aspergillus/Candida BK virus induced cystitis.

Vaccination of Cancer Patients They respond less well to vaccines than normal host. Live bacterial/viral vaccines should not be given. Vaccination should not be given concurrently with cytotoxic chemotherapy. Vaccination of Cancer Patients Receiving Chemotherapy Use in Indicated Patients Vaccine Intensive chemotherapy DiphtheriaPrimary series tetanus and boosters as (diphtheria, necessary pertussis, tetanus; DPT) for children 14 mg%) Calcitonin 4 to 8 U/kg IM/SC every 12 hours zz Refractory cases—Plicamycin and Gallium nitrate may be added. zz

zz

Ectopic Acromegaly Clinical Features zz zz zz

Serum sodium level 400,000/µL —— This indicates advanced stage cancer and poor prognosis —— Does not require treatment. Eosinophilia >5000/µL —— Dyspnoea due to pulmonary infiltrates —— Oral/inhaled glucocorticoids —— Treat the underlying cancer. Thrombophlebitis —— Leads to deep vein thrombosis/pulmonary embolism —— Low molecular weight heparin—5 days —— Coumarin—for 3–6 months —— Keep the INR between 2–3.

Neurologic Syndromes Neurologic Paraneoplastic Syndromes Syndrome Brain Limbic encephalitis

Brainstem encephalitis

Cerebellar degeneration

Opsoclonus/ myoclonus

Spinal cord Necrotizing myelopathy

Onset: subacute Sensory loss; diffuse, asymmetric, numbness/ paresthesias, dysesthesia/pain Sensory ataxia: pseudoathetosis ± encephalomyelitis Motor Onset: subacute neuronopathy Weakness: arms > legs Usually asymmetric Axonal neuropathies Sensorimotor Distal motor and neuropathy sensory loss Most common para­neoplastic neuropathy, especially with >15% weight loss Axonal neuropathy Mononeuritis Weakness and/ multiplex or sensory loss in the distribution of multiple nerves Onset: acute to subacute Neuromyotonia Weakness: distal and (Isaacs) proximal Stiffness Fasciculations Amyloid Distal symmetric neuropathy axonal loss: small > large Autonomic symptoms prominent

Features

Antibody target

Neoplasm/ Percentage

Onset: subacute Confusion Memory loss Temporal lobe seizures Vertigo Cerebellar: ataxia, nystagmus Ocular: diplopia, gaze palsies Cerebellar: ataxia, dysarthria

Hu

SCLC, testicular cancer, breast, colon, bladder, lymphoma

Hu

SCLC

Enteric neuropathy

Yo Tr Glutamate receptors Ri (NOVA) Hu Neurofilament

Ovary, uterus, SCLC, Hodgkin’s lymphoma

Demyelinating neuropathies

Involuntary eye movements: rapid, random directions Ataxia Encephalopathy

Hu

SCLC (90% of cases), breast, ovary, prostate

Not known

Lymphoma

None

Many neoplasms

Not known

Cryoglobulinaemia, leukaemia, lymphoma

Voltage-gated Thymoma potassium channels Not known

Multiple myeloma

Autonomic neuropathies

Weakness: paraplegia Not known or quadriplegia Sensory loss: spinal level Urinary incontinence

SCLC, lymphoma

Contd...

Hu Gastroparesis Intestinal pseudoobstruction Esophageal achalasia Dysphagia

Thymoma, SCLC

Anti-MAG

Sensory > motor Distal, symmetric Gait disorder Tremor Slowly progressive NCV: Long distal latencies, Conduction block uncommon

MAG

MGUS, IgM M-protein in 85%

Multifocal motor neuropathy

Slowly progressive Motor Distal > proximal Asymmetric NCV: Motor conduction block Motor axon loss (late)

GM1 ganglioside

MGUS, IgM M-protein in 20%

Neuro­ blastoma, lung, breast

Peripheral nerve Neuronopathies

Ch-12.indd 889

Sensory neuronopathy

Contd...

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Manual of Practical Medicine Contd...

Contd...

Anti-sulfatide

Slowly progressive Sensory > motor Distal, symmetric Demyelinating or axonal

Sulfatide

MGUS, IgM M-protein in 90% with demyelinating neuropathy

Myopathy with anti-decorin antibodies

>50 years of age Proximal symmetric weakness Mildly elevated creatine kinase

Decorin

Waldenström’s macroglobulinaemia, IgM M-protein

POEMS

Sensorimotor neuropathy Symmetric Mixed demyelinating and axonal

Not known

Multiple myeloma, IgG or IgA M-protein in 90%

Rippling muscle disease

Cramps induced by touching muscle Muscle waves induced by percussion Electrically silent

Not known

Thymoma

CIDP

Chronic or relapsing β-Tubulin in 20% Motor > sensory Distal and proximal weakness Usually symmetric NCV: Conduction block, slow sensory and motor conduction velocities

MGUS, IgM or IgG M-protein in 15%, lymphoma

Scleromyxoedema

Skin papules Raynaud’s phenomenon Proximal muscle weakness High creatine kinase Myopathic electromyography

Not known

MGUS, IgG or IgA M-protein

Neuromuscular junction LEMS

Myasthenia gravis

Weakness: proximal and distal Ocular: ptosis May improve with exercise Dry mouth Rapid repetitive stimulation: increment

Voltagegated P/Q calcium channels

Weakness Cranial: ocular, face, bulbar Respiratory, limbs, trunk Fatigue Slow repetitive stimulation: decrement

Nicotinic acetylcholine receptor

Males >40 Rapid-onset weakness Necrosis on muscle biopsy May improve with treatment of cancer

Not known

Females >40 Proximal muscle weakness Skin rash

Not known

Especially with weight loss >15% Wasting > weakness

Not known

SCLC in 60% of cases, especially older and smoking history

Dermatomyositis

Type II atrophy

Thymoma in 10%, especially >30 years

Causes zz zz zz

Lung cancer Lymphoma Mediastinal cancers/metastasis.

Clinical Features zz zz zz zz

Lung, breast, alimentary tract

zz

Swelling of face, neck, upper extremities and chest Dilated superficial veins over the chest Chest pain, cough and dyspnoea, haemoptysis Headache, nasal congestion, epistaxis In severe obstruction—proptosis, glossal and laryngeal oedema.

Investigations zz zz

Ovarian, nasopharyngeal

zz

Many neoplasms

Sputum cytology Chest X-ray and thorax.

Management zz

zz zz

Contd...

Ch-12.indd 890

ONCOLOGIC EMERGENCIES Superior Vena Caval Obstruction

Muscle Necrotizing myopathy

Abbreviations: POEMS, polyneuropathy, organomegaly, endo­crino­pathy, myeloma and skin pigmentation; CIDP, chronic inflammatory demyelinating polyneuropathy; SELC, small cell lung cancer; MGUS, monoclonal gammopathy of undetermined significance; MAG, myelin-associated glycoprotein; NCV, nerve conduction velocity; LEMS, lambert-eaton myasthenis syndrome.

zz

Dexamethasone 4 mg 6th hourly orally Radiation for non-small cell lung cancer and metastatic tumours Chemotherapy for small cell lung cancer and lymphoma Maintain airway Surgery is useful in benign lesions.

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Oncology

Increased Intracranial Pressure (Brain Metastasis)

Intracerebral Leucocytostasis (Ball’s Disease)

Causes

zz

Metastatic brain tumour from lung—breast cancer.

Clinical Features zz zz zz

zz zz

Management

zz zz

zz

Dexamethasone 4 to 8 mg IV or orally 6th hourly Whole brain irradiation For solitary lesions—surgery followed by radiotherapy Intubation—hyperventilation-mannitol infusion (maintain PCO2 at 25–30 mm Hg) Stereotactic radiosurgery for inaccessible lesions.

Meningeal Carcinomatosis Involvement of leptomeninges either by primary or metastatic tumour.

� � �

Lung cancer Melanoma Lymphoma.

�

Breast cancer Acute leukaemia

Clinical Features zz zz zz

Headache, vomiting, gait abnormalities Cranial nerve palsies, mental changes Seizures, limb weakness, decreased deep tendon reflexes.

Investigations zz zz zz

CT/MRI before LP to rule out parenchymal metastasis LP—CSF cytology, elevated protein level MRI—Hydrocephalus/smooth or nodular enhance­ ment of meninges.

Treatment zz

zz zz

Ch-12.indd 891

zz zz

Intrathecal chemotherapy (methotrexate, cytarabine, thiotepa) Local radiation therapy IV arabinoside for meningeal lymphoma.

Whole brain irradiation Aggressive antileukaemic therapy.

Seizures Causes zz zz zz zz

zz �

Visual disturbance Ataxia, stupor Dizziness Coma, death.

Management

zz

Causes

Potential fatal complication of acute leukaemia More common with myelogenous leukaemia It occurs when the peripheral blast cell count is more than 1 lakh/µL Brain invasion with blast cell through endothelial damage results in haemorrhage.

Clinical Features zz zz

CT and MRI with contrast.

zz

zz

zz

Headache, nausea, vomiting Papilloedema Behavioural changes, seizures, focal neurological deficits.

Investigations

zz

zz

Primary/metastatic tumour Metabolic disturbance Radiation injury Chemotherapy-related encephalopathy CNS infections/cerebral infarction Drugs—etoposide, busulphan, chlorambucil.

Management zz

Anticonvulsant therapy with phenytoin.

Spinal Cord Compression Haematogenous spread of cancer to vertebral bodies.

Causes zz zz zz zz

Lung cancer Breast cancer Prostate cancers Multiple myeloma.

Site of Lesion Vertebral column more involved than other bones Thoracic spine—70% zz Lumbosacral spine—20% zz Cervical spine—10%. zz

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Manual of Practical Medicine Clinical Features zz zz zz zz zz zz

zz

Localised back pain and tenderness Pain precedes neurological deficits Pain aggravated by coughing and sneezing Radicular pain—unilateral or bilateral Loss of bowel and bladder control Pain worsens when the patient is supine (in disc lesions pain is relieved in supine positions) Signs of cord compression.

Investigations zz

zz

X-ray of spine —— Erosion of pedicles (winking owl sign) —— Increased interpedicular distance —— Vertebral destruction and collapse. MRI spine —— Gadolinium-enhanced MRI for intramedullary lesions —— In case of poor MR images, myelography or CT with myelography.

Management zz zz zz

High dose dexamethasone—8 mg 6th hourly Radiation therapy Surgery and chemotherapy.

Malignant Effusions Malignant Pericardial Effusion Causes zz zz zz zz zz

Lung cancer Breast cancer Leukaemias and lymphoma Radiation Drug induced.

Radiation zz

zz

Acute inflammatory effusive pericarditis (within months) Chronic effusive pericarditis with thickened pericardium (up to 20 years after irradiation).

Management zz

zz zz

zz

Malignant Pleural Effusion Caused by invasion by tumour or obstruction to lymphatic drainage.

Management zz

zz

zz zz zz zz zz

Ch-12.indd 892

Dyspnoea, cough, chest pain Distended jugular veins Hepatomegaly Peripheral oedema Paradoxical pulse and pulsus alternans Friction rub and cardiac tamponade.

Drainage of pleural fluid followed by instillation of sclerosing agents Resistant effusion—pleurectomy.

Malignant Ascites Cause Peritoneal carcinomatosis Controlled by systemic chemotherapy and rarely intra­ peritoneal instillation of chemotherapeutic agent.

Airway Obstruction Causes zz zz

Intraluminal tumour growth Extrinsic compression.

Management zz

zz

zz

Obstruction proximal to larynx—tracheostomy is life saving Distal obstructions—laser treatment, photodynamic therapy and stenting Emergency radiotherapy and glucocorticoids may open the airway.

Haemoptysis Causes zz zz

Clinical Features zz

Cardiac tamponade warrants immediate pericardiocentesis Uncontrolled disease—pericardiocentesis with sclerosis Sclerosis—30–60 mg Bleomycin instillation and with­drawal after 10 minutes Recurrent accumulation—subxiphoid pericardiotomy.

About 20% of patients with lung cancer Metastasis from breast, colon, kidney, melanoma and carcinoid tumours.

Management zz zz zz zz zz

Blood transfusion Oxygen Emergency bronchoscopy Surgery/Nd: YAG laser therapy Bronchial artery embolisation.

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Oncology

Intestinal Obstruction

Management

Causes

zz

zz zz

Colorectal and ovarian cancers Metastatic lesions of lung and breast cancers and melanoma.

Clinical Features � � � �

� Vomiting Colicky pain � Abdominal pain Constipation Visible peristalsis �  High pitched bowel sounds Palpable tumour masses.

zz zz

Biliary Obstruction (Fig.12.1) Causes zz zz zz zz

Investigations zz

zz

Plain X-ray abdomen erect: —— Multiple air fluid level —— Dilation of small or large bowel USG abdomen.

Prognosis zz zz zz

Overall prognosis is poor Acute caecal dilation is a surgical emergency Median survival 3 to 4 months.

Management zz zz zz zz

Nasogastric decompression Antispasmodics Surgery Self-expanding metal stents.

Urinary Obstruction Causes zz zz

Stents for ureteral obstructions Percutaneous nephrostomy for hydronephrosis Suprapubic cystostomy for bladder outlet obstruction.

Pancreatic cancer Bile duct carcinoma Hepatoma Metastasis from gastric, colonic, breast and lung cancers.

Clinical Features zz zz zz

High coloured/light coloured stools Jaundice, pruritus Malabsorption leading to weight loss.

Investigations zz zz

zz

USG/CT abdomen Percutaneous transhepatic/Endoscopic retrograde cholangiopancreatography MRCP (Figs 12.2A to E).

Management zz zz

Stenting/surgical bypass Radiotherapy/chemotherapy.

Other Emergencies zz

Lactic acidosis

Prostate/cervix cancer Radiation therapy for pelvic tumours.

Clinical Features zz

zz zz zz zz

Outlet obstruction results in bilateral hydronephrosis and renal failure Flank pain dysuria Proteinuria, haematuria Polyuria, anuria Rising urea and creatinine value.

Investigations zz zz

Ch-12.indd 893

Renal USG CT abdomen to identify retroperitoneal mass/ lymphadeno­pathy.

Fig. 12.1:  Periampullary carcinoma with obstructive jaundice

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B

A

D

C

E

Figs 12.2A to E:  (A) MRCP filling defects seen in distal CBD (calculi) with dilated proximal CBD, hepatic ducts; (B to E) calculus in cystic duct zz zz zz zz

Hypoglycaemia Adrenal insufficiency Bone metastasis and spontaneous fractures Minimal change/membranous glomerulonephritis.

METASTATIC CANCER OF UNKNOWN PRIMARY SITE Biologic Behaviour zz

zz zz zz

Ch-12.indd 894

Primary becomes apparent during the course of illness in 20% Primary diagnosed at autopsy in 60% Primary not traced even at autopsy in 20% Median survival 6 to 12 months.

Fig. 12.3:  MRCP—periampullary mass compressing biliary tract causing obstructive jaundice

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895

Oncology

Clinical Evaluation

Ultrastructure

Suggested clinical evaluation of patients with metastatic cancer of unknown primary site zz History: Smoking history, asbestos exposure, abdo­ minal pain zz Physical examination: Lymph nodes, thyroid, skin zz Men: Prostate zz Women: Breasts, pelvic examination zz Laboratory evaluation: Stool evaluation for occult blood; urinalysis; complete blood count; liver function tests; calcium, electrolytes, creatinine; measurement of serum levels of hCG, AFP, CEA, and CA-125 (women); chest X-ray; abdominal and pelvic CT; mammography.

Actin-myosin filaments Secretory granules

Pathological Evaluation or Biopsy Possible pathologic evaluation of biopsy specimens from patients with metastatic cancer of unknown primary site: Evaluation/findings Suggested primary site or neoplasm

Histology (Hematoxylin and Eosin Staining) Psammoma bodies, papillary configuration Signet ring cells

Ovary, thyroid Stomach

Immunohistology Leukocyte common antigen Lymphoid neoplasm (LCA, CD45) Leu-M1 Hodgkin’s disease Epithelial membrane antigen Carcinoma Cytokeratin Carcinoma CEA Carcinoma HMB45 Melanoma Desmin Sarcoma Thyroglobulin Thyroid carcinoma Calcitonin Medullary carcinoma of the thyroid Myoglobin Rhabdomyosarcoma PSA/prostatic acid phosphatase Prostate AFP Liver, stomach, germ cell Placental alkaline phosphatase Germ cell B, T cell markers Lymphoid neoplasm S-100 protein Neuroendocrine tumour, melanoma Gross cystic fluid protein Breast, sweat gland Factor VIII Kaposi’s sarcoma, angiosarcoma

Flow Cytometry B, T cell markers

Ch-12.indd 895

Lymphoid neoplasm

Rhabdomyosarcoma Neuroendocrine tumours Desmosomes Carcinoma Premelanosomes Melanoma

Cytogenetics Isochromosome 12p; 12q(-) t(11;22)

Germ cell Ewing’s sarcoma, primitive neuro­ ectodermal tumour t(8;14) Lymphoid neoplasm 3p(-) Small cell lung carcinoma; renal cell carcinoma, mesothelioma t(X;18) Synovial sarcoma t(12;16) Myxoid liposarcoma t(12;22) Clear cell sarcoma (melanoma of soft parts) t(2;13) Alveolar rhabdomyosarcoma 1p(-) Neuroblastoma

Receptor Analysis Oestrogen/progesterone Breast receptor

Molecular Biologic Studies Immunoglobulin, bcl-2, T-cell Lymphoid neoplasm receptor gene rearrangement.

Management Protocol Presentations that dictate specific therapies in patients with CUPS. Clinicopathologic features

Suspected primary site

Suggested therapy

Squamous cell carcinoma, cervical node

Head and neck cancer

Radical neck dissection; radiotherapy ± chemotherapy

Carcinoma, axillary nodes (female)

Breast cancer

Breast radiotherapy or mastectomy, systemic adjuvant therapy

Peritoneal carcinomatosis (female)

Ovarian cancer

Debulking surgery, cisplatin-based chemotherapy

Pleural effusion, adeno­ Breast cancer carcinoma cells oestrogen and/or progesterone receptor positive

Systemic therapy for metastatic breast cancer

Contd...

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Staging

Contd... Clinicopathologic features

Suspected primary site

Suggested therapy

Poorly differentiated cancer, age WBCs Renal Mg2+, Ca2+

Topical use in cutaneous lymphoma

CI-pregnancy Breastfeeding CI- pregnancy Breastfeeding

Decreased renal function delays clearance

Isomeric analogue of cyclophosphamide More lipid soluble Greater activity vs testicular neoplasms and sarcomas Must use MESNA Liver and tissue metabolism required Disulfiram-like effect with ethanol Acts as MAOI HBP after tyrosinase-rich foods Metabolic activation

Liver activation Barbiturates enhance/cimetidine diminishes

Maintain high urine flow; osmotic diuresis, monitor intake/output K+, Mg2+ Emetogenic-prophylaxis needed Full dose if CrCl >60 mL/min and tolerate fluid push Contd...

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Manual of Practical Medicine Contd... Drug Carboplatin

Examples of usual doses 365 mg/m2 IV q3–4 weeks as adjusted for CrCl

Toxicity Marrow platelets > WBCs Nausea Renal (high dose) Sensory neuropathy

Interactions, issues Reduce dose according to CrCl: AUC = dose/(CrCl + 25) to AUC of 5–7 mg/mL per min Monitor renal function

15–25 mg/d qd × 5 IV bolus or continuous IV

Pulmonary Skin effects Raynaud’s hypersensitivity

Actinomycin D

10–15 µg/kg per day qd × 5 IV bolus

Mithramycin

15–20 µg/kg qd × 4–7 (hypercalcaemia) or 50 µg/kg qod × 3–8 (antineoplastic)

Marrow Nausea Mucositis Vesicant Alopecia Marrow Liver Renal Mucositis Hypocalcaemia Nausea Vesicant Myelosuppression

Inactivate by bleomycin hydrolase (decreased in lung/skin) O2 enhances pulmonary toxicity Cisplatin-induced decrease in CrCl may increase skin/lung toxicity Reduce dose if CrCl platelet) Alopecia Hypotension Hypersensitivity (rapid IV) Nausea Mucositis (high dose)

Hepatic metabolism—renal 30% Reduce doses with renal failure Schedule-dependant (5 day better than 1 day) Late leukemogenic Accentuate antimetabolite action

Teniposide (VM-26)

150–200 mg/m2 twice per week for 4 weeks

Marrow Alopecia

Amsacrine

100–150 mg/m2 IV qd × 5

Marrow Mucositis Nausea CV-arrhythmia (avoid hypokalaemia)

Decrease dose by 30% if liver or renal failure

Topotecan

20 mg/m2 IV q3–4 weeks over 30 min or 1.5–3 mg/m2 q3–4 weeks over 24 h or 0.5 mg/m2 per day over 21 days

Marrow Mucositis Nausea Mild alopecia

Reduce dose with renal failure No liver toxicity

Irinotecan (CPT II)

100–150 mg/m2 IV over 90 min q3–4 weeks or 30 mg/m2 per day over 120 h

Diarrhoea: “early onset” with cramping, flushing, vomiting; “late onset” after several doses Marrow Alopecia Nausea Vomiting Pulmonary

Prodrug requires enzymatic clearance to active drug “SN 38” “Early diarrhoea” likely due to biliary excretion Late diarrhoea, use “high-dose” loperamide (2 mg q2-4 h) Contd...

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Oncology Contd... Drug

Examples of usual doses

Toxicity

Interactions, issues

Doxorubicin and daunorubicin

45–60 mg/m2 dose q3–4 weeks or 10–30 mg/m2 dose q week or continuous–infusion regimen

Heparin aggregate; coadministration increases clearance Tylenol, BCNU increase liver toxicity Radiation recall

Idarubicin

10–15 mg/m2 IV q 3 weeks or 10 mg/m2 IV qd × 3 150 mg/m2 IV q3 weeks

Marrow Mucositis Alopecia Cardiovascular acute/chronic Vesicant Marrow Cardiac (less than doxorubicin) Marrow Cardiac Marrow Cardiac (less than doxorubicin) Vesicant (mild) Blue urine, sclerae, nails

Nausea Immunosuppression Neurologic Renal Marrow Liver Nausea

Excretes in urine Reduce dose for renal failure Inhibits adenosine deaminase

Epirubicin Mitoxantrone

12 mg/m2 qd × 3 or 12–14 mg/m2 q3 weeks

Indirect DNA-Interacting Agents Antimetabolites Deoxycoformycin 4 mg/m2 IV every other week

6-Mercaptopurine

75 mg/m2 PO or up 500 mg/m2 PO (high dose)

6-Thioguanine

2–3 mg/kg per day for up to 3–4 weeks

Azathioprine

1–5 mg/kg per day

2-Chlorodeoxyadenosine

0.09 mg/kg per day qd × 7 as continuous infusion

Hydroxyurea

20–50 mg/kg (lean body weight) PO qd or 1–3 g/d

Methotrexate

15–30 mg PO or IM qd × 3–5 or 30 mg IV days 1 and 8 or 1.5–12 g/m2 per day (with leucovorin) 375 mg/m2 IV qd × 5 or 600 mg/m2 IV days 1 and 8

5-Fluorouracil

Cytosine arabinoside

100 mg/m2 per day qd × 7 by continuous infusion or 1–3 g/m2 dose IV bolus

Marrow Liver Nausea Marrow Nausea Liver

Marrow Renal Fever Marrow Nausea Mucositis Skin changes Rare renal, liver, lung, CNS Marrow Liver/lung Renal tubular Mucositis Marrow Mucositis Neurologic Skin changes Marrow Mucositis Neurologic (high dose) Conjunctivitis (high dose) Noncardiogenic pulmonary oedema

None established None established Interacts with heparin Less alopecia, nausea than doxorubicin Radiation recall

Variable bioavailability Metabolize by xanthine oxidase Decrease dose with allopurinol Increased toxicity with thiopurine methyltransferase deficiency Variable bioavailability Increased toxicity with thiopurine methyltransferase deficiency Metabolizes to 6-MP, therefore reduce dose with allopurinol Increased toxicity with thiopurine methyltransferase deficiency Notable use in hairy cell leukaemia

Decrease dose with renal failure Augments antimetabolite effect

Rescue with leucovorin Excreted in urine Decrease dose in renal failure NSAIDs increase renal toxicity Toxicity enhanced by leucovorin Dihydropyrimidine dehydrogenase deficiency increases toxicity Metabolizes in tissues Enhances activity of alkylating agents Metabolizes in tissues by deamination

Contd...

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902

Manual of Practical Medicine Contd... Drug Azacytidine

Examples of usual doses 750 mg/m2 per week or 150–200 mg/m2 per day × 5–10 (bolus) or (continuous IV)

Gemcitabine

1000 mg/m2 IV weekly × 7

Fludarabine phosphate

25 mg/m2 IV qd × 5

Asparaginase

25,000 IU/m2 q3–4 weeks or 6000 IU/m2 per day qod for 3–4 weeks or 1000–2000 IU/m2 for 10–20 days

Pemetrexed

Pralatrexate Antimitotic Agents Vincristine

1–1.4 mg/m2 per week

Vinblastine

6–8 mg/m2 per week

Vinorelbine

15–30 mg/m2 per week

Paclitaxel

135–175 mg/m2 per 24-h infusion or 175 mg/m2 per 3-h infusion or 140 mg/m2 per 96-h infusion or 250 mg/m2 per 24-h infusion plus G-CSF

Toxicity Marrow Nausea Liver Neurologic Myalgia Marrow Nausea Hepatic Fever/”flu syndrome” Marrow Neurologic Lung Protein synthesis Clotting factors Glucose Albumin Hypersensitivity CNS Pancreatitis Hepatic Anaemia Neutropaenia Thrombocytopaenia Myelosuppression Mucositis Vesicant Marrow Neurologic GI: ileus/constipation; bladder hypotonicity; SIADH Cardiovascular Vesicant Marrow Neurologic (less common but similar spectrum to other vincas) Hypertension Raynaud’s Vesicant Marrow Allergic/bronchospasm (immediate) Dyspnoea/cough (subacute) Neurologic (less prominent but similar spectrum to other vincas) Hypersensitivity Marrow Mucositis Alopecia Sensory neuropathy CV conduction disturbance Nausea-infrequent

Interactions, issues Use limited to leukaemia Altered methylation of DNA alters gene expression

Dose reduction with renal failure Metabolised to F-ara converted to F-ara ATP in cells by deoxycytidine kinase Blocks methotrexate action

Supplement folate/B12 Caution in renal failure Active in peripheral T cell lymphoma

Hepatic clearance Dose reduction for bilirubin >1.5 mg/dL Prophylactic bowel regimen

Hepatic clearance Dose reduction as with vincristine

Hepatic clearance

Premedicate with steroids, H1 and H2 blockers Hepatic clearance Dose reduction as with vincas

Contd...

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903

Oncology Contd... Drug Docetaxel

Examples of usual doses 100 mg/m2 per 1-h infusion q3 weeks

Nab-paclitaxel

Ixabepilone Estramustine phosphate

14 mg/kg per day in 3–4 divided doses with water >2 h after meals Avoid Ca2+-rich foods

Hormonal Agents Tamoxifen

10 mg orally BD

Aromatase inhibitors are used in hormone responsive breast cancer (Postmenopausal) i.  Anastrozole

1 mg/day

ii.  Letrozole iii. Exemestane Leuprolide acetate and goserelin acetate

2.5 mg/day 25 mg/day given as monthly subcutaneous depot injection should be monitored

Toxicity Hypersensitivity Fluid retention syndrome Marrow Dermatologic Sensory neuropathy Nausea infrequent stomatitis Neuropathy Anaemia Neutropaenia Thrombocytopaenia Myelosuppression Neuropathy Nausea Vomiting Diarrhoea CHF Thrombosis Gynaecomastia

Interactions, issues Premedicate with steroids, H1 and H2 blockers

Hormone flare after 7–14 days of treatment (bone pain, erythema, hypercalcaemia) Endometrial cancer, DVT

Hormone flare does not require stopping therapy. Long-term administration is not associated with systemic antioestrogen effect

Caution in hepatic insufficiency

Hot flushes, sweating, vaginal dryness/bleeding Hot flushes and night sweats Hot flushes, sweating, alopecia Flare up of symptoms

Signs of neurologic dysfunction or urinary obstruction

Megestrol acetate and 40 mg QID PO Medroxyprogesterone 10 mg OD PO Antiandrogens are used in advanced prostate cancer

Weight gain, fluid retention, hot flushes

Also used in cancer cachexia

i.  Bicalutamide

150 mg/day

ii. Flutamide

250 mg tid

Nausea, vomiting, alopecia/ hirsutism gynaecomastia, ILD, heart failure Nausea, vomiting, gynaecomastia HTN, SLE like syndrome, insomnia

Progestational Agents

Gonadotrophin agonists Immunotherapy Selective Agents Trastuzumab

4 mg/kg over 90 minutes On week 1 and 2 mg/kg over 30 minutes weekly

Rituximab

Administered weekly for 1 month

Chills and fever hypersensitivity

Added on to first line therapy in metastatic breast cancer with over expression of her 2 gene Used in CD 20 positive low grade NHL Contd...

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Oncology Contd... Drug Regorafenib

Examples of usual doses Second line colorectal cancer

Sunitinib Vandetanib

Renal cell carcinoma, Pancreatic neuroendocrine tumour Medullary thyroid cancer

Cabozantinib

Medullary thyroid cancer

Axitinib

Renal cell carcinoma, second line

Proteasome Inhibitors Bortezomib Carfilzomib Histone Deacetylase Inhibitors Vorinostat Romidepsin mTOR Inhibitors Temsirolimus Everolimus

Miscellaneous Arsenic trioxide Vismodegib

Neuropathy, thrombocytopaenia

Cutaneous T cell lymphoma, second line Cutaneous T cell lymphoma

Diarrhoea, thrombocytopaenia, embolism, fatigue Vomiting, conduction defects, cytopaenias

Renal cell carcinoma Renal cell, breast cancer, pancreatic neuroendocrine, subependymal giant-cell astrocytoma,

Thrombocytopaenia, fatigue Stomatitis, fatigue

APL Metastatic basal cell carcinoma

Prolonged QTc Hair loss, muscle spasm, dysgeusias

Gastric Cancers zz

zz

Adenocarcinoma—localized lesions—early surgery Advanced unresectable—may benefit by chemo­ therapy and radiation Metastatic disease—palliation by chemotherapy.

Oesophageal Cancer zz zz

zz zz zz

Squamous cell/adenocarcinoma Surgical resection of oesophagus or chemoradiation followed by resection Unresectable growth—chemotherapy and radiation Metastatic disease—palliation by chemotherapy Obstructive complication—stenting.

Colon Cancer zz zz

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Adenocarcinoma—surgical resection. Regional lymph node involvement—5FU and Levamisole for 12 months.

Interactions, issues

Diarrhoea, rash, prolonged QTc, hypertension, thrombosis Hypertension, poor wound healing, fistulas, osteonecrosis, proteinuria Diarrhoea, fatigue, hand-foot syndrome

Multiple myeloma, mantle cell lymphoma Multiple myeloma, second line

Therapy of Selected Cancers zz

Toxicity Hypertension, hand-foot syndrome thrombosis, perforation Fatigue, diarrhea, neutroppanias

CHF, thrombocytopaenia, tumour lysis

zz zz

zz

zz

Or 5 FU and Leucovorin for 6 months. FU, irinotecan, capecitabine, and oxaliplatin have been used to treat the metastatic colorectal cancer. Addition of irinotecan to FU/LV regimen prolongs survival rate. Three more new monoclonal antibodies have been approved for the treatment of metastatic colonic cancer. Bevacizumab targets vascular endothelial growth factor (VEGF); cetuximab and panitumumab target epidermal growth factor (EGFR). Liver resection if the metastasis is confined to liver in selected cases.

Rectal Cancer • Recurs locally after surgery • Postoperative radiation and 5FU are recommended.

Anal Cancer zz

zz

Chemotherapy and radiation offer high cure rates than surgical resection This modality preserves anal sphincter and faecal continence.

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906

Manual of Practical Medicine

Breast Cancer Tylectomy—lumpectomy and axillary lymph node dis­section zz As effective as modified radical mastectomy zz Adjuvant chemotherapy—for patients with tumour size more than 1 cm or axillary node involvement or oestrogen receptor (ER) negative cancer or has over expression of human epidermal growth factor receptor-2 (HER-2) especially in premenopausal women. zz ER positive breast cancers—tamoxifen 20 mg/day for 5 years. Tamoxifen is useful only in premenopausal women. In postmenopausal women, the aromatase inhibitors anastrozole, letrozole, and exemestane have replaced tamoxifen for adjuvant hormone therapy. zz Chemotherapy should be considered if there is no response to hormonal treatment. zz In her-2-overexpressing cancers, addition of tras­ tuzumab to first line chemotherapy improved survival rate. zz In women with more than one osteolytic metastasis, the monthly administration of zoledronic acid 4 mg IV improves the quality of life and survival. zz In inflammatory or unresectable cancers (Peau d’ orange changes or erythema involving larger area), because of high likelihood of metastasis at the time of diagnosis, surgery and radiation to control local lesion may have added effect in addition to initial chemotherapy. zz Radiation therapy—selected women with axillary nodal involvement. zz

Prostate Cancer zz zz

zz

zz

Prostatectomy or radiation therapy Metastatic diseases—bilateral orchiectomy with LHRH analogues Hormone refractory disease—palliation by anthra­ cyclines, taxanes, vinblastine and estramustine Anaemia and bone pain—transfusions, growth factors and radiations.

Testicular Cancer zz zz

zz zz

Most curable malignancy with chemotherapy. Inguinal orchiectomy rather than trans-scrotal approach to prevent tumour spread to inguinal nodes. For seminoma—radiation therapy. For metastatic disease—cisplatin containing regimens.

Cancer Cervix zz zz

Carcinoma in situ—endocervical cone biopsy Microinvasive disease—abdominal hysterectomy.

Advanced local disease—Surgery followed by chemo­ therapy and radiation. Inoperable cancer—Disease controlled with radiation zz

Metastatic disease—Cisplatin-based chemotherapy A vaccine for HPV has recently been approved for young women to prevent and reduce the incidence of cervical carcinoma.

Ovarian Cancer Staging and surgical treatment include: Abdominal hysterectomy, zz Bilateral oophorectomy, zz Lymph node sampling, zz Omentectomy, zz Peritoneal cytology, zz Removal of all gross tumour. zz

Renal Cell Carcinoma zz zz zz

zz

Localized tumour—surgical resection Adjuvant therapy is not effective Metastatic disease—interferon α and interleukin 2 (response rate 15–30%) Sunitinib and sorefanib have been approved for the treatment of metastatic renal cancer. They are more active and better tolerated than previous drugs.

Bladder Cancer zz

zz zz

zz

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Unifocal tumour confined to mucosa—cystoscopy and trans­urethral resection—fulguration-repeated every 3 months Locally invasive cancer—surgical resection Multifocal mucosal disease—intravesical BCG or thiotepa or mitomycin C Metastatic/recurrent disease—cisplatin containing regimens.

Tumour localized to ovary—Surgery is curative. Extension of tumour—Surgery followed by chemotherapy.

Endometrial Cancer Surgery and radiation.

Head and Neck Cancer Early lesions—Surgery, radiation or both Chemotherapy added to radiation improves survival in nasopharyngeal cancers. Disseminated disease—Chemotherapy.

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907

Oncology

Lung Cancer

Cancer with Unknown Primary Sites

Most patients have unresectable disease.

This mode of presentation is common in 5% of cancer patients. Chemotherapeutic regimens do not improve survival. zz Cervical adenopathy —— Most likely to be squamous cell carcinoma —— Most likely to be from head and neck cancer —— Can be cured by radiation therapy. zz Midline mass —— Mediastinum/retroperitonium —— Extragonadal germ cell cancer —— Resection with cisplatin-based chemotherapy.

Small Cell Lung Cancer Limited disease Combination chemotherapy zz Response rate 90% (median survival 12–18 months; cure rate 5–15%). zz For patients with chemotherapy induced complete remission, prophylactic whole brain radiation therapy is advocated to prevent brain metastasis. zz

Extensive disease—Cure is rare (median survival is 6–9 months). Non-small Cell Lung Cancer Early lesion—Surgical resection Unresectable lesion—Potentially curable by radiotherapy Metastatic disease—Cisplatin-based combination chemotherapy. Erlotinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR), is advised for non-small cell lung cancer.

Malignant Melanoma Removal of tumour by excision biopsy. Deeper invasion—Resection followed by high dose interferon Systemic disease Dacarbazine zz Interferon α zz Interleukin 2. zz

Sarcomas Soft Tissue Sarcoma Early lesion—Surgical resection Local or regional recurrence—Adjuvant radiation therapy Metastatic disease zz Doxorubicin zz Ifosfamide zz Dacarbazine. Osteogenic Sarcoma Surgical resection followed by adjuvant chemotherapy

SYMPTOM CONTROL IN SEVERE CANCER Pain Scale for Grading Pain Grade 1 Pain relieved by occasional mild analgesics Grade 2 Pain requiring regular mild analgesics Grade 3 Pain requiring regular medium strength analgesics Grade 4 Pain requiring regular strong analgesics Grade 5 Pain not controlled by regular strong analgesics. Try to eliminate pain. Do not be miserly with analgesics. The analgesic ladder Nonopioid—NSAIDs (Aspirin, paracetamol, diclo­ fenac, etc.) zz Weak opioid—Codeine, Dihydrocodeine, Dextropro­poxyphene zz Strong opioid—Morphine, Diamorphine, Buprinorphine. Relieve the pain by moving up the ladder. Oral morphine 10 mg QID or TID or 30 mg rectal suppository. zz

Local Measures Injection of anesthetics—Spinal-epidural-intrathecalsubara­chnoid. zz Neurosurgical ablation—neurectomy, sympathec­ tomy, cordotomy, hypophysectomy. zz TENS—Transcutaneous electrical nerve stimu­lation. zz

Isolated pulmonary metastasis—Surgical resection.

Nausea and Vomiting

Kaposi’s Sarcoma

Causes

Local radiation therapy or vinblastine

zz

Palliation therapy—Liposomal Doxorubicin.

zz

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Radio/chemotherapy Uraemia/hypocalcaemia

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908

Manual of Practical Medicine zz zz zz zz zz

Raised intracranial pressure Intestinal obstruction Oesophageal reflux Delayed gastric emptying Gastric irritation.

Antiemetics zz zz zz zz zz

Ondansetron 4–8 mg TID PO/IV Haloperidol 1–20 mg PO Cyclizine 50–100 mg PO Metoclopramide 10–20 mg QID or TID PO Cisapride 10–20 mg QID or TID PO Stop NSAIDs and give H2 blockers.

Pruritus Causes zz zz zz zz

Drug reaction Cholestatic jaundice Renal failure Reticular system malignancy.

Constipation Causes zz zz zz

Management zz zz zz

Extravasation Extravasation of chemotherapeutic agents may occur from venous infusion resulting in erythema, ulceration, pain due to severe local tissue injury.

Management zz

Management

Hiccup zz zz zz

zz

Stimulate pharyngeal nerve—cold drinks Reduce gastric distention—metoclopramide Elevate PaCO2—hold breath, re-breathe into paper bag Haloperidol.

Breathlessness Causes zz

zz zz zz zz

Malignant pericardial effusion/pleural effusion —— Aspiration of fluid and intracavitary instillation of Bleomycin. Pulmonary infection—appropriate antibiotics Mass lesion—external beam radiotherapy Cardiac failure—treatment of failure Consider supplementary oxygen/morphine.

Lactulose Senna Bisacodyl.

Complications of Therapy

zz

Liquid paraffin for external use and antihistamine.

Reduced fluid and food intake Lack of mobility Opioid analgesics.

zz

zz zz

Stop the infusion Aspirate 5 mL of blood from the venous line to remove any residual drug Instillation of appropriate agent to neutralize the chemical reaction Local hot or cold compress Skin grafting if needed.

Myelosuppression and Risk of Infection Peak incidence of myelosuppression—7 to 14 days after chemotherapy Neutropaenia zz

zz

Greater risk of infection when neutrophil count is 10 mg/dL S. creatinine >10 mg/dL S. phosphate >10 mg/dL Increasing symptomatic hypocalcaemia.

Human Antibody Infusion Reactions Infusion of rituximab: Adverse reactions: Headache, fever, chills, nausea Bronchospasm and hypotension in 1% of cases Stop the infusion and restart with slow rate.

Interstitial Pneumonitis

Haemolytic Uremic Syndrome

Stop the implicated agents and institute glucocorticoids.

Most common causative agent is mitomycin Other agents—cisplatin, bleomycin, gemcitabine HUS manifests 4–8 weeks after chemotherapy HUS is characterised by microangiopathic haemo­lytic anaemia, thrombocytopaenia and renal failure.

Haemorrhagic Cystitis This complication is common with cyclophosphamide/ Ifosfamide.

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910

Manual of Practical Medicine Recommendations for Antiemetic Therapy Drugs

Dose

Route

Interval

5–10 mg

PO or IV

4–6th hourly

Phenothiazines Prochlorperazine Prochlorperazine

25 mg

Per rectum

4–6th hourly

Chlorpromazine

10 mg

PO

4–6th hourly

Trimethobenzamide

100 mg

PO or IM

4–6th hourly

Serotonin receptor antagonists Granisetron

1–2 mg

IV or PO

30 minutes before

Ondansetron

8–32 mg

IV

chemotherapy

Dolasetron

100 mg

IV or PO

Butyrophenone Droperidol

1–5 mg

IV

4–6th hourly

Metoclopramide

2–3 mg/kg

IV –q 2h × 3 doses

Before chemotherapy

50 mg

PO or IV

4–6th hourly

1–2 mg

PO or IV

tid or qid

10–30 mg

IV

Before chemotherapy

Antihistamine Diphenhydramine Anxiolytic Lorazepam Glucocorticoid Dexamethasone

Alopecia

Second Malignancy

This complication is caused by doxorubicin and cyclo­phosphamide. Alopecia is reversible on cessation of therapy.

Only certain class of anticancer drugs cause this complication. Acute myelomonocytic leukaemia—5 years after use of Alkylating agents. Following radiation second solid tumour develop­ment occurs in the second decade.

Clinical Features zz zz zz zz zz

Fatigue Oliguria Purpura Hypertension Pulmonary oedema. Urine—hematuria, proteinuria, granular cast. Plasmapheresis and plasma exchange are indicated.

Altered Growth Stunted physical growth is seen in children treated with chemotherapy/radiotherapy. Intellectual impairment—there is conflicting evidence.

Impaired Fertility This complication is more variable—subfertile to loss of fertility. Cytotoxic drugs are potentially teratogenic—advise contraception.

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Psychological Effects Common manifestations—anxiety/depression Proper counseling and reassurance.

Late Effects of Cancer Therapy Surgical Procedure Procedure

Effect

Amputation

Functional loss

Lymph node dissection

Risk of lymphoedema

Ostomy

Psychosocial impact

Splenectomy

Risk of sepsis

Adhesions

Risk of obstruction

Bowel anastomoses

Malabsorption syndromes

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911

Oncology

Radiation Therapy

Ch-12.indd 911

Chemotherapy

Organ

Effect

Organ

Drug

Effect

Bone

Premature termination of growth, osteonecrosis

Bone

Glucocorticoids

Osteoporosis, avascular necrosis

Soft tissues

Atrophy, fibrosis

Brain

Brain

Neuropsychiatric deficits, cognitive dysfunction

Methotrexate, ara-C, others

Neuropsychiatric deficits, cognitive decline?

Thyroid

Hypothyroidism, Graves’ disease, cancer

Peripheral

Vincristine, platinum

Neuropathy, hearing loss nerves

Salivary glands

Dry mouth, caries, dysgeusia

Eyes

Glucocorticoids

Cataracts

Eyes

Cataracts

Heart

Anthracyclines

Cardiomyopathy

Heart

Pericarditis, myocarditis, coronary artery disease

Lung

Bleomycin

Pulmonary fibrosis

Lung

Pulmonary fibrosis

Methotrexate

Pulmonary hypersensitivity

Kidney

Decreased function, hypertension

Kidney

Platinum, others

Liver

Decreased function

Decreased function, hypomagnesaemia

Liver

Various

Altered function

Intestine

Malabsorption, stricture

Gonads

Gonads

Infertility, premature menopause

Alkylating agents, others

Infertility, premature menopause

Any

Secondary neoplasia

Bone marrow

Various

Aplasia, myelodysplasia, secondary leukaemia

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CHAPTER

13

Geriatric Medicine

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914

Manual of Practical Medicine One of the most striking changes in the demography of the world has been the increased proportion of elderly individuals in the population. The relevance of this to health and social services is that there is an exponential increase in disability, and mental and physical morbidity, in individuals over the age of 75 years.

AGEING Ageing can be described, from a physiologic stand­ point, as a progressive constriction of the homeostatic reserve of every organ system. This decline, referred to as homeostasis is evident by the third decade and is then gradually progressive. The rate and extent of this decline of each organ system of the body is influenced by genetic factors, environment, diet and personal habits (the rate of deterioration in organ function often can be reduced by factors such as regular exercise, or accelerated by bad habits such as cigarette smoking or heavy alcohol consumption). Therefore, with advancing age, there may be a moderate decline in organ function. This remains unchanged in some elderly individuals, whereas in others it is so severe that it leaves them seriously incapacitated. It should also be borne in mind that the effects of ageing are usually insufficient to interfere with the function of an organ under baseline conditions, but the changes may be sufficient enough to reduce the reserve capacity of the organ in presence of stress of a mild illness or unaccustomed exercise and precipitate a crisis. The practical value in defining the characteristics of normal ageing is that this provides a baseline against which the signs and symptoms of disease in elderly patients can be assessed. Multiple pathology is so common in old age that elderly individuals free from disease form a biological elite.

Postulated Mechanisms for Ageing 1. Ageing may be due to cumulative spontaneous somatic mutations. 2. Ageing may result from errors in protein synthesis. 3. Ageing may be a result of ongoing DNA rearrangements. 4. Ageing may be a result of damage by free radicals. An abrupt decline in any system or function is always due to disease and not due to “Normal Ageing”.

Some Physiological Effects of Ageing zz

Ch-13.indd 914

Skin and integuments: Changes within the connective tissue result in the skin losing its elasticity and

becoming wrinkled. The appearance is similar to that associated with dehydra­tion, so that the dehydration is easily missed in elderly patients. A decline in the number of sweat glands in the elderly results in difficulty in regulation of body temperature especially in warm weather and they are susceptible to heat stroke. There is diffuse loss of hair, and the hair also becomes finer. In some individuals there is depigmen­ tation of hair (grey hair). zz Musculoskeletal system: There is a decline in the number of anterior horn cells with ageing which results in muscle weakness and wasting. The process often is accentuated by the physical inactivity and may be minimised by taking regular physical exercise. zz Smell and taste sensation: There is a decline in taste sensation and the sense of smell with ageing, resulting in decreased appreciation of flavour of food. zz Joints: There is development of degenerative changes in the joints, especially the weight bearing joints like the knee joint, with ageing, resulting in osteoarthritis. Degeneration of the cervical and lumbar vertebrae and their intervertebral discs may lead to the develop­ ment of cervical spondylosis and lumbar spondylosis. zz Immune function: Ageing, poor nutrition and chronic ill health in many old people interact with each other to interfere with immune function. Results of this include an atten­uated inflam­matory response so that the local and systemic effects of infection are masked, leading to atypical presentation of infectious diseases. A reduced immune surveillance in the elderly predisposes them to the development of malignancy.

Characteristics of Disease in Old Age There are differences of emphasis in the approach to old people compared with young people, due to presence of certain characteristic features of disease in the elderly. zz Multiple aetiology and pathology: Several disease processes may combine to produce a symptom in an elderly individual (e.g. recurrent falls may be due to the presence of a combination of postural hypo­ tension, decreased righting reflexes, decreased visual acuity due to cataract and muscle weakness). This is in contrast to disease presentation in the young, whereby the same symptom may be due to any one of the above mentioned abnormalities. In the elderly, therefore, treating each aetiology of the problem alone may do little good to the patient and treating all may be of great benefit.

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915

Geriatric Medicine Signs and Symptoms of Age Related Physiological Changes and their Consequences and Disease States in the Elderly Organ/system

Age-related physiological change

Symptoms/signs caused by age-related physiological change

Symptoms/signs caused by disease

 1. General

a. Increased body fat

Increased volume of distribution of fat soluble drugs

Obesity

b. Decreased total body water

Decreased volume of distribution of water soluble drugs

Anorexia

a. Presbyopia

Decreased accommodation

b. Lens opacification

Increased susceptibility to glare

Decreased acuity of vision (cataract formation)

 3. Ears

Decreased high frequency acuity

Difficulty in discriminating words if background noise is present

Deafness (sensorineural)

 4. Endocrine

a. Impaired glucose tolerance

Stress hyperglycaemia

Diabetes mellitus

b. Decreased thyroxine clearance and/or production

Decreased T4 requirement in hypothyroidism

Thyroid dysfunction (hypothyroidism or hyperthyroidism)

d. Decreased vitamin D absorption and activation

Osteopenia

Osteoporosis; osteomalacia

 5. Respiratory system

Decreased lung elasticity and increased chest wall stiffness

Ventilation-perfusion mismatch and decreased PO2

Dyspnoea

 6. Cardiovascular system

a. Decreased arterial compliance and increased systolic blood pressure

Hypotensive response to volume depletion or loss of atrial contraction

Syncope

b. Decreased β adrenergic responsiveness

Decreased cardiac output

Heart failure

c. Decreased baroreceptor sensitivity and decreased SA node automaticity

Impaired blood pressure response to standing (postural hypotension)

Heart block

a. Decreased hepatic function

Delayed metabolism of drugs

Cirrhosis

b. Decreased gastric acidity

Decreased calcium absorption on empty stomach

Osteoporosis; vitamin B12 deficiency

c. Decreased colonic motility

Constipation

Faecal impaction (leading to urinary incontinence or spurious diarrhoea)

 8. Renal

Decreased GFR

Impaired excretion of some drugs

Increased serum creatinine

 9. Genitourinary system

a. Vaginal/urethral mucosal atrophy

Dyspareunia; asymptomatic bacteriuria

Symptomatic urinary tract infection

b. Prostate enlargement

Increased residual urine volume

Urinary incontinence; urinary retention

10. Nervous system

a. Decreased brain catecholamine synthesis

–

Depression

b. Decreased brain dopaminergic synthesis

Stiff gait

Parkinson’s disease

c. Decreased righting reflexes

Increased body swaying

Recurrent falls

d. Decreased stage 4 sleep

Early morning awakening

Sleep apnoea

e. Brain atrophy

Forgetfulness

Dementia; delirium

 2. Eyes

c. Decreased testosterone

 7. GIT

zz

Ch-13.indd 915

Non-specific presentation of disease: Some present­ ations of disease are common in old age, in particular the ‘geriatric giants’ namely urinary incontinence, acute confusion, immobility and falls. Diseases may also present atypically in the elderly.

zz

Many findings that are abnormal in young age may be relatively common in old people (bacteriuria, premature ventricular ectopics, isolated systolic hyper­ tension, low bone mineral density, impaired glucose tolerance and uninhibited bladder contract­ions).

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916

Manual of Practical Medicine zz zz zz zz

Rapid deterioration can occur if disease is untreated. Complications are common. More time is required for recovery. There is impaired metabolism and excretion of drugs. Doses of drugs may need lowering.

Atypical Presentation of Disease in Elderly The effect of age changes, impaired immunological function, poor nutrition, multiple pathology, sensory deficits, psychiatric disorders and intercurrent drug treatment interact to both modify and mask the typical symptoms and signs of disease in many elderly patients. Disorders Presenting with Atypical Features in Elderly Patients Disorders

Atypical presentation

Myocardial infarction

Confusion, weakness, fatigue, breathlessness and palpitations without chest pain. May also present with unexplained sweating, vomiting, postural hypotension or bowel urgency

Bronchopneumonia

Confusion and rapid respiration, no pyrexia and minimal chest signs

Appendicitis

Confusion, constipation or diarrhoea, no pyrexia and few localising signs

Peptic ulcer

Anaemia, haematemesis or melaena without previous symptoms of dyspepsia

Urinary tract infection

Confusion and urinary incontinence, no pyrexia or increased frequency or dysuria

Dehydration

No thirst, and skin changes indistinguishable from those of ageing

Hypothyroidism

Lethargy and general deterioration with no other characteristic symptoms and signs

Thyrotoxicosis

Apathy, weight loss and cardiac signs (atrial arrhythmias) without anxiety, excess sweating or heat intolerance

Diabetes mellitus

Asymptomatic until onset of complications, e.g. nephropathy, neuropathy or retinopathy

Brain tumour

Confusion, drowsiness and focal neurological signs without headache or papilloedema

Urinary Incontinence Confusion and immobility associated with acute ill­ness often result in urinary incontinence. This usually settles with resolution of the illness, but in a propor­tion of cases, the incontinence persists. A common neurological cause of chronic urinary incontinence is damage to the cerebral cortex with damage to normal bladder inhibition, so that the bladder has a small volume and increased tone, and empties frequently (uninhibited bladder). Disorders that are responsible for this are cerebrovascular disease, Alzheimer’s disease or Parkinson’s disease. Spinal cord damage due to multiple sclerosis, trau­ma or a tumour, though less common in the elderly, can cause bladder dysfunction. Damage to afferent parasympathetic fibres in disorders such as diabetic autonomic neuropathy gives rise to a large volume atonic bladder in which there is a continuous dribbling overflow incontinence. Local causes of urinary incontinence may be due to pressure on the bladder due to faecal impaction, or prostatic enlargement. Stress incontinence is often due to weakness of the pelvic floor muscles, especially in multiparous and postmenopausal women. In post-menopausal women, atrophic changes in the vagina may be accompanied by similar abnormalities in the Drugs that may Affect Continence Medications NSAIDs

Examples COX 2 inhibitors

Alcohol

Effects on continence Nocturnal diuresis due to fluid retention Frequency, urgency, polyuria, sedation, delirium

Sedatives/ Hypnotics Narcotic analgesics

Benzodiazepines

Excess sedation, delirium

Morphine derivatives

Giants of Geriatric Medicine

Anticholinergics

These refer to four of the most common causes of incapacity in elderly patients referred to a geriatric unit, namely acute confusion, urinary incontinence, immobility and falls.

Antipsychotics

Dicyclomine, antihistamine Haloperidol, thioridazine Amitriptyline Trihexyphenidyl All dihydropyridines Furosemide, bumetanide Enalapril, lisinopril

Retention, faecal impaction, delirium, excess sedation Retention—overflow

Acute Confusion Acute confusional state in an elderly patient usually is the result of organic disease, or a manifestation of drug toxicity (esp. sedatives, hypnotics, antiemetics, or anticholinergics).

Ch-13.indd 916

Antidepressants Antiparkinsonians Calcium channel blockers Loop-diuretics ACE inhibitors Vincristine

Retention, rigidity, sedation Retention—overflow Retention—overflow Nocturnal diuresis due to fluid retention Polyuria, urgency, frequency Drug induced cough causing stress incontinence Urinary retention

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917

Geriatric Medicine mucosa of the urethra and trigone due to lack of oestrogen resulting in urinary frequency and urge inconti­nence. Drugs such as diuretics may cause incontinence. Poor mobility and thereby a delay in reaching the lavatory may be the cause for incontinence. In some patients, urinary incontinence is a mani­ festation of anxiety, or an attention-seeking device.

Management • The mainstay of management of urinary incontinence is proper and adequate toilet training in which the patient is encouraged to develop the habit of regular emptying of the bladder. • Faecal impaction if present should be treated. • An oestrogen cream should be used where there is atrophic vaginitis. • If there is stress incontinence, exercises for the pelvic floor should be taught to the patient. • In men, prostatectomy may relieve overflow incontinence. • As a last resort, intractable urinary incontinence should be managed by devices such as catheters, urinals, incontinence pads or marsupial pants.

Immobility Age related changes in the neurological and mus­culo­­ skeletal system and a high prevalence of disorders such as stroke, Parkinson’s disease, osteo­arthritis and osteoporosis, interact to make poor mobility one of the most common problems to afflict elderly patients. Since there often is little reserve capacity in skeletal muscles, even a short duration of bed-rest may render the patient immobile. It is therefore essential that an active rehabilitation programme be instituted as soon as possible after an episode of acute illness in order to prevent development of prolonged incapacitation.

Falls There is an increased incidence of falls with advancing age. Falls in the elderly usually have a plethora of causes. 50% are due to tripping or an accident. About 10% are related to loss of consciousness or dizziness (due to vertebrobasilar insufficiency). For the rest there is no clear cause. Drug intake may be an important cause of falls (drugs causing postural hypotension, sedation or cardi­ac dysrhythmias). Alcohol consumption may also cause falls in the elderly. The consequences of falls in the elderly may be detrimental to the patient especially with develop­ment of fracture neck of femur or head injury resulting in subdural haematoma. Prevention of falls in the elderly is very important as even a single fall can shatter the patient’s confi­dence, even if no serious injury has been sustained. Physiotherapy, which includes learning techniques to get up from the bed or floor and moving about carefully in the house, may be of great benefit to the patient. Postural Hypotension Detection of presence of postural hypotension in the elderly is important as it is common in them and is also a common cause of falls and poor mobility. Typical times of occurrence of postural hypotension are after meals, on exertion, and on getting up sud­ denly from the lying posture, especially at night. This may also manifest transiently with intercurrent illnes­ses (e.g. viral fever). Postural hypotension may be due to venous insuf­ ficiency in the legs, autonomic neuropathy, drugs (diuretics, nitrates, antihypertensives, antidepres­sants, sedatives), or decreased baroreceptor response to pressure changes.

Risk Factors for Fall and Possible Rehabilitation Measures

Ch-13.indd 917

Risk factors

Medical intervention

Rehabilitation

Reduced visual acuity

Refraction, cataract surgery

Safety measures at home

Reduced hearing

Removal of wax, evaluation for hearing

Hearing aid if needed

Vestibular dysfunction

ENT/Neurological evaluation

Avoidance of drugs that affect the vestibular system

Dementia

Correct the treatable causes

Avoid sedation, home safety measures

Proprioceptive dysfunction

Correct vitamin B12 level, treat cervical spondylosis

Correct size footwear, walking aid

Postural hypotension

Screen the drugs consumed

Elevation of head end-bed

Sedatives

Use lowest effective dose

Slow and steady walk

Antihypertensives

Avoid postural hypotension

Check BP lying and standing

Musculoskeletal disorders

Neurological evaluation

Exercise and gait training

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918

Manual of Practical Medicine This can be managed by reducing the dose or stopping the causative drug. Patient may be taught the art of getting up slowly in stages from the lying posture. A trial of legcompression stockings may be of help. Fluid-retaining drugs such as fludrocortisone 0.1 mg per day orally may be helpful in those severely affected.

Principles of Management of Geriatric Problems zz zz

zz

Avoid prolonged bed-rest whenever possible. Patients should be positioned in the upright posture several times daily. Skin over pressure points should be inspected frequently.

Some Adverse Reactions of Drugs Noticed in Geriatric Patients Drugs

Side effects

1.

Sedatives and hypnotics

Confusional states, falls, incontinence

2.

Antiemetics and neuroleptics

Parkinsonian syndrome, confusional state, postural hypotension, tardive dyskinesia, drowsiness, susceptibility to hypothermia

3.

Diuretics

Dehydration, electrolyte imbalance, postural hypotension

4.

NSAIDs

Dyspepsia, upper GI bleed, oedema, cardiac failure

5.

Anticholinergics and antidepressants

Confusional states, urinary retention, constipation, dry mouth

Some Drugs to be Avoided/Used with Caution in Disorders in the Elderly Disorder

Drugs to be avoided/used with caution

1. Hypertension

Use vasodilators with caution as it can precipitate postural hypotension and stroke β blockers and calcium channel blockers to be used with caution in presence of conduction defects and incipient cardiac failure β blocker aggravates existing peripheral vascular insufficiency

2. CCF

Use diuretics with caution as it can cause dehydration and electrolyte imbalance

3. IHD

Use digoxin with care as digoxin toxicity may be precipitated especially when there is impaired renal excretion Sublingual nitroglycerin to be administered in the lying posture as it may precipitate postural hypotension and falls if administered in the sitting or standing posture

4. Mural thrombus

Oral anticoagulants (warfarin) to be used with caution as there may be increased activity due to reduced plasma binding of the drug Prolonged use of heparin may exacerbate pre-existing osteoporosis and produce pathological fractures

5. Bronchial asthma/COPD

Adrenaline must not be used as it can precipitate coronary vasospasm Theophylline to be used with caution as impaired hepatic oxidation/hydroxy­lation can increase plasma level of the drug to toxic levels β agonists (salbutamol) to be given in minimal optimal dose as it may precipi­tate tachycardia and IHD Prolonged administration of steroids to be avoided as it may result in exacer­bation of pre-existing osteoporosis and electrolyte imbalance (hypokalaemia)

6. Parkinson’s disease

Avoid anticholinergics as it can precipitate glaucoma, urinary retention and confusional states

7. Cerebrovascular accidents

Antioedema measures to be used with caution as it may precipitate dehydration and electrolyte imbalance

8. Diarrhoea

Fluid and electrolyte loss should be carefully monitored and their replacement must be meticulous. Hypovolaemia and haemoconcentration can result in stroke, peripheral vascular occlusion and gangrene

Mannitol may precipitate renal failure and LVF when used in patients with impaired renal function

Avoid use of antispasmodics or antimotility agents as they may produce paralytic ileus

Ch-13.indd 918

9. Constipation

Avoid prolonged use of laxatives as they may produce hypokalaemia

10. Hypothyroidism

Replacement therapy with L-thyroxine should be initiated with minimal optimal dose and then gradually increased over 2 to 3 weeks. Initial high dose replacement may precipitate IHD

11. Hyperthyroidism/senile tremors

Initiate propranolol therapy with caution as its serum level may be increased due to decreased first pass metabolism through the liver

12. Psychiatric disorders

Antipsychotic drugs must be used with caution as they may cause falls and confusional states

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919

Geriatric Medicine zz

zz

zz

zz

zz

Ch-13.indd 919

Drug therapy in the elderly should be employed only after non-pharmacologic means have been considered and tried. Once pharmacotherapy has been decided upon, the drug should be started with the minimal optimal dose and thereafter the dose may be increased gradually as required. The number of drugs administered should be as few as possible. The dosage schedule of the drugs administered should be such that maximal patient compliance is attained as decreased compliance due to memory deficit is common in geriatric patients. It must always be kept in mind, while prescribing drugs to geriatric patients that older people are more likely to have adverse drug reactions due to the following factors: —— Drug clearance is often markedly reduced due to decreased renal plasma flow and GFR and a reduced hepatic clearance (due to decrease in

——

——

activity of the drug metabolising microsomal enzymes and a decrease in blood flow to the liver). Volume of distribution of drug is affected due to decrease in total body water and increase in body fat (water soluble drugs become more concentrat­ed and fat soluble drugs have longer half-lives). Serum albumin levels decline with ageing and so there is decrease in protein binding of some drugs (e.g. phenytoin, warfarin) and thereby more of the free (active) drug is available.

Drugs Cleared by the Kidney which should be Closely Monitored in the Elderly 1. Antibiotics Gentamicin, streptomycin, kanamycin 2. β blocker Atenolol, sotalol 3. Cardiac glycoside Digoxin 4. Psychotropic drugs Lithium

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CHAPTER

14

Substance Abuse

Ch-14.indd 921

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922

Manual of Practical Medicine

ALCOHOL Alcoholic Equivalents Whisky 30 ml Wine 100 ml Beer 250 ml

Metabolism of Alcohol 1 Unit 1 Unit 1 Unit

1 unit = 10 gm

Safe weekly limits of alcohol For males 21 units/week For females 14 units/week

Risk Factors for Alcoholic Liver Disease Drinking Pattern The average intake of alcohol of male cirrhotics was 160 gm/day/8 years. For most individuals, the dangerous dose is more than 80 gm of alcohol/day. The duration of consumption is also important. The liver injury is unrelated to the type of beverage. Continuous alcohol drinking is more dangerous than inter­mittent consumption. Sex

Alcohol is metabolised by: a. Microsomal ethanol oxidising systems (MEOS) b. Alcohol dehydrogenase. The MEOS is inducible by alcohol and microsomal P450 increases after alcohol. Alcohol is metabolised by oxidation, converted to acetaldehydes by catabolising enzymes (ADH) and further converted to acetate by enzyme acetaldehyde dehydrogenase. Consumption of alcohol results in gain of empty calories (nutritionally valueless). 1 gm of alcohol = 7 kilo calories. Alcohol is excreted through the lungs and also by body secretions (urine and sweat).

Effect of Alcohol on Liver Mechanism of Liver Injury zz zz

Women develop higher blood ethanol values following a standard dose intake and it progresses from alcoholic hepatitis to cirrhosis even if they stop drinking. It is because the alcohol dehydrogenase, from the gastric mucosa contributes to alcohol metabolism. There is also a lower level of ADH.

Direct toxic effect of alcohol. Acetaldehyde —— Acetaldehyde binds with phospholipids, amino­ acid residues, and sulphhydryl groups and thus becomes reactive and toxic. It affects the plasma membranes by depolymerising proteins and altering surface antigens. —— Acetaldehyde binds to tubulin and impairs the microtubules of the cytoskeleton.

Genetics zz

zz

zz

The patient with HLA-B8, is more susceptible to alcoholic hepatitis. The heterozygotes for the ADH gene 2 have impaired metabolism of acetaldehyde. Hepatitis B and C act as a co-factor for alcoholic liver disease.

Nutrition zz

zz

zz

Liver function does not improve with alcohol abstinence especially when dietary protein remains low. Alcohol increases the daily requirement of choline, folic acid and other nutrients. Protein deficiency promotes the toxic effect of alcohol.

Other Mechanisms of Liver Injury by Alcohol Include zz zz zz zz zz zz zz zz

Morphological Change zz

Gastric First-pass Metabolism The majority of oral ethanol is rapidly absorbed by passive diffusion from the stomach and the duo­denum. But it has recently been suggested that after food, significant first-pass metabolism of ethanol occurs in the stomach mediated by gastric ADH.

Ch-14.indd 922

Changes in the intracellular redox potential Mitochondrial swelling Liver cell water and protein retention Hypermetabolic state Increased liver fat Immunological liver damage Fibrosis Cytokine mediated injury.

zz

Fatty liver: Fatty liver is defined as the presence of more than 5 gm of fat/100 gm of liver tissue. The fat may be in the macrovesicular form (large droplet). In the more severely affected condi­tions, fatty change is diffuse (usually fat accumu­lates in zones 3 and 2). Alcoholic hepatitis —— Liver cell damage (typical ballooning degener­ation and areas of necrosis).

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923

Substance Abuse Predominant neutrophilic infiltration. Both pericellular (chicken wire appearance) and perivenular fibrosis. The prominent features of alcohol hepatitis is the Mallory body or Mallory hyaline (also seen in primary biliary cirrhosis, Wilson’s disease and drug intake-amiodarone). Cirrhosis: Cirrhosis in alcoholics is of micronodular type. The formation of the nodules is often slow, because of a presumed inhibitory effect of alcohol on hepatic regeneration. ——

——

——



zz

Clinical Syndromes Fatty Liver zz

zz

The patients are usually asymptomatic, the diag­nosis being made when an enlarged, smooth, firm liver is present. Nausea and vomiting with periumbilical, epigastric or right upper quadrant pain with jaundice are present in severe fatty liver.

Lab Features zz zz

zz

zz

zz

zz

Hyperbilirubinaemia AST/ALT >2 in 80% of the cases (high ratio is due to pyridoxine deficiency). Alkaline phosphatase is elevated (less than 300 IU/dl) in the absence of cholestasis. GGT/Alkaline phosphatase ratio is 5 or higher in 50% cases. Blood levels of GGT more than 30 U and carbo­ hydrate deficient transferrin more than 20 U are useful serological markers of heavy drinking (specificity and sensitivity >70%). These tests are also useful in monitoring abstinence. Other blood tests that can be useful in identifying individuals consuming 6 or more standard drinks/day include—increased MCV (>91) and serum uric acid (>7 mg/dl).

Acute Alcohol Hepatitis zz

zz

Ch-14.indd 923

The usual symptoms are anorexia, nausea, malaise, weak­ness, vague abdominal pain, icterus, weight loss, or fever. The physical signs are: —— Hepatomegaly (95%) —— Hepatic tenderness (50–60%) —— Signs of portal hyper­tension (40–70%) ——  Stigmata of chronic liver disease and alcoholism (30–60%) —— Jaundice (55%) —— Fever (50%)

 pper GI bleeding (30%) and evidence for hepatic U encephalopathy.

Lab Features zz zz zz

Hyperbilirubinaemia Transaminases (AST, ALT) are elevated Prothrombin time is prolonged.

Hepatic Cirrhosis zz

zz

It may be asymptomatic 10–20% of patients but commonly presents with complications and stig­mata of chronic liver disease. Hypogonadism and feminization are common in male cirrhotic patients.

Lab Features zz zz zz zz

zz

Transaminases are increased Hypoalbuminaemia Prothrombin time is prolonged The other features are leukopaenia, thrombocyto­ paenia and anaemia Liver biopsy and ultrasound are essential for diag­nosis.

Prognosis The levels of prothrombin time and bilirubin are used to determine the discriminant function, which esti­mates prognosis in alcoholic hepatitis. Discriminant Function = 4.6 × Increased PT (sec) + Serum Bilirubin (mg) A value of >32 is bad.

Treatment The pathogenic mechanisms in alcoholic hepatitis involve cytokine release—TNF and the perpetuation of injury by immunological processes. Therefore, patients with severe alcoholic hepatitis defined as discrimination factor >32 can be tried with steroids—Prednisone 40 mg/ day (immunosuppressive effect) for four weeks and then taper or pentoxifylline. zz Abstinence from alcohol (total and immediate). zz Dietary supplementation (proteins and vitamins and electrolytes). zz Avoid precipitating factors (infection, bleeding). zz Treatment of withdrawal syndrome. zz Treatment of complications (ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepa­tic encephalo­pathy, upper GI bleeding). zz Hepatic transplantation is indicated in selected cases of acute alcoholic hepatitis and alcoholic cirrhosis.

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924

Manual of Practical Medicine

Alcohol and Central Nervous System (CNS)

2. 3. 4. 5.

Acute Intoxication Ethanol is a CNS depressant. It directly and indirectly interferes with gamma aminobutyric acid receptor function and predominantly affects frontal cortical control. The CNS changes occur at lower blood levels in the case of females and occasional alcoholics and higher levels in the case of chronic alcoholics (Fig. 14.1). CNS Symptoms and Levels of Ethanol in Blood 1. Euphoria (25–50 mg/dl)

In-coordination (50–100 mg/dl) Ataxia (100–200 mg/dl) Stupor (200–400 mg/dl) Coma (400–900 mg/dl).

Alcoholic Coma It is a serious disorder and occurs in 5% of hospital admission. The inhalation of the vomitus is frequently fatal due to anoxaemia from acute distress (Mendel­son’s syndrome).

Withdrawal Syndrome This syndrome is present in chronic alcoholism (regular basis for 5–10 years) with evidence of depen­dence.

Fig. 14.1  Ill-effects of alcohol

Ch-14.indd 924

04-Jan-18 2:22:22 PM

925

Substance Abuse The features are anxiousness, tremulousness and irrita­bility, shakes or jitters, nausea, vomiting and more specifically nightmares, night terrors or black­outs. The syndrome occurs after a period of abstinence (12–36 hours). It also causes alcohol withdrawal fits (rum fits). These fits do not produce EEG chan­ges, and are treated with chlordiazepoxide and carbamazepine. The conventional anticonvul­sants are less effective.

Central Pontine Myelinosis

Alcohol Dementia

It is due to predominant axonal neuropathy of the dying back type, affecting the somatic and autonomic nervous system. The clinical features are distal paraesthesia (in the feet and hands), weakness and wasting of the distal muscles (legs and arms) and loss of DTR. The ANS features are abnormal pupillary reaction, tachycardia and orthostatic hypotension.

It is due to excessive alcohol intake. The clinical feature is mild to diffuse global dementia due to atrophy of the cerebral cortex and enlargement of the ventricles. The other features are antisocial behav­iour, dysarthric speech, tremor, ataxic gait and peripheral neuropathy. It is not due to thiamine deficiency.

Treatment zz zz

Withdrawal of alcohol Multivitamin replacement.

Marchiafava-Bignami Syndrome It is described in Italian drinkers of crude red wine and other alcoholics. It presents as a subacute dementing illness, and later progresses rapidly to fits, rigidity, paralysis, coma and death. It is due to demyelination and axonal damage in the corpus callosum, cerebral white matter, optic chiasma and middle cerebellar peduncle.

Cerebrovascular Disease Consumption of large quantity of alcohol is the most common cause of stroke in the young. It also increases the risk of stroke in people of all ages. CVA is much more likely to occur after a binge of alcohol consump­tion. The increased risk of stroke is thought to be due to factors like increased viscosity of blood, coagulation defects and dysrhythmias. The possible conse­quences of high alcohol consumption are intracerebral haemor­rhage, cerebral infarction, or subarachnoid haemor­rhage. Alcoholics are also prone to develop subdural haema­toma as a consequence to head injury while in an intoxicated state.

Alcoholic Cerebellar Degeneration It is due to degeneration of cerebellar cortex (Purkinje cells) and superior and anterior part of the vermis. The clinical features are ataxia, progressive unsteadiness of gait with more involvement of the lower limbs than the upper limbs. There is no speech disturbance or nystagmus.

Ch-14.indd 925

It is a rare disorder occurring in alcoholics and a number of other disorders (liver, renal, metabolic dis­ orders). It is characterised by rapid onset of flaccid or spastic quadriplegia with involvement of bulbar muscles (dysarthria, dysphagia).

Peripheral Neuropathy

Saturday Night Palsy This is a condition whereby there is compression trauma to the radial nerve in the radial groove leading to wrist and finger drop. This is a consequence of an alcoholic binge over the weekend (Saturday) and abnor­mal posturing of the arm during the stuporous state of alcohol intoxication. This palsy usually recovers within 8–12 weeks with conservative manage­ment.

Alcoholic Myopathy It is characterised by severe muscle pain and tender­ness, myo­globinuria and renal damage with hyper­kalaemia. It is due to direct effect on muscle.

Tobacco Alcohol Amblyopia It is an uncommon complication of alcoholics. It is characterised by sudden or subacute bilateral visual failure with bilateral centrocaecal scotomas.

Nutritional Deficiency Syndrome Wernicke-Korsakoff’s Syndrome (Confabulation Psychosis) It is characterised by a triad of ophthalmoplegia (nystag­ mus and impaired ocular abduction), cerebel­lar ataxia, and confusional state. The other clinical features are lethargy, inattentiveness, disorientation (to place, person, and time) and loss of recent memory and altered consciousness. The gaps in memory are filled in by imaginary and often graphic accounts of events (confabulation).

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926

Manual of Practical Medicine It is due to inadequate intake of thiamine. The pathological changes are hyperaemia with multiple small haemorrhages in the upper brainstem, hypo­thalamus, thalamus adjacent to third ventricle and the mamillary bodies.

zz

zz

It also produces haemorrhagic lesions of the duodenal villi. The clinical features are diarrhoea (secondary to increased small bowel motility) and electrolyte imbalance.

Pellagra

Haematology

It is characterised by diarrhoea, dementia and derma­titis.

It manifests as a reversible acute and chronic disorder of blood cells. zz RBCs : Macrocytic anaemia, hypersegmented neutrophils, reticulocytopenia and hyperplastic bone marrow. zz WBCs: Decreased granulocyte mobility and adherence with hypersegmentation. It impairs the delayed hypersensitivity response to newer antigens. It produces toxic granulocytosis. zz Platelets: Mild thrombocytopenia, hypersplenism (cirrhosis), decrease in platelet aggregation and inhibition of release of thromboxane can occur.

Pregnancy and Alcohol Foetal Alcohol Syndrome Maternal alcohol consumption in the first four weeks of conception is teratogenic and it manifests as craniofacial abnormalities (micro-ophthalmia, elongated mid-face, longer upper lip with poorly developed philtrum) and CNS abnormalities in the foetus (intellectual impairment and developmental delay). Alcohol consumption in the later stage of pregnancy results in intellectual deficit, auditory and visual deficits, and hyperkinetic syndromes in the offspring. Other defects noted are VSD or ASD, aberrant palmar crease and limitation of joint movement. It is due to acetaldehyde formation in the placenta. The predisposing factors are PEM, vitamin deficiency and zinc deficiency and synergism with heavy tobacco usage.

Gastrointestinal Oesophagus zz zz

Oesophagitis Mallory-Weiss syndrome: It is characterised by longi­ tudinal tear in the mucosa at gastro-­oesophageal junction in chronic heavy drinkers during violent vomiting.

Stomach zz zz zz

Gastritis Peptic ulcer The clinical features are epigastric pain, nausea, and vomiting.

Pancreas zz zz zz zz

Acute pancreatitis Chronic pancreatitis Pseudopancreatic cyst Pancreatic carcinoma.

Small Bowel zz

Ch-14.indd 926

It interferes with absorption of B-vitamins and nutrients.

Cardiovascular System It reduces the myocardial contractility and causes peripheral vasodilatation. One or two drinks/day over long periods may increase HDL cholesterol. But three or more drinks/day result in dose dependent increase in BP (it returns to normal within a week of abstinence). Chronic heavy drinking manifests as cardio­ myopathy (unexplained arrhythmia in the presence of LV impairment) and mural thrombi in LA and LV.

Holiday Heart Syndrome The development of atrial or ventricular arrhythmias occurs after a binge in individuals showing no other evidence of heart disease.

Respiratory System Alcohol consumption may exacerbate bronchial asthma (particularly by red wine).

Genitourinary System Modest alcohol dose (blood alcohol level is 100 mg/dl or even less) intake manifests as increased sexual drive, decrease in erectile capacity and testicular atrophy, shrinkage of the seminiferous tubules and loss of sperms. In women, it manifests as amenorrhoea, (due to decrease in ovarian size and absence of corpora lutea) and abortion.

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927

Substance Abuse Acute urinary retention may occur after a bout of heavy alcohol consumption.

zz

Bone Alcohol intake manifests as fracture (due to alteration of calcium metabolism) and osteonecrosis of femoral head.

Endocrine zz

zz

zz

zz

It manifests as hypoglycaemia and hyperglycaemia (in heavy alcohol drinking). Reversible decrease in serum thyroxine (T4 and T3).

Skin zz zz zz zz

Psoriasis Discoid eczema Rosacea Low-grade bacterial and fungal skin infections.

Alcohol and Malignancy

zz

Psychological zz

Alcohol consumption predisposes to development of fol­lowing malignancies: zz Carcinoma of liver zz Carcinoma of oral cavity zz Carcinoma of pharynx zz Carcinoma of larynx zz Carcinoma of oesophagus zz Carcinoma of pancreas zz Carcinoma of breast.

zz

Alcohol and Lymphatic System

zz

There is lower risk of developing lymphoma in alcoholics. Alcohol consumption may cause pain at site of lymph node or extralymphatic involvement in patients with Hodgkin’s lymphoma.

Alcohol and Drug Interactions zz

zz

zz

zz

Ch-14.indd 927

Sedatives: The sedative effects of alcohol are increased by concurrent intake of sedatives, hypnotic, or opioid drugs. There is gross impairment of psychomotor function. Antihypertensive drugs (vasodilators): The vasodila­tor effect of ethanol is exaggerated with concurrent intake of vasodilator antihypertensive agents, leading to risk of postural hypotension. Aspirin and other NSAIDs: Incidence of gastric irritation and upper GI bleed is increased with concurrent intake of alcohol and NSAIDs. Insulin: There is an increased risk of developing severe hypoglycaemia in diabetic patient on insulin when there is an excessive intake of alcohol.

Monoamine oxidase inhibitors: Some alcoholic drinks contain tyramine and so there may be a risk of developing severe hypertension in patients taking MAO inhibitors and consuming alcohol. Oral contraceptives: Women taking oral contra­ceptives eliminate alcohol slowly and so the effect of alcohol is prolonged. Metronidazole, chloral hydrate and disulfiram: These drugs inhibit aldehyde dehydrogenase activity and lead to accumulation of acetaldehyde. When alcohol is also consumed along with any one of these drugs, the level of acetaldehyde rises markedly leading to facial flushing, tachycardia, hypotension, dyspnoea, nausea and vomiting. Warfarin: Acute alcohol intoxication potentiates the hypoprothrombinaemic effect of warfarin lead­ing to bleeding tendencies.

zz zz zz

Anxiety Depression Personality change Misuse of other drugs Cognitive impairment.

Social zz zz zz

zz

Family problems, marital discord Financial problems Repeated road traffic accidents, driving offences Employment (e.g. absenteeism, especially on Mon­day, poor performance) Sexual abuse.

Alcoholic Coma zz

zz

zz

zz

zz

zz

At levels >400 mg/dl—respiratory depression and coma. Insert endotracheal tube before gastric lavage (3 mm from midline Increase in vault density—Paget’s disease, fluorosis, diffuse increase in thickness-acromegaly, thalassaemia Localised increase in thickness—Paget’s disease, meningioma, osteomyelitis, leukaemia, histiocytosis Luscent areas—multiple myeloma, Paget’s (osteoporosis circumscripta), malignancy, hyperpara­thy­roidism.

Intracranial Calcification zz

zz zz

Pineal body, gliomas, meningiomas, craniopharyn­giomas Tram-line calcification—Sturge-Weber syndrome Ring calcification—cerebral aneur ysm, TB, toxo­­plasmosis.

Sella Turcica zz zz zz zz

Normal size—AP diameter 11–16 mm and depth 8–12 mm Enlargement—pituitary adenoma Erosion of clinoids—raised ICT Erosion of lamina dura of dorsum sellae—tumour or aneurysm.

Air Sinuses zz zz zz

Thickened mucosa—chronic sinusitis Enlarged sinuses—acromegaly Fluid level—after trauma (maxillary sinus-infraorbital fracture, sphenoid sinus-fracture base of the skull).

X-ray Hands Soft Tissues zz

zz

zz

Ch-15.indd 940

Generalised increase in thickness—spade like hands in acromegaly, sausage digit in psoriatic arthropathy Soft tissue calcification—CREST—scleroderma, dermatomyositis Localised thickness—gout, pericapsular inflamma­ tion, soft tissue tophus in gout, rheumatoid nodules, Bouchard and Heberden nodes in osteoarthritis.

Fig. 15.12  Renal osteodystrophy

Joints Symmetrical peripheral small joints except DIP— rheumatoid arthritis zz Pitting of nails with DIP and skin lesions—psoriasis zz Osteoarthritis—DIP (Heberden’s nodes)/PIP (Bouchard’s nodes) with osteoporosis. zz

Deformities zz

zz

zz

Ulnar deviation and subluxation—rheumatoid arthritis—Swan neck, boutonniere deformity Look for syndactyly or polydactyly—pulmonary stenosis/ASD/Laurence-Moon-Biedl syndrome Short metacarpals—pseudo-hypoparathyroidism (Knuckle-Knuckle-Dimple-Dimple Syndrome), pseudopseudo hypoparathyroidism Turner’s syndrome.

Erosion of Terminal Phalangeal Tufts (Fig. 15.12) Seen in sarcoid, hyperparathyroidism, scleroderma with ‘pseudoclubbing’ and psoriasis. Coarse Trabeculations Chronic haemolytic anaemia, Paget’s disease, Lipidoses— Gaucher’s syndrome.

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941

Imaging Modalities in Internal Medicine Middle Phalanx Subperiosteal erosion along the radial border is an early sign of hyperparathyroidism.

CONTRAST STUDIES They are performed either with an IV contrast or with an oral contrast such as barium or gastrograffin. IV contrast should be used with caution in renal failure patients and ensure good hydration and diuresis (IV fluids and Mannitol). IV contrast can result in anaphylaxis, bronchospasm, and pulmonary oedema. The newer non-ionic contrast agents are safer. GI studies with contrast: Barium swallow, barium meal, small bowel follow through, and colonic enema. Double contrast technique with air and barium is very useful to demonstrate surface mucosal pattern. The lesions are more well seen by distending the gut wall—tumour, diverticula, polyps, ulcers and fistula (Fig. 15.13). Cholangiography: It can be performed in many ways. Oral cholecystography: Give oral contrast 12 to 24 hours prior to the study. Failure to visualise the gallbladder—acute cholecystitis, peritonitis, pancreatitis and gallstone disease. This test is not useful when serum bilirubin is elevated.

Endoscopic retrograde cholangiopancreatography (ERCP): A catheter is passed with the help of endoscope through the ampulla into the common bile duct (CBD) and X-rays are taken after injecting the contrast medium. It demonstrates the lesion in the biliary tree and the pancreatic ducts. Antibiotic prophylaxis with ciprofloxacin 750 mg PO two hours prior to the procedure is advisable. Therapeutic Manoeuvres zz zz zz

Sphincterotomy with CBD stone removal Dilatation of benign biliary strictures Palliative stents for bile duct obstruction in malignancy.

Complications zz zz zz zz

Ascending cholangitis Pancreatitis Perforation Haemorrhage.

Intravenous Urography Pyelography (IVU or IVP) A good preparation is essential for obtaining detailed clinical information after IVP (Fig. 15.14). Nephrogram

Percutaneous transhepatic cholangiography (PTC): This investigation is useful to demonstrate dilated ducts in obstructive jaundice. Bleeding tendency, cholangitis, ascites, and allergy are contraindications for this test.

(The image of kidneys as a result of contrast diffusing through them in early stage of contrast excretion) zz Absent: Non-functioning kidney (infarction, severe GN) zz Delayed: Renal artery stenosis zz Intense: In obstruction and glomerulonephritis zz Prolonged: In obstruction, chronic GN, renal vein thrombosis, and ATN

Fig. 15.13  Achalasia cardia

Fig. 15.14  Intravenous pyelogram

Intravenous cholecystography: It is useful in suspected choledocholithiasis and is seldom indicated.

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942

Manual of Practical Medicine zz zz zz

Non-visualised kidney: Renal agenesis Nephrectomy: Surgical removal along with 12th rib Non-functioning kidney: Obscured by bowel gas or perinephric abscess.

Small Kidney ( 40 mm of CSF/ H2O (negative Queckenstedt’s test).

Ch-16.indd 960

zz

Diagnostic (cytology, culture of fluid) Therapeutic (for relief of cardiac tamponade).

Needle A pleural aspiration needle is used.

Procedure zz zz

zz

zz

This is done under ECG and ECHO monitoring The procedure is carried out under strict aseptic precau­tions If the patient is anxious, 10 mg of IV diazepam may be used Different sites can be chosen to perform the proce­­dure.

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961

Procedures

Xiphisternal or Epigastric Route zz zz

zz

zz

zz

zz

zz

It is the safest and recommended route. The patient is made to recline comfortably with a back rest at an angle of 45°. The skin and deep tissues are infiltrated with 10 ml of 2% lignocaine solution. The needle is pushed in posteriorly at an angle of 45° to the skin in the direction of the left shoul­der. As the skin and subcutaneous tissue is pierced, the resistance due to diaphragm is felt. On piercing this, needle enters the pericardial cavity. Needle is then advanced slowly with suction applied to the syringe. Entry into the pericardial sac is confirmed when fluid is aspirated into the syringe. The needle is inserted further by about 5 to 7 cm and aspiration of fluid continued. If the needle is advanced too far, the myocardium will be felt knocking against the tip of the needle and will cause the needle to grate against the myocardium whereby a crunching sensation will be felt.

Apical Route zz

zz

The apical impulse is palpated. The needle is then inserted about 2 cm medial to the cardiac apex or if cardiac apex is not palpable, 2 cm medial to the lateral edge of cardiac dullness, in the 4th or 5th intercostal space. This route carries a greater risk of injury to the coronary arteries and contamination of the pleural space when the pericardial fluid is purulent.

Parasternal Route The needle is introduced in the fifth left intercostal space just to the left of the sternum and aimed straight backwards. The internal mammary artery lies about 2 cm lateral to the sternal edge and the needle must pass medial to this and laceration of the artery is the main complication of this route. In huge pericardial effusion, same procedure can be done to the right of sternum. One more posterior approach is also possible.

Complications zz zz zz zz zz zz zz zz

zz

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Vasovagal reaction (bradycardia, hypotension) Haemopericardium Arrhythmias Pneumopericardium Pyopericardium Contamination of pleural cavity Injury to coronary, internal mammary arteries Laceration of myocardium (ventricle), lung, oesophagus Peritonitis.

Aftercare zz zz zz zz

ECG monitoring is continued for further 2 hours Pulse and BP is recorded every 15 minutes for 2 hours A chest X-ray is taken if complications are sus­pected Complications are uncommon after 2 hours.

ASCITIC FLUID ASPIRATION (PARACENTESIS) Indications zz zz

Diagnostic Therapeutic (in cases of respiratory embarrassment due to tense ascites or removal of ascitic fluid when the liver is healthy).

Procedure zz zz zz

zz

An IV needle is used for the procedure The patient is made to lie supine on a firm surface The procedure is carried out under strict aseptic pre­cautions Any one of the various sites may be chosen for drainage of ascitic fluid.

The different sites that can be chosen are: 1. Midline (midway between pubic symphysis and umbilicus after emptying the urinary bladder). 2. Spinoumbilical line (junction of the medial 2/3rd and lateral 1/3rd of the spinoumbilical line). In case of minimal ascites, a sitting posture may be adopted. The IV needle used for aspiration is attached to a catheter which is attached to a collecting bag. One to two litres of fluid may be drained in one sitting over 4 hours. In case of liver disease, following each para­ centesis, salt free albumin is infused intravenously to replace the loss of protein in the ascitic fluid.

Complications zz zz zz zz zz

Vasovagal attack Hepatic encephalopathy Peritonitis Injury to the bowel or bladder Persistent leakage through puncture wounds in malignant ascites.

Dry Tap zz zz

Omental patch occluding the tip of the needle Perforation of a viscus.

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Manual of Practical Medicine

Aftercare

Procedure (Fig. 16.3)

Patient should be monitored for 24 to 48 hours after aspiration to detect development of complications.

The procedure can be done at any one of the following sites: 1. Sternal body or manubrium 2. Posterior iliac crest 3. Tibia (medial aspect just below the tibial tubercle) 4. Spinous process of vertebra 5. Site of bone infiltration or tumour.

BONE MARROW ASPIRATION Indications zz

zz zz zz zz zz zz

Unexplained anaemias, granulocytopenia, thrombo­­cyto­penia Aplastic anaemia Leukaemias Kala-azar Malaria Partially treated enteric fever (bone marrow cul­ture) Bone tumours and myeloma.

zz

zz

zz

zz

zz

Contraindication Bleeding disorder.

Needles (Fig. 16.2) There are three types of needles that can be used. They have a stylet and the length of the needle to be inserted into the marrow cavity can be adjusted with the use of a guard. 1. Salah’s needle with side screw 2. Klima needle with central screw (will not slip) 3. Bone marrow trephine needle (Jamshidi-Swain or Islam needle for bone marrow biopsy).

Fig. 16.2  Bone marrow aspiration needles

Ch-16.indd 962

zz

The posterior iliac crest and tibia are the preferred sites in children. The procedure is carried out under strict aseptic precautions. Local anaesthesia (5 ml of 2% lignocaine) is infil­trated from the skin up to the periosteum. The bone marrow needle is then pushed in through the skin and subcutaneous tissues up to the peri­osteum. The guard of the needle is adjusted so that only a further 5 mm can be advanced into the bone marrow. The needle is held at right angles to the bone and with firm pressure and a clockwise counter­clock­wise action pushed through the outer cortex until a sensation of decreased resistance is felt when the marrow cavity is entered. The stylet is removed, a 10 or 20 ml syringe is attached to the needle, and with sharp suction up to 0.5 ml of marrow is aspi­rated into the syringe to avoid mixing with peri­pheral blood. While aspirating, patient experiences an excruciating suction pain indicating that the needle is in the marrow. If no marrow is aspirated the needle is rotated or the stylet replaced and the needle cautiously advanced or retracted. If marrow is still unobtainable, a differ­ent site is chosen.

Fig. 16.3  Bone marrow aspiration

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963

Procedures zz

zz

zz

zz

Slides must be well cleaned and readily available for making immediate smears. Bone marrow particles can be seen in the smear of the aspirate. A drop of aspirate is placed on the slides from which blood can be removed using a syringe with fine needle. The remaining material can be smeared so as to get a pure bone marrow smear. Alternatively the material can be placed in a watch glass with EDTA from which blood can be removed using Pasteur’s pipette and the remaining bone marrow particles can be smeared. Good smears are obtained by placing a drop of aspirate 1 cm from the end of a clean slide. By using a second smooth slide, a 3 to 5 cm film is made from the particles. The particles should leave a trail of cells. A minimum of 10 slides should be made and stained immediately.

LIVER BIOPSY Indications zz zz

zz zz zz zz zz zz

zz

Dry Tap zz zz zz zz

Faulty technique Hypoplasia/aplasia of bone marrow Tightly packed marrow Myelofibrosis.

Complications of Sternal Puncture zz

zz zz zz

Injury to the underlying large vessel or heart in the sternal approach leading to fatal haemorrhage. Pericardial tamponade Mediastinitis Pneumomediastinum.

Contraindications zz zz zz zz zz zz zz

zz zz

The posterior iliac crest is the preferred site for per­form­ing trephine biopsy. The patient is placed in the right or left lateral position with the back comfortably flexed, and the medial expansion of the uppermost crest is chosen. The skin overlying the crest is incised with a scal­pel. The needle is then introduced with stylet in place with a boring motion (clockwise and counterclockwise) in the direction of anterior superior iliac spine until there is a decrease in resistance. Stylet is removed and the needle is further advanced till 2 to 3 cm of marrow is obtained. Marrow specimen is removed with the distal cutting edge of the needle. The instrument containing the specimen is withdrawn by rotation along its axis with quick full twists. Smear must be made immediately and stained with eosin and hema­toxylin after decalcification. A part of the biopsy material can be utilised for Leishman’s stain. In trephine biopsy, histology is well delineated and myelofibrosis can be confirmed.

Ch-16.indd 963

Bleeding disorder Known hepatocellular malignancy Unwilling or uncooperative patients Presence of tense ascites (may lead to continuous leak) Dilated biliary radicle (may lead to bile peritonitis) Vascular tumours Infected right pleural space or septic cholangitis.

Liver Biopsy Needles zz

TREPHINE BIOPSY

Unexplained hepatomegaly/hepatosplenomegaly Infiltrative disorders (sarcoid, malignancy, granu­ lo­­matous lesions, lymphomas, storage dis­orders like haemochroma­tosis and Wilson’s disease) Pyrexia of unknown origin Carcinoma (suspected hepatoma or metastasis) Cholestasis of uncertain origin Persistent abnormal liver function tests Cirrhosis Chronic hepatitis (chronic active hepatitis, chronic persistent hepatitis, chronic lobular hepatitis) Alcoholic liver disease.

Menghini’s needle (aspiration needle) vim Silverman’s or Klatskin needle (cutting needle) Trucut biopsy needle.

Procedure The patient should be adequately prepared before performing liver biopsy. Injection vitamin K one ampoule is given intramus­ cularly daily for 3 consecutive days before the procedure. Blood grouping and cross-matching of the patient’s blood must be done and a bottle of compatible blood should be kept in readiness at the time of procedure. Caution The procedure should not be performed when: Prothrombin time is prolonged >3 sec above the control zz Platelet count < 50,000/cmm zz Bleeding time, clotting time or partial thrombo­plastin time is prolonged. zz

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Menghini’s Needle zz

zz

zz

zz

zz zz

zz

zz

The tip of the needle is not bevelled. A separate track making needle is present. A small guard with a head and flattened stalk which fits in with the barrel of the base of the needle. Since it is flattened and not circular, it can allow free flow of blood and saline and not the biopsied material. The patient lies along the edge of the bed in the supine posture. The biopsy may be performed in the 8th or 9th intercostal space in the mid-axillary line, or one intercostal space below that of liver dullness obtained in full expiration in the mid-axillary line. The procedure is carried out under strict aseptic precautions. The procedure is performed under local anaesthesia. A track is made in the subcutaneous tissue up to the liver (not in the liver) with the track making needle. The patient is asked to hold his breath in expiration and the Menghini’s needle with the guard on and with a saline filled syringe is passed through the readymade track. Before entering into the liver, the unwanted tissue that would have entered the needle, should be syringed off by pushing saline. With suction on, the needle must be pushed into the liver and withdrawn immediately like a bonnet drill. Now the liver tissue is inside the biopsy needle and the same can be pushed into a bottle with formalin by injecting saline in the syringe. A cord-like liver tissue can be obtained if the liver is not cirrhotic. The success rate of the procedure using this needle is approximately 75%.

vim Silverman’s Needle This is a larger needle and has a stylet, barrel and biforked biopsy blade which is longer than the needle and which has to be rotated to 180° to get a good biopsy material. The advantage of this needle is that it has a success rate of approximately 95%. The disadvantage is that it is more traumatic.

Trucut Needle It has a trocar and cannula. The trocar is longer than the cannula. The skin is nicked with a scalpel blade and the biopsy needle is advanced slowly with the patient breathing quietly. The needle is advanced till it begins to swing with respiration. The needle is then slightly withdrawn until it stops swinging. The patient is then instructed to hold his breath in expiration and the needle is thrust for about 2 to

Ch-16.indd 964

3 cm into the liver. The inner trocar is advanced holding the outer cannula with the cutting sheath still. The outer cutting sheath is then advanced over the inner trocar to cut the liver in the biopsy notch. The needle (trocar and cannula) is then quickly withdrawn after completing the proce­dure.

Aftercare The patient is instructed to lie on the right side for four hours and to remain in bed for 24 hours. Pulse rate and blood pressure are recorded hourly.

Complications zz

zz

zz

zz zz zz

Shock is usually caused by rapid loss of blood from a large vessel or vascular tumour Severe pain may be caused by bleeding or leakage of bile. Pain may be referred to the shoulder tip Septicaemia may result from needling an infected bile duct or liver abscess Pneumothorax Biliary peritonitis (injury to gallbladder) Bacterial peritonitis (injury to hepatic flexure of colon).

KIDNEY BIOPSY Patients with renal glomerular disease may present with similar clinical features yet have conditions rang­ ing from trivial to life threatening. Their prognosis and treatment depend on the renal pathology, and histological examination of the kidney is often the only way to make the diagnosis. Needle biopsy provides a sample of about 20 to 30 of the 2,000,000 glomeruli and so is unhelpful and may give mislead­ing results in patchy conditions such as reflux nephropathy. It is most valuable in assessing and, in particular, indicating the prognosis of patients with diffuse glomerular disease.

Contraindications Laceration of the kidney may cause haemorrhage, which may lead to nephrectomy. The risk is small and biopsy should be done only if the other kidney is normal. A single kidney or major abnormality of the contra­ lateral kidney are contraindications, in the presence of any haemorrhagic tendency, including advanced uraemia. The platelet count should be over 1,00,000/ml and the prothrombin time must be normal. Biopsy should not be done on shrunken kidneys because they are difficult to locate, the histological findings

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965

Procedures are often non-specific, and the results are unlikely to provide information of any therapeutic relevance.

Procedure Before starting the procedure, grouping and crossmatching of the patient’s blood must be done and a bottle of compatible blood should be kept ready. The procedure should be explained to the patient, and patient should practice holding his breath in inspiration. Biopsy is unsafe if patient cannot cooper­ate. Informed consent may be obtained in writing. Renal biopsy is potentially hazardous. Premedication with intravenous diazepam makes the procedure less unpleasant for the patient; general anaesthesia is required only for infants and young children. The patient is placed in the prone position. Biopsy may be done under ultrasound guidance. The site of choice is the edge of the lower pole of the left kidney. This avoids major renal vessels and is likely to contain more cortex than medulla. The radiologist marks the surface anatomy on the skin and information of the depth of the kidney from the skin is given. The skin is prepared and the skin and sub­cutaneous tissues are anaesthetised. An exploring needle is then inserted into the lumbar muscles and then advanced 5 mm at a time until a definite swing with respiration show that the point is within the kidney. The patient is asked

to hold his breath in inspiration each time the needle is advanced. After locating the kidney the local anaesthetic is injected along the track formed, while withdrawing the needle. A 11.4 cm trucut needle is used for obtaining the biopsy specimen. A nick is made in the skin with the point of a scalpel blade and then the biopsy needle is advanced towards the kidney. The cannula of the biospy needle is closed over the obturator. The obturator is longer than the cannula and has a bevelled edge. After introduction of the biopsy needle, the appearance of a large arc of swing of the needle indicates that the kidney has been located. With the tip of the needle just within the kidney, the patient is asked to hold his breath in inspiration. The obturator is pushed in and the cannula is then pushed over the length of the obturator, to cut the specimen. The obturator handle is kept firmly fixed with one hand while the cannula is pushed in with the other hand. The obturator and the cannula are withdrawn after completing this procedure. A successful biopsy produces a strip of kidney up to 20 mm long. The specimen is divided into three portions. One portion is sent for light microscopy exam­­ination, the second portion for electron micro­scopy examination and the third for immuno­fluorescent microscopy.

Aftercare and Complications zz

Indications Clinical syndrome

Indications for biopsy

Asymptomatic proteinuria

Protein excretion more than 1 gm/24 hours Red blood cells in urine Impaired renal function

Haematuriamacroscopic and microscopic

Urography and cystoscopy do not show source of bleed

Acute nephritic syndrome

Persisting oliguria

Nephrotic syndrome

Adults: Unless cause is apparent from extrarenal manifestations Children: Only if haematuria also present, or if proteinuria persists after trial of corticosteroid

Acute renal failure

Ch-16.indd 965

zz

zz

zz

zz

The patient should remain in bed for 24 hours. Pulse and blood pressure are checked every hour for four hours and thereafter for every four hours. The most important complication of renal biopsy is haemorrhage, which may be perirenal, causing joint pain and sometimes a palpable mass as well as signs of blood loss. There may be persistent heavy haematuria and sometimes clot retention. Minor haematuria is common and usually settles quickly. Continuing haemorrhage should be treat­ed by blood transfusion.

SETTING UP A DRIP

No obvious precipitating cause

Indications

Obstruction of the renal tract excluded

zz

Chronic renal failure

Radiographically and ultrasonographically normal kidneys

zz

Renal allograft

To differentiate rejection from cyclosporine toxicity and to diagnose recurrence of original disease

zz

Replacement of fluids (blood products, colloids or electrolyte solutions) To provide a route for administering intravenous medication or nutrition Monitoring of central venous pressure.

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Manual of Practical Medicine

Precautions zz

zz

zz

zz

No absolute contraindications exist, but particular care is needed in some circumstances: In presence of incipient heart failure an extra circulating fluid load may result in severe pulmonary oedema. If a  blood transfusion or intravenous infusion is essential this problem may be alleviated by giving diuretics simultaneously. In presence of renal failure it is important that the fluid and electrolyte loads, as well as the amount of drugs given, do not exceed the excretory capacity of the kidney. In patients with impaired immune responses or damaged heart valve, a drip site is an important portal for the entry of potentially fatal infection. If small veins with inadequate blood flow are cannulated, inflammation may occur at the vene­ puncture site.

Procedure Choice of Vein The most convenient site for peripheral cannulation is the non-dominant forearm (left forearm in a right handed individual and vice versa). This permits comfortable mobility of the dominant arm and allows the dominant arm to carry out activities like writing, eating, etc. Veins of the elbow should be avoided if possible, as the cannula is difficult to fix firmly, and uncomfortable immobilisation of the joint is required. The dorsum of the hand is a convenient site. Veins near the ankle may be used in a restless patient as the leg is often easier to immobilise. Other sites of cannulation are the jugular, subclavian, or saphenous veins.

Venepuncture Clothing is removed from the limb and a tourniquet is applied to occlude venous return. A suitable super­ficial vein is selected and the area around the chosen site should be cleaned well with an alcohol swab. The needle is pierced through the skin parallel to the vein chosen to be cannulated, with the bevelled edge facing upwards. The vein is then pierced by moving the needle in the direction of the vein and continued for a distance in the lumen of the vein. The tourniquet is then released and the IV fluid set is connected and allowed to flow into the vein. The rate of flow of the fluid is controlled by use of an adjustable valve attached to the IV set.

Ch-16.indd 966

The fluid or blood is usually present in a collapsible plastic bag. If the fluid is present in a rigid bottle, an air inlet tube will be required to prevent the formation of a vacuum when fluid flows out of the bottle into the IV set. The site of cannulation is firmly fixed with adhesive plaster. A segment of the tube of the IV set close to the needle is folded upon itself into a loop and fixed so as to allow free movement of the limb cannulated.

Problems When no veins are visible or palpable, a ‘blind’ cannu­lation of the jugular or subclavian vein may be per­formed. Alternatively, a ‘cut down’ procedure may be employ­ed. A small incision is made at the elbow or ankle and, with a tourniquet on the limb, a vein is displayed by blunt dissection of subcutaneous tissue and is under direct vision. Appearance of inflammation at the site of cannu­lation is an indication for prompt removal of the cannula. The local infection will not clear or respond to treatment as long as the foreign material is present. Persistent infection may lead to bacteraemia. An unexplained fever in a patient with a drip is often due to inflammation at the venepuncture site.

ADMINISTRATION OF INTRAVENOUS CYTOTOXICS The administration and management of intravenous cytotoxic drugs is a specialist’s task, requiring extensive knowledge and practical experience about the pharma­ cology, toxicology, and effectiveness of these drugs.

Procedure Patient should be adequately informed about the pro­ cedure to be adopted and also of the side effects that may be expected as a result of cytotoxic drug adminis­tration. The needle is introduced into the vein as explained above. The patency of the vein and the needle is confirmed by injecting about 5 to 10 ml of isotonic saline and watching the vein carefully. A large vein, prefer­ably on the dorsum of the hand is selected. Cytotoxic drugs should never be injected into the veins of the leg. After injecting the drug, flushing with isotonic saline is done to prevent the drug from leaking from the puncture site.

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967

Procedures

Contraindications for Cytotoxic Therapy zz

zz

zz zz

Low RBC, WBC or platelet count. A fresh blood count should always be obtained before adminis­tering cytotoxic drugs. Dysfunction of an organ which may be worsened by the cytotoxics to be used or which is the organ of excretion for that drug. For instance, cisplatin, a renal toxic drug, should be avoided in renal failure. Known hypersensitivity to the cytotoxic drug. Presence of infection, whereby administration of the cytotoxic drug may be postponed.

Problems Extravasation Many cytotoxics are very vesicant and if they extra­vasate they may cause severe tissue damage. If, despite careful adminis­tration, extravasation does occur, the injection is stopped immediately and the following procedure is adopted. zz Withdraw any remaining drug by aspirating through the needle. zz Instillation of 50 mg hydrocortisone into the site of cannulation via the IV needle. zz Removal of the IV needle and instillation of a further 50 mg of hydrocortisone subcutaneously into the swollen area. zz Analgesics may be administered in the presence of severe pain.

Local Reactions Redness and irritation sometimes develop along the vein being injected as a local reaction to the drug, especially when small veins are used. This may be reduced by further dilution achieved, for example, by injecting the drug into a fast flowing infusion or injecting it more slowly. Intravenous hydro­cortisone may be used at the end of the procedure.

Pain on Administration Some drugs (especially dacarbazine, vinblastine, and mustine) cause muscular and venous pain on adminis­ tration. This pain is felt along the vein and not just at the site of the needle, and so is different from that caused by extravasation. Further dilution or injection into a fast running infusion often alleviates the problem.

Ch-16.indd 967

Complications zz

zz

zz

zz

Many cytotoxic drugs cause severe emesis. It is therefore mandatory to ensure a good antiemetic cover prior to administration of the cytotoxic drug. Cytotoxic therapy may culminate in bone marrow depres­sion causing infection and fever. Patients with a suspected potential infection should have an imme­d iate blood count performed. Sepsis in presence of neutropenia is an emergency and urgent measures should be adopted for its treatment. Patients may develop severe stomatitis and should be advised on proper oral hygiene. Metabolites of some cytotoxic drugs like ifosfa­ mide and cyclophosphamide may cause a chemical cystitis and patients should therefore be advised on adequate fluid intake.

PERCUTANEOUS CENTRAL VENOUS CANNULATION Central venous pressure is the resultant of venous blood volume, right ventricular function and venous tone. Rapid changes in blood volume, especially asso­ciated with impaired right heart function, is the most common reason for monitoring central venous pres­sure. Infusion of antibiotics, chemotherapeutic agents, and other substances irritant to veins and tissues are best administered through a line whose tip lies in a central vein. Drugs used in resuscitation of cardiac arrest should be given through a central line if one is available. This route is also widely used for long-term intra­venous alimentation. It is also used for insertion of a Swan-Ganz catheter to monitor the pulmonary artery and left atrial pres­sure and also for introduction of intracardiac pacing devices. Venepuncture should be avoided at any site in which there is sepsis. Apical emphysema or bullae contraindicate infra­clavi­ cular or supraclavicular approaches to the sub­clavian vein. A carotid artery aneurysm precludes using the internal jugular vein on the same side.

Procedure Strict aseptic precautions should be observed during the insertion of the cannula.

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Equipment One of the following equipment may be used. 1. Catheter through cannula: Cannula on the outside of a needle is placed in the vein and the needle is with­ drawn. A catheter is then inserted into the vein. When the catheter is in position the cannula is withdrawn. 2. Catheter over needle: The needle and the catheter are placed in a arm vein. The needle (which is attached to a wire) is withdrawn, and the catheter advanced into position. 3. Catheter over guide wire: A flexible guide wire is inserted into the vein through a needle. After removal of the needle the catheter is inserted over the wire, which guides it into the central vein.

Methods of Insertion Arm veins: A tourniquet is applied on the limb. If the patient is conscious the skin should be infiltrated with a local anaesthetic. The median (basilic) arm veins are the safest approach to the central venous system. The catheter to be introduced through the vein should have a mini­mum length of 600 mm. External jugular vein: The external jugular vein runs from the angle of the mandible to behind the middle of the clavicle and joins the subclavian vein. The patient is placed in a 20° head down position with the head turned to the opposite side. In this position the external jugular vein becomes prominent and can be cannulated. Internal jugular vein: The internal jugular veins run behind the sternomastoid close to the lateral border of the carotid artery. The vein may be cannulated with a low incidence of major complications by an approach well above the clavicle. The patient is placed in a 20° head down position with the head turned to the opposite side. The right side is preferred to avoid injury to the thoracic duct. The sternomastoid muscle, cricoid cartilage, and carotid artery are identified. With the other hand the carotid artery is palpated and protected at the level of the cricoid cartilage. The needle is attached to a saline filled syringe and inserted just lateral to the artery. The needle is directed towards the feet. Gentle aspiration is maintained as the needle is advanced. A flush of blood into the syringe signifies entry into the vein. The cannula is then introduced towards the central vein. Infraclavicular subclavian vein: The subclavian vein is particularly suitable for administering long term parenteral nutrition. It is widely patent even in states of circulatory collapse, so that subclavian venepuncture may pro­vide the only route for rapid infusion.

Ch-16.indd 968

Diameters of Needles or Cannulae and Lengths of Catheters Recommended for Each Route of Insertion Route of insertion

Outside diameter of needle or cannula

Minimum length of catheter (mm)

Arm vein

14 G

600

External jugular vein

16 or 14 G

200

Internal jugular vein

16 or 14 G

150

Subclavian vein

16 or 14 G

150

Complications Immediate

Immediate or late

Late

•  Arterial puncture

•  Air embolism

•  Myocardial perfo­­ra­ tion and tamponade

•  Cardiac arrhythmias

•  Catheter embolus

•  Hydrothorax

•  Injury to thoracic duct •  Pneumothorax

•  Infection

•  Injury to nerves

•  Venous thrombosis

Puncture and catheterisation of the subclavian vein is a blind procedure, and so may result in compli­cations, most common being pneumothorax. Subclavian vein lies in the angle formed by the medial one-third of the clavicle and the first rib, in which the subclavian vein courses over the first rib to enter the thoracic cavity. The patient rests supine, tilted 20° head down. Either side may be used although the right side is preferable. The patient’s head is turned to the opposite side. The midpoint of the clavicle and the suprasternal notch should be identified. The needle is attached to a saline filled syringe and inserted below the lower border of the midpoint of the clavicle. The needle tip is advanced close to the under­ surface of the clavicle, aiming at the suprasternal notch. While the needle is advanced, gentle suction should be maintained on the syringe, and a flush of blood indicates that the vein is entered. The cannula is then passed into the vein. A chest radiograph should always be taken after the procedure to check for pneumothorax.

Checking after Insertion of Cannula Blood should be aspirated to ensure that the catheter is in a vascular space before injecting fluid. If the line is connected to a bottle of fluid that is lowered below the patient, blood should flow freely under the influ­ence of gravity. On connecting to a column of fluid for measure­ments of central venous pressure the fluid column should show slow oscillations related to respiration and quicker oscillations related to the heart beats.

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969

Procedures A chest radiograph should be taken to confirm that the position of the tip is above the right atrium, prefer­ably not more than 2 cm below a line joining the lower borders of the clavicles.

Maintenance of Central Venous Cannulation Once satisfactorily placed, the catheter should be fixed carefully to prevent inadvertent withdrawal or move­ment further into the vein. Strict aseptic precautions should be maintained. The IV set should be changed daily. Injecting drugs into the venous catheter or taking blood samples through it should be avoided. Regular bacteriological monitoring of the venepuncture site should be carried out. If an infection occurs, the catheter should be removed immediately. It is important to maintain a continuous flow through the catheter to prevent reflux of blood and clotting. After making intermittent measurements of venous pressure, using a simple manometer filled with saline solution, the infusion should be turned on. In case of clot formation, it may be possible to clear the catheter by injecting 2 to 5 ml heparinised saline under pressure.

PASSING A NASOGASTRIC TUBE There are two main indications for passing a naso­gastric tube. One is to aspirate stomach contents, as in ‘acute abdomen’ and the other is to maintain nutrition of the patient. A large nasogastric tube (size 16 FG) may be used for aspiration and a smaller nasogastric tube (size 3 mm diameter) may be used for feeding.

Procedure The procedure is explained to the patient in order to obtain maximum cooperation from the patient. The patient may be seated in a reclining posture with the head bent slightly forwards. The nose is lubricated with lignocaine jelly via an appli­cator. The nasogastric tube is also lubricated with lignocaine jelly and passed along the floor of the nose. Resistance is felt as the tip reaches the nasopharynx. At this point the patient is asked to swallow his saliva or small feeds of water may be given. This helps to advance the tube into the oesophagus without resis­tance. Never force the passage of a nasogastric tube if persistent resistance is encountered.

Ch-16.indd 969

At 40 cm, in the adult, the gastro-oesophageal junc­tion is reached. The tube is passed beyond this junction. It is now essential for the confirmation of the presence of the tip of the tube in the stomach. This is done by aspirating fluid through the nasogastric tube and confirming its acidic nature by litmus paper test. If no aspirate is obtained, a radiograph to confirm the tip of the nasogastric tube may be taken. Insufflation of air with simultaneous auscultation over the epigastrium is an additional confirmatory sign. The tube outside is then closed with a stopper and anchored on the forehead with an adhesive tape.

Problems Choking usually indicates the tube has entered the trachea and should be withdrawn immediately. Difficulties in passing the tube may occur at any point along the route. a. Nose: If one nostril is narrowed by a deviation of the nasal septum, the other nostril is used to pass the tube. In the event of persistent difficulty in passing the tube, a topical vasoconstrictor (0.5% ephedrine) may be intro­duced into the nostril to facilitate passage of the tube. b. Oropharynx: Reflex gagging by the patient may direct the tube into the mouth. This problem may be tackled by: i. Withdrawing the tip of the tube into the naso­ pharynx and reintroducing it again into the oropharynx. ii. Cooling the tube in the refrigerator to stiffen it so that it is less likely to coil. iii. Observing the passage of the tube through the mouth with a depressor on the tongue and using a pair of long forceps to guide the tube down. c. Oesophagus: A stricture or pharyngeal pouch may prevent the tube from passing.

Aftercare and Complications zz

zz

zz

Most fine bore tubes can be left in place for several weeks, but they have been known to coil in the stomach and re-enter the oesophagus. The visible tube markings are checked regularly to detect insidious slipping out of the nasogastric tube. The main complications of the procedure arise from passage into the bronchial tree, or perforation of the pharynx or oesophagus. Perforation of the oesophagus is increased by the presence of oesophageal disease or cardiomegaly.

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Manual of Practical Medicine

URETHRAL CATHETERISATION Indications Temporary catheterisation is indicated as an emer­gency measure to relieve the pain of acute retention. This is most common in men with prostatic disease and bladder outflow obstruction, but it can also be due to clotting of blood in the bladder, urethral stricture, the failure of sphincter relaxation associated with post­operative pain, or in neurogenic bladder. A catheter also allows accurate measurement of urine output after major surgery. Catheterisation to assess hourly urine output is helpful in assessing the fluid loss in uncooperative or comatose patients with intravascular volume contraction. Catheterisation is also indicated in an unconscious or a conscious female with stroke who is bed bound. Prolonged catheterisation is best avoided but may be necessary in a few male patients with prostatic enlarge­ ment, who are unfit for prostatectomy. Some patients with neurological problems, such as multiple sclerosis, or spinal trauma, may require prolonged catheterisation.

Contraindications Catheterisation is best avoided when urethral injury is suspected. Urinary tract infections are very difficult to eradi­cate in the presence of a catheter, and so if a patient has an infection, an indwelling catheter should be avoided when possible.

Choice of Catheters If catheterisation is done to drain the bladder as a temporary measure, and then removed, a non-retain­ing urinary catheter like the Gibbon’s catheter may be used. If catheterisation is done with intention to retain the catheter for few days, a self retaining catheter like the Foley’s catheter may be used. If catheterisation is to be performed in the presence of associated haematuria, a three way catheter, with an additional channel to run in sterile fluid for irrigation and removal of clots in the catheter lumen may be used. This is otherwise known as ‘haematuria catheter’. The catheters are usually made of ‘latex’ to make it as biologically inert as possible. If a catheter is to be kept in place for more than a few days, a silicone catheter is preferred. A very large catheter has a tendency to damage the male urethra by causing periurethritis and later stricture

Ch-16.indd 970

formation. A very fine catheter may be easily clogged by blood or debris. It is, therefore, best to choose a catheter of medium size. The urinary catheters are sized using the system invented by Charriere and sometimes called French gauge. The Charriere gauge is defined by the circum­ ference of the catheter in millimeters. A 14 Charriere catheter is a good first choice in an uncomplicated case.

Procedure The procedure is explained to the patient. The procedure is carried out using strict aseptic precautions. The urethra is anaesthetised using 15 to 20 ml of 2% lignocaine jelly. In man, after the anaesthetic gel has been installed, it should be massaged carefully down the urethra by stroking down the anterior surface of the penis.

Catheterisation in Males Sterile gloves are used by the examiner and the penis is swabbed with antiseptic solution. The foreskin, if present, is retracted and cleansed as well. The penis is held upwards, and the tip of the catheter is inserted into the meatus. The catheter is passed gently down the urethra until it reaches the penoscrotal junction. The tip of the catheter now rests against the external urethral sphincter. By pulling the penis downwards between the patient’s thighs at this stage, the natural curves of the urethra can be straightened and the catheter can be advanced without difficulty through the sphincter and prostatic urethra into the bladder. At this stage urine normally flows through the cathe­ter confirming its right positioning. If no urine appears, and the catheter seems to be inserted correctly, flushing of the catheter to remove any blocks in the lumen may result in normal urine flow. After confirmation of position of the catheter in the above manner, the balloon is inflated to retain the catheter in the bladder. The retracted foreskin of the penis is replaced to avoid danger of paraphimosis. The catheter is then attached to a sterile drainage bag.

Catheterisation in Females The female urethra is comparatively short and straight and catheterisation is not usually difficult. The patient should be asked to lie with her thighs apart and her knees comfortably flexed. After introduction of the local anaesthetic gel into the urethra and after swabbing the perineum with an antiseptic solution, the external urethral meatus is exposed by separating the labia. The urethral opening is identified and the catheter is introduced.

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971

Procedures

Problems

Procedure

If the patient is tense or insufficient time has been allowed for the topical anaesthetic to take effect the catheter may be held up because of spasm of the urethral sphincter. If the patient is asked to try gently to void when the catheter tip reaches it, the sphincter may relax sufficiently to let the catheter through. When the balloon of a Foley’s catheter is blown up the patient should feel no pain. Pain suggests that the balloon is being inflated in the urethra. If this occurs the balloon must be deflated and the catheter reposi­tioned. There may be a failure of the catheter balloon to deflate when the catheter removal is attempted. The best way to deal with this problem is to use a fine wire stilette introduced down the inflation channel to burst the balloon. If this fails ultrasound guided percuta­neous needle puncture of the balloon is re­com­­mended. An indwelling catheter almost always leads to a urinary tract infection within days or weeks. The effects of this can be minimised by regular bladder washouts with saline or dilute chlorhexidine solution. When an infection is established, even the most inten­sive antibiotic treatment is unlikely to make the urine sterile until the catheter is removed. Long term catheterisation is commonly associated with the formation of stones in the bladder.

A heparinised syringe is used (1 cc containing 1000 units). Aseptic precautions are used. Local anaesthesia is given at the site of puncture. The brachial artery is felt just medial to the biceps tendon. To prevent injec­tion of lignocaine into the artery, always apply suction to the syringe before injecting the local anaesthetic. With the bevelled edge facing upwards, the needle is advanced towards the brachial artery, with constant suction applied to the syringe. As the blood enters into the syringe, it may be seen to pulsate into the syringe with its own force. About 5 to 6 cc of the sample is adequate. After the procedure, apply firm pressure over the site of puncture with a sterile gauze, and apply a crepe bandage over it. Blood sample is then injected directly into the blood gas electrodes from the syringe without transferring it into any other container. Blood gas analysis should be carried out within 5 minutes. If a delay is inevitable, cooling the syringe and its contents in ice with subsequent rewarming to body temperature before analysis is done in order to minimise errors caused by continued metabolism of the white cells within the blood sample.

The Specimen It is important to record the volume of urine drained from the bladder after introduction of the catheter. A sample of the urine drained is sent to the microbiology lab for analysis.

ARTERIAL PUNCTURE This is done to measure arterial blood gas tension (PaO2, PaCO2), oxygen saturation (SaO2) and pH.

Contraindications zz zz

Bleeding diathesis (platelet count < 30,000/µl). A relative contraindication is diastolic BP > 120 mm Hg.

Site of Puncture The brachial artery just above the elbow crease of the nondominant arm (left arm in a right handed individual) is preferred. Second preference is the radial artery. Avoid the femoral artery since the femoral vein is larger than the artery and often blood is drawn from the vein, which gives erroneous results.

Ch-16.indd 971

TRACHEOSTOMY Tracheostomy means making an opening into the trachea. Tracheostomy means converting this opening to a stoma on the skin surface.

Indications zz

zz

zz

zz

Relief of upper airway obstruction (foreign body aspi­ ration, acute epiglottitis, acute laryngeal oede­ma). Bronchial toilet to remove excessive bronchial secretions as may occur in coma, CVA, head injury, drug overdosage, cervical cord lesions, myaesthenia gravis or tetanus. To reduce dead space by 30 to 50% and improve respiratory efficiency. It may be required when there is need for prolonged assisted ventilation.

Types zz

zz

Elective temporary tracheostomy: It is a planned procedure done under general anaesthesia as a temporary stage in the management of reversible problems like acute epiglottitis. Pe r man e nt t ra c h e ost o my : This proce dure involves remo­val of the larynx (laryngectomy or

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zz

laryngo­pharyngectomy) with the tracheal remnant being brought out to the surface as a permanent opening to the respiratory tract. Emergency tracheostomy: This procedure is not prefer­ red. It has only a very few indications like a large laryngeal tumour requiring emergency relief of the obstruction.

Tracheostomy Tubes zz

zz

zz

Silver Jackson tube: It is used for temporary tracheostomy and has an inner and an outer tube. Portex tube: There is only one tube and may be cuffed or uncuffed. Redcliffe tube: It is a single right angled tube useful in patients with a thick and fat neck.

zz

zz

Removal of Tube The tracheostomy tube can be removed once the patient can sleep for a night with the tube corked.

Complications zz

Procedure

zz

Elective Tracheostomy

zz

The patient is positioned with a sandbag or pillow under the shoulders in order to extend the neck and bring the trachea forwards. A horizontal incision is made through the skin and subcutaneous tissue down to the muscles. The incision is made about 2 fingers breadth above the sternum. The muscles are retracted on either side with retractors. The pretracheal fascia is identified and a vertical incision is made through it between the third and fourth tracheal rings. A semicircular wall of the trachea is removed from either side and a tracheostomy tube is inserted through this defect. The wound is closed loosely with 4/0 silk sutures.

Humidification is necessary to prevent crusting of secretion and is done by instilling normal saline drops down the tracheostomy tube at regular intervals. The tracheostomy tube should not be disturbed for the first 48 hours and thereafter the inner tube is cleaned at regular intervals.

Surgical emphysema around the root of the neck and upper chest due to tight suturing of the tracheostomy tube. This may lead to mediastinal emphysema if not relieved promptly. Block of tracheostomy tube may occur if there is improper humidification or poor toileting. Tracheal erosion and haemorrhage.

ENDOTRACHEAL INTUBATION This is an emergency procedure for providing ade­quate ventilation in cases of respiratory failure.

Types (Fig. 16.4) 1. Oral: These are larger tubes of sizes 8, 9, and 10 that are passed orally. 2. Transnasal: These are smaller tubes of sizes 6 and 7 and are passed through the nasal cavity.

Emergency Tracheostomy Patient is positioned in a similar manner as in elective tracheostomy. One per cent lignocaine is infiltrated from the cricoid cartilage to the manubrium of sternum, which is the line of incision. A 6 cm vertical incision is made in the midline. Dissection is carried on in the vertical plane up to the trachea. The first tracheal ring is palpated and a horizontal incision is made at the level of the second tracheal ring. A semicircle of tracheal wall is removed and the tracheostomy tube inserted.

Postoperative Care zz zz

Ch-16.indd 972

Good nursing care with strict aseptic precautions. There is increased secretion formation in the first 48 hours after the procedure and needs to be removed every 1/2 hour for 48 hours and thereafter for every 1 to 2 hours.

Fig. 16.4  Endotracheal tubes

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973

Procedures Oral vs Transnasal Intubation Oral intubation

Transnasal intubation

1.

Easy to perform

Difficult to perform

2.

Whole procedure done under direct visualisation

Initial part of procedure is blind

3.

Tubes may be bitten or extruded by use of tongue or lips

Epistaxis may occur

4.

Larger tubes can be passed

Only small tubes can be passed

5.

Suitable for short term ventilation (24–48 hours)

Suitable for long-term ventilation

——

——

Transnasal Intubation

The sizes of the tubes indicate their internal dia­ meter in millimeters. Endotracheal tubes may be cuffed or uncuffed. Cuffed endotracheal tubes are preferred as they keep the tube in position.

Procedure Oral Intubation The patient is positioned supine with his neck exten­ded. Visualisation of the oropharynx, nasopharynx and vocal cords is done using a laryngoscope blade. The lateral flange of the blade is placed on the lateral aspect of the

Ch-16.indd 973

tongue so as to deflect the tongue to one side and obtain proper visualisation. The endotracheal tube of appropriate size is then introduced into the trachea through the vocal cords. The cuffed endotracheal tube is then inflated with the aim to keep the tube in position.

This is a blind procedure initially when the tube is introduced through the nasal cavity. The passage of the tube through the nasal cavity is facilitated by instilling 1% ephedrine drops in the nostrils. Presence of a deviated nasal septum or nasal polyps make the procedure difficult. After entering the oropharynx, the tube can be guided through the vocal cords into the trachea by visualisation through a laryngoscope.

Complications 1. Intubation of either bronchus, usually the right, leads to collapse of the lung. This can be rectified by withdrawing the tube above the level of the carina. 2. Obstruction to the tube because of blockage by secretions. 3. Tracheal dilatation due to over-distention of the cuff leading to subsequent infection and stenosis.

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Laboratory Reference Values Serum Biochemistry Albumin Alpha fetoprotein Ammonia Bilirubin (Total) Direct Indirect Bicarbonate Blood gas (arterial) pH PO2 PCO2 Calcium Total Ionized Ceruloplasmin Chloride Cholesterol LDL cholesterol Total cholesterol HDL cholesterol VLDL Copper Creatinine Ferritin Male adults Female adults

Lab Reference.indd 975

3.5 to 5 gm/dl < 30 µg/l 80 to 100 µg/dl 0.2 to 1 mg/dl 0.1 mg/dl 0.8 mg/dl 20 to 30 mEq/l 7.35 to 7.45 80 to 105 mm Hg 35 to 45 mm Hg 9 to 11 mg/dl 4.5 to 5.5 mg/dl 25 to 50 mg/dl 95 to 110 mEq/l < 100 optimal 100 to 129 near or above normal 130 to 159 borderline high 160 to 189 high ≥ 190 very high < 200 desirable 200 to 239 borderline high ≥ 240 high < 40 low ≥ 60 high 35 to 100 mg/dl 75 to 150 µg/dl 0.5 to 1.2 mg/dl 25 to 250 ng/ml 20 to 200 ng/ml

Folate Plasma Red cell Glucose fasting (plasma) Glycated haemoglobin Homocystine Iron Transferrin saturation Lactate Lipase Lipoprotein (a) Magnesium Myoglobin Osmolality Phosphate Potassium Protein (Total) Sodium Triglycerides (fasting) Troponin I Troponin T Urea nitrogen Urea Uric acid Vitamin B12

2 to 12 ng/ml 150 to 600 ng/ml 65 to 110 mg/dl 4 to 8% 5 to 15 µmol/l 50 to 150 µg/dl 25 to 50% 0.7 to 1.4 mmol/l 0 to 160 IU/l 0 to 3 mg/dl 1.5 to 2.5 mEq/l 20 to 85 µg/l 270 to 300 mOsm/kg 3.5 to 4.5 mg/dl 3.5 to 5 mEq/l 6 to 8 gm/dl 135 to 145 mEq/l < 160 mg/dl 0–0.4 µg/l 0–0.1 µg/l 10 to 20 mg/dl 20 to 40 mg/dl 3 to 8 mg/dl 300 to 900 pg/ml

Serum Enzymes ALT (SGPT) AST (SGOT) Acid phosphatase Alkaline phosphatase Amylase Creatine kinase Male Female

10 to 40 IU/l 10 to 40 IU/l 1 to 5 IU/l 3 to 13 KA units/l (40 to 100 IU/l) 30 to 180 IU/l 30 to 200 IU/l 30 to 150 IU/l

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Manual of Practical Medicine MB fraction Gamma glutamyl transpeptidase LDH 5’ Nucleotidase

< 10 IU/l (usually < 5% of total CPK) 25 to 75 IU/l 100 to 300 IU/l 5 to 15 IU/l

Haematologic Values 1. Bleeding time 5 to 10 minutes 2. Clotting time 10 to 15 minutes 3. Fibrin degradation products < 8 µg/ml 4. Fibrinogen 200 to 400 mg/dl 5. Partial thromboplastin time 25 to 35 sec. (activated) 6. Prothrombin time 10 to 15 sec. 7. Complete haemogram a. Haematocrit   Females 35 to 40%   Males 40 to 45% b. Haemoglobin   Females 13 to 15 gm/dl   Males 15 to 17 gm/dl c. RBC count   Males 4.5 to 5.5 millions/cmm   Females 4 to 4.5 millions/cmm d. Mean corpuscular Hb 25 to 35 pg/cell e. MCHC 30 to 35 gm/dl f. MCV 78 to 98 fl g. RBC life span 120 days h. WBC count    Total count 4000 to 11,000 cells/cmm    Differential count P60, L35, E5 i. Platelet count 2 to 5 lakhs/cmm j. Life span 10 days 8. Clot retraction time Onset at 1 hour and Completion at 6 hours 9. Reticulocyte count 0.5 to 1.5% 10. ESR Males 0 to 20 mm/hr Females 0 to 30 mm/hr 11. CRP < 10 mg/l 12. Complement C3 75 to 150 mg/dl C4 25 to 50 mg/dl 13. Immunoglobulins IgA 100 to 500 mg/dl

Lab Reference.indd 976

IgM IgG IgE IgD

50 to 250 mg/dl 800 to 1800 mg/dl < 0.025 mg/dl 0 to 8 mg/dl

Urine Calcium Catecholamines Copper Cortisol Creatinine Males Females 5 HIAA Hydroxy proline Metanephrine Vanillylmandelic acid Protein Sodium Urobilinogen

0 to 250 mg/day < 500 µg/day 25 to 100 mg/day 25 to 100 mg/day 1 to 2 gm/day 0.5 to 1.5 gm/day < 9 mg/day 25 to 75 mg/day < 0.9 mg/day 2 to 8 mg/day 0 to 150 mg/day 100 to 250 mEq/day 1 to 3.5 mg/day

Stool Normal weight Fat Stercobilinogen

< 200 gm/day < 7 gm/day 40 to 280 mg/day

Sweat Sodium Chloride

< 60 mEq/l < 70 mEq/l

Hormones Growth hormone Insulin Thyroxine (T4) Triiodothyronine (T3) TSH Parathormone Prolactin Males Females Free testosterone Males Females

< 8 ng/ml < 20 µU/ml 5 to 12 µg/dl 80 to 200 ng/dl 0.4 to 6.2 µU/ml 10 to 50 pg/ml 5 to 15 ng/ml 5 to 25 ng/ml 50 to 250 pg/ml 1 to 5 pg/ml

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Laboratory Reference Values Progesterone Males Females   Follicular phase   Luteal phase   1st trimester   3rd trimester   Post-menopausal LH Males Females   Follicular phase   Luteal phase   Midcycle   Post-menopausal FSH Males Females   Follicular phase   Luteal phase

Lab Reference.indd 977

< 0.5 ng/ml 0.1 to 1.5 ng/ml 2.5 to 28 ng/ml 9 to 47 ng/ml 55 to 255 ng/ml < 0.5 ng/ml 0 to 9 IU/l 1.4 to 11.5 IU/l 0.1 to 16 IU/l 20 to 75 IU/l 8.5 to 46.5 IU/l 2.5 to 20 IU/l 3 to 20 IU/l 1.5 to 10 IU/l

  Midcycle   Post-menopausal Cortisol (morning) Aldosterone ACTH (8 AM-supine, fasting) β-hCG   Nonpregnant

977

10 to 23 IU/l 18 to 126 IU/l 8 to 25 µg/dl 10 to 150 ng/l < 60 pg/ml 3 mIU/ml

CEREBROSPINAL FLUID Glucose Total protein WBC’s DC Chloride Pressure Volume

TC L M N

40 to 70 mg/dl 20 to 50 mg/dl < 5/µl 60 to 70% 30 to 50% 0% 116 to 122 mmol/l 50 to 180 mm water 150 ml

04-Jan-18 2:24:11 PM

Index Page numbers followed by f refer to figure.

A Abacavir 139 Abatacept 852 Abdomen 33, 401 palpation 408f plain film of 430 plain X-ray of 428, 938f regions of 405, 405f surface of 406 Abdominal scan 944 Abductor pollicis longus 626 Abetalipoproteinaemia 697 Abortion 768 Abortive poliomyelitis 126 Abram’s needle 959f Abscess 760, 824, 934, 945 Abulia 571 Acanthosis nigricans 6f, 800, 802, 881 Accommodation reflex pathway 600 Accommodation reflex, testing for 601f Acetaldehyde 922 metabolism of 922 Acetoacetic acid 812 Acetohexamide 808 Acetone 812 Acetylsalicylic acid 849 Achalasia 349 cardia 417f, 418, 418f, 941f Achilles tendon 848 Acid-base balance 564 disorders of 564 disorders 567 Acid-fast bacilli 95f Acidophilic 756 Acidosis metabolic 566 severe 814 Acipiomox 807 Acne 782, 783f, 851 Acoustic neuroma 615, 960 Acquired immunodeficiency disorders 515 syndrome 132, 133 diagnoses 133, 134

Index.indd 979

Acrocentric chromosome 41 Acrodermatitis enteropathica 67f Acromegalic facies 12 hand 18, 19f Acromegaly 753f, 793, 752, 756, 836 Acro-paraesthesia 645 Actin-myosin filaments 895 Actinomycetoma 184 Actinomycosis 93, 376 abdominal 93 Activated partial thromboplastin time 523 Acyanotic Ebstein’s anomaly 239 Acyanotic Fallot 250 Adalimumab 432, 852 Addison’s disease 783f, 785f, 795, 829 causes of 784 idiopathic 772 Adductor longus 626 Adductor pollicis 626 brevis 626 Adenocarcinoma 387, 905 Adenolymphangitis, acute 163 Adenoma 756, 781, 789, 792 neck-parathyroid 777f plurihormonal 752 sebaceum 5f toxic 765 Adenovirus 771 Adequate hydration 842 Adipose tissue 796 Adipsic hypernatraemia 759 Adjunctive therapy 767 Adjuvant chemotherapy 898 Adrenal adenoma 756, 781, 791 androgens, secreting 780 carcinomas 781, 791, 830 crisis 787 glands 780 hyperplasia of 780, 781 rest cell 792 Adrenal hyperplasia 756 bilateral 784, 789

congenital 791, 792 noncongenital 792 Adrenal insufficiency 138, 775, 784, 830, 832, 894 secondary 784 Adrenal mass lesions 945 right 789f Adrenergic blockers 287 Adrenergic inhibitors alpha 295 centrally acting 295 Adrenergic stimulants 356 Adrenergic symptoms 829 Adrenocortical carcinoma 791, 898 Adrenocorticotropic hormone 887 Adrenolytic agents 784 Advanced local disease 906 Aerodigestive tract, cancer of upper 877 Aerophagia 402 Aflatoxin B1 879 African trypanosomiasis 151 Agammaglobulinaemia 845 Agnosia, types of 579 Air barium enema 883 embolism 958 sinuses 940 Airway collapse, common sites of 359f obstruction 892 pressure, continuous positive 391 tone disturbances 821 Akinetic mutism 570 Albendazole 148 Albumin excretion rate 824 Alcohol 425, 427, 758, 822, 840, 916, 922 abuse 780, 836 binge 829 consumption, excessive 878 dehydrogenase 922 dementia 925 dependence 928 hepatitis, acute 923 ill-effects of 924f

04-Jan-18 2:25:25 PM

980

Manual of Practical Medicine ingestion 789 inhibitory effect of 923 intake 800 metabolism of 922 withdrawal 927 seizures 928 Alcoholic cerebellar degeneration 925 cirrhosis 451 coma 924, 927 hepatitis 922 liver disease 451, 879, 922, 963 myopathy 925 pancreatitis 471 Alcoholism 923 chronic 781, 924 Aldose reductase inhibitors 822 Aldosterone producing adrenal adenoma 780 producing carcinoma 780 secreting 780 Aldosteronoma 793 Alexia 584 Alfa-1 anti-trypsin deficiency 879 Alkaline phosphatase elevated 31, 882, 923 serum 435, 842 Alkalosis 566, 780 metabolic 550, 566 Alkylating agents 877, 898 Alkylators 899 Allergic angiitis 868 bronchopulmonary aspergillosis 181, 183 reactions 498, 806 Allergy 941 systemic 801 Allesthesia 644 Allochiria 644 Allodynia 645, 736 Allogeneic bone marrow transplantation 531 stem cell transplant 531 Alloxan 794 Almotriptan 683 Alogliptin 809 Alopecia 800, 858, 910, 859 areata 7, 7f types of 7 universalis 7 Alpha fetoprotein, serum 462, 882 Alphavirus 129f Alport syndrome 549 Alprostadil 823 Alstrom syndrome 801 Aluminium bone disease 839 toxicity 778

Index.indd 980

Alzheimer’s disease 916 Amaurosis fugax 597, 873 Ambiguous genitalia 790 Amblyopia, toxic 596 Amenorrhoea 768 American College of Cardiology 837 American College of Rheumatology 845 American Heart Association 837 American trypanosomiasis 152 Amikacin 372, 374, 542 Amiloride 286 inhaler 368 Amino acid residues 922 Aminoaciduria 801 Aminoglutethimide 784 Aminophylline 290 Amiodarone 762 induced thyrotoxicosis 773 induced toxicity 773 Amitriptyline 684 Amlodipine 295 Ammonia 565 Amnesia 572 post-traumatic 572 Amnesic-dysnomic aphasia 585 Amoebiasis 146 life cycle of 146f Amoebic abscess 449 dysentery 426 liver abscess 448f drainage 449f Amoxicillin 88, 420, 426, 542 clavulanate 542 Amphetamine 866 Amphotericin B 184, 886 Ampicillin 88, 426, 708, 711 Amrinone 289, 307 Amylase, serum 468 Amyloidosis 759, 847, 853, 862, 866, 882, 942 primary 862 Amyotrophic lateral sclerosis 692, 693 Anabolic steroids 834, 841 Anacrotic pulse 195 Anaemia 482, 488, 489, 520, 833, 861, 962 causes of 482 chronic 123 classification of 482, 483 extreme 881 lymphocytosis 786 macrocytic 779, 926 megaloblastic 486, 488, 779 microangiopathic haemolytic 526 microcytic 482 mild 513 myelophthisic 503 normochromic 858 normocytic 483, 786, 858

pernicious 487f, 488f, 772, 786, 795, 878 sideropenic 489 signs 483 simple 489 symptoms 483 Anaerobic bacteriae 92 infection 92, 655f Anaesthesia 644 Anakinra 852 Anal cancer 879, 882, 883, 905 candidiasis 177 Analgesic 841 nephropathy 847 Anaphylactic shock 40 Anaphylaxis, systemic 49 Anaplasmosis 111 Anaplastic carcinomas 830 Anarthria 584 Anatomic destruction 784 Ancillary diagnostic supportive tests 681 Ancylostoma 157f braziliense 167 caninum 167 Androgen 877 agents 834 deficiency 792 resistance 792 therapy 791 Androgenic steroids 879 Android obesity 17 Anencephaly 825 Aneurysm 678, 758 after rupture of 679 before rupture of 679 common sites of 678 formation, aetiopathogenesis of 678 Angina 33, 313, 873 newer drugs in 304 nocturnal 191 pectoris 32, 191 causes of 192 postinfarct 309 Anginal pain, characteristics of 191 Angiogram, pulmonary 394 Angiography 680, 942 non-invasive 954 pulmonary 352, 942 selective 884 Angioma 945 Angiosarcoma liver 877 Anidulafungin 184 Ankle clonus 624f jerk 638 Ankylosing spondylitis 17, 430, 713, 844, 853, 854, 854f, 939f

04-Jan-18 2:25:25 PM

981

Index Ankylosis 848 Ankylostomiasis 156 life cycle 156 Ann-Arbor classification 516, 517 staging 517f Anogenital warts 123 Anomalous pulmonary venous connection 256 Anorchia, congenital 792 Anorectal atresia 825 dysfunction 821 Anorexia 402, 760, 859, 908, 923, 928 nervosa 72, 836, 840 syndrome consists of 880 Anosmia 589 Anosognosia 579 Antacids 425 Anterograde amnesia 572 Anthrax 83 Anthropometric classification 12 Anti-arrhythmics 861 Antibiotic 425, 861, 898 therapy 497 Antibody dependent cell-mediated cytotoxicity 49 Anticancer drugs, classification of 898 Anti-cardiolipin 860 antibodies 860 Anticholinergics 357, 822, 916, 918 Anticoagulant 523, 672, 702 therapy 301 Anticonvulsants 838, 840 principles of 656 Antidepressants 792, 918 Antidiuretic hormone 758 Anti-elastase hypothesis 361 Antiemetic 908, 916, 918 therapy 910 Antiepileptic drug 659 Antigen 50 altering surface 922 presenting cells 45 Antiglobulin test, indirect 490f Anti-hyperlipidemics 861 Antihypertensive drugs 291, 861, 927 therapy 298 Anti-inflammatory agents 822 drugs 357 Anti-insulin receptor antibody 794 Antimetabolites 898, 901 Antimitotic agents 902 Anti-Müllerian hormone 791 Antineutrophil cytoplasmic antibodies 868

Index.indd 981

Anti-nuclear antibodies 858 Antioestrogens 778 Antiphospholipid antibody 861, 873 syndrome 866, 872 Antiplatelet drugs 673 therapy 301 Antipsychotics 861, 916 Antireceptor antibodies 49 Antiresorptive agents 841 Antiretroviral therapy 139 Antisickling agents 493 Antithymocyte globulin 497 Antithyroid drugs 765, 773, 861 Antituberculosis drugs 372, 373 reserve 372, 374 Antitumour antibiotics 900 Anuria 403 Anxiety 789, 927 Aorta 246, 247, 252, 254, 258, 264, 268, 273, 280, 300f abdominal 870, 945f ascending 300f coarctation of 254, 255f syndromes, coarctation of 255 Aortic arch 870 syndrome 870 Aortic dissection 33, 299 acute 32 Aortic incompetence 847 Aortic murmurs 208f Aortic regurgitation 192, 207, 215, 273, 273f, 274f, 856 Aortic root, ballooning of 14f Aortic stenosis 33, 192, 207, 218, 271, 271f common causes 271 congenital 253 signs 271 subvalvular 254 supravalvular 253 symptoms 271 types, congenital 253 valvular 253 Aortic thrills 207 Aortic valve lesions 863 Aortic wall involvement 273 Aortoarteritis 558f Aortocoronary bypass 758 Aorto-pulmonary level shunt 240 Apert syndrome 245 Apex beat, position of 334 Apex-pulse deficit 195 Aphagia 402 Aphasia 583, 585, 683 Aphonia 584 Aphthous stomatitis 932 Aphthous ulcer 62f Apical ballooning syndrome 314f

Apical impulse 205, 206f, 337 abnormalities of 206 confirmation of 337 Apical thrills 208 Apixaban 303 Aplastic anaemia 495, 496f, 962 aetiology of 495 Aplastic bone marrow 496f Aplastic crisis 493 transient 123 Apneustic breathing 336, 574 Apnoea-hypopnoea index 359 Apoprotein CII deficiency, familial 834 Apoproteins 833, 834 Appendicitis 916, 934 acute 34 Apraxia 578 ideational 579 ideomotor 578 types of 578 Arachnodactyly 20f Archicerebellum 640 Arcuate fasciculus 585f Arcus senilis 9, 9f, 204 Arenavirus 113 Argatroban 303, 527 Arginine vasopressin 750, 758, 887 Argyll Robertson pupil 204 Arm claudication 870 Arm veins 968 Aromatic amines 877 Arrhenoblastoma 792 Arrhythmias 307, 752, 859, 961 classification of 230f treatment of 308 Arrhythmogenic right ventricular dysplasia 314, 315f Arsenic 866, 877, 928 Arterial blood gas 394 analysis 352 blood pressure, control of 38 gas 813 hypertension, pulmonary 393, 865 pulse 194 puncture 971 Arteriovenous malformation 681 types of 681 Arteritis 669, 853 temporal 866, 869 Artery, pulmonary 244, 246, 247, 252, 254, 256, 258, 260, 262, 264, 268, 273, 867 Arthralgia 869, 873 vague 845 Arthritis 103, 262, 844, 854, 859, 869, 873 degenerative 842 inflammatory 844

04-Jan-18 2:25:25 PM

982

Manual of Practical Medicine mutilans 857 peripheral 430 psoriatic 844, 853, 856, 857 septic 844 suppurative 824 symmetrical 844 seronegative 857 traumatic 844 Arthritogenic bacteria 856 Arthrodesis 852 Arthropathy, neuropathic 821 Arthroplasty 852 Arthus reaction 49 Asbestos 877 Ascariasis 156, 157, 159f life cycle 157 Ascaris lumbricoides 159f life cycle of 158f Ascites 457, 941 causes of 457 malignant 892 Ascitic fluid aspiration 961 examination 428 Ascorbic acid 63, 68 Aseptic meningitis 131 Aspergilloma 181, 183, 948f Aspergillosis 181 Aspergillus 886 flavus 182f fumigatus 181, 182f fungal ball 182f niger 182f Aspirate bone marrow 502 Aspiration 449 pleural 958 site of 958 therapeutic 958 Aspirin 673, 849, 927 Asthma 354, 356, 760 acute severe 355, 358 atopic 354 brittle 355 chronic 355 episodic 355 exercise-induced 355 extrinsic 354 intrinsic 354 late onset 354 nocturnal 354, 358 non-atopic 354 Astrocytoma 685, 791 Astrovirus 130 Asymmetrical oligoarthritis 857 Ataxia congenital 696 episodic 701 idiopathic late onset 701

Index.indd 982

neuropathy 702 telangiectasia 661, 698, 800 Ataxic breathing 336 Ataxic disorders 695, 698, 699 Ataxic gait 633 Ataxic hemiparesis 674 Ataxic syndromes, intermittent 697 Atazanavir 140 Atenolol 295, 919 Atheroembolic disease 866 Atheromatous disease 752 Atherosclerosis 665 acceleration of 834 Atherosclerotic cardiovascular disease 837 disease, detect 948 fusifom aneurysm 945f plaques 665f Athetosis 629, 779 Atlantoaxial dislocation 733 classification 733 Atlanto-occipital synostosis 733 Atonic seizures 654 Atorvastatin 837 Atrial enlargement 220f left 207, 219, 220f right 219, 220f extrasystole 234, 234f fibrillation 232, 232f, 233, 265, 307, 308, 322 flutter 232, 232f, 234, 308, 322 level shunt 239 myxoma 265, 756, 866 right 266f pressure 202 septal defect 244, 257 types of 244f septostomy 394 tachycardia 232, 233 ectopic 231 multifocal 231, 231f Atrioventricular nodal reentrant tachycardia 230 Atrioventricular reentrant tachycardia 230 Atrium left 244, 246, 247, 257, 258, 260, 264, 268, 273, 280, 318 right 244, 247, 256-258, 260, 264, 273, Atrophic gastritis 878 Atrophic hypothyroidism, primary 786 Atrophic papilloedema 594 Atropine 789 Audiometric tests 612 Auditory function 611 Auditory meatus, internal 617 Auscultation

importance of 342 technique of 342 Auscultatory areas 342 gap 199 Austin Flint murmur 208, 217, 275, 276 Autoimmune diseases 50, 786 disorders 59, 515, 873 hepatitis 445, 447 lymphocytic hypophysitis 751, 758 orchitis 772 Autoimmunity 820 Autologous bone marrow transplantation 531 Autologous stem cell transplant 531 Autonomic disorders, peripheral 821 Autonomic neuropathy absence of 829 causes of 712 classification of 821 Autonomous ovarian hormone secretion 791 Autosomal dominant 759 disorder 777 inheritance 42 Autosomal recessive 759, 801 inheritance 42 Auxiliary liver transplantation 472 Avascular necrosis 851 Axial arthritis 844 Axial spondyloarthritis 856 diagnosis of 854 Axonal neuropathies 889 Axonotmesis 735 Azathioprine 747, 860 Azilsartan 297 Azithromycin 78, 88, 373 Azotaemia 403

B B cell lymphoma 848 B lymphocytes 132 Babinski’s sign 634, 635 Bacillary dysentery 88, 426 Bacillus anthracis 83f Bacillus Calmette-Guérin vaccination 371 Back ache, low 722 Back pain inflammatory 854 low 853 Baclofen 928 Bacteraemia, severe 886 Bacterial colitis 429 endocarditis 866

04-Jan-18 2:25:25 PM

983

Index infection 74, 135, 425 peritonitis 964 spontaneous 458 thyroiditis 771 Bacterially contaminated food 878 Bacteriuria 539, 915 asymptomatic 539, 542 biochemical tests for 541 Bacteroides fragilis 711 Balanitis 178 Balantidiasis 149 Bald tongue 11 Ball’s disease 891 Balloon mitral valvuloplasty 267f valvuloplasty, percutaneous 267 Baltic myoclonus 698 Bambuterol 357 Barber’s chair sign 649 Barium enema 428, 430, 430f meal 428 series 421 swallow 418, 418f Barking cough 327 Barnett’s classification 730 Barrel chest 334 Barrett’s oesophagus 878 Bartter’s syndrome 781 Basal cell nevus 876 Basal ganglia 619, 620f calcification 690f, 779 connections of 620 Basic life support 321 Basilar artery 664 aneurysm 951f syndromes 667 Basilar impression 733 Basophil 500, 756 cell 477 Basophilia, causes of 500 Basophilic stippling 482 B-cell lymphoma, diffuse large 518 neoplasms 504 peripheral 504 Beam radiotherapy, external 908 Beau’s line 24, 24f Beck’s triad 320 Becker’s dystrophy 743 prognosis 743 Bed side lung function tests 347 Bed sore 959 Bed wetting 583 Bedside cardiovascular reflex test 712 Bedtime insulin 799 Beef insulin 796 Behçet’s syndrome 866, 871

Index.indd 983

Belching 402 Belimumab 860 Bell’s palsy 12, 610 Bell’s phenomenon 610 Benazepril 287 Bence-Jones proteins 48 proteinuria causes of 522 idiopathic 522 Bendopril 296 Bendroflumethiazide 286 Benedict’s syndrome 631 Benfothiamine 61 Benzene 877 Benzopyrene 928 Benzthiazide 286 Berger’s disease 548 Beta blockers 312, 834, 836 Beta cell tumour 831, 832 Beta thalassaemia 495f major 494 minor 494 Bethanechol 731 Bevacizumab 463 targets vascular endothelial growth factor 905 Bicarbonate generation 565 reabsorption 565 Biceps 626 jerk 638 reflex, inverted 637 Bicuspid aortic valve, congenital 273f Bi-fascicular block 223 Biguanide 807, 808 Bile acid sequestrants 836 Bile duct carcinoma 893 common 941 Bile salts 427 Bilevel positive airway pressure 353 Biliary cirrhosis 452 aetiology of primary 452 primary 452, 772 colic 34 obstruction 893 tract neoplasms 899 Bilirubin metabolism of 437 serum 436 Binet system 513 Binocular diplopia 601 Binocular visual loss 593 Bioartificial liver 473 Biopsy 868, 895 mucosal 430

pleural 958 procedures, types of 896 Biosynthesis of cholesterol, inhibition of 838 Biosynthetic function, tests of 435 Biotin 63, 68 Biots breathing 336 Biphasic murmurs 216 Bipyramidal lesion 632 Bisferiens pulse 198f Bismuth subsalicylate plus 420 Bisphosphonates 841 Bitemporal hemianopia 756 Bitot’s spot 57, 57f Bivalirudin 303 Bladder 412, 944 atony 821 cancer 879, 883, 884, 906 carcinoma 760, 898 dysfunction 731 Blast cells 520f Bleeding assessment of 423 disorders 522, 524 tendency 941 Bleomycin induced fibrosis 862 Blindness 801 Blink reflex 606 Blood analysis, automated full 482 cholesterol, diet therapy of high 837 collect 751 dyscrasias 850 flukes 168 loss 423 anaemia 483 pressure 198, 199, 672, 770 normal 200 products, manipulation of 497 smear, peripheral 883 stem cell transplantation, peripheral 532 tests 539 transfusion 493, 497 vessel damage, mechanisms of 865 Blood-brain barrier, drug crossing 373 Bloody tap 959 B-lymphocytes 46 Body hair distribution, decreased 8 Bone 775, 847, 927 avascular necrosis of 873 conduction test, absolute 612 cysts 776 marrow 488f, 503f, 508, 520f, 876, 944 aplasia of 963 aspiration 496, 514, 883, 962, 962f aspiration needles 962f culture 962

04-Jan-18 2:25:25 PM

984

Manual of Practical Medicine depression 850 diseases, primary 495 examination 505 hyperplastic 926 hypocellular 495 hypoplasia of 963 normal 496f recipients 30 relapse 512 toxicity 897 marrow transplant 497, 529, 531 allogeneic 510 syngeneic 510 types of 530 mass, measurement of 841 metabolism 140 metastasis 883, 894 mineral density, low 915 necrosis, ischaemic 859 pain 842 relief of 897 remineralisation, accelerated 779 tuberculosis 370 tumours 962 Bony ankylosis 844 erosion 844 tenderness 854 Boot-shaped heart 250f Borderline tuberculoid types 4 Bordetella pertussis 85 Bornholm disease 131 Borrelia infection 26 Bosentan 394 Bouchard’s nodes 940 Boutonniére deformity 845, 940 Bovine cough 327 Bow legs 60f Bowel disease, inflammatory 429, 879 Bowel function 837 Bowel gangrene 945f Bowel sounds 413 Bowman’s space 544f Bowstring sign 723 Brachial plexus lesion 622 Brachioradialis 626 Brachytherapy 896, 897 Bradyarrhythmias sick sinus syndrome 237 Bradycardia 26, 768, 961 Bradylalia 584 Bradypnoea 335 Bragard test 723 Brain abscess 886 biopsy 709 death 681 herniations, types of 687f

Index.indd 984

metastasis 891 control of 897 oedema, diffuse 675 scanning 942 tumour 682, 760, 916 Brainstem 605, 705f encephalitis 889 Brassy cough 327 Break-bone fever 129 Breast cancer 876, 879, 882, 884, 906 familial 876 Breast carcinoma 758, 898 Breastfeeding 660 Breath sounds 342 absent 343 Breath-holding test 347 Breathing apneustic 574f atoxic 574f cluster 574f deep 712 patterns, abnormal 336 Breathlessness 881, 908 Bretylium 322 Brivanib 463 Broad complex tachycardia, management of 236 Broad spectrum antibiotics 822 Broca’s aphasia 584, 585 Broca’s area 584 Brock’s syndrome 365 Bromocriptine 754 Brompheniramine maleate 822 Bronchial asthma 353, 918 management of 356 types 354 Bronchial breath sound 342 types of 342 Bronchial circulation 327 Bronchiectasis 363, 934 dry 365 middle lobe 365 right lung 366f right sided 365f sicca 365 upper lobe 364 Bronchitis, chronic 327, 360, 361 Bronchogenic carcinoma 385 Bronchogram 366f Bronchopneumonia 375, 916 Bronchopulmonary segments 326 Bronchorrhoea 327 Bronchoscope rigid 353 uses of 352 Bronchoscopy 352, 884 Bronchovesicular breath sound 343

Brown fat 944 Brown tumours 776 Brown-Sequard syndrome 651 Brucellosis 90, 844 Brufen 850 Brugada syndrome 237, 237f Brugia malayi 161 Bruising 851 Brush border hydrolysis 427 Bubonic plague 90 Buccal spray 799 Buccofacial apraxia 579 Budd-Chiari syndrome 466 Bulbar dysarthria 586 palsy 694 causes of 693 progressive 693 poliomyelitis 127 Bulimia 72 Bumetanide 285 Bundle branch block left 222, 222f right 222, 222f Bunyavirus 113 Bupropion hydrochloride 931 Burkitt’s lymphoma 876, 878 Burning pain 727 Burr cells 482 Busulphan 891 Butcher’s warts 123 Butyrophenones 755

C Cachexia 880, 908 Cacosmia 590 Cadaver donor selection 471 Cadmium poisoning 839 Café au lait macule 4f Café-au-lait spot 660f Calcitonin 774, 841, 842 actions of 774 Calcium 60, 66, 427, 774, 775, 813, 841, 895 channel blockers 287, 295, 312 gluconate 564 Calf muscles hypertrophy 769f Call-Fleming syndrome 679 Caloric testing 613, 614f Canadian Heart Association grading of angina 191 Canal paresis 613 Cancer 113, 876, 880, 886, 887, 929 aetiology of 878 anorexia 880 arises 876 cachexia 880

04-Jan-18 2:25:25 PM

Index cell biology of 876 cervix 906 chemotherapy agents 899 classification of 877 death, leading cause of 879 eradication of 896 familial 876 inoperable 906 laryngeal 882 oesophageal 878, 881, 883, 905 pancreatic 879, 882, 883 screening 885 severe 907 small bowel 879, 881, 883 syndromes, familial 876 testicular 880, 883, 884, 906 therapy 896 late effects of 910 principles of 896 vaccination of 886 Candesartan 297 Candida 135 albicans 886 endophthalmitis 178 with chlamydoconidia 177f Candidal endocarditis 178 Candidal funguria 178 Candidiasis 176 mucocutaneous 176, 177, 786, 795 Candiduria 542 Candle flame jet 266f Capillary wedge pressure, pulmonary 318 Caplan’s syndrome 846 Capreomycin 372, 374 Captopril 286, 296 Carbamazepine 658, 758-760, 861 Carbidopa 689 Carbohydrate 52, 427, 428, 804, 837 energy yielding 52 intolerance, classification of 826 metabolism 796 source of 52 transport, potentiation of insulin stimulation of 805 Carbon monoxide 815 Carcinogens 876-878 Carcinoid 760, 830 syndrome/crisis 433 tumours 433, 887 Carcinoma 781, 963 breast 778, 841 large cell 387 lung 958 metastatic 758, 841 pancreatic 899, 926 periampullary 893f Carcinomatosis 866 meningeal 891 peritoneal 892

Index.indd 985

Cardiac abnormalities 243, 255, 257, 258, 259, 261 angiography 942 anomalies 825 arrest 320 causes 320 arrhythmia 767, 847, 932, 968 asthma 191 catheterisation 267, 269, 272, 275, 315 chamber hypertrophy 947 cirrhosis 453 conduction defects 856 defects 15 defibrillator, implantable 308f disease 204 disorders 865 enzymes 306 failure 281, 767, 815, 853, 908, 918 classification of 282 congestive 283, 781, 851 high output 282, 842 treatment of 284, 908 glycoside 919 lesion, nature of 286 malformations 256 malposition 240, 242f manifestations 863 myocytes 876 oedema 36 resuscitation 322 resynchronisation therapy 290f scanning 942 surgery 323 tamponade 40, 320 relief of 960 toxicities 288 transplantation 323 valves 209f Cardiogenic pulmonary oedema 285 management of 289 Cardiogenic shock, treatment of 307 Cardiomyopathy 313, 317, 752, 810, 847, 863 congestive 313 non-ischaemic dilated 282 peripartum 317 primary 317 restrictive 314, 315f secondary 317 Cardiopulmonary resuscitation 321 Cardiovascular causes 332 disease 929 disorders 59, 329, 573, 821 infections 886 involvement 109 syphilis 104 system 55, 189, 300, 847, 915, 926 Carditis 262

985

Carey Coombs murmur 208, 217 Carotenaemia 4, 57 Carotid angiogram 671f artery dissection 205 internal 665 pulse 202 pulse 322 normal 197f shudder 207 system 678 territory 663 thrill 207 Carpal tunnel syndrome 737, 752, 849 Cartilage loss 844 Caspofungin acetate 184 Castell’s method 412 Catabolising enzymes 922 Catamenial epilepsy 660 Catamenial pneumothorax 383 Cataplexy 582 Cataract 779, 810, 914 congenital 205 formation 818 Catatonia 571 Catecholamines 357 Catheter intravenous 886 over needle 968 Caudal regression 825 Caudate nucleus 629 Causalgia 645, 736 Causalgic pain 35 Causing parkinsonism 690f Cavernous sinus 604, 605, 675 lateral wall of 617 thrombosis 760 Cavitating lesions 934 Cavity 346 thick-walled 346 thin-walled 346 tuberculous 948f Cefepime 367, 542, 708, 711 Cefixime 542 Cefotaxime 542, 708, 711 Cefpodoxime proxetil 542 Ceftazidime 367, 542, 708, 711 Ceftibuten 542 Ceftriaxone 78, 88, 542, 708, 711 Cefuroxime axetil 542 Celiac sprue 879 Cell abnormal 877 cycle regulators 877 division 476 physiology of 476f mediated immunity 133 percentage of 877

04-Jan-18 2:25:25 PM

986

Manual of Practical Medicine Cellular bone marrow 495 Central airway involvement 364 Central core disease 744 Central cyanosis 194 Central lesion 613 Central nervous system 300, 776, 847, 851, 924 diseases 596 disorders 138, 760 infections 116, 886 neoplastic disease of 685 symptoms 849 Central neurogenic examination 574f hyperventilation 574 Central pontine myelinosis 925 Central retinal artery occlusion 596f vein occlusion 596f Central scotoma 591 Central venous cannulation maintenance of 969 percutaneous 967 catheters, insertion of 896 Central vertigo 615 Centriacinar emphysema 360 Centronuclear myopathy 744 Cerebellar afferent fibres 641f artery anterior inferior 668, 669 duperior 668 superior 668 ataxia 668, 800, 873 aetiology of 697 degeneration 889 dysarthria 586 dysfunction 640, 642f efferent fibres 640f, 641f haemorrhage 676 hemisphere, lesions of 642 lesion 633, 641, 643 causes of 643 localisation of 642 posture 17 signs 703 Cerebello-pontine angle 608 Cerebellum 640, 665, 954f anatomy of 640f functional divisions of 640 nuclei of 640 Cerebral abscess 251f right 655f aneurysm 940 angiography 686, 942 artery

Index.indd 986

aneurysm of anterior 679 anterior 664 middle 664, 665 territory, anterior 671f blood supply 664 cortex 641f functional areas of 584f functional localisation of 670f damage 791 diplegia 725 haemorrhage 663 infarction 663, 672 malaria 143, 145 oedema, treatment of 672 palsy 725 tumours 685 Cerebro-ocular-dysplasia muscular dystrophy 744 Cerebrotendinous xanthomatosis 698 Cerebrovascular accident 760, 918 disease 573, 810, 925 disorders 662 types of 668 Cerivastatin 837 Certolizumab pegol 432, 852 Ceruloplasmin, serum 463 Cervical adenopathy 907 angina syndrome 720 canal stenosis 717 cancer 878, 880 cord lesion 853 dislocation 847 enlargement 715 joints 845 lymphadenopathy, bilateral 882 spinal cord injury, acute central 718 spine 714, 891 spondylosis 720, 721, 844, 914 signs 720 symptoms 720 sympathetic chain 882 Cervicofacial actinomycosis 93 Cervicomedullary junction 726 Cervix cancer 883, 884 carcinoma 898 Cestodes 156, 170 Cetuximab 905 Chaddock reflex 635 Chagas’ disease 152, 282 Chain disease, heavy 48 Chamberlain’s line 735 Chancroid 98, 98f Chapel Hill classification 866 Charcot’s joint 821 Charcot-Marie Tooth disease 740

Chédiak-Higashi syndrome 4 Cheilitis 488 Chemopreventive agents 904 Chemoprophylaxis 145 Chemotherapeutic agents 908 Chemotherapy 517, 521, 881, 897, 898, 911 combination 907 cycle of 897 primary 521 principles of 374, 897 Chemstrip 812 Chest deformities 334 expansion 338 measurement of 338 film 934 flat 334 movement of 335 pain 31, 265, 330, 870, 932 atypical 870 symmetry of 334 syndrome, acute 493 wall anterior 340 lateral 340 posterior 341 X-ray 349, 937f Cheyne-Stokes breathing 336 Chickenpox 118, 350 pleomorphism 118f Chickenwire fibrosis 450f Chikungunya 129f, 130 virus infection 130 Child’s classification, modified 456 Chimerism 43 Chlamydia 376, 856 life cycle of 99f trachomatis 99 infections 100 Chlamydial infections 99 Chlamydophila 99 pneumoniae infections 101 psittaci–psittacosis 101 Chloral hydrate 927 Chlorambucil 891 Chloroquine 145, 146, 847, 850 Chlorothiazides 286 Chlorpromazine 684, 831, 857, 861 Chlorpropamide 759, 760, 806, 808 Chlorthalidone 286 Cholangiography 941 Cholangitis 941 Cholecalciferol 774 Cholecystitis 934 acute 941 Cholecystography, intravenous 941 Cholera 88, 89

04-Jan-18 2:25:25 PM

987

Index Cholestasis absence of 923 tests of 435 Cholestatic jaundice 881, 908 Cholesterol 837 esters 833 serum 770 synthesis 837 Cholestyramine 427, 822, 836 Cholinesterase inhibitors 822 Chondrocalcinosis 779 Chordate tendineae, rupture of 268 Chorea 262, 629, 779, 873 causes of 629 Choreoathetosis, paroxysmal 630 Choriocarcinoma 765, 898 Choristoma 752 Choroid tubercle 332 Christmas disease 528 Chromium 68, 69 Chromophobe 756 cells 750 Chromosomal abnormalities 41 Chromosomal disorders 243 common 44 Chromosomal translocations 876 Chromosome 44, 45 analysis 514 metacentric 41 recurring sites of 876 structural aberration of 42 submetacentric 41 X 45 Y 45 Chronic disease, anaemia of 489 Churg-Strauss disease 868 syndrome 865, 866 Chylomicrons 833 Chylothorax causes 382 Chylous ascites 458 Cicatricial alopecia 7 Cilazapril 287 Ciliary function, assessment of 365 Cilnidipine 296 Cimetidine 420, 755, 792 Ciprofloxacin 78, 88, 372, 374, 542 Circadian rhythm sleep disorders 581, 583 Circle of Willis 664f Circumduction gait 632 Cirrhosis 446, 451, 454f, 923, 926, 945, 963 complications of 453 macronodular 450, 451f micronodular 451f micronoular 451 of liver, causes of 450 pathophysiologic consequences of 451 postinfarct 452

Index.indd 987

Cirrhotic facies 12 Cisapride 908 Cisplatin 898 containing regimens 906 Cisplatin-based combination chemotherapy 907 Cisternal puncture 960 Cisternography 756 Clarithromycin 373, 420 plus 420 Classical complement pathway 858 Claudication, neurogenic 35, 721 Claw foot 21 Claw hand 97f Clinoryl 849 Clivus canal line 735 Clofazimine 373 Clofibrate 760, 838 Clomiphine 880 Clonazepam 658 Clonidine 295, 712, 822, 833, 932 Clonus 624 Clopidogrel 301 Clostridial myonecrosis 82 Clostridium perfringens 82f Clostridium tetani 80f Clubbing 330, 331f causes of 331 grading of 331 theories of 331 unidigital 332 Cluster headache 682 Coagulase-negative staphylococci 75 Coarse trabeculations 940 Cobalamin 68 deficiency 489 Cobalt 69 Cobbler’s chest 334 Cocaine 866 Coccidioides immitis 179 Coccidioidomycosis 179, 866 Coccidiomycosis 179f Cockayne syndrome 698 Cod fish vertebra 840f Codeine 822 Coeliac disease 427, 795, 838, 870 sprue 878 Cogan’s syndromes 866 Cognitive scales 588 Cogwheel breathing 336 Coin sound 345 Coitus 755 Colchicine 425, 427 Cold caloric testing 575 Cold intolerance 768 Cole-cecil murmur 217 Colestipol 836 Coliforms 458

Colitis 430f ischaemic 433 Collagen vascular 840 disease 379, 742, 865 disorder 329, 384, 427, 669 Collapsed abscess cavity 448f Collapsing pulse 195, 197f Coloboma of iris 204 Colon 944 cancer 905 tumours 887 Colonic cancer 752 Colonic haustrations, loss of 430f Colonic obstruction 34 Colonic polyps 752 Colonoscopy 425, 883 Colorectal cancer 879, 881, 883 incidence of 879 Colorectal carcinoma 898, 899 Colour blindness 332 Colourless sputum, large amount of 327 Coma 570, 573, 812, 815 causes of 572 metabolic 573, 576 pupillary defects in 575f respiratory patterns in 574f structural 576 tropical 573 vigil 570 Commissurotomy 267 Community-acquired infections 86 pneumonia, treatment of 376 Compensatory emphysema 361 Complement deficiency diseases 48 Complete basilar syndrome 667 Complete blood count 895 Complete heart block, congenital 260 Concomitant strabismus 602 Conduction aphasia 585 Conduction defects 847 Conductive deafness 614 Confabulation psychosis 925 Confusion 570 acute 916 Confusional state, acute 858 Congenital ataxia, common symptoms of 696 Congenital disorders 696 Congenital heart diseases classification of 239 incidence of 240 Congenital mitral stenosis, types of 264 Congruous hemianopia 592 Conjunctival reflex 634 Conjunctivitis 856, 868 Conn’s syndrome 780, 781 Connective tissue disease 866 undifferentiated 862

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988

Manual of Practical Medicine Connective tissue disorders 317, 319, 843 Conradi-Hunermann syndrome 245 Consciousness 570, 572 state of 574, 576 Consecutive optic atrophy 597 Consensual light reflex, testing for 601f Constipation 402, 695, 767, 822, 908, 918 Constitutional disease 134 Constrictive pericarditis 458, 859 Continuous murmurs, classification of 215 Contraceptive pills, oestrogen containing 835 Contusion 718 Conus lesion 728f Convergence retraction nystagmus 604 Cooley’s anaemia 494 Coombs’ test, indirect 490f Copper 68, 69 level, serum 463 Cor pulmonale 395 causes of 395 Cord intradural lesions of 728 sign 675 Cornea 204 flat 204 Corneal reflex 606, 610, 634 Corneal-conjunctival reflex 606f Coronary angiogram 272 angiography 304, 942 arteriovenous fistula 262 artery anomalous origin of 262 bypass 810, 827 congenital abnormalities of 261 disease 192, 224, 282, 305f, 873 bypass thrombosis 873 heart disease 929 myocardial infarction 847 syndrome, acute 300, 301f vasculitis 847 Corpus callosum 705f Corpus striatum 665 Corrigans pulse 195 Cortex 669 Cortical bladder 729 Cortical branches 666 Cortical dementia 572 Cortical dysarthria 586 Cortical sensations 649 Cortical venous thrombosis 674, 674f Corticobulbar system 618 Corticospinal system 618 tract 618f Corticosteroid 432, 497, 708, 836, 851

Index.indd 988

resistant asthma 355 therapy 374 Corticotropin releasing hormone 887 Cortisol 828 Cortisone 751 Corynebacterium diphtheria 79f Cosyntropin test 786 Cotrimoxazole 426 Cotton wool spots 816 Cough 318, 327, 386, 852 chronic 928 dry 327 mechanism of 327 nocturnal 327 paroxysmal 327 persistent 882 productive 327 short 327 syncope 327 types of 327 Coumarin 806 Courvoisier’s law 409 Coxiella burnetii 111 Coxsackie virus 771 infections 130 Crack pot resonance 341 Crackles 343, 345 mechanism of 343 types 343 Cramps 781 abdominal 760, 881 Cranial arteritis 869 bruit 683 Cranial nerve 589, 597, 598, 604, 605, 611, 615, 693, 820 examination of 589 lesions of fifth 607 neuropathies of 858, 882 nuclei 589f second 590 seventh 607 twelfth 617 Cranial-cerebrovascular accidents 847 Craniopharyngioma 685, 750, 751, 756759, 784, 791 Craniosynostosis 767 Craniovertebral junction anomalies 732 classification 732 C-reactive protein 848 Creatinine 813, 895 serum 860 Cremasteric reflex 634, 634f Crescentic glomerulonephritis 866 Crest syndrome 865 Cretinoid face 12 Creutzfeldt-Jakob disease 709

Cricoarytenoid 845 Crigler-Najjar syndrome 438, 439 Crocodile tears, syndrome of 611 Crohn’s disease 429-431, 854 Cromakalim 298 Cryofibrinogenemia 866 Cryoglobulinaemia 48 mixed 866 Cryoglobulinaemic vasculitis 866 Cryptic miliary tuberculosis 369 Cryptococcus 181f, 886, 887 neoformans 136, 181 Cryptogenic cirrhosis 452 Cryptorchid testis, abdominal 880 Cryptorchidism 880 Cryptosporidia 135 Cryptosporidiosis 148 Crystalluria 554 Crystals 536, 536f Cullen’s sign 406, 467 Cumulative spontaneous somatic mutations 914 Curability of cancers 898 Curative radiation therapy 896 Curvature disorders 713 Cushing’s disease 70, 781, 814 Cushing’s syndrome 12, 781, 782, 783f, 788, 793, 810, 836, 839, 887, 888 adrenal 781, 782, 784 classification of 781 ectopic 781, 782, 784 periodic 782 pituitary 781, 782, 784 Cutaneous afferent innervation 643 flushing 836 larva migrans 167, 168f leishmaniasis 150, 151 leukocytoclastic vasculitis 866 lupus, subacute 859 mucormycosis 183 vasculitis syndromes 865 Cutaneous anthrax 83 lesion of 83f Cutaneous disease, diffuse 862 Cyanide 815 Cyanosis causes 193 intermittent 194 peripheral 193, 194 types 193 Cyanotic Fallot 249 Cyanotic heart disease 216 Cyclin dependent kinase 877 Cyclizine 908 Cyclo-oxygenase-2 inhibitors 850 Cyclophosphamide 513, 760, 860, 879 Cycloserine 372, 374

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989

Index Cyclosporine 431, 497, 840 Cyst, percussion of 413 Cystic bronchiectasis 364f Cystic fibrosis 366, 399, 760, 793 Cystic kidney 825 Cysticercosis 171 calcified lesions of 655f Cystitis 539 signs of 540 symptoms of 540 Cystourethrogram, micturating 942 Cytarabine 508 Cytogenetics 895 Cytokine 46, 778 antagonist 851 production, ectopic 775 Cytomegalovirus 121, 121f, 136 mononucleosis 121 retinitis 122, 122f Cytoplasmic defect 483 Cytoskeleton, microtubules of 922 Cytotoxic drugs 840, 958, 959, 967 T lymphocyte associated antigen-4 852 therapy 967

D Dabigatran 303, 304 Dacarbazine 898, 907 Dacryocystitis 868 Dactylitis 854 Daily energy requirements 53 Dalteparin 301 Darbepoetin 491 Darunavir 140, 446 Dasatinib 510 Daunorubicin 508 Dawn phenomenon 802 Dawson finger 705f de Quervain’s thyroiditis 771 Deafness 614, 615, 849 Death, causes of 853 Decerebrate posture 18 Deespine’s sign 345 Deficiency, causes of 61 Dehydration 778, 787, 914, 916, 918 Dehydro-epiandrosterone 751 Dejerine-Roussy syndrome 652 Dejerine-Sottas disease 741 Delavirdine 140 Delirium causes of 571 tremens 760, 928 Demeclocycline 759 Dementia 62, 571, 694 causes of 571

Index.indd 989

subcortical 572 treatable causes of 572 Demyelinating disease 718 disorders 704 neuropathies 738, 889 Dengue 129f fever 129 haemorrhagic fever 129 shock syndrome 129 Dense prolonged nephrogram 942 Dense triangle sign 675f Dental dysplasia 800 Depression 850, 927, 930 Dermal atrophy 847 Dermatitis 62 artefacta 23 herpetiformis 23, 427 perioral 63 Dermatographia 5 Dermatolymphangioadenitis 163 Dermatomyositis 741, 742, 845, 940 idiopathic 741 Dermopathy 772 Desmopressin 760 Devic’s disease 704, 718, 725, 726f Dexamethasone 708 Dextrocardia 242, 242f Diabetes 800, 816f, 819f, 825 acute complications of 810 insipidus 757 mellitus 6, 299, 427, 537, 544, 546f, 752, 786, 792, 794, 802, 811f, 815, 816, 833, 835, 836, 839, 915, 916, 942, 960 classification of 793 complications 811f long standing 879 poorly controlled 835 pregestation 826 uncontrolled 802 Diabetic amyotrophy 818 complications 810 cystopathy 822 diarrhoea 822 erectile dysfunction 823 foot 823, 824 disease 821 hand syndrome 819 ketoacidosis 573, 780, 810 nephropathy 546, 824, 828 neuropathy 819, 820f management of 822 types of 818 retinopathy 816-818 Dialysis 560 bone disease 839

Diaphoresis 928 Diarrhoea 62, 402, 424, 425, 833, 859, 918 acute 402, 424 inflammatory 425 non-inflammatory 425 chronic 426 classification of 424 large bowel 426 mechanism of 424 osmotic 424 secretory 424 severe 780 small bowel 426 Diastolic accentuation 216 failure 283 heart failure 283, 284 hypertension 768, , 780 murmur 213, 214, 215f, 217 Diazoxide 298, 794 Diclofenac 849 Dicrotic pulse 198f Didanosine 139 Dietary deficiency 838 fibre 52 DiGeorge syndrome 778 Digital gangrene, peripheral 847 Digital rectal examination 883 Digitalgia paraesthetica 645 Digitalis 288, 425, 792 toxicity 322 Digitate warts 123 Digitoxicity, management of 288 Digoxin 394, 919 specific fab antibody fragment 288 Diltiazem 295, 394 Dilutional hyponatraemia 562 Dimpling sign 18 Dipeptidyl peptidase IV inhibitors 809 Diphenoxylate 822 Diphtheria laryngeal 79 pharyngeal 79 Diphyllobothrium latum life cycle 175, 176f Diplopia 601, 870 crossed 601 uniocular 601 Dipstick testing 534 Dipylidium caninum 170 Direct Coombs’ test 490f, 491, 860 Discoid rash 859 Discontinue amiodarone 773 Disequilibrium syndrome 573 Disopyramide 861 Disproportionate tachycardia 313 Disseminated candidiasis 177 chronic 886

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990

Manual of Practical Medicine Disseminated gonococcal infection 866 Disseminated intravascular coagulation 529 Disseminated invasive candidiasis 178 Disseminated tuberculosis 96 Disulfiram 927 Diuretic 294, 425, 781, 861, 917, 918 intractable ascites 459 resistant ascites 459 Diverticula 941 Dizziness 668, 870, 931 DNA-interacting agents direct 899 indirect 901 Dobutamine 285, 288, 307, 394 dopamine-phosphodiesterase inhibitors 290 Dock’s murmur 217 Doll’s eye movement 575, 613 Domperidone 822 Dopamine 285, 288, 307 agonists 689 antagonists 684 Down’s syndrome 18, 18f, 19f, 243, 250, 772, 794 Downbeat nystagmus 605 Doxazosin 731 Doxorubicin 907 Doxycycline 542 Dracunculiasis, life cycle 166, 166f Dreamless sleep 579 Dressler’s syndrome 319 Droperidol 789 Drowsiness 850, 918 Drug 762, 829, 832, 838 eluting stents 311 fever 28 groups of 898 hypersensitivity 866 induced dystonia 630 instillation of 958 interaction 836, 850 intercurrent 916 prophylaxis, anti-HIV 141 reaction 881, 908 therapy 293, 294, 731, 849 principles of 690 toxicity 866 Drug-diphenyl hydantoin 758 Drug-induced hypoglycaemia 830 lupus 861 Dry tap, causes of 502 Dubin-Johnson syndrome 440 Duchenne dystrophy 742, 743f Duke’s criteria 280 Dumb rabies 128 Duodenal ulcer 34 co-existence of 421

Index.indd 990

Duodenum carcinoma 760 Dupuytren’s contracture 18, 19f Dysaesthesia 736 Dysalbuminemic hyperthyroxinemia, familial 762 Dysarthria 584, 586, 695, 870 rigid 586 Dysarthria-Clumsy hand syndrome 674 Dysbetalipoproteinaemia 835 Dysdiadochokinesia 641 Dysequilibrium syndrome 696 Dysesthesia 644 Dysfibrinogenaemia 882 Dysfunction, autonomic 80 Dysgerminoma 898 Dysgraphia 584, 585 Dyskinetic pupils 818 Dyslexia 584, 585 Dysmetria 641 Dyspepsia 849, 850, 918 Dysphagia 402, 415, 417, 584, 695, 847, 870 causes of 415 mechanical 415 neuromuscular 416 Dysphonia 584 Dyspnoea 190, 313, 318, 329, 870, 927, 928 grading of 329 mechanism of 329 Dyssomnias 581 Dyssynergia 640 Dystonia 629 causes of 630 paroxysmal 630 plus syndromes 630 symptomatic 630 types of 630 Dystrophia myotonica 745 Dystrophic nails 800 Dysuria 403, 883

E Ear 641f Eaton-Lambert syndrome 386, 748 Ebstein’s anomaly 257, 257f Ebstein-Barr virus 120f, 515 Ecadotril 288 Ecchymosis 23f Echinococcosis, life cycle 174 Echinococcus granulosus 174 eggs 171f life cycle of 174f Echolalia 584 Eclampsia 873 Edematous pancreatitis, acute 468f Edrophonium 747

Edward’s syndrome 20, 244 Efavirenz 140 Egg-shaped heart 259f Ehler-Danlos syndrome 680, 840 Ehrlichiosis 111 Eisenmenger’s syndrome 248, 248f, 249, 399 Ejection fraction 282 Ejection systolic murmur 213, 214f, 217 Elastography, transient 437 Elbasvir 446 Elbow 845 Elective temporary tracheostomy 971 Elective tracheostomy 972 Electrical alternans 226, 321f Electrolyte 796, 813, 895 imbalance 561, 918 Electrophoresis, serum 520f Electrophoretic mobility 833, 834 Elephantiasis 164f Eletriptan 683 Eliciting Puddle’s sign 413f Embolus, pulmonary 834 Embryology 249 Embryonal carcinoma 898 Embryonal rhabdomyo carcinoma 898 Emergency tracheostomy 972 Emotional fibres 610 Emotional instability 577 Emphysema 360, 361, 399, 934 special varieties of 361 subcutaneous 339 types of 360, 361f Empty delta sign 675 Empty sella syndrome 757 Empyema 381, 760, 958 thoracis 381 treatment for 381 Enalapril 286, 296 Enamel dysplasia 779 hypoplasia 779 Encephalitis 708, 758, 760, 791, 886 Encephalomyelitis, acute disseminated 704 Encephalomyopathies, mitochondrial 698 Encephalopathy 466 acute 768 Endemic flea-borne typhus 110 Endemic haemoptysis 328 Endemic syphilis 107 Endobronchial tuberculosis 370 Endocannabinoid system 72 Endocardial fibroelastosis 318 Endocarditis 79, 847 infective 265, 278, 279f, 280 non-infective 281 prophylaxis 280

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991

Index Endocervical cone biopsy 906 Endocrine 59, 386, 915, 927 cells 793 disorders 138, 572, 749, 810, 814, 821 disturbances 573 gland responsible 761 infections 886 neoplasia, multiple 789 syndromes 887 system 56 Endocrinopathy 890 Endometrial cancer 841, 906 Endomyocardial disorders 314 Endoscopic biopsy 884 retrograde cholangiopancreatography 883, 934, 941 pancreatography 469f Endoscopy 422 complications of 422, 443 therapeutic 424 Endotracheal intubation 972 tubes 972f Enfuvirtide 140 Enoxaparin 301 Enoximone 289 Enprostil 420 Entamoeba histolytica 135, 146, 147f Entecavir 446 Enteric fever 86, 962 Enterobius vermicularis 160, 161f life cycle 160, 160f Enterococcal infections 76 Enterococcus 823 faecalis 76 faecium 76 Enteropathic arthritis 853 Enthesitis 854 Environmental triggers 794 Enzyme 435 defects, congenital 816 serum 435, 742 Eosinopenia, causes of 499 Eosinophilia 166, 786, 847, 889 Eosinophilia-Myalgia syndrome 499 Eosinophils 46, 499 cell 477 Eosinophiluria 554 Ependymoma 685 Epicondylitis 845 Epiconus lesion 728f Epidemic conjunctivitis 131 Epidemic louse-borne typhus 110 Epidemic pleurodynia 131 Epidermal growth factor receptor 907 Epidermoid carcinoma 387 Epididymal pain 869

Index.indd 991

Epidural abscess 719, 719f haemorrhage 719 Epilepsy 652, 659, 760 Epinephrine 285, 815, 828, 829 Epinephrine, hypersecretion of 812 Episcleritis 847 Epithelial transport 427 Epoprostenol 394 Eprosartan 297 Epstein-Barr virus 112, 119, 136 Equivocal Babinski sign 635 Erectile dysfunction 883 Ergot alkaloids 866 Ergotamine 683 Erlotinib 463 Ertapenem 542 Eruptive xanthomas 834 Erythema infectiosum 123 marginatum 23, 262, 845 multiforme 859 necrolytic migratory 833 nodosum 5f, 23, 430, 845 leprosum 98 Erythrocytes cell 477 Erythrocytosis 882, 889 Erythromycin 426, 822 Erythropoietin 478, 491, 501, 909 Erythrovirus 112 Escherichia coli 85, 85f enterohaemorrhagic 86 entero-invasive 86 enteropathogenic 86 enterotoxigenic 86 Esophageal dysfunction 821 ESR-platelet correlation 30 Etanercept 852, 855 Ethacrynic acid 285 Ethambutol 372, 373 Ethanol 830 Ethionamide 372, 374 Ethnicity 861 Ethosuximide 658 Etoposide 891 Etravirine 140 Euglycaemia 802 Eunuchoidal hand 18 European League Against Rheumatism 845 Eustachian tube, obstruction of 882 Ewing’s sarcoma 760, 898 Exaggerated tendon reflexes 637 Exanthems 26 Excisional biopsy 884 Excretins 808 Exenatide 809 Exhaled nitric oxide 356 Exogenous drugs 829

insulin 830 iodine consumption 762 sex steroids 791 Exophthalmos 772 Exostosis 779 Expiratory airflow, duration of 347 Expiratory polyphonic wheeze 343 Extension defects 845 Extensive cellulitis 823 Extensive lung involvement 881 Extensor pollicis brevis 626 longus 626 Extra-adrenal paraganglioma, left 790f Extracardiac obstructive shock 39 Extradural haematoma 948f lesions of cord 728 Extra-intestinal amoebiasis 147 pathogenic strains 86 Extraluminal gas 934 Extramedullary lesions of cord 727 Extraocular muscle paresis 818 Extrapulmonary tuberculosis 95 Extrapyramidal system 619, 688f Exudative maculopathy 817 Eye 9, 947 changes, grading of 764 examination of 332 infections 116 inspection of 598 involvement 165 movements, spontaneous 577 Eyelid 204 retraction 764f

F Fabry’s disease 314 Face 8 Facial canal 608 Facial nerve 607, 608, 610 course of 609f lesion 608 motor functions of 608f nuclei, central connections of 609f Facial oedema, less common causes of 37 Facies, types of 12 Facioscapulohumeral dystrophy, prognosis 743 Factitious hypoglycaemia 830 Facultative gram-negative bacilli 823 Falciparum malaria 829, 832 severe 145 False localising signs 686 False platelet counts 511 False-positive serologic tests 106

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992

Manual of Practical Medicine Famotidine 420 Fanconi syndrome, aetiology of 549 Fanconi’s anaemia 20f Fanconi’s syndrome 549, 839 Fascicular block 223 left anterior 223f left posterior 223f Fasting hyperglycaemia 802 hypoglycaemia 829, 831 Fat 52, 427, 428, 804 solubilisation 426 types of 53 Fatigue 313, 781, 837, 881 Fatty acid monounsaturated 53, 837 oxidation inhibitors 807 polyunsaturated 53, 837 saturated 837 synthesis 796 Fatty liver 466, 922, 923 disease, nonalcoholic 449 of pregnancy, acute 441 severe 923 Faulty technique 963 Febrile convulsions 26 Fecal haemoccult test 883 Fed hypoglycaemias, causes of 832 Felbamate 658 Felodipine 296 Felty’s syndrome 848 Femoral nerve root 723, 725f stretch test 723 Femoral root pain 723 Fenamides 849 Fenoprofen 850 Ferritin, serum 466 Fever 26, 29, 30, 778, 787, 859, 928 black 150 continuous 27f intermittent 26 neutropenic 30 patterns of 26 periodicity of 141 post-transplantation 30 recurrence of 141 remittent 26, 27f tertian 26, 28f undulant 90 Fibre 804 arrangement of 715 neuropathies, small 737, 820 Fibreoptic bronchoscope 353 oesophagoscopy 455 Fibrillation 632 Fibro sure 437

Index.indd 992

Fibro test 437 Fibroblast growth factors 877 Fibrocalculous pancreatopathy 793 Fibrocellular crescentic glomerulonephritis 549f Fibroid uterus 410 Fibrosing alveolitis 858 Fibrosis 347, 817, 844, 922 pulmonary 864f types of 347 upper lobe 347 Fibrotic diseases 314 Fibrotic disorders 314 Filarial worm in blood 164f Filariasis 164f lymphatic 163 pathology, lymphatic 163 Filariform larvae 159f Fine needle aspiration 884 Finger arachnodactyly 19 clubbing 404 flexion 638 polydactyly 19 syndactyly 19 Finger-finger-nose test 628f Finger-nose test 627f Fish-eye disease 834 Fishgold’s bimastoid line 736 Fishgold’s digastric line 736 Fissured tongue 10, 11f Fistula 941 sign 613 Flares, spontaneous 844 Flatworms 168 Flexion extension injury 718 Flexor digitorum profundus 626 sublimis 626 Flexor pollicis longus 626 Flip test 723 Flocculonodular lobe, lesion of 642 Flow cytometry 895 Fluconazole 180, 184, 542, 886 Fluctuating visual acuity 818 Fludarabine 513 Fludrocortisone 822 Fluid 561 analysis, pleural 379 cytology, pleural 884 thrill 412 Flukes 156, 168 Fluorine 67 Fluorosis 940 Flurbiprofen 850 Fluvastatin 837 Focal adult-onset dystonia 630 Focal neurological deficit 683, 686

Focal proliferative glomerulonephritis 545f Focal seizures 654 Focal skeletal disorder 842 Foetal alcohol syndrome 926 development 825 Foetor hepaticus 404 Folate deficiency 488 causes of 487 Folate, metabolism of 487 Folic acid 63, 68, 427, 847 Follicular cell 774 Follicular lymphoma 876 Food poisoning 425 Foot drop 632 pat test 628 Foramen magnum 726 Forced expiratory volume 348 Forced vital capacity 348 Foregut carcinoids 756 Formoterol 357 Fosamprenavir 140 Fosinopril 287, 296 Foul smell 590 Fracture 714 spontaneous 894 Framboesia 107 Frank haemoptysis 328 Fredrickson’s classification 834 Free radical scavengers 691 Friction fremitus 339 Friction rub 414 Friedreich’s ataxia 699, 794 signs 699 symptoms 699 Froin’s syndrome 960 Frontal lobe functions 587 lesions 587 Frontal lobe disease bilateral 587 dominant left 587 nondominant right 587 Fronto-mesencephalic-pontine pathway 602 Frovatriptan 683 Fructose 815 1, 6-diphosphatase 829 Fukuyama congenital muscular dystrophy 744 Fulminant hepatic failure 459 Fungal ball 948f infections 135, 137, 176 toxins 878 Fungus 751

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993

Index Funicular pain 727 Funnel chest 334 Furious rabies 128 Furosemide 285, 290, 564, 840 Fusobacterium 711

G Gabapentine 658 Gaisbock syndrome 501 Gait 632 abnormalities of 632, 641 Galactorrhoea 752 Galactosemia 832 Gallavardin phenomenon 217 Gallbladder 408 atony 821 disease 833 disorders 33 palpation of 409 Gallium-67 scan 944 Gallstone disease 941 Gamma-glutamyl transpeptidase 436 Ganavastatin 837 Ganglioneuroma 752 Gangrene, dry 867f Gas and bloating symptoms 433 diffusion capacity 352 gangrene 82 Gasserian ganglion lesions causes 607 Gastric acidity, decreased 878 adenocarcinoma 881 asthma 355 cancer 881, 883, 905 carcinoma 878, 898 distension, reduce 908 first-pass metabolism 922 irritation 880, 908 peristalsis 406 secretion 750 surgery 838, 878 ulcer 34, 421f, 434, 850 benign 421f malignant 421f Gastrinoma 750, 833 Gastritis 103, 926 Gastrointestinal anthrax 83 bleeding 422, 849, 850 upper 918, 923 cancers, common manifestation of 880 disease 379 disorders 821, 840, 930 endoscopy, upper 422 malignancies 434

Index.indd 993

mucormycosis 183 system 415, 847 toxicity 909 tract 55, 863, 915 ganglioneuromas 788, 789 hypomotility 768 infection 886 side effect 838 tuberculosis 96 tumours 830 virus infections 130 Gastro-oesophageal reflux disease 418 Gastroparesis 800, 822 Gaucher’s disease 384 Gaucher’s syndrome 940 Gaze palsy, horizontal 668 Gegenhalten phenomenon 623 Gemfibrozil 838 Genes 876 mutations of 876 Genetic 922 causes 313 classification 691 disease 876 disorder 242, 834 Genital herpes 117 HSV infection 117 infections 116 mycoplasmas 102 Genitourinary 810 disorders 821 system 915, 926 tuberculosis 95, 370 Gentamicin 367, 542, 711, 919 aerosol 367 Genu valgum, causes 20 Genu varum, causes 20 Geriatric medicine 913 giants of 916 Geriatric unit 916 Germ cell neoplasms 898 tumours 791 Germ line mutation 879 German measles 125 Gestational diabetes mellitus 802 diagnosis of 826 Ghon’s focus 368 Ghon’s lesions 368 Giant cell arteritis 682, 866, 869 myocarditis 313 Giardia lamblia 135, 147, 148f Giardiasis 147 Gibson murmur 217 Gigantism 15, 752, 756 types of 15

Gilbert’s syndrome 439 Gingival pain 932 Gittleman’s syndrome 781 Glabellar reflex 606, 638 Glabellar tap 640f Glargine insulin 797f Glasgow coma scale 570 Glaucoma 810, 818, 851 Glaucomatous optic disc 596f Glibenclamide 808 Gliclazide 808 Glimepiride 808 Glioblastoma multiforme 954f Glioma 685, 750, 759 Glipizide 808 Glitazar 809 Globus pharyngeus 402 Glomerular disease 544 primary 547 Glomerular disorders 539 primary 537 Glomerular haematuria 535 Glomerular injury 881 Glomerular proteinuria 537, 538 causes of 537 Glomerulonephritis 547, 872 acute 547 proliferative 859 Glomerulopathy 543 classification 543 management of 548 primary 543 secondary 543 Glomerulosclerosis diffuse 824 segmental 545 Glomerulus, normal 544f Glossitis 488 Glossopharyngeal nerve 615 Glucagon 812, 828 test 831 Glucagon-like peptide-1 807, 808 Glucagonoma 6, 750, 793, 833 Glucocorticoid 794 tapering of 787 therapy 840 Gluconeogenesis 812 Glucose 6-phosphatase 829 dependent insulinotropic polypeptide 808 dose 803 homeostasis 828 intolerance 833 low plasma level of 828 metabolism 298 monitoring, invasive frequent 795 peripheral utilisation of 831

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994

Manual of Practical Medicine phosphorylation 796 tolerance impaired 781, 803, 832, 915 test, intravenous 803 transport increases 796 molecules, translocation of 805 Glucosidase inhibitors, alpha 807 Glucowatch biographer 795 Glutamate antagonist 691 Gluteus maximus 627 medius 626 minimus 626 Glyburide 808 Glycaemic index 52 Glycated haemoglobin 801 Glycogen synthetase 829 Glycogenesis 796 Glycogenolysis 828 activating 812 Glycolysis 796 Glycoprotein 301 IIB IIIA inhibitors 673 myelin-associated 890 Glycosuria, alimentary 803 Goitre 772 multinodular 773 Golimumab 432, 852 Gonadotrophic hormone 751 Gonadotrophin agonists 903 Gonadotrophin releasing hormone 750, 751 Gonadotropin 887 Gonadotropin-releasing hormone 751, 840 Gonococcal conjunctivitis 79 infection 78 meningitis 79 urethritis 79f Gonorrhoea, uncomplicated 79 Goodpasture’s syndrome 350, 548, 866 Gordon reflex 635 Gout 844, 940 chronic 844 Gouty arthritis 837 Gradenigo’s syndrome 607 Graft-versus-host disease 532 chronic 862 Graham-steell murmur 217, 277 Gram-negative bacilli 92 enteric bacteria 85 rods 85f Gram-positive bacilli 79f, 80f, 83f cocci 75f organisms 381

Index.indd 994

Granular casts 554 Granules, secretory 895 Granulocyte colony-stimulating factor 479 macrophage colony-stimulating factor 479 Granulocytopenia 962 Granulocytosis 889 Granuloma 317, 750, 759, 945 inguinale 99 Granulomatosis 866 Granulomatous disease 758, 785 lesions 963 thyroiditis 771 Granulosa cell 791 Graphaesthesia 649 Grasp reflex 637 Graves’ disease 765, 766, 772, 795 hyperthyroidism of 765 Gravid uterus 410 Gravidarum 406 Grazoprevir 446 Great vessels, transposition of 258f Grey-Turner’s method 408 sign 406 Groping reflex 637 Growth hormone 752, 828, 887 releasing hormone 750, 887 excess 752 secretion, excess 752 Growth altered 910 retardation 800 Guanabenz 295 Guanethidine 295 Guanidinosuccinic acid 556 Guanosine monophosphate, cyclic 823 Guillain-Barré syndrome 126, 610, 736, 738, 739, 760, 960 treatment of 739 Guinea worm infection 166 Guinea-pig kidney cells 120 Gustatory sweating 822 Gynaecomastia 792, 888 Gynoid obesity 17

H Haemangiomas 945 Haematemesis 328, 422 Haematochezia 402, 423, 881 Haematocrit 860 Haematologic syndromes 888 Haematological disorders 138, 415

malignancies 504 manifestation 779 Haematology 475, 926 Haematomyelia 719 Haematopoiesis 476, 476f normal 476 Haematopoietic cells 478f growth factors 476, 478, 480 stem cell 477 differentiation 477 transplantation 531 system 59 Haematospermia 883 Haematuria 404, 534, 545 catheter 970 causes of 535 intermittent 535 microscopic 883 nonglomerular 535 Haemochromatosis 465, 466f, 751, 778, 879, 963 classification 465 idiopathic 465 Haemodialysis, complications of 560 Haemoglobin 801 concentration 908 Haemoglobinopathy 801 Haemolysis 483 Haemolytic anaemia 483, 490, 801, 847, 858, 881 chronic 940 crisis 493 jaundice 438 uremic syndrome 526, 909 Haemopatoiesis 476f Haemopericardium 961 Haemophilia A 527 B 528 Haemophilus 492 ducreyi 98 influenzae 84, 188, 711, 886 Haemoptysis 328, 882, 892 causes of 328 severity of 328 types of 328 Haemorrhage 483, 816, 941 preretinal 817 putaminal 676 subarachnoid 299, 678, 680 subconjunctival 108f subhyaloid 683 thalamic 676 vitreous 818 Haemorrhagic cystitis 909 peritoneal fluid 469 Haemosiderosis, pulmonary 265

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995

Index Haemothorax 382, 958 Hair 6 colour of 8 follicle growth stages 6, 7f growth, phases of 7 loss of 7 premature graying of 800 types of 6 Hairy cell leukaemia 513, 898 Hairy leucoplakia 11, 137f Hairy tongue 11 black 11f Half-half nail 25f Hallucinations 928 Haloperidol 760, 908 Hamman’s mediastinal crunch 346 Hamstrings 627 Hand joints, arthritis of 844 Hansen’s disease 4, 96 Harrison’s sulcus 59, 334 Harvix 447 Hasenclever index 517 Hashimoto’s disease 767 Hashimoto’s thyroiditis 771, 772, 786 Hashitoxicosis 765 Head and neck cancer 879, 882, 884, 898 injury 750, 760 Headache 681, 682, 752, 756, 760, 837, 838, 849, 852, 931 types of 682 Hearing defective 847 loss 868 tests 613 subjective 612 Heart 752 block 237, 307, 308, 863 acquired complete 261 complete 232, 239f first degree 237 second degree 237, 238f third degree 237 blood supply of 305f catheterisation, right 394 chambers 202f disease 138 acyanotic 216 congenital 239, 240, 241F ischaemic 298, 863 valvular 264 failure 283, 313 acute 284, 285 backward 283 chronic 286 congestive 378, 761, 829, 832 dystolic 283, 284 forward 283

Index.indd 995

left sided 283 right sided 283 types of 283f malformations left 239 right 239 murmurs 213 rate abnormalities 821 response 712 sound 209 first 209 fourth 211 second 210 third 211 Heberden’s nodes 940 Heel pad thickness 21 Heel-knee test 628f Heimlich’s manoeuvre 345 Heinz bodies 482 Helicobacter pylori 91, 419, 515 diagnosis of 419 infection 878 vaccine 92 HELLP syndrome 441 Helminthic infestations 156 Hematoxylin 895 Hemianopia 591 altitudinal 593, 593f Hemiballismus 629 Hemiblock 223 left anterior 223 left posterior 223 Hemidiaphragm bilateral elevated 351 elevated 882 Hemidystonia 630 Hemiparesis 683 Hemiplegia cruciata 726 Hemiplegic gait 632 posture 18 Hemisphere, functions of left 586 Hemithorax opacity 349 Hemochromatosis 793 Hemoptysis 868 Hemorrhages, common sites of 64 Henoch-Schönlein purpura 547, 548, 865, 866 Heparin-induced thrombocytopenia 526, 527f Hepatic artery angiography 883 cirrhosis 923 coma 460, 573 types of 460 disorders 840 encephalopathy 460, 961

excretory function 440 extraction of insulin, decreases 805 failure 781, 815, 830 fibrosis, detect 437 glycogen synthase, increases 805 glycogenolysis 830 regeneration 923 segments 435 tenderness 923 triglyceride synthesis 838 venous thrombosis 458 Hepatitis 103, 111, 850 A vaccine 447 acute 372, 444, 836 B 844 chronic 445, 446 virus 131f, 879 C 443f chronic 445 virus 515, 879 causes of chronic 444 chronic 444, 445, 963 active 444, 772, 963 classification of chronic 444 D 131f, 445 prevention of 447 symptoms in 442f virus 130, 440, 794 Hepatobiliary disorders 137, 838 flukes 170 scan 943 Hepatoblastomas 791 Hepatocellular carcinoma 462, 830, 879, 882, 883, 899 aetiology 462 jaundice 437 Hepatocyte nuclear factor 793 Hepatoma 462, 463f Hepatopulmonary syndrome 462 Hepatorenal syndrome 461 Hepatotoxicity 850 Hereditary 759, 820 ataxia 695 biochemical disorders 695 breast 880 fructose intolerance 832 multiple exostosis 876 renal diseases 551 sensory motor neuropathy 740 spherocytosis 491, 492f syndromes 879 Heredito-degenerative dystonias 630 Heritable biosynthetic defects maternal transmission 767 Hermaphrodite, True 791 Herniations, types of 687 Herpangina 131

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996

Manual of Practical Medicine Herpes genitalis 116f Herpes gladiatorum 116 Herpes labialis 115f Herpes simplex encephalitis 709f virus 136 Herpes virus 115f infections 115 Herpes zoster 33, 119, 119f ophthalmicus 607, 607f vaccine 187 virus 136 Herpetic eye infections 117 Heteronymous hemianopia 591 Heterophile antibody tests 120 Heterozygotes 494, 922 Heterozygous familial hypercholesterolaemia 836, 838 Heubner’s recurrent artery 674 Hexamethylmelamine 898 Hiccough 402, 881 Hiccup 402, 908 Hill’s sign 274 Hilus cell 792 hyperplasia 792 Hip 845 fracture of 840 Hippel-Lindau disease 789 Hirsutism 783f, 800 Histiocytosis 758, 940 Histocompatibility antigens 50 Histone deacetylase inhibitors 905 Histoplasma 178f capsulatum 178 Histoplasmosis 136, 178 type of 179 Hodgkin’s disease 371, 515, 518, 896 classical 516 non-classical 516 Hodgkin’s lymphoma 504, 517f, 518, 778, 927 Hoffman’s reflex 636, 636f Hoffman’s syndrome 768, 769f Holiday heart syndrome 926 Holt-Oram syndrome 18, 243, 244 Homan’s sign 35 Homeostasis 914 Homocystinuria 14 Homogentisic acid 845 Homonymous hemianopia 591 Homozygotes 494 Honeycomb lung 350 Honey-moon phase 798 Hookworm 156, 157f life cycle of 157f Hormonal therapy 823 Hormones thyroxine 751 Horn cell anterior 726 lesion, anterior 621

Index.indd 996

Horner’s syndrome 332, 386f, 388, 668, 713, 882 acute 713 congenital 713 Howell-Jolly bodies 482 Human antibody infusion reactions 909 Human herpes virus 122, 515 types 122 Human immunodeficiency virus 132f, 137, 138, 374, 425, 441, 515, 543 infection 132-134, 372, 451 syndromes of 133 Human insulin 796 Human pancreatic polypeptide 789 Human papillomavirus 122, 880 Humerus, fracture of 840 Humoral hypercalcaemia 775 Humoral immunodeficiencies 48 Hungry bone syndrome 779 Huntington’s chorea 629, 794 Huntington’s disease 629 Hydatid cyst 175f, 934 Hydatid thrill 413 Hydatidiform mole 765 Hydralazine 287, 789, 857, 861 Hydrazine 928 Hydrocele 164f Hydrocephalus 825 Hydrochlorothiazide 286, 861 Hydroflumethiazide 286 Hydrogen ion homeostasis 565 disturbances of 566 Hydrolysis 426 Hydronephrosis 942 Hydropneumothorax 958 right 345f Hydrops foetalis 123 Hydroxyurea 898 Hymenolepiasis nana 175 life cycle 175 Hyoscyamine 731 Hypalgesia 644 Hyperactivity, autonomic 928 Hyperacute rejection 50 Hyperalbuminaemia 775 Hyperaldosteronism 781 idiopathic 780 primary 780 secondary 781 Hyperalgesia 644 Hyperalimentation 832 parenteral 776 Hyperalphalipoproteinaemia, familial 835 Hyperbilirubinaemia 825, 923 Hypercalcaemia 228, 520, 573, 759, 777, 778, 787, 842, 881, 882, 888 causes of 775 familial benign 777 severe 775

Hypercalcaemic crisis 778 Hypercalciuria 842 Hyperchloremic acidosis 566 Hypercholesterolaemia 882 familial 835 polygenic 835 Hyperdynamic apical impulse 207 Hyperesthesia 644 Hyperglycaemia 140, , 788, 820, 827, 837, 851 complications 827 postpartum 802 Hyperintense signals 705f Hyperkalaemia 66, 226, 226f, 227f, 564, 787 causes of 564 Hyperkeratosis 857 Hyperkinesia 688 Hyperkinetic pulse 195, 197f causes 195 Hyperlipidaemia 140, 822 familial combined 836 lipoprotein type 835 multiple lipoprotein-type 835 Hyperlipoproteinaemia 299, 833, 834, 836, 851 familial type-3 835 secondary 836 Hypermagnesaemia 226, 779 Hypermetabolic state 922 Hypermetabolism 752 Hypernatraemia 65, 562, 573 normovolaemic 562 Hyperosmia 590 Hyperosmolar coma 573, 810, 814 Hyperparathyroidism 756, 776f, 778, 839, 841, 940 endocrine causes of 778 primary 775, 776, 841 secondary 559, 778 tertiary 778 Hyperpathia 645, 736 Hyperpituitarism 789 Hyperplasia, micronodular 781 Hyperpnoea 335 Hyperprolactinaemia 755 Hyperpyrexia 28, 766 causes of 28 Hyperreninaemia, primary 781 Hypersecretory disorders 752 Hypersegmented neutrophils 926 Hypersensitivity, reactions 49 Hypersplenism 926 Hypertelorism 8, 8f Hypertension 207, 293, 294, 780, 802, 816, 816f, 861, 869, 918, 931, 932 accelerated 200, 781 causes of 200 complications of 299 control of 790

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997

Index episodic 201 investigation of 292 labile 201 malignant 28, 200, 204f, 293 management of 293 paradoxical 201 paroxysmal 201 pregnancy induced 873 pulmonary 33, 392-395, 846, 934 venous 393 resistant 201 systemic 192, 290, 291f transient 200 Hypertensive crisis, management of 299 emergency 200 renal disease 865 retinopathy 204 states 201 urgency 200 Hyperthyroid face 12 Hyperthyroidism 761, 762, 763f, 766, 772, 778, 789, 793, 810, 839, 915, 918 Hypertonia 622 Hypertonic bladder 729 saline infusion test 760 inhalation 368 Hypertransradiant hemithorax, unilateral 349 Hypertrichosis, causes of 8 Hypertriglyceridaemia 752, 801, 834, 835, 838 familial 835 primary 834 Hypertrophic cardiomyopathy 218 Hypertrophic obstructive cardiomyopathy 192, 315, 316f midventricular type 316f Hypertrophic osteoarthropathy 331, 881 Hypertrophic pulmonary osteoarthropathy 845, 882 Hypertrophied fibrocartilaginous tissue 752 Hypertrophy 844 biventricular 222 left ventricular 219, 221f, 299 Hyperuricaemia 801, 837 Hyperviscosity syndrome 847 Hypervitaminosis C 64 D 60 Hypervolaemic hypernatraemia 562 Hypesthesia 644 Hypnotics 916, 918 Hypoalbuminaemia 458, 861, 923 Hypoalphalipoproteinaemia, familial 834 Hypocalcaemia 226, 227f, 573, 778, 780, 814, 825 disorder 778, 779

Index.indd 997

Hypocalciuria 777 Hypocalciuric hypercalcaemia, familial 775, 777 Hypochromia 482 Hypochromic anaemia 486 Hypochromic microcytes 485f Hypocomplementemia 859, 861, 866 Hypocretin neurons, number of 582f Hypoesthesia 644 Hypoglossal nerve 617 Hypoglossal nucleus 617 Hypoglycaemia 755, 800, 802, 806, 810, 814, 815, 820, 821, 825, 827-831, 882, 894 reactive 832 signs of 829 symptoms of 828, 829, 831 unawareness 831 Hypoglycaemic coma 573 episodes, recurrent 800 symptoms 802 unawareness 800 Hypogonadism 71, 138, 839, 840 Hypogonadotrophic hypogonadism 750, 823 Hypokalaemia 65, 226, 227f, 550, 563, 759, 780, 781, 813, 814 causes 65, 563 Hypokalaemic alkalosis 782 Hypokinesia 688 Hypokinetic pulse 195, 197f causes 195 Hypomagnesaemia 226 Hyponatraemia 65, 562, 573, 787, 888 mild 888 normovolaemic 562 severe 888 Hypoparathyroidism 690f, 779f, 786, 795 idiopathic 772, 778 surgical 778 Hypopharynx 879 Hypophosphataemia 66, 839 Hypophosphataemic rickets 59 familial 839 Hypophosphatasia 839 Hypopituitarism 750, 751 Hypoplastic thumb 20f Hypoproliferative marrow 483 Hyporeflexia 812 Hypotension 778, 787, 927, 961 orthostatic 199, 821, 822 postural 199, 298, 914, 917, 918 Hypothalamic causes 750 disorders 70 hamartoma 752, 791 lesions 574 Hypothalamus 750 Hypothermia 229, 229f, 918

Hypothyroid face 12 phase 771 Hypothyroidism 427, 702, 755, 767, 769f, 773, 835, 836, 844, 915, 916, 918, 960 chronic primary 791 congenital 767, 768f primary 770 secondary 770 subclinical 770 Hypotonia 623, 641, 812 causes of 623 Hypotonic polyuria 757 Hypouricaemia 761 Hypoventilation 395 Hypovolaemic hypernatraemia 562 Hypovolemic shock 39 Hypoxia 573 Hysterectomy, abdominal 906 Hysterical rigidity 623

I Iatrogenic virilisation 791 Ibuprofen 850 Icteric leptospirosis 108 Icterus 923 Idiopathic skeletal hyperostosis, diffuse 856 Ifosfamide 907 Ilaprazole 420 Ileal ulcer 850 Ileocaecal syndrome 886 Iliac crest, posterior 962 fossa, right 409f Iliofemoral disease 955f Iloprost 394 Imatinib mesylate 510 Imidapril 297 Immobility 917 Immotile cilia syndrome 3 Immune 445 cells, dispersed 45 complex disease, local 49 function 914 globulin, anti-HAV 447 leptospiruric phase 108 mechanism 794 regulatory T-cells 46 response 141 system 45 abnormality 800 thrombocytopenic purpura 524 Immunisation 139 Immunity, basis of 45 Immunity-viral diseases 113

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Manual of Practical Medicine Immunochromatographic dipstick methods 144 Immunodeficiency combined 48 states 48 Immunoglobulins 46 disorders of 48 Immunological liver damage 922 Immunology 45, 46, 50 Immunosuppression 472 causes of 376 Immunosuppressive therapy 561 Inattention hemianopia 593 Incisional biopsy 884 Incongruous hemianopia 592 Incretins 808 Indapamide 286 Indinavir 140 Indirect thrombin inhibitors, pros and cons of 303 Indomethacin 849, 850 Infarct left ventricular 224 locations 674 pulmonary 934 Infarction 873, 941 crisis 492, 493 Infection 55, 59, 758, 759, 791, 814, 887 asymptomatic 133 congenital 154 deep 824 relapse of 539 Infectious diseases 73, 547, 866 immunisation against 185 Infectious injury 551 Infectious mononucleosis 119 Infective endocarditis acute 278 development of 278 subacute 278 Infertility 768 Infiltration 317 local 778 Infiltrative disorders 963 Inflammation anaemia of chronic 489 chronic 853 Inflammatory demyelinating polyneuropathy, chronic 739, 890 Infliximab 114, 350, 432, 852, 855 Influenza 114f vaccine 186 Infraclavicular subclavian vein 968 Infraspinatus 625 Inhalational anthrax 83 Inhaled glucocorticoids 356 Inhaled insulin 798

Index.indd 998

Inherited immunodeficiency disorders 515 Inherited salt losing tubulopathies 550 Inhibiting residual insulin secretion 812 Inorganic nutrients 65 Inotropic-vasopressor agents, action of 289 Insomnia 581, 837, 838, 931 Inspiratory tracheal descent 337 Insulin 751, 809, 810, 829, 830, 927 actions of 795, 796 allergy 801 analogues 796 antibodies 830, 831 autoantibodies 795, 829, 831, 832 delivery 799 systems 799 dependent diabetes mellitus 828 detemir 798 glargine 797 glulisine 797 infusion 827 inhalers 799 like growth factor 807, 830 lipoatrophy 801 mediated glucose transport, potentiation of 805 oedema 801 pens 799 pump therapy external 799 implanted 799 pumps 799 receptor autoantibodies 829, 832 regimens 798 resistance 800 secretagogues 805 secretion increased 829 suppression of 831 sensitisers 807 syringes 799 therapy 795, 826 aggressive 825 complications of 800 goals of 795 principles of 809 time table 793 treatment 815 Insulinoma 70, 750, 831-832 Insulinotropins 807 Insulitis 794 Intention tremor 631, 641 Intercapillary glomerulosclerosis, diffuse 546f Intercostal vessels and nerves 958 Interleukin 479, 767, 907, 909 Interlobular lymphatics 934

International classification of sleep disorders 581 Internationally recognised staging system 884 Internuclear lesions 602 ophthalmoplegia, right 603f Interphalangeal joint arthritis, distal 857 Interstitial cell tumours of testes 791 Interstitial fibrosis 846 Interstitial lung disease 384, 399 Interstitial nephritis 850 acute 551 chronic 551 Interstitial pneumonias idiopathic 385 non-specific 385 Interstitial pneumonitis 909 Interstitial pulmonary diseases, chronic 384 Intervertebral disc prolapse 721 Intestinal absorption of calcium, increased 775 amoebiasis 147 culture, small 428 dysfunction, small 821 flukes 170 human nematodes 156 infections 86 malabsorption 488 obstruction 880, 893, 908 pathogenic strains 85 perforation 859 peristalsis 406 schistosomiasis 169 surgery 838 Intestine small 434 vasculitis of 859 Intoxication, acute 924 Intra-abdominal infection 86 Intracavitary nodule 948f Intracerebral bleed 677f haemorrhage 675 primary 662 leucocytostasis 891 Intracranial calcification 940 haematoma 678 hypertension, benign 684 pressure increased 891 raised 881, 908 saccular aneurysms 680 tension 959 tuberculosis 706 tumours 594, 880

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Index Intraepithelial dysplasia 137 Intrahepatic cholestasis benign recurrent 441 of pregnancy 441 Intramedullary lesions of cord 727 Intraspinal tuberculosis 707 Intrauterine growth retardation 873 life 476 Intravenous cytotoxics, administration of 966 Invasive aspergillosis 181 life-threatening 181, 183 Invasive tests needing endoscopy 92 Invasive therapy 823 Iodine 67, 68 containing drugs 767 deficiency 767 Irbesartan 297 Iridodonesis 204 Iritis 856 Iron 67, 68, 427 deficiency 67 anaemia 483, 484, 484f, 485f, 495, 881 causes of 484 dextran-IV 485 excess 67 metabolism 484 therapy, parenteral 485 Irregularly irregular rhythm 195 Irritability 829, 849 Irritable bowel syndrome 432 Ischaemia 822 myocardial 224 prominent 823 Ischaemia-gangrene, severe 824 Ischaemic attack, transient 663 Ishihara chart 593f Islet cell antibodies 795 neoplasms 898 tumour 882 Isletitis 794 Islets of Langerhans 793 Isolated dextrocardia 243 Isolated systolic hypertension 200, 915 causes of 291 Isometric exercise 218 Isoniazid 372, 861 Isosorbide dinitrate 287 Isosorbide mononitrate 287 Isospora belli 135 Isosporiasis 149 Isradipine 296 Itraconazole 184 Ivabradine 304

Index.indd 999

J Japanese B encephalitis 130 pathogenesis 130 Jarisch-Herxheimer reaction 106 Jaundice 4, 403, 437, 438, 923 causes 437 congenital 438 obstructive 438, 893f postoperative 472 types 437 Jaw jerk 606, 638 Jerky nystagmus 603 cause of 603 grading of 603 types of 603 Jet-lag syndrome 583 Joint 914, 940 mobility 819 protection 849 sense 647 stiffness 845 tuberculosis 370 Jones criteria 262 Jug handle appearance 245f Jugular foramen 617 Jugular reflux, abdominal 203 Jugular vein external 968 internal 968 Jugular venous pressure 201, 318 measurement of 202f Jugular venous pulse 202, 203, 203f abnormalities of 203 Junctional tachycardia 230, 233, 308 Juvenile hypothyroidism 791 idiopathic arthritis 844 mitral stenosis 265 myoclonic epilepsy 652 onset spondyloarthritis 853

K Kala-azar 149, 962 Kallmann’s syndrome 750, 792 Kanamycin 372, 374, 919 Kaopectate 822 Kaposi’s sarcoma 136, 907 Karnofsky performance index 885 Kartagener’s syndrome 243 Katayama syndrome 169 Kawasaki’s disease 112, 866, 870 Kawasaki’s syndromes 866 Kayser-Fleischer ring 9f, 404, 404f, 463 Keith-Wagner-barker grading 204 Keratoconjunctivitis sicca 847 Keratopathy 851

999

Ketoacidosis 815, 825 Ketoconazole 184, 784 Ketones 813 Ketoprofen 850 Ketorolac tromethamine 684 Ketostix 812 Ketotifen 356 Kidney 300, 408, 565, 778, 830, 944 bilateral contracted 942 bimanual palpation of 410f biopsy 964 contracted 558f disease, chronic 556 injury, acute 552 large 942 left 411 non-functioning 941, 942 non-visualised 942 palpation of 410 transplantation 561, 828 tubulointerstitial disease of 550 Killip classification 307 Klaus, height index of 735 Klebsiella pneumoniae 351, 376 Klinefelter’s syndrome 15, 41, 43, 680, 792, 794, 880 Klippel-Feil anomaly 733 Klippel-Feil syndrome 245 Knee 845 jerk 638 reflex, inverted 637 Knuckle-knuckle-dimple-dimple sign 18 syndrome 940 Kocher-Debre-Semalaigne syndrome 768 Koilonychia 23, 24f Korotkoff’s sounds 199 Korsakoff’s syndrome 62 Kronig’s isthmus 340 Krukenberg’s tumour 881 Kussmaul’s breathing 336 Kussmaul’s sign, causes of 203 Kwashiorkor 54, 55f, 56 Kyphoscoliosis 335 Kyphosis 335f

L Labyrinthine disorders, peripheral 614 lesion 613 Lacosamide 658 Lacrimal gland disorders 821 Lacrimation 609 Lactic acidosis 140, 815 Lactulose 425

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1000

Manual of Practical Medicine Lacunar infarction 673 syndromes 674 Lagophthalmos, bilateral 764f Lambert-Eaton myasthenic syndrome 890 Lamivudine 139 Lamotrigine 658 Landolfi’s sign 204, 274 Lanreotide 754, 833 Lansoprazole 420 Lanugo hairs 6 Laryngoscopy 884 Larynx 879, 929, 944 Lasegue test 723 Latent diabetics 803 Latex test 848 Latissimus dorsi 625 Laurence-Moon-Biedl syndrome 19, 70, 794, 940 Lecithin-cholesterol-acyl transferase deficiency 834 Ledipasvir 446 Leflunomide 851 Legionella 84 pneumonia 376 Legionnaires disease 84 Leishmania donovani 149 life cycle of 150f Leishmaniasis 149 control of 151 mucocutaneous 151 mucosal 151 prevention of 151 Lemniscal system 644 Lennox-Gastaut syndrome 652 Lens 205 fibres 876 Lentigines 756 Leonine facies 12, 97f Leopard syndrome 243 Lepirudin 303, 527 Lepra reactions 97, 98 Leprechaunism 800 Leprosy 96, 97f lepromatous 97, 97f Leptin 70 Leptomeninges, involvement of 891 Leptospirosis 107, 108 Lethargy 762, 767 Leucine aminopeptidase 436 Leucocytes 536 Leucocyturia 545 Leucopenia 858 Leukaemia 499, 504, 531, 760, 816, 841, 845, 858, 877, 878, 880, 940, 962 acute 506f, 507f, 891 lymphocytic 887 relapsed 898

Index.indd 1000

Leukaemoid reaction 499 Leukopenia 858 Leukotriene antagonists 357 LeVeen or Denver shunt 459 Levetiracetam 658 Levine test 191 Levodopa 689 Levofloxacin 542 Levosimendan bolus 285 Lhermitte’s sign 649, 732 Libman-Sacks endocarditis 281 Lichen planus 859 Lidocaine 322 Light chain disease 48 Light reflex 600 pathway of 600, 600f Limb 59 girdle muscular dystrophy 743 kinetic apraxia 578 lower 628f Limbic encephalitis 889 Linagliptin 809 Lincoln’s ataxia 700 Lindsay nail 24, 25, 25f Linea nigra 406 Linear scleroderma 862 Linifanib 463 Lipemia retinalis 834 Lipid metabolism 796 Lipodystrophic states 800 Lipohypertrophy 801 Lipolysis, activating 812 Lipoma 945 Lipoprotein classification of 833 composition, classification of 833 high density 834 intermediate density 834 lipase 70, 796 deficiency, familial 834 low density 834 Liposomal doxorubicin 907 Lisinopril 286, 296 Lispro insulin 796 Listeria 887 Listerial infections 886 Listeriosis 82 Lithium 759, 767, 775, 840, 861, 919 Live donor transplantation 472 Liver 407, 411, 441, 448f, 752, 796, 925, 944 abscess 448, 448f causes 448 biopsy 463, 466, 963 needles 963 percutaneous 436 cell failure, signs of 404 water 922

cirrhosis of 450, 457, 458, 761 disease 37, 806 active 837 acute 841 anaemia of 489 chronic 372, 858, 923 decompensated 792 metabolic 463 disorders 372 failure 829 fat, increased 922 function tests 431, 435, 895 persistent abnormal 963 injury mechanism of 922 palpation of 409 segmental anatomy of 435f span 411 transplantation 456, 471 Lobar pneumonia 375 Lobular hepatitis, chronic 963 Locked-in syndrome 571 Loffler’s endocarditis 315 Loperamide 822, 833 Lopinavir 140 Lordotic posture 17 Losartan 297 Loudness balance test, alternate biaural 612 Lovastatin 837, 861 Low grade fever 845 Low plasma volume polycythaemia 501 Lower lung field bronchiectasis 364 Lumbar canal stenosis 717, 721 disc prolapse 722 symptoms 722 enlargement 715 lordosis 743f puncture 679, 959 headache 682, 684 needle 959 spine 714 extension of 854 spondylosis 720, 844, 914 Lumbosacral spine 891 Luminal phase 426 Lung 116, 830, 848, 929, 961 abscess 377 biopsy 394 borders of 326 cancer 879, 880, 882, 884, 907 types of 385 carcinoma 758, 760 cavities 351 disease 376 chronic 282 inflammatory 928 suppurative 328 fields, increased translucency of 934

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1001

Index flukes 170 function tests 347, 928 injury, acute 390 lymphatic drainage of 332 parenchyma 958 right 386f sequestration of 364 transplantation 399 tumour of 778 volume 348f estimation 348 Lupus anticoagulants 859 band test 858 erythematosus 772 nephritis 858 WHO classification of 548 peritonitis 859 Luteomas 791 Lyme borreliosis 109 disease 109, 866 Lymph node 847 biopsy 884 regional 882 sampling 906 syndrome, mucocutaneous 870 tuberculosis 95, 370 Lymphadenitis, tuberculous 370 Lymphadenopathy 138, 404, 415, 845 generalised 847 local 847 regional 103 Lymphangitis 823 carcinomatosis 934 Lymphatic filariasis, life cycle of 163f Lymphoblastic leukaemia, acute 511 Lymphocytes 498, 774 atypical 120f cell 477 migration of 45 Lymphocytic leukaemia, chronic 512, 887, 898 thyroiditis, chronic 772 Lymphocytopenia, causes of 498 Lymphocytosis, causes of 498 Lymphogranuloma venereum 100, 100f Lymphoid 898 leukemia, WHO classification of 504 malignancies 504 organs primary 45 secondary 45 Lymphoma 137, 515, 752, 758, 767, 760, 816, 830, 841, 845, 848, 866, 878, 880, 881, 942, 898 pregnancy 518 Lymphopenia 858 Lynch syndrome 879 Lytic bone metastasis 775

Index.indd 1001

M Macroadenoma 756 Macroalbuminuria 538 Macrocytosis 482, 487f causes of 486 Macrodantin 861 Macroglobulinaemia 775 Macroglossia 10, 768 Macronutrients 52 Macrophage colony-stimulating factor 479 Macrovesicular steatosis 449 Macula, examination of 597 Maculopapular rash diffuse 859 irregular 124f Maddrey index 436 Madras motor neuron disease 693 Madura foot 93f Maduromycosis 184 Magnesium 68, 427, 780 deficiency 780 Maladie-de-Roger syndrome 246 Malaise 859, 923 Malaria 2, 141, 144, 962 chronic 141 noninvasive transdermal detection of 145 severe 143 vaccine 145 Malarial parasite, life cycle 142f Malformation, congenital 125, 853 Malignant lymphoma, risk for 515 Malignant solitary pulmonary nodule 350 Mallampati classification 359, 360f Mallory body 923 Mallory hyalin 923 Mallory-Weiss syndrome 926 Malnutrition 54, 822 Mammary arteries, internal 961 Mammogram 882 Mammography 895 diagnostic 884 Mammosomatotrophs secrete prolactin 750 Manganese 68 Mantle cell lymphoma 876 Marantic endocarditis 281 Marasmus 54, 55f, 56 Marchiafava-Bignami syndrome 925 Marfan’s syndrome 14, 18, 19, 243, 680, 840 Marinesco-Sjögren syndrome 698 Marrow stem cell, nature of 478 Masks, non-rebreathing 353 Mass lesion 908, 945 midline 907

Massive pulmonary embolism, pathophysiology of 396f Mast cell series 46 Mastitis 178 Mastocytosis 840 Maturation disorder 483 Maximal expiratory flow rate 348 Mazzotti test 165 McCune Albright syndrome 752, 791 McGregor’s line 735 McRae’s line 735 Mechanical ventilation, complications of 392 Medial medullary syndrome 667, 668 Medial pontine syndrome 668 Median rhomboid glossitis 11, 11f Mediastinal emphysema 361 Mediastinal mass 387 anterior 388f common 388 posterior 388f Mediastinitis 963 Mediastinum anterior 387, 388 middle 388 posterior 388 superior 387, 388 Medium potency thiazide diuretics 286 Medium vessel vasculitis 866 Medulla 669 oblongata 665 Medullary carcinoma 774 Medullary cystic disease 552 Medullary syndrome 668f lateral 651, 667, 668 Medulloblastoma 685 Medullo-spinal compressions, progressive 734 Mefloquine 146 Mega ureters 942 Megaloblastic disease 488 Megaloblasts 488f Meglitinide 807, 808 Meig’s syndrome 379, 458 Melaena 402, 423 Melanoma 899 familial 876 malignant 907 Melkersson-Rosenthal syndrome 611 Membranous glomerulonephritis 881, 894 Memory 578 components of 578 short-term 578 types of components of 578 Mendelson’s syndrome 924 Menghini’s needle 964 Meniere’s disease 614 Meningioma 685, 758, 759, 800, 940 left parasagittal 687f

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1002

Manual of Practical Medicine Meningitis 126, 706, 758, 760, 791, 959, 960 empirical treatment of 708 meningococcal 78 tuberculous 95, 370 Menorrhagia 768 Mental functions, examination of higher 572 retardation 71, 767 Meralgia paraesthetica 645 Meropenam 542, 708 Mesangial proliferative glomerulonephritis 545, 548f Mesenchymal tumours, large 830 Mesenteric artery inferior 256 occlusion 847 Mesenteric blood flow 750 Mesial temporal lobe epilepsy 652 Mesothelioma 760 pleural 380f Meta-131-iodobenzyl- guanidine 789 Metabolic alkalosis, mild 781 Metabolic disorders 144, 319, 697, 749, 925 Metabolic syndromes 881 Metabolism 59 inborn errors of 670 Metacloproamide 833 Metaiodobenzylguanidine 943 Metals, heavy 425 Metastatic disease 905 Meteorism 934 Metformin 808, 815 Methenamine silver stain 180f Methicillin resistant 711 sensitive 711 Methotrexate 427, 850, 959 Methoxyflurane 759 Methyclothiazide 286 Methyl xanthines 357 Methyldopa 295, 755, 857 Methysergide 434, 866 Metoclopramide 789, 822, 833, 908 Metolazone 286, 775 Metoprolol 295 Metronidazole 148, 420, 426, 432, 449, 711, 927 plus 420 Metyrapone test 786 Mexican hat cells 482 Micafungin sodium 184 Microadenomas 756 Microalbuminuria 538 Microcytosis 482 Microglossia 10 Microinvasive disease 906

Index.indd 1002

Micronized glyburide 808 Microsomal ethanol oxidising systems 922 Microsporidia 135 Microstomia 863f Microvascular oculomotor palsy 600, 600f Microvesicular steatosis 449 Micturition 789 Mid lung field bronchiectasis 364 Midbrain 664, 669 syndromes 670f Mid-diastolic murmur 215, 215f Middleton’s manoeuvre 409 Mid-pontine syndromes 668 Mid-systolic murmurs 213 Miglitol 808 Migraine 682, 866, 873 prophylactic treatment of 684 Milder disease 842 Miliary mottling 350, 369f Miliary tuberculosis 96, 369 non-reactive 370 Milk maid sign 629 Milk-alkali syndrome 775 Mill wheel murmur 217 Miller Fisher’s syndrome 739 Milrinone 289, 394 bolus 285 Mimic paralysis 611 Mineralo-corticoid 780, 786 Minimal change disease 544f Minipolymyoclonus 632 Minocycline 861 Minoxidil 298 Miosis 600 Misoprostol 420 Mitochondrial disorders 44 Mitosis, increased number of 877 Mitoxantrone 898 Mitral annulus disorders 268 Mitral leaflet anterior 280 disorders 268 posterior 280 Mitral regurgitation 207, 211, 218, 268, 268f, 269f Mitral stenosis 208f, 209, 211, 264, 264f, 266f Mitral valve area, normal 264 prolapse 270f, 271f syndrome 218, 270 prosthetic disorders, primary 268 vegetation 280f Mitral valvotomy, open 267 Mitral valvular abscess, large 280f Mixed connective tissue disease 861 M-mode echocardiography 945

Mobius’ syndrome 611 Moexipril 287 Molecular adsorbent recirculating system 473 Molsidomine 287 Molybdenum 68 dietary deficiency of 878 Monoamine oxidase inhibitors 690, 760, 927 Monoarthritis 844 Monoclonal gammopathy 890 Monocular visual loss 593 Monocytes 499 cell 477 Monocytopenia, causes of 499 Monocytosis, causes of 499 Monofilament test 821, 822f Monomelic amyotrophy 694 Mononeuritis 858 multiplex 869 Mononeuropathy 818 syndrome of 737 Monospot 120 Moon face 783f Morant-Baker’s cyst 845 Morning stiffness 844 Morphea 862 Morphine 789 sulphate 312 Morphoea and linear scleroderma 865 Moses’s sign 35 Motility disorder 417 Motor dysphagia 416 Motor function, examination of 608 Motor homunculus 619f Motor neuron disease 691, 693 secondary causes of 694 lesion lower 620 upper 602, 618 Motor paralytic bladder 729 Motor polyneuropathy 820 Motor stroke 674 Motor system 575, 605 Motor unit 620 signs of 620 Motor weakness 722 Mouth dry 918 ulcerations 886 Movement disorders 688 classification 688 Moxifloxacin 376 Mucinous ascites 458 Mucor 183, 183f Mucormycosis 183 pulmonary 183

04-Jan-18 2:25:27 PM

1003

Index Mucositis 897 Mucous membrane lesions 103 Muga scan 942 Muller’s sign 274 Müllerian duct structures 791 Multidrug resistant, management of 373 Multifocal leukoencephalopathy, progressive 704 Multikinase inhibitors 904 Multilobed neutrophil 487f Multinodular goitre, toxic 765 Multiple cranial nerve palsy, causes of 617 Multiple medium sized pulmonary nodules 351 Multiple myeloma 519, 520, 521, 840, 841, 845, 862, 887, 898 cells 520f plasma cell 519f Multiple myelomatosis 839 Multiple sclerosis 702, 703, 703f, 704, 705f, 760, 916, 960 periventricular plaque in 705f Multiple spine secondaries 954f Multisystem atrophy 691 disease 547 Mumps 126, 126f, 771 virus 794 Mural thrombus 918 Murine typhus 110 Murmurs continuous 215, 215f, 216 diastolic 216 functional 217 innocent 216 late diastolic 215 late systolic 213, 214f Levine and freeman’s grading of 213 pre-systolic 215 systolic 213, 214f, 217 Murphy’s punch 411f Murphy’s sign 409 Muscle 336f, 608, 796, 847 abdominal 626 atrophy of 800 biopsy 742 disease inflammatory 746 primary 633 diseases 622 mass, loss of 880 power, testing of 625 sensitivity 648 temporal 605 tone, types of 623f wasting 621, 622, 844 distal 621 small 621, 622f

Index.indd 1003

types of 621 unilateral 622 weakness 416, 781, 914 Muscular atrophy, progressive 692, 693 Muscular dystrophy 742 classification 742 congenital 744 types of 744 Musculoskeletal pain 32 Musculoskeletal system 59, 859, 914 Myalgias 837, 845, 869 Myasthenia gravis 693, 746, 748, 748f, 763f, 772, 795, 858 congenital 748 Myasthenic crisis 747 Myasthenic facies 12 Myasthenic syndrome 748 Mycetoma 184 foot 93 Mycobacteria, atypical 94 Mycobacterium tuberculosis 95f, 135 Mycophenolate mofetil 432, 860 Mycoplasma 384 hominis 102 infections 102 pneumonia 102, 376 Mydriasis 600 Myelitis 858 transverse 725f Myelocytic leukaemia, acute 887 Myelodysplastic syndromes 514 Myelofibrosis 503, 503f, 963 Myelogram 730f appearance 730 Myelography 722 Myeloid 898 leukaemia acute 504 chronic 509, 898 WHO classification of 500 Myeloma 519, 775, 778, 890, 942, 962 nephropathy 545 non-secretory 520 Myelopathy compressive 726 necrotizing 889 non-compressive 718 transverse 873 Myeloproliferative disorders 500 Myelosclerosis, primary 503 Myelosuppression 908 peak incidence of 908 Myerson’s sign 689 Myocardial infarction 32, 304, 311, 847, 870, 916, 932 acute 33 anterior wall 310 painless 821 Myocardial injury 224

Myocardial necrosis 224 Myocardial stunning 309 Myocarditis 131, 312, 317, 859 Myocardium, laceration of 961 Myoclonic seizures 654 Myoclonus 631, 889 causes of 631 generalised 631 metabolic 631 Myoglobin 307 Myo-inositol depletion 820 Myokymia 632 Myopathic syndromes 882 Myopathy 752, 837, 847, 851, 859 congenital 744 mitochondrial 744 Myositis 859 Myotonia 624, 625 congenita 745 Myotonic dystrophy 12, 794 Myxoedema coma 770

N Nafcillin 711 Nail 23, 177 bed angle, normal 331f black 25, 25f blue 25 dystrophy 847 pitting 25f structure of 24f Nalmefene 928 Naproxen 850 Naratriptan 683 Narcolepsy 582 Narcotic analgesics 916 Narrow complex tachycardia 230 Nasal diphtheria 79 disease 868 prongs 353 Nasolacrimal reflex 609 Nasopharyngeal carcinoma 878 Nasopharynx 879, 973 cancer of 882 Natalizumab 432 Nateglinide 807, 808 National Cholesterol Education Programme 836 National Diabetes Data Group 802 Natural killer cells 46, 133 Nausea 402, 668, 760, 787, 829, 836, 837, 849, 852, 859, 869, 870, 880, 923, 927, 928, 931 Nebivolol 295 Neck examination of 332

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1004

Manual of Practical Medicine stiffness 707f veins, examination of 201 Necrotising aspergillosis, chronic 181, 183 Nedocromil sodium 356 Needle biopsy 884 Neisseria gonococci 79f Neisseria meningitidis 711 Nelfinavir 140 Nemaline myopathy 744 Nematodes 156 Neo-adjuvant chemotherapy 898 Neocerebellum 640 lesion of 642 Neomycin 427 Neoplasia 414, 741, 793, 876 Neoplasm 457, 751, 866 benign 877 malignant 877 secondary 136 Neoplastic disease 760 Nephrectomy 942 Nephritic syndrome 12 acute 965 classification of 543 Nephrocalcinosis 777f Nephrogram 941 Nephrolithiasis 842 Nephrology 533 Nephropathy 543, 792 Nephrotic syndrome 12, 544, 546, 781, 836, 859, 861, 965 causes of 544 Nerve accessory 615 compression syndromes 842 conduction velocity 890 entrapment, relief of 822 fibres 750 lesion postganglionic 607 third 598 root 722 compression 723 thickening, causes of 741 Nervous system 59, 87, 569, 859, 915 autonomic 710f, 712, 727, 829 Nesiritide bolus 285 Neuralgia 736 Neurapraxia 735 Neuraxial anomalies 732 Neuroarthropathy 845 Neuroblastoma 898 Neurocutaneous syndromes 660 Neurocysticercosis 173f, 655f Neuroepithelioma, peripheral 898 Neurofibroma 388f, 660f, 685, 788, 789 Neurofibromatosis 660, 876

Index.indd 1004

Neurohypophysis 750 disorder of 757 Neuroimmunophilin 691 Neuroleptic 918 malignant syndrome 29 Neurologic disease 134 disorders 583 paraneoplastic syndromes 889 syndromes 889 Neurology 858, 944 Neuromas, mucosal 789 Neuromuscular disorders 395 junction 608, 890 system 620 Neuromyelitis optica 704, 725 Neuromyopathy 882 Neuronitis, vestibular 614 Neuronopathy 889 Neuropathy 792, 821 anatomical classification of 818 autonomic 800, 818, 820, 847, 889 entrapment 737, 821, 847 Neuroprotective therapy 690 Neurosarcoid 759 Neurosyphilis 104 asymptomatic 104 Neurotmesis 735 Neurotoxic drugs 822 Neurotransplantation 690 Neutropenia causes of 498 cyclic 26 Neutrophilia, causes of 498 Neutrophils 498 cell 477 polymorphs 46 Nevirapine 140 New York Heart Association 190 Newer oral anticoagulants 303 pros and cons of 303 Niacin 62, 68 Nicardipine 296 Nickel 69, 928 Nicorandil 298 Nicotinamide 62 Nicotine 760, 789 Nicotinic acid 62, 794, 836 Niemann Pick’s disease 384 Nifedipine 295, 394 Nightmares 931 Nitazoxanide 148 Nitrate 287, 312, 878, 917 converting bacteria 878 exogenous sources of 878 Nitrendipine 296 Nitroglycerin 285, 287, 290

Nitroprusside 285, 290 Nitrosamines 928 Nixon’s method 412 Nizatidine 420 N-nitrosonornicotine 928 Nocardia 886 asteroides 94f Nocardiosis 93 Nocturia 403 Nocturnal dyspnoea, paroxysmal 190 Nodular glomerulosclerosis 824 Nodules, subcutaneous 262 Non-bacterial thrombotic endocarditis 281, 886 Non-cardiogenic pulmonary oedema 290, 814 Non-cicatricial alopecia 7 Non-drug therapy 293 Non-energy yielding carbohydrates 52 Non-Hodgkin’s lymphoma 517, 518 Non-hormonal therapy 823 Noninvasive glucose monitoring 795 Noninvasive positive pressure ventilation 363 Noninvasive tests 92, 437 Non-islet cell tumour hypoglycaemia 887, 888 Non-ketotic hyperosmolar state 814 Non-organ specific disorders 50 Non-pancreatic neoplasm 829 Non-paralytic poliomyelitis 127 Non-peristaltic contractions 416 Nonpolyposis syndrome 879 Non-sexually transmitted treponematoses 107 Non-small cell carcinoma 387 lung cancer 387, 907 carcinoma 899 Non-ST elevation myocardial infarction 302f Nonsteroidal anti-inflammatory drugs 849 Non-stroke syndromes 664 Non-valvular atrial fibrillation 232 Non-β-cell tumour 830 Noonan’s syndrome 243, 252 Norepinephrine 307, 815, 828 deficiency 821 Norfloxacin 542 Norovirus 130 Nortriptyline 932 Norwalk agent 130 Nosocomial infections 86 pneumonia 376 Nuclear defects 483

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1005

Index lesion 607 causes 607 midbrain lesions 574 regulatory proteins 877 Nucleic acids 112 Nucleus 605 Numerical chromosome aberrations 41 Nutrients, classification of 52 Nutrition 51, 621, 922 state of 16 Nutritional deficiency syndrome 925 Nutritional disorders classification of 53 pathological causes of 54 Nutritional origin, oedema of 37 Nystagmus 603, 641 central 604 direction of 604, 615 horizontal 603, 668 pathophysiology of 603 peripheral 604 rotatory 603 types of 603 upbeat 604 vertical 603

O O’ Sullivan-Mahan criteria 825 Oat cell carcinoma 387 Obesity 17, 69, 802, 834 central type of 17 generalised 17 syndromes of 71 types of 17, 70 Obstructive pulmonary disease, chronic 360, 928, 929, 934 Obstructive sleep apnoea-hypopnoea syndrome 358 Occipital lobe disease bilateral 588 right 588 functions of 588 lesions of 588 Octreotide 456, 754, 831, 833 Ocular defects 15 motility 575, 577 motor nerve palsy, combined 605 movements 599f, 601 muscles, external 598 toxicity 850 Oculocephalic reflex 613 Oculomotor nucleus 597f Oculopharyngeal dystrophy 743 Odynophagia 402

Index.indd 1005

Oedema 35, 37, 38 aetiology of 36 causes of 37 fast 36 generalised 36 idiopathic 37 localised 36, 37 lymphatic 37 macular 810 pathophysiology of 36, 36f peripheral 821 pre-menstrual 37 pulmonary 265 slow 36 types of 36 vasogenic 672 venous 37 Oeosinophilic fascitis 862 Oesophageal candidiasis 177f, 178 dysphagia, causes of 417 infections 886 reflux 880, 908 smooth muscle, disorders of 416 spasm 33, 417f stricture 417f Oesophagogastroduodenoscopy, therapeutic 422 Oesophagoscopy 884 Oesophagus 116, 137, 434, 926, 929, 961, 969 Oestrogen 751, 755, 775, 794, 841, 857 secreting tumours 792 therapy 841 Ofloxacin 78, 372, 374 Olecranon bursitis-ulnar deviation 845 Olfactory hallucinations 590 Olfactory nerve 589 anatomy of 589f Oligoarthritis 844 Oligodendroglioma 685 Oliguria 403 renal causes of 553 Olmesartan 297 Ombitasvir 446 Omentectomy 906 Omeprazole 420 plus 420 Onchocerciasis 165 Onchocercomata 165 Oncogenes 877 formation of 876 Ondansetron 908, 928 One and a half syndrome 602 Onycholysis 857 Oophorectomy, bilateral 906 Oophoritis 126, 772 Ophthalmoscopy 593, 594f

Opioid analgesics 908 Opisthotonus 18, 80 Oppenheim reflex 635 Opponens pollicis 626 Opportunistic infections 139 Opsoclonus 889 Optic atrophy 595, 683 causes of 595 classification of 595 primary 595f secondary 595, 595f Optic disc 817f infiltration of 594 Optic nerve 590, 593, 705f damage 594 head and fundus, inspection of 593 thickening of 703f Optic neuropathy 818 Optokinetic nystagmus 603 Oral antidiabetic agents 805, 808 Oral candidiasis 177f, 178 Oral cavity 929 nonhealing ulcers of 882 tumour of 879 Oral cholecystography 941 Oral contraceptives 836, 857, 879, 927 Oral facial infections 115 Oral first-line drugs 542 Oral glucose tolerance test 832 Oral hairy leukoplakia 11f Oral intubation 973 Oral labial HSV infection 117 Oral lesions 137, 868 Oral ulcer 850, 858, 859 Oral vasodilators 286 Orbicularis oculi reflex 606 Orbit 947 Orbital fissure 604 Orchiectomy, bilateral 906 Orchitis 126 Organ biopsies 858 specific disorders 50 syndromes 137 surface marking of 407 Ornidazole 449 Ornithosis 101 Oropharynx 879, 969 tumour of 882 visualisation of 973 Orthodox sleep 579 Orthopnoea 190, 318 causes 190 mechanism 190 Osteitis 103 fibrosa cystica 776 Osteoarthritis 844, 848, 853, 914, 938, 940

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1006

Manual of Practical Medicine Osteogenesis imperfecta 9f, 839, 840 Osteogenic sarcoma 842, 898, 907 Osteolysis 778 Osteolytic lesion 776f Osteomalacia 60, 838, 839f, 841, 938 Osteomyelitis 824, 940 Osteoporosis 839, 840, 840f, 848, 851, 940 circumscripta 940 male 841 periarticular 844, 847 Osteotomy 852 Otitis media 868 Ovarian 792 cancer 880, 883, 884, 906 familial 876 cyst 410, 791 failure, primary 786 function, disordered 880 teratoma 762 tumours 791 Ovaries, cancer of 880 Overlap syndrome 862 Owl eye inclusions 121f Oxcarbazepine 658 Oxprenolol 295 Oxybutynin 731 Oxygen therapy 353 long-term 363 Oxytetracycline 829 Oxytocin 760

P Pacemakers, cochlear implants 955 Paget’s disease 733, 775, 842, 842f, 938, 940 Pain 31, 32, 34, 967 abdominal 33-34, 778, 869, 870 insensitive structures 682 leg 721 lower retrosternal 330 musculoskeketal 844 neuropathic 32, 820 oesophageal 33 pericardial 32 pleural 32, 330 sciatic 722 secondary 883 sensitive structures 681 venous 35 Painful hepatomegaly, causes of 414 Palatal reflex 615, 634 Pale fundus 205 Paleocerebellum 640 Palilalia 584 Palliative radiation therapy 897 Palmar erythema 847

Index.indd 1006

Palmomental reflex 637 Palpating trachea, methods of 337f Palpebral fissures 598 Palpitation 192, 829 P-aminosalicylic acid 374 Panacinar emphysema 360 P-ANCA predominant 866 Pancoast syndrome 330 Pancoast tumour 386, 386f, 882 Pancreas 434, 435, 926 carcinoma 760 Pancreatectomy 793 Pancreatic calcification 470f disease 838 islet cell tumour 752, 887 neuroendocrine tumours 756 polypeptide disturbances 821 transplantation 822 Pancreatitis 126, 815, 934, 941 acute 34, 467, 467f, 926 chronic 470, 470f, 879, 926, 945 pathogenesis of 834 severe acute 469 tropical 471 Pancytopenia 495 Pannus formation 844 Pansystolic murmur 213, 214f Pantoprazole 420 Pantothenic acid 68 Papaverine 823 Papillary muscle disorders 268 involvement of 268 Papillary necrosis 942 Papillitis 597 Papilloedema 332, 593, 594, 594f, 597, 683, 959 causes of 594 chronic 594 Papillomatosis, laryngeal 123 Pappenheimer bodies 482 Papule 22f Para-aortic nodes 411 Paracentesis 961 therapeutic 459 Paraesthesia 644, 736 Parainfluenza 114 Paramyotonia congenita 745 Paramyxovirus 113 Paraneoplastic endocrine syndromes, common 887 haematologic syndromes 888 syndrome 694, 702, 882, 887 type of 881 Parapharyngeal sinus pituitary adenoma 752 Paraphasia 584

Paraplegia 723, 728 causes of 728 Parapneumonic effusion 381 Paraseptal emphysema 361 Parasitic infection 425 Parasomnias 582 Parasternal route 961 Parasternal thrills, left lower 208 Parathormone 774, 775, 778 actions of 774 Parathyroid 777f adenoma 777f agenesis of 778 glands 778 disorder of 774, 778 granulomatous disease of 778 hyperplasia of 789 surgery 779 Parietal bone fracture, right 948f Parietal lobe disease bilateral 587 dominant left 587 nondominant right 587 functions of 587 lesions 587 Paritaprevir 446 Parkinson disease 688, 795, 916-918 Parkinson plus syndrome 691 Parkinsonian face 12 posture 17 syndrome 918 Parkinsonism causes of 690 plus syndromes 691 spectrum of 688 treatment of 691 Paronychia 177 Parosmia 590 Parotid enlargement 847, 872 gland 608 Pars compacta, smudging of 690f Parvovirus 112 infections 122, 123 Passive lung collapse 384f Patellar clonus 624f Patent ductus arteriosus 207, 247, 247f, 248f, 249f Paul-Bunnel tests 120 Pavor nocturnus 582 Peak expiratory flow rate 348, 349 Pectoral reflex 638 Pectoralis major 625 Pectus carinatum 334, 334f Pectus excavatum 334, 334f Pedigree chart, symbols in 41f

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1007

Index Pegvisomant 754 Pel-Ebstein fever 26, 516f Pellagra 4, 62, 926 Pelvis 938 Pendular knee jerk 641 Pendular nystagmus 603 Pendular reflex 637 Penicillin G 711 resistant 711 sensitive 711 Penicillium marneffei infections 184 Pentamidine 794, 829 Pentology of Fallot 250 Pepper pot skull 776 Peptic ulcer 33, 418, 421, 837, 849, 853, 916, 926 disease 418, 419 complications of 422 injurious factors 419 pain 34 pathogenesis 418 protective factors 419 treatment of 420 Perianal mass, sensation of 882 Pericapsular inflammation 940 Pericardial effusion, malignant 892, 908 Pericardiocentesis 960 Pericarditis 33, 226f, 309, 318, 847, 859, 863 acute nonspecific 131 Pericardium 848 Perilymphatic leaks 614 Perinatal varicella 118 Perindopril 287 Perioral tremor 631 Peripheral nerve 622, 651, 820, 889 Peripheral nervous system 869 infections 116 Peripheral neuropathy 61, 134, 702, 735, 760, 847, 856, 869, 925 classification of 735 pathogenesis 735 symptoms 736 Peripheral pulses, examination of 196f Peripherally acting adrenergic inhibitors 295 Peritoneal cytology 906 Peritoneal dialysis complications of 560 intermittent 560 Peritoneovenous shunt 459 Peritoneum 848 Peritonitis 934, 941, 961 pain of 34 pyogenic 457 Permanent pacemaker 239, 308 Persistent flaccid paraplegia 729

Index.indd 1007

Persistent hepatitis, chronic 444, 963 Persistent painful testicular swelling 883 Pertussis 85 Pes cavus 21, 21f causes 21 Petechiae 23f Petrous bone 608 apex of 617 Phaeochromocytoma 776, 778, 788, 789, 793, 810 Phagocytic deficiency diseases 4, 48 Phagophobia 402 Phalanx, middle 941 Phantom limb 645 Pharmacotherapy 931 Pharyngitis 76 Phenacetin 879 Phenformin 815 Phenobarbitone 658 Phenothiazines 755, 760, 789, 792 Phentolamine 823 Phenylbutazone 806, 829 Phenylephrine 285 Phenylketonuria 4, 244 Phenytoin 658, 702, 794, 806, 814, 831, 857, 861 Phosphate 60 buffer pair 565 Phosphodiesterase inhibitors 289 Phospholipids 833 Phosphorus metabolism 774 Photodynamic therapy 897 Phrenic nerve 882 Phycomycosis 183 Phyloquinone 68 Pigeon chest 59, 334 Piloerector dysfunction 821 Pimobendan 289 Pinacidil 298 Pindolol 295 Pineal hyperplasia syndrome 801 Pinworm 160 Pioglitazone 808 Piperacillin 542 Pirenzepine 420 Piroxicam 849 Pituitary adenoma 685, 751, 756, 791 dependent bilateral adrenal hyperplasia 781 gland 750 hormone 770 anterior 750 production, deficient 751 hyperplasia 756, 757 hypothyroidism 767 insufficiency 829 lobe, posterior 750

necrosis, postpartum 767 region, hypothalamus-posterior 758 tumour 754f, 756, 762, 784 syndromes, familial 756 Pizza pie appearance 122f Placental abruption 873 Plague 90 septicaemic 90 Plant alkaloids 898 Plantar reflex 634, 635 warts 122 Plasma 830, 831 cell disorders 519 dyscrasias 519 leukaemia 519 exchange 747 insulin 830 renin activity 786 thrombin time 523 Plasmodium falciparum 143, 144f, 145, 702 infection 143f Plasmodium malariae 26, 144, 145 Plasmodium ovale 144 Plasmodium vivax 145 Platelet 926 adenosine diphosphate 849 count 523, 860 importance of 452 Platybasia 732 Platypnoea 191 Pleomorphic cells 877 Plethora, pulmonary 246f Pleural cavity, contamination of 961 Pleural effusion causes of 378 malignant 881, 892 Pleural fluid formation, mechanism of, mechanism of 378 Pleuritis 868 Plexopathy, syndrome of 737 Plummer nail 24 Plummer-Vinson syndrome 878 Pneumaturia 404 Pneumococcal meningitis 77 Pneumococcal pneumonia 376 Pneumococcal vaccine 77 Pneumococci 77 Pneumocystis carinii 350, 561, 771 pneumonia 349, 377 thyroiditis 771 Pneumocystis jiroveci 134, 155, 180 cystic forms of 180f infection, management of 135 pneumonia 180 Pneumocystis pneumonia 137, 155

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1008

Manual of Practical Medicine Pneumocystosis 180 Pneumomediastinum 963 Pneumonia 12, 33, 374, 376, 377, 760, 814, 846, 928 atypical 376 cause of 887 characteristics of 376 classification 374 development of 375 ventilator-associated 377 Pneumonic plague 90 Pneumopericardium 961 Pneumothorax 33, 383, 384f, 760, 846, 935, 958, 964 spontaneous 383 Poland’s syndrome 19 Poliomyelitis 126 virus 126 paralytic 127 Polonium 928 Polyangitis, microscopic 865, 866 Polyarteritis 858 nodosa 845, 866, 867f Polyarthropathy syndrome 123 Polyclonal gammopathies 522 Polycystic disease 448f, 945 Polycystic kidney 552f, 942 disease 551 Polycystic liver disease 448 Polycystic ovary 792 syndrome 792, 802 Polycythaemia vera 500 diagnosis of 501 Polycythaemia, secondary 501 Polydactyly 19, 20f, 940 Polydipsia 758, 759, 781, 802 Polyendocrine autoimmune syndromes 795 Polymorphic ventricular tachycardia 235 Polymyositis 693, 741, 742, 858, 861 classification 741 idiopathic 741 Polyneuropathy 818, 890 relapsing 737 Polynuclear aromatic hydrocarbons 928 Polyphagia 802 Polyposis coli, familial 876 Polyps 941 Polyradiculopathy, abdominal 820 Polythiazide 286 Polyuria 403, 759, 781, 802 Pons 608, 665, 669 Pontine syndromes 668, 668f inferior 669 lateral 668 Pork insulin 796 Porphyria 760, 794 acute intermittent 836

Index.indd 1008

Portal hypertension 453 classification 453 signs of 923 Portal venous system 455f Portex tube 972 Posaconazole 184 Positive end expiratory pressure 391 Positron emission tomography 944 Post lumbar puncture headache 959 Post-ductal coarctation 254 Posterolateral column syndrome, causes of 732 Post-exposure prophylaxis 125, 447 Postnecrotic cirrhosis aetiology 452 pathogenesis 452 Post-tussive suction 345 Post-tussive syncope 327 Potassium 65, 563 channel openers 298 sources 65 wasting diuretics 814 Potency loop diuretics, high 285 Pott’s spine 954f Practolol 857 Prader-Willi syndrome 794 Pramlintide 809 Pravastatin 837 Prazosin 731, 928 Precocious puberty, causes of 791 Prednisolone 751, 781 Prednisone 447, 833 Preeclampsia 873 Preganglionic trigeminal nerve lesions 607 Pregeniculate lesions 592 Pregnancy loss, recurrent 873 toxemia of 441 Preleukaemic syndromes 514 Premature sexual developmental disorders 791 Preprandial blood glucose level 826 Pressure overload, chronic 282 support ventilation 391 Primaquine 146 Primidone 658 Primitive reflexes 637 Prinzmetal angina 191 Procainamide 857, 861 Procarbazine 898 Prochlorperazine 684 Proctitis 103 Proctoscopy 883 Progestational agents 834, 903 Progesterone 751 acetate 751

Progressive anaemia, chronic 483 Proinsulin 830 Prolactinoma 755 Prolactin-secreting pituitary tumours 755 Proliferative glomerulonephritis, diffuse 547f Promyelocytic leukaemia, treatment of 508 Propafenone 861 Propionic acid 850 compounds 849 Propranolol 425, 684, 829, 831 Proptosis 868 Propylthiouracil 767, 861 Prosapagnosia 579 Prostaglandin 778, 823 synthesis inhibitors 759 Prostate cancer 883, 884, 906 carcinoma 760, 899 Prostatic infection, treatment of 542 Prostatitis 539 Prosthetic sounds 213 valves, complications of 323 Protease-antiprotease hypothesis 361 Proteasome inhibitors 905 Protein 50, 53, 427, 428, 443f, 804, 837 energy malnutrition 54, 55 glycosylation 820 immunological detection of 884 increased acute phase 848 kinase antagonists 904 losing enteropathy 458 metabolism 796 serum 435 synthesis 796 Proteinuria 403, 536, 859 asymptomatic 965 overflow 536 pathophysiologic classification of 536 types of 538 Prothrombin time 435, 923 Protionamide 374 Proton pump inhibitor 833 Proto-oncogenes 876 activation of 876 Protozoal infections 134, 141 Proximal muscle wasting 621 Proximal myopathy 768 Pruritus 801, 838, 881, 908 Pseudo bronchiectasis 365 Pseudoachalasia 418 Pseudo-Babinski sign 635 Pseudobulbar dysarthria 586 Pseudobulbar palsy 693, 694 causes of 693 Pseudo-clubbing 332

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1009

Index Pseudo-coma 571 Pseudo-Cushing’s syndrome 781 Pseudocyst 945 pancreas 468f Pseudogout 844 Pseudohaemoptysis 328 Pseudohypercalcaemia 775 Pseudohyperkalaemia 511 Pseudohyperparathyroidism 778 Pseudohypertension 200 Pseudohypoglycaemia 511 Pseudohypoparathyroidism 18, 740, 779, 780f Pseudohypoxaemia 511 Pseudomembranous colitis 82 Pseudomonas infection 367, 376 Pseudomyotonic reflex 637 Pseudopancreatic cyst 469f, 926 pigtail drainage 469f Pseudopapilloedema 595 Pseudo-pseudo hypoparathyroidism 780, 940 Pseudosyringomyelia 821 Pseudotabes 821 Pseudotumour cerebri 594 Pseudo-von Graefe’s sign 598 Psoralen plus ultraviolet light 857 Psoriasis 25f, 844 Psychiatric disorders 59, 138, 581, 916, 918 Psychogenic abdominal pain 35 Psychosis 760, 849, 858 Psychotropic drugs 919 Pterygoids 606 Ptosis bilateral 9f, 599 complete 600 partial 600 unilateral 91, 598 Puberty precocious 791 premature 800 Pubic symphysis 961 Puddle’s sign 413, 413f Pulmonary artery, idiopathic dilatation of 261 embolism, acute 229, 229f embolus, filling defect-indicates 397f function tests 356 hypertension classification of 393 primary 393, 393f, 399 stenosis assessment of severity of 253 congenital 12 tuberculosis, bilateral 369f Pulsatile liver 409 causes of 414

Index.indd 1009

Pulse deficit 195 polio immunisation 127 rate 194 volume 195 Pulseless disease 870 Pulsus alternans 198, 201 Pulsus bigeminus 198 Pulsus bisferiens 196 Pulsus dicroticus 197 Pulsus paradoxus 198, 198f, 201 reverse 198 Pulsus parvus et tardus 197f Pupil 204 reactivity 576 size 600, 576 sparing 600 Pupillary disorders 821 Purpura, generalised 23 Pursed lip breathing 336, 360f Pyelogram, intravenous 884, 941f Pyelonephritis 539, 759, 847, 853 acute bacterial 539 chronic 539, 942 signs of 540 symptoms of 540 Pylorus, lesions of 881 Pyoderma gangrenosum 23, 430, 847 Pyogenic abscess, management of 449 Pyopericardium 961 Pyothorax 958 Pyramidal system 726 Pyramidal tract lesion absence of 635 signs of 618 Pyrazinamide 372, 373 Pyridoxine 63, 68 Pyruvate carboxylase 816, 829 dehydrogenase 796, 816 Pyuria 403

Q Q-fever 111 Quadrantic hemianopia 593 Quadriceps femoris 627 Quadriplegia 847 Quadruple rhythm 211 Qualitative platelet disorders 524 Quantitative platelet disorders 524 Quantitative pseudomotor axon reflex test 712 Quartan fever 26 Queckenstedt’s test 960 Quinapril 287, 296 Quincke’s sign 274

Quinethazone 286 Quinidine 146, 425, 857 effect 228, 228f Quinine 829 Quinoline methanol 146 Quotidian fever 27f

R Rabeprazole 420 Rabies 127, 128, 128f vaccine 187 Rabson-Mendenhall syndrome 800 Raccoon eye sign 204 Rachitic rosary 59 Radial reflex, inverted 637 Radiation injury 891 Radiation therapy 896, 911 toxicity of 897 Radiculopathy 651, 818 Radiocopper loading test 463 Radiofrequency ablation, complications of 233 Radioimmunoassay 831 Radioimmunotherapy 897 Radioiodine 765 therapy 773 Radioisotope scanning 942 Radionuclear scan 539, 831 Radionuclide therapy 896, 897 Radiotherapy 750, 881 Rai system 513 Rai therapy 766 Raltegravir 140 Ramipril 287, 297 Ramsay Hunt syndrome 119, 611, 698, 702 Random monophonic wheeze 343 Ranitidine 420 bismuth citrate plus 420 Ranke’s complex 368 Ranolazine 304 Rapid tumour cell 909 Rash 838, 852 Rat bite fever 26, 109 Raynaud’s phenomenon 862f, 865, 870 primary 864 secondary 864 Reactive arthritis 844, 853, 856 Reactive hypoglycaemia, idiopathic 832 Reader’s paratrigeminal syndrome 607 Recombinant tissue plasminogen activator 673 Recommended daily protein intake 53 Reconstructive plastic surgery 896 Rectal cancer 905 tumours 887

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1010

Manual of Practical Medicine Recurrent laryngeal nerve, involvement of 882 Red cell aplasia 123 Red glass test 601 Red nail 25 Red pin test 591 Redcliffe tube 972 Reed-Sternberg cell 515, 516f Re-expansion pulmonary oedema 958 Reflexes 606, 633, 722 abdominal 633, 634 examination of 610 eye movements 577 inverted 637 ocular movements 575 pharyngeal 634 pupillary 600 Refractory ascites 459 Refractory cardiac failure, causes of 284 Refractory epilepsy, reactive 657 Refsum’s disease 741 Regional lymph node, extent of 885 Regurgitation, pulmonary 215f, 277 Reinfection 539 Reiter’s disease 856 Reiter’s syndrome 844, 845 Relapsing fever 26, 108 Rem sleep behaviour disorders 582 Remitting ataxic syndromes 697 Renal allograft 965 Renal angiography 942 Renal artery bruit 292 stenosis 292, 558f, 781, 941, 942 left sided 558f Renal biopsy 551 Renal calcium excretion, decreased 775 Renal calculi, multiple 777f Renal carcinoma 881, 899 Renal cell carcinoma 778, 879, 882, 884, 906 Renal disease 806, 840 anaemia due to 489 end-stage 559 Renal disorders 138 Renal failure 298, 372, 761, 829, 831, 850, 853, 859, 869, 908 acute 552, 775, 965 chronic 6, 556, 557f, 755, 839, 965 Renal glycosuria 803 Renal insufficiency 520 Renal involvement 103, 863 Renal ischaemia 869 Renal oedema 37 Renal osteodystrophy 839, 940f Renal pain 35 Renal scan 943 Renal system 847 Renal transplantation 561

Index.indd 1010

Renal tubular acidosis 555, 772 cells 536 epithelial cells 554 Renal tumour 942 Renal ultrasonography 539 Renal vein 406 level of 406 thrombosis 941, 942 Renin inhibitors 298 Rennin secreting tumour, primary 781 Repaglinide 808 Reproductive system 59, 367 Reserpine 295, 755 Residual stigmata 105 Resorcinols 357 Respiration 217, 574, 576 Respiratory acidosis 566, 567 Respiratory diseases 333, 353, 929 classification of 353 Respiratory disorders 346 Respiratory distress syndrome 389, 825 Respiratory failure 815 causes of 352 types of 352 Respiratory infection, upper 852 Respiratory obstruction 767 Respiratory papillomatosis 123 Respiratory patterns, abnormal 337f Respiratory syncytial virus infections 114 Respiratory system 55, 325, 846, 915, 926 examination of 333 Respiratory tract inspection 333 Rest pain 35, 824 Restrictive diseases 353 Reticular system malignancy 908 Reticulocyte 482 count, absolute 480 index 481 Reticulocytopenia 926 Retina 205, 300 Retinal artery thrombosis 873 degeneration 801 haemorrhage 683 involvement 868 vasculitis 859f Retinitis pigmentosa 596f Retinoblastoma, familial 876 Retinochoroiditis 154 Retinol 56, 68 Retinopathy 792, 810, 816, 850, 851 background 816 preproliferative 817 proliferative 817, 817f Retrobulbar neuritis 597, 703f Retrograde ejaculation 822 pyelogram 942

Retroperitoneal inflammation, haemorrhage 934 Reversible ischaemic neurological deficit 663 Reye syndrome 466 Rhabdovirus 113, 127f Rheumatic diseases inflammatory 844 non-inflammatory 844 Rheumatic fever 262, 263, 844, 845 diagnosis of 262 prevention of 263 Rheumatic heart disease 263 Rheumatoid arthritis 772, 840, 844, 846, 846f, 847, 858, 861, 940 Rheumatoid nodule 844, 846, 853, 940 Rhinocerebral mucormycosis 183 Rhizopus 183 Rhomboids 625 Rhonchi 343 Ribavirin 446 Riboflavin 62, 68 Ribonucleoprotein 862 antigen 861 Rickets 59, 59f, 60f Rickettsial disease, classification of 110 Rickettsial fever 111 Rickettsial infections 110 diagnosis of 111 Rickettsialpox 111 Riedel’s lobe 409 Riedel’s struma 771, 773 Riedel’s thyroiditis 773 Rifabutine 373 Rifampicin 372, 373, 535, 838 Rifampin 78 Right ventricular enlargement, causes of 207 Ring calcification 940 Ring shadows 934 Rinne’s test 611, 612f Risus sardonicus 80 Ritonavir 140, 446 Rituximab 852, 860 infusion of 909 Rivaroxaban 303 River blindness 165 Rizatriptan 683 Rocker-bottom foot 20, 21f Rocky mountain spotted fever 111, 866 Romberg’s test 647, 647f Romhilt and Estes point score system 221 Root lesions 621 Rose Waaler test 848 Rosiglitazone 808 Rossolimo’s reflex 637 Rotavirus 130, 794 Roth spots 205 Rotor syndrome 440

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1011

Index Round worms 156 Rovsing’s sign 411 Rub pericardial 212 pleural 345 Rubella 125 infection 125 virus 794 Rubeosis iridis 818 Ruddy complexion 5 Rufinamide 658 Rugger-Jersey spine 938, 939f Rule of hundreds 230 Rumours, solid 877, 881 Rytand’s murmur 217

S Saccharomyces cerevisiae 797 Sacral prominences 848 sparing 651 spine 714 Sacroiliitis 430, 857 Saddle back fever 26 Saddle pulmonary embolism 397f Sagittal sinus 675 Salicylates 815, 829, 849 Saligenines 357 Salivary secretion, cessation of 897 Salivation, excessive 695 Salmeterol 357 Salmonella 771, 856 infection 3, 492 Salt loading 822 Salycylates 829 Sandostatin 754 Saquinavir 140 Sarcoidosis 750, 751, 758, 844, 845, 866 Sarcoma 800, 876, 907 Saturday night palsy 925 Saxagliptin 809 S-benzoil thiamine-o-monophosphate 61 Scalded skin syndrome 74f Scalene lymph node 332 Scapular reflex 634 Scarlet fever 76 Schamroth’s sign 331 Schatzki ring 417 Schilling test 487 Schirmer’s test 609 Schistiocytes 482 Schistosoma 168f haematobium 169f infection 879 species, life cycle of 168f Schistosomiasis 168 chronic 169

Index.indd 1011

Schober’s test 722f, 854 Schwabach test 612 Schwannomas 756 Sciatic nerve root 723, 724f Scimitar syndrome 243 Sclera 204 blue 9f, 204 Scleritis 847, 847f, 868 Scleroderma 12, 845, 858, 861, 863f, 864f, 940 classification of 862 localised 862 Sclerokeratitis 859f Scleromalacia perforans 847 Sclerosing pan encephalitis, subacute 709 Sclerosis systemic 862, 864 tuberous 661, 661f, 876 Scoliosis 335f Scorbutic rosary 335 Screening microalbuminuria, methods of 538 Scrub typhus 111, 111f Scurvy 64 Secnidazole 426 Secondary erythrocytosis, causes of 501 Secretory functions, examination of 609 See saw nystagmus 604 Seizure 850, 858, 891, 931 age-related causes of 653 attack 657 atypical absence 654 classification of 652 disorder 873 drug of 659 generalised 654 psychogenic 660 Selective oestrogen receptor modulators 841 Selenium 68, 69 Sella turcica 754f, 940 Seminoma 778, 898 Senile tremors 918 Sensation, modalities of 645 Sense of smell, loss of 589 Sensorimotor neuropathy, subacute 737 Sensorimotor stroke 674 Sensorineural deafness 614 Sensorium, altered 778 Sensory aphasia 585 cortex, function of 649 deficits 916 dermatomes 645 dissociation 649 fibres, arrangement of 645 functions, examination of 608 inattention 649

lesions 650, 650f signs of 651 symptoms of 651 loss 652, 722 motor polyneuropathy, mixed 820 paralytic bladder 927 pathways 644 stroke 674 system 605, 643 Sepsis 814, 829, 832 Serological tests 31 Serositis 795, 858 Serotinergic drugs 684 Serpiginous lesions 168f Serratus anterior 625 Serum homocysteine, elevated 488 Sex chromosome aneuploidy 42 Sex-linked disorder 750 Sexual disorders 790 Sexual dysfunction 298 Sexually transmitted chlamydia trachomatis infection 101 Shagreen patch 5f Sheehan’s syndrome 751, 758, 767, 785 Sherrington’s law of reciprocal innervation 633 Sherwood Jones classification 329 Shift-work sleep disorders 583 Shigella 856 Shock 38, 207, 814 cardiogenic 38, 39, 40, 307 classification of 38 control mechanism 38 distributive 39 oligemic 39 pleural 958 septic 40 type of 38 Shone complex syndrome 243 Short acting insulins action profile 797 Shoulder abduction relief sign 720 hand syndrome 845 Shunt lesions 239 Shy-Drager syndrome 760 Sicca symptoms 872 Sickle cell anaemia 493f disease 492 trait 759 Sickle prep test 493 Sickness, serum 844, 865 Siegel’s pneumatic speculum 613 Sigmoid sinus thrombosis, right 675f Sigmoidoscopy 425, 430, 883 Sildenafil 394 Silver Jackson tube 972 Simeprevir 446 Simian crease 19f

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1012

Manual of Practical Medicine Simon focus 369 Simvastatin 837, 861 Sine scleroderma 862 Single gene disorders 42, 243 mutations 834 Single photon emission computed tomography 944 Single voided urinary metanephrine 789 Singultus 402 Sinotubular ectasia 14f Sinus bradycardia 307, 308 causes of 194 enlarged 940 tachycardia 231, 233, 308 causes of 194 thrombosis, dural 674, 675f Sinusitis 181, 183, 868, 940 Sister Mary Joseph nodule 881 Sitagliptin 809 Sitophobia 402 Situs ambiguous 242f Situs inversus 242, 825 totalis 242, 242f Situs solitus 242f Sjögren’s syndrome 9, 12, 772, 858, 871, 872 Skeletal anomalies 732 defects 14 deformity, progressive 842 manifestations 59 muscle 805 CNS syndrome 744 tuberculosis 95 Skin 177, 406, 847, 858, 914 atrophy 851 cancer 880 changes 54, 62, 862 kwashiorkor 55f colour of 23 disorders 137 erythema 897 examination of 4 functions of 21 lesions 23, 756 primary 22 site of 23 terminology of 22 malignant tumours of 5 pigmentation of 4, 890 rash 837, 850 sepsis, local 959 structure of 22f Skull, base of 617 Sleep 579 apnoea 752 syndromes 582

Index.indd 1012

bruxism 583 centre 581 deprivation 581 disorders 581, 583 extrinsic 581 intrinsic 581 enuresis 583 function of 581 neuroanatomy of 581 slow wave 579 stages of 579 study 359 talking 579 terrors 582 wake system 580f walking 579 Slow virus disease 709 Small bowel obstruction, mechanical 34 Small cell lung cancer 387, 887, 890, 907 carcinoma 898 Small pox 124, 124f Small vessel vasculitis 866 Smell 914 perversion of 590 testing sense of 589 Smoking index 3, 929 Snellen’s chart 590f Snider’s test 347 Snout reflex 638 Snow man appearance 257f Sodium 65, 561 cromoglycate 356 ferric gluconate 485 nitroprusside 287, 815 source 65 valproate 658, 684 Soft tissue 934, 940 calcification 779, 800, 940 sarcoma 898, 907 tophus 940 Solid tumours, treatment of 877 Solitary gland 944 Solitary pulmonary nodule 350, 351f benign 350 causes of 350 Somatostatin 456 clinical uses of 750 synthetic analogue of 754 Somatostatinoma 793, 833 Somatotrophs secrete growth hormone 750 Somnambulism 582 Somnolence 767 Somogyi phenomenon 802 Sorafenib 463 Sorbitol 425, 815 accumulation 820

Sotalol 919 Space-occupying lesions 791 Sparfloxacin 373 Spastic gait 632 Spastic paraplegia, causes of pure 725 Speech 583 discrimination audiometry 612 disturbances 641 syndromes 585 Spherical red cells 492f Spherocytes 482 Spina bifida 825 Spinal artery syndrome anterior 716 posterior 717 canal, measurement of 717 causes, acute 725 cord 641f, 669, 715, 889 blood supply of 715 compression 883, 891 cross-section of 715f damage 916 disorders 717 enlargements 715 lesion 134, 603, 621, 726 posterolateral sclerosis of 731 segments 715 syndrome 730f tracts of 716, 716f traumatic lesions of 718 tumours classification 685 vascular syndromes of 716 watershed areas of 717 deformity 335 forward flexion 854f muscular atrophy 695 poliomyelitis 127 root 651 syphilis 719 tumours 960 Spine 59, 713, 938 movement of 713, 721 Spinocerebellar 640 ataxia 700, 701 Spinolamellar line 735 Spinomotor system 617 Spinothalamic system 644 Spinothalamic tract 651 Spinoumbilical measurement 407 Spirapril 287 Spirochetal diseases 103 Spirometry 347 measurements 348 Spironolactone 286, 792 Spleen 408, 411, 412, 944 palpation of 409, 410f percussion of 412

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1013

Index Splenectomy 492 Split liver transplantation 472 Spondylitis 853, 857 Spondyloarthritis, undifferentiated 853 Spondyloarthropathy 844, 853 Spontaneous pneumothorax primary 383, 384 secondary 384 Sporangia 183f Spreading anaerobic infection 824 Spurious haemoptysis 328 Spurious results, causes of 482 Spurling’s sign 720 Sputum 327, 928 collection 371 colour of 328 cytology 387, 884 examination 347 odour of 328 Squamous cell 387, 905 carcinoma 778 Squint 602 S-T segment depression, causes of 224 Stapedial reflex 610 Staphylococcal folliculitis 74f infections 74 pneumonia 376 toxin-mediated diseases 75 Staphylococcus aureus 74, 75, 75f, 118, 351, 771, 823 Statistical risk disease 794 Status asthmaticus 355 Status epilepticus 657 aetiology 657 classification 657 Stavudine 139 Steatohepatitis, nonalcoholic 450f Steatorrhoea 833 Steatosis 449 Stem cell diseases 478 therapeutic application of 478 Stenosis, pulmonary 252, 252f, 253, 277, 940 Stenotic mitral valve 265 Stepping gait, high 632 Stereognosis 649 Sterile pyuria 404 Sternocleidomastoid muscle, testing of 616 Sternomastoid, unilateral paralysis of 616 Steroid 788, 814, 840, 847, 958 equivalents 788 toxicity 853 Stierlin sign 428 Stiff neck 683 Stiffman’s syndrome 794

Index.indd 1013

Stimulate pharyngeal nerve 908 Stomach 434, 926, 929, 944 Stomatitis 850 Stomatocytes 482 Storage disorders 314, 963 Strabismus 602 paralytic 602 Straight leg raising test 723 Straight line dullness 341 Streptococcal infections 76 Streptococci, group B 823 Streptococcus agalactiae 711 bovis bacteraemia 879 pneumonia 77f, 711, 771, 886 pyogenes 76f viridans 886 Streptomycin 372, 919 Streptozotocin 794 Stress 820 psychological 845 ulcer 420 Stretch test 724f, 725f Striae 851 atrophica 406 Stridor 345 laryngeal 345 String sign 428 Stroke 232, 662, 663 cardiac causes 662 classification of 662 completed 662 haematological causes 662 major causes 662 mimics, functional 663 pathophysiology of 663 syndromes 664 unusual causes 662 Strongyloides 159f stercoralis 159 life cycle of 159f Strongyloidiasis 159 life cycle 159 Struma ovarii 762 Stupor 812 Sturge-Weber syndrome 661 Subarachnoid haemorrhage, complications of 679 Subclavian steal syndrome 673 Subcutaneous fat, absence of 800 Subcutaneous insulin infusion, continuous 799 Subfalcine herniation 687 Substance abuse 828, 921 Succussion splash 345, 345f, 414 Sucking reflex 638 Sucralfate 420 Sudomotor 821

Sulcus tumour 386 Sulfamethoxazole 542 Sulfasalazine 432 Sulfonamide 806, 829 Sulfonylurea 805, 806, 829, 830 drugs, pharmacology of 808 therapy 806 Sulindac 849 Sulphasalazine 851 Sumatriptan 683 Sunitinib 463 Superior vena cava 244, 246, 247, 256, 258, 260, 264, 268, 273, 333 obstruction 333f, 890 syndrome 882 Supinator jerk 638 Suprapubic aspiration 534 Suprasellar calcification 756 Supraventricular tachycardia, paroxysmal 230 Swan neck deformity 845 Sweating 829 excessive 845 Swelling, mitochondrial 922 Swinging light test 593 Sycosis barbae 74f Sydenham’s chorea 262, 629 Synchronised-intermittent mandatory ventilation 391 Syncope 192 Syndactyly 20f, 940 Synesthesia 644 Synovectomy 852 medical 852 Synovial cell hyperplasia 844 Synovial fluid 848 inflammatory cells 844 Synovitis 858 Synthetic heparin derivatives 303 Syphilis 103, 106, 719, 751, 866 congenital 105 cranial 719 diagnosis 719 late benign 104 latent 104 meningeal 105 meningovascular 105 pathology 719 primary 103 secondary 103, 104f signs 719 symptoms 719 tertiary 104 Syphilitic chancre, primary 104f Syringobulbia 731 Syringomyelia 730, 731f Systemic disorders 23, 55, 59, 495 Systemic immune complex disease 49

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1014

Manual of Practical Medicine Systemic lupus erythematosus 844, 857, 861 classification of 858 Systemic Lupus International Collaborating Clinic Criteria 858 Systemic sclerosis, progressive 862

T Tabes dorsalis 719 Tabetic facies 12 Tachyarrhythmias 194, 229 Tachy-Brady syndrome 237 Tachycardia 211, 230, 829, 927, 928 broad complex 235 multifocal 233 severe 766 supraventricular 308 Tachypnoea 335, 390 Tacrolimus 432 Tactile agnosia 579 extinction 64649 fremitus 339 Tadalafil 823 Taenia saginata 170, 171f life cycle 171 Taenia solium 170, 171, 171f egg oncosphere embryo 173f life cycle of 172, 173f Takayasu’s arteritis 866, 870 Takayasu’s disease 866 Tako tsubo cardiomyopathy 314, 314f Tamoxifen 775, 778 Tamponade, pericardial 963 Tangier disease 834 Tapeworm 156, 170 adult 171f Tardive dyskinesia 918 Taste perception, distortion of 880 sensation 914 Taxanes 898 Tazobactam 542 T-cell immunodeficiencies 48 lymphoma 878 neoplasms 504 Technetium-sestamibi scan 777f Teeth, blunting of root of 779 Telangiectasia 800 bulbar conjunctiva 661f Teletherapy 896 Telmisartan 297 Temporal lobe disease bilateral 588 dominant left 588

Index.indd 1014

disease, nondominant right 588 functions of 587 lesions of 587 Temporomandibular joint 845 Temporo-mesencephalic-pontine pathway 602 Tenderness over chest wall 339 Tendon reflexes abnormalities of 636 absent 636 deep 635, 639f Tenofovir alafenamide 446 Tenofovir disoproxil fumarate 446 Tenosynovitis 847 Tensilon test 747 Tension headache 682, 684 pneumothorax 383, 384 Teratocarcinoma 898 Terazosin 731 Terbinafine 184 Terlipressin 456 Terry nail 25 Testes, cancer of 880 Testicular failure, acquired 792 feminizing syndrome 880 mass, painless 883 sensation, loss of 821 Testing joint position sense 647f Testing vibration sense 648f Testosterone 751 biosynthesis 792 Tetanus 80 opisthotonus 81f Tetracycline 420, 426 plus 420 Tetralogy of Fallot 249, 249f, 251f, 253 Thalamic syndrome 667 Thalamoperforate syndrome 667 Thalamus 664, 669 Thalassaemia 494, 940 alpha 494 major 494 minor 494 types 494 Thalidomide 432, 522, 767 Thallium-291 scanning 942 Theca cell 791 Theophylline 425 Therapy 842 Thermoregulatory sweat test 712 Thiamine 61, 68 Thiazide 794 adverse effects of 294 diuretics 760, 775, 836, 841 Thiazolidinediones 807, 808 Thick pus 958

Thioacetazone 372 Thomson’s disease 745 Thoracic actinomycosis 93 cage abnormality 395 duct 968 expansion anterior 338f assessment of upper 338f kyphosis 855 manifestations 386 movement anterior 338 assessment of posterior 338, 338f spine 714, 891 Thoracolumbar spine 714 Thoracostomy 382 Thorium dioxide 879 Threadworm 160 Thrombin inhibitors, direct 303 Thromboangiitis obliterans 929 Thrombocytes cell 477 Thrombocythaemia 502 Thrombocytopenia 524, 529, 858, 873, 908, 926, 962 Thrombocytopenic purpura, idiopathic 772 Thrombocytosis 889 causes of 502 primary 502 Thromboembolic disease, recurrent 841 Thromboembolism 309 pulmonary 396, 398 Thrombolysis 311, 673 Thrombolytic therapy 311 Thrombophlebitis 889 migratory 881 Thrombopoietin 480 Thrombotic thrombocytopenic purpura 525, 866 Thumb sign 15f Thunderclap headache, causes of 679 Thymoma 746, 760 Thyroid 752, 944 bruit 772 carcinoma 899 disease 762, 767 disorders 761 dysfunction 915 amiodarone induced 773 failure 897 function amiodarone effects on 773 tests, patterns of 762 gland anatomy of 761 physiology of 761 hormone 791, 794, 840, 841

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1015

Index isotope scanning of 943f malignant tumours of 773, 774 medullary carcinoma of 789 releasing hormone 750 scan 943, 947 stimulating immunoglobulin 761, 765 storm 766 surgery 766 Thyroidectomy, subtotal 765 Thyroiditis 762, 770, 795 acute 771 chronic 767, 772 lymphocytic 772 painless 772 pyogenic 771 silent 772 struma lymphomatosa, chronic 772 subacute 771 suppurative 771 Thyrotoxic ophthalmopathy 762f Thyrotoxicosis 427, 693, 762, 763f, 773, 775, 814, 916 factitia 762 rapid deterioration of 766 Thyrotropin receptor stimulating antibody 766 releasing hormone 761 Thyroxine binding globulin 761 serum 770 therapy 766 Tiagabine 658 Tibia, fracture of 840 Tibialis anterior 627 Tibialis posterior 627 Tick typhus 111 Ticlopidine 673 Tics causes of 631 complex multiple 632 Tietze’s syndrome 32 Timolol 684 Tinidazole 148, 426, 449 Tinnitus 615, 849 Tip nuclei free 162f Tip-therm test 821, 821f Tissue-dwelling human nematodes 161 life cycle 161 Titration regimen 765 T-lymphocytes 45 Tobacco alcohol amblyopia 925 Tobramycin 367, 542 Tocilizumab 852 Tofacitinib 852 Tolazamide 808 Tolbutamide 808 Tolmetin 849 Tongue 9, 11 dryness of 10

Index.indd 1015

geographic 10, 11f ironed out 11 pallor of 10f tumour of 882 Tonsillitis 76 Topical steroids 860 Topiramate 658, 928 Torsades de pointes 236f Torsional nystagmus 604 Total anomalous pulmonary venous connection 256 types of 256f drainage 257f Toxic oil syndrome 862 Toxic shock syndrome 75 Toxicity 849-851 acute 58 chronic 58 Toxicology 966 Toxins 414, 438, 572, 794, 816 Toxoplasma gondii 135 Toxoplasmosis 154, 751, 940 life cycle of 154f Trace metals 928 Trace minerals 68 Trachea, position of 334 Tracheal stridor 345 Tracheal Tug-Oliver’s sign 337 Tracheostomy 971 permanent 971 tubes 972 Trandolapril 287 Transcutaneous electrical nerve stimulation 822 Transfusion-transmitted infections 497 Transhepatic cholangiography, percutaneous 941 Transitory attacks, recurrent 734 Transnasal intubation 973 Transoesophageal echo 280f, 394 Transudative pleural effusions, causes of 378 Transverse myelitis, acute 725 Transverse sinus thrombosis, right 675f Trapezius jerk 638 muscle, testing of 616 unilateral paralysis of 616 Traube’s space 341 Trauma 759, 791, 792, 793, 853 Traumatic pneumothorax 383, 384 types 383 Trematodes 156, 168 life cycle 168 Tremors 689, 829, 932 causes of 630 classification of 631 types of 631 Trephine biopsy 963

Treponema pallidum 103, 105f Trepopnoea 191 Treprostinil 394 Triamterene 286 Triceps jerk 638 Triceps reflex, inverted 637 Trichinella spiralis 166, 313 life cycle of 167f Trichinellosis 166 Trichinosis 166 Trichlormethiazide 286 Trichomonas vaginalis 149f Trichomoniasis 148 Trichuris trichiura 161, 162f life cycle 161, 162f Tricuspid atresia 260, 260f types 260 Tricuspid regurgitation 211, 266f, 277 signs 277 symptoms 277 Tricuspid stenosis 211, 275 causes 275 Trigeminal nerve 605 Triglyceride 833 synthesis 796 Trilogy of Fallot 250 Trimetazidine 304 Trimethoprim 542 Triple stimulation test 751 Trismus 80 Trivalent oral live poliovirus vaccine 127 Troisier’s sign 404, 404f Trophozoites 149f Tropical splenomegaly syndrome 141 Trousseau’s syndrome 882 Trucut needle 964 Truncus arteriosus 259 Trypanosoma brucei, life cycle of 152f Trypanosoma cruzi 313 life cycle of 153f Trypanosomiasis 151, 153 Tsutsugamushi fever 111 Tuberculate macroconidia 178f Tuberculin test 371 Tuberculoid leprosy 97, 97f Tuberculoma 95, 656f, 954f Tuberculosis 95, 368, 374, 427, 718, 760, 844 congenital 374 laryngeal 370 management of 371 natural history of 368 pericardial 96 pleural 95 post-primary pulmonary 369 primary 368 Tuberculous meningitis, complications of 708

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1016

Manual of Practical Medicine Tubular proteinuria 537, 538 causes of 537 Tubulointerstitial disease, causes of 550 Tumour 758, 759, 791, 792, 934, 941, 945 antigens 50 brushings, cytologic examination of 883 compressing portal 882 contain somatic mutations 876 extension of 906 extent of primary 885 localisation of 831 lysis syndrome 909 malignant 389, 876 marker 462, 878 serum level of 884 miscellaneous 830 pancreatic 750 pleural 958 plop 213 recurrent 944 secretory 756 study of 876 suppressor genes 876 loss of function of 876 types of 685 Tuning fork tests 611 Turner’s syndrome 19, 41, 243, 772, 794, 940 Two-point discrimination 649 Tylosis palmaris et plantaris 878 Typhlitis 886 Typhoid fever 2 vaccine 187 Typical psoriatic nail dystrophy 857 Tyrosinaemia 879

U Ulcer 10, 419, 941 benign 421 leg 847 malignant 421 production, pathogenesis of 419 Ulcerative colitis 429, 430, 430f, 432, 854 Umbilicus 405 Unilateral hilar enlargement, causes of 349 Unresolved pneumonia, causes of 375 Unstable angina 33, 191, 300 acute management of 302f Upper lobe carcinoma, right 386f Uraemia 228, 573, 801, 822, 836, 881 Uraemic syndrome 556 Urea breath test 92 Ureter duplex 825 Ureteral infections 886

Index.indd 1016

Ureterosigmoidostomy 879 Urethral catheterisation 970 Urethral stricture 970 Urethritis 539 Uric acid 298 Urinary antiseptics 543 bladder 729f palpation of 410 casts 535, 535f catheters, care of 541 haemosiderin 491 incontinence 916 infection complicated 540 uncomplicated 540 obstruction 893 retention 883, 918 schistosomiasis 169 tract infection 539, 540, 543, 916 lower 539 symptoms of 540 treatment of 541 upper 539 Urine 535, 845 analysis 534 collection, midstream 534 copper excretion 463 eosinophils 539 glucose 813 osmolality 553 protein electrophoresis 539 sodium 553 specimens, collection of 534 sulfonylurea 830, 831 test 789 Urography pyelography, intravenous 941 Urticaria 859 Uveitis, anterior 854, 854f

V Vaginal bleeding 841 Vague abdominal pain 923 Vagus nerve 615 nuclei 616f stimulation 657 Valsalva manoeuvre 218 Valsartan 297 Valves infiltration of 847 involvement 263 mechanical 272f replacement 268 Valvuloplasty 267 complications of 268 Vancomycin 426, 708, 711 Vanillylmandelic acid levels 789

Vardenafil 823 Varenicline 928, 931 Variceal bleeding 455, 456 Varicella congenital 118 pneumonia 118 vaccine 119 zoster immune globulin 119 infections 117 virus 117, 886 Varicose veins 35 Variola 124 Vasa nervosum-neuropathy 847 Vascular disease 802 peripheral 299, 810, 828 Vascular disorder 758, 810 pulmonary 395 Vascular endothelial growth factor 818 Vascular pain 820 arterial occlusion, peripheral 35 Vascular thrombosis, recurrent 873 Vasculitis 742, 847, 853, 867 mimics 866 primary 866 secondary 866 syndromes 865 Vasoactive agents, intracavernosal injection of 823 Vasodilator parenteral 287 therapy 286 Vasopressin 285 Vasovagal reaction 961 Vedolizumab 432 Veins large 947 over chest wall 333 pulmonary 258, 260, 264, 268, 273 thrombosis, deep 396 Vellus hairs 6 Velpatasvir 446 Vena cava inferior 244, 247, 252, 254, 256, 258, 268, 273 obstruction, causes of superior 333 Veno-occlusive disease 532 Venous hypertension, right sided 458 Ventilation 321 assist-control mode 391 assisted 358 control mode 391 failure 695 inverse ratio 391 mechanical 391 modes of 391 Ventilatory capacity, abnormal 348 Ventricle, right 256, 258, 260, 264, 273

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1017

Index Ventricular aneurysm 309 bigeminy 235f ectopics 234f extrasystole 234 types of 235 fibrillation 236, 236f, 307, 322 flutter 235, 236f hypertrophy, right 221, 221f, 244 infarction, right 310 level shunt 240 septal defect 207, 245, 246f classification 245 tachycardia 235, 236f, 308 classification of 235 Venturi masks 353 Verapamil 295, 684, 831 Vermis, lesion of 642 Vernet syndrome 616 Vertebra fracture of 840 spinous process of 962 Vertebral artery 664, 667 syndromes 667 Vertebral column 715 Vertebrobasilar system 678 Vertigo 614, 849 benign positional 614 lesions causing 614 peripheral 615 positional 613 severity of 615 Very low density lipoprotein 833 Vesical calculi 939f Vesicular breath sound 342 Vestibular function, test of 613 Vestibulocochlear nerve 611 Vibration sense 648 Vibrio cholera 89f Vildagliptin 809 Vim Silverman’s needle 964 Vinblastine 760 Vincristine 760 Vinyl chloride 862, 879, 928 Vipomas 750 Viral diseases 112 disorders, classification of 112 hepatitis 441, 450 infection 113, 425, 794 orchitis 792 pneumonia 376 respiratory disorders 114 Virchow’s node 404 Virilising congenital adrenal hyperplasia 791 Viruses, electron micrograph of 442f

Index.indd 1017

Visceral infections 116 leishmaniasis 149, 151 organs, ischaemia of 873 pain sense, loss of 821 reflexes 642 Vision 57 colour 593 Visual acuity, testing of 590 agnosia 579 field concentric constriction of 593 defects 592f testing of 591 fixation 604 Visuospatial functions 578 Vitamin 56, 428 A 56, 68, 427, 840 deficiency, WHO classification of 57 dietary deficiency of 878 functions of 57 toxicity 57 B1 61, 68 B12 63, 68, 427, 451, 488 deficiency, causes of 486 metabolism of 486 B2 62, 68 B3 68 B6 63, 68 B7 68 B9 68 C 63, 68 functions of 63 D 58-60, 68, 427, 839 deficiency 58, 60, 839 dependent rickets 839 malabsorption of 839 metabolism 58f metabolites, supplementation of 841 D3 774 status 58 deficiencies 572 E 60 deficiency 697 K 61, 68, 427, 435 antagonist 303 excess 61 Vitiligo 4f, 772, 786 Vocal cords 973 Vocal fremitus 339 Voglibose 808 Voice hoarseness of 882 persistent hoarseness of 882 sounds 344

Vomiting 402, 668, 760, 778, 787, 829, 849, 869, 870, 880, 923, 927, 931 von Hippel-Lindau syndrome 661, 879 von Recklinghausen’s disease 615, 660 von Willebrand disease 528, 530 von-Gierke’s disease 836 Voriconazole 184 Vulva, carcinoma of 899 Vulvar candidiasis 177

W Wackenheim’s line 735 Waddling gait 633 Waldenstrom’ macroglobulinaemia 521 Wallenberg syndrome 651 Warfarin 303, 304, 312, 927 pros and cons of 303 therapy, chronic 860 Wartenberg’s reflex 637f Wartenberg’s sign 636 Wasted leg syndrome 694 Watch test 611 Water deprivation test 758, 759 hammer pulse 195 insoluble fibres 52 soluble fibres 52 Weber’s syndrome 667 Weber’s test 612, 612f Wegener’s disease 758 Wegener’s granulomatosis 379, 865, 866, 868 Weight gain 768 Weight loss 833 Weil’s disease 107, 108f Weil’s syndrome 108 Werner syndrome 800 Wernicke’s aphasia 585, 665 Wernicke’s area 585 Wernicke’s encephalopathy 62 Wernicke-Korsakoff’s syndrome 925 West African trypanosomiasis 153 Westermark’s sign 934 Wheeze expiratory polyphonic 344f fixed monophonic 343, 344f random polyphonic 344f sequential inspiratory 344f types of 343, 344f Whipple’s disease 866 Whipple’s triad 828, 831 Whipworm 161 White cell 498 scan 943 White clot syndrome 526 White coat hypertension 200

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1018

Manual of Practical Medicine White nail 25, 25f causes 25 Whooping cough 85 Wide pulse pressure, signs of 274 Wilkins echocardiography score 267 Williams syndrome 243, 253 Wilms’ tumour 898 familial 876 Wilson’s disease 404, 463, 464f, 465f, 778, 963 management of 465 Wind angina, second 191 Withdrawal syndrome 924 Wolff-Parkinson-White syndrome 231, 231f, 321 Wolfram’s syndrome 794 Woolsorter’s disease 83 Word blindness 584, 585 Wrist fracture of 840 joints, widening of 59f

Index.indd 1018

sign 14, 15f Wuchereria bancrofti 161, 164f

X Xanthelasma 204 Xanthomas 835 Xeroderma pigmentosum 698 Xerostomia 847, 931 X-linked ataxia 698

Y Yaws 107 Yellow fever 129 vaccine 188 Yellow nail syndrome 25 Yersinia pestis 91f Young stroke 669 causes 669

Young’s syndrome 363

Z Zalcitabine 139 Zenker’s diverticulum 417 Zidovudine 139 Zinc 67, 68, 427, 780 acetate 465 deficiency 67f, 780 dietary deficiency of 878 Zollinger-Ellison syndrome 422, 426, 789 Zolmitriptan 683 Zona fasciculata 780 Zona glomerulosa 780 Zona reticularis 780 Zonisamide 658 Zoonotic nematodes 166 Zygomycosis 183

04-Jan-18 2:25:29 PM