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

The API (Association of Physicians of India) Textbook of Medicine consists of 28 sections across two comprehensive volum

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

Table of contents :
Cover......Page 1
Preface......Page 6
Acknowledgements......Page 8
Contributors......Page 11
Contents......Page 26
1.01- The Practice of Medicine......Page 44
2.01- Pain-Mechanisms and Management......Page 52
2.02- Headache......Page 55
2.03- Chest Pain......Page 59
2.04- Acute Abdomen-Non-Surgical Causes......Page 63
2.05- Cough......Page 68
2.06- Haemoptysis......Page 72
2.07- Jaundice......Page 75
2.08- Upper Gastrointestinal Bleeding......Page 82
2.09- Fever of Unknown Origin......Page 85
2.10- Generalised Lymphadenopathy......Page 90
2.11- Dizziness and Vertigo......Page 92
2.12- Syncope......Page 96
2.13- Coma......Page 100
3.01- Conventional Radiology......Page 106
3.02- Ultrasound in Medicine......Page 121
3.03- Computed Tomography......Page 127
3.04- MRI in Medicine......Page 134
3.05- Nuclear Imaging......Page 143
3.06- Positron Emission Tomography......Page 156
4.01- Introduction and Scope of Clinical Pharmacology......Page 162
4.02- Rational Use of Drugs......Page 166
4.03- Adverse Drug Reactions and Pharmacovigilance......Page 168
4.04- Prescribing in Special Situations......Page 171
4.05- New Drug Development......Page 176
4.06- Pharmacoeconomics......Page 178
5.01- An Overview of the Immune System......Page 180
5.02- General Concepts of Immunoinflammatory Disorders......Page 189
5.03- Immunology of Infectious Diseases......Page 192
5.04- Primary Immunodeficiency Disorders-A Clinical Approach......Page 194
5.05- Laboratory Investigations in Immune-Mediated Diseases......Page 198
5.06- Pharmacological Manipulation of the Immune System......Page 202
5.07- Immunology of Organ and Haematopoietic Stem Cell Transplantation......Page 207
6.01- Introduction to Medical Genetics......Page 212
6.02- Mendel and Beyond......Page 216
6.03- Clinical and Molecular Cytogenetics......Page 223
6.04- Genetic Tests......Page 232
6.05- Inborn Errors of Metabolism......Page 236
6.06- Molecular Genetics, Human Genome Project and Genomic Medicine......Page 244
6.07- Gene Therapy......Page 249
6.08- Genetic Counselling and Prenatal Diagnosis......Page 252
6.09- Pharmacogenomics and Personalised Medicine......Page 258
6.10- Cancer Genetics......Page 260
7.01- Basic Considerations in Critical Care......Page 266
7.02- Monitoring of Critically Ill Patients......Page 270
7.03- Fluid and Electrolyte Balance in Health and Disease......Page 275
7.04- Acid-Base Disorders......Page 282
7.05- Enteral and Parenteral Nutrition in Critically Ill Patients......Page 289
7.06- Acute Respiratory Failure......Page 294
7.07- Sepsis and Acute Respiratory Distress Syndrome......Page 299
7.08- Mechanical Ventilation......Page 306
7.09- Non-Invasive Ventilation......Page 314
7.10- Hypotension and Shock......Page 320
7.11- Cardiopulmonary Resuscitation......Page 325
7.12- Brain Death and Support of the Brain-Dead Organ Donor......Page 332
8.01- Bone and Mineral Metabolism in Health and Disease......Page 336
8.02- Investigations and Diagnosis of Bone Disorders......Page 342
8.03- Rickets and Osteomalacia......Page 348
8.04- Osteoporosis......Page 352
8.05- Developmental Disorders of Bone......Page 356
8.06- Miscellaneous Bone Disorders......Page 359
9.01- Epidemiology and Basic Considerations of Diabetes......Page 362
9.02- Pathogenesis of Type 1 Diabetes Mellitus......Page 367
9.03- Pathogenesis of Type 2 Diabetes Mellitus......Page 370
9.04- Clinical Features and Diagnosis of Diabetes Mellitus......Page 374
9.05- Lifestyle Modifications in Management of Diabetes......Page 379
9.06- Oral Anti-Diabetic Drugs......Page 382
9.07- Insulin Therapy......Page 386
9.08- Newer Modalities of Treatment in Type 2 Diabetes Mellitus......Page 390
9.09- In-Hospital Management of Diabetes Mellitus......Page 393
9.10- Hypoglycaemia......Page 397
9.11- Diabetic Ketoacidosis, Hyperosmolar Hyperglycaemic State and Lactic Acidosis......Page 402
9.12- Infections in Diabetes Mellitus......Page 407
9.13- Macrovascular Complications of Diabetes......Page 411
9.14- Microvascular Diseases-Pathogenesis of Chronic Complications......Page 415
9.15- Diabetes and Kidney Disease......Page 418
9.16- Diabetic Retinopathy......Page 420
9.17- Diabetic Neuropathy......Page 425
9.18- Sexual Dysfunction in Diabetes......Page 428
9.19- The Diabetic Foot......Page 430
9.20- Diabetes and Pregnancy......Page 433
9.21- Prevention of Diabetes Mellitus......Page 436
10.01- Basic Considerations of Endocrinology......Page 440
10.02- Endocrine Disorders-A Clinical Approach......Page 446
10.03- Disorders of Hypothalamus and Pineal Gland......Page 450
10.04- Disorders of Anterior Pituitary......Page 453
10.05- Disorders of Posterior Pituitary......Page 460
10.06- Disorders of Thyroid Glands......Page 462
10.07- Disorders of Parathyroid Glands......Page 473
10.08- Disorders of Adrenal Glands......Page 476
10.09- Disorders of Puberty......Page 485
10.10- Disorders of Growth and Development......Page 489
10.11- Disorders of Gonads......Page 495
11.01- Introduction and Principles of Diagnosis in Dermatology......Page 504
11.02- Cutaneous Infections......Page 513
11.03- Infestations and Insect Bites......Page 518
11.04- Eczemas......Page 523
11.05- Drug Reactions......Page 530
11.06- Abnormal Vascular Responses......Page 534
11.07- Papulosquamous Disorders......Page 537
11.08- Autoimmune Bullous Disorders......Page 541
11.09- Disorders of Pigmentation......Page 544
11.10- Disorders of Skin Appendages......Page 550
11.11- Cutaneous Responses to Physical Factors......Page 555
11.12- Genodermatoses......Page 558
11.13- Skin in Connective Tissue Diseases......Page 563
11.14- Skin in Systemic Diseases......Page 569
11.15- Leprosy......Page 577
11.16- Sexually Transmitted Infections......Page 584
11.17- Premalignant Conditions and Malignant Tumours of the Skin......Page 589
11.18- Therapy of Dermatological Diseases......Page 592
12.01- Basic Considerations in Cardiology......Page 598
12.02- Cardiovascular Diseases-A Clinical Approach......Page 604
12.03- Electrocardiology......Page 613
12.04- Exercise Testing......Page 623
12.05- Echocardiography......Page 628
12.06- Cardiac Imaging......Page 638
12.07- Nuclear Cardiology......Page 648
12.08- Cardiac Catheterisation and Angiocardiography......Page 653
12.09- Pharmacotherapy of Cardiovascular Disorders......Page 658
12.10- Heart Failure......Page 664
12.11- Heart Failure Management......Page 667
12.12- Acute Rheumatic Fever......Page 672
12.13- Valvular Heart Disease (I)......Page 680
12.14- Valvular Heart Disease (II)......Page 686
12.15- Infective Endocarditis......Page 695
12.16- Atherosclerosis......Page 704
12.17- Ischaemic Heart Disease......Page 709
12.18- Acute Coronary Syndrome......Page 716
12.19- Acute Myocardial Infarction......Page 720
12.20- Hypertension......Page 728
12.21- Management of Hypertension......Page 734
12.22- Secondary Hypertension......Page 741
12.23- Bradyarrythmias......Page 745
12.24- Tachyarrhythmias......Page 750
12.25- Sudden Cardiac Death......Page 756
12.26- Congenital Heart Disease......Page 759
12.27- Heart in Systemic Disease......Page 767
12.28- Disorders of Myocardium......Page 771
12.29- Diseases of the Pericardium......Page 780
12.30- Surgical Management of Heart Disease......Page 789
12.31- Diseases of the Aorta......Page 793
12.32- Vascular Disorders of the Extremities......Page 800
12.33- Pregnancy and Heart Disease......Page 807
13.01- Clinical Approach-Gastrointestinal Disorders......Page 812
13.02- Investigations-Gastrointestinal Disorders......Page 817
13.03- Endoscopy-Diagnostic and Therapeutic Utility......Page 820
13.04- Diarrhoea and Malabsorption......Page 825
13.05- Constipation-Diagnosis and Management......Page 830
13.06- Gastrointestinal Bleeding......Page 834
13.07- Oesophageal Disorders......Page 842
13.08- Diseases of the Stomach and Duodenum......Page 849
13.09- Diseases of the Pancreas......Page 856
13.10- Functional Gastrointestinal Disorders......Page 862
13.11- Abdominal Tuberculosis......Page 866
13.12- Inflammatory Bowel Disease......Page 872
13.13- Ischaemic Bowel Disorders......Page 877
13.14- Gastrointestinal Symptoms in Systemic Diseases......Page 880
14.01- Basic Considerations of Hepatobiliary Disorders......Page 884
14.02- Hepatobiliary Disorders-A Clinical Approach......Page 889
14.03- Hepatobiliary Disorders-Investigations......Page 894
14.04- Hepatobiliary Disorders-Imaging......Page 898
14.05- Acute Viral Hepatitis......Page 905
14.06- Chronic Viral Hepatitis......Page 910
14.07- Chronic Non-Viral Hepatitis......Page 913
14.08- Alcoholic Liver Disease......Page 916
14.09- Cirrhosis of the Liver......Page 921
14.10- Extra-Hepatic Portal Venous Obstruction......Page 926
14.11- Non-Alcoholic Fatty Liver Disease......Page 928
14.12- Acute Liver Failure......Page 931
14.13- Inherited Metabolic Disorders of the Liver......Page 935
14.14- Parasitic Diseases of the Liver......Page 938
14.15- Toxic and Drug Induced Liver Injury......Page 941
14.16- Liver Transplantation......Page 942
14.17- Pregnancy and Liver Disease......Page 944
14.18- Liver in Systemic Disease......Page 948
14.19- Tumours of the Liver......Page 951
14.20- Diseases of Gall Bladder and Biliary Tract......Page 954
15.01- Haematopoiesis......Page 958
15.02- Anaemia-A Clinical Approach......Page 965
15.03- Splenomegaly-A Clinical Approach......Page 969
15.04- Iron Deficiency Anaemia......Page 971
15.05- Megaloblastic Anaemia......Page 976
15.06- Hereditary Haemolytic Anaemia......Page 981
15.07- Acquired Haemolytic Anaemia......Page 990
15.08- Aplastic Anaemia......Page 995
15.09- Acute Leukaemia......Page 999
15.10- Chronic Myeloid Leukaemia and Other Myeloproliferative Disorders......Page 1006
15.11- Myelodysplastic Syndromes......Page 1009
15.12- Chronic Lymphocytic Leukaemia......Page 1013
15.13- Lymphoid Neoplasms......Page 1017
15.14- Plasma Cell Dyscrasias......Page 1022
15.15- Bleeding Disorders......Page 1027
15.16- Platelet Disorders......Page 1030
15.17- Disorders of Coagulation......Page 1033
15.18- Hypercoagulable Disorders......Page 1039
15.19- Transfusion Medicine......Page 1043
15.20- Haematopoietic Stem Cell Transplantation......Page 1047
16.01- Epidemiology......Page 1054
16.02- Virology, Immunology and Diagnosis......Page 1057
16.03- Pathophysiology and Clinical Features......Page 1060
16.04- Antiretroviral Therapy......Page 1066
16.05- Drug Resistance......Page 1069
16.06- Non-Opportunistic Infections......Page 1072
16.07- Opportunistic Infections......Page 1075
16.08- Non-Pharmacologic Interventions and Prevention......Page 1079
17.01- Basic Considerations of Infections......Page 1082
A. General Considerations......Page 1085
17.02- Laboratory Diagnosis of Infections......Page 1087
17.03- Syndromic Approach to Infectious Diseases......Page 1091
17.04- Anti-Microbial Therapy-An Overview......Page 1094
17.05- Infections in the Immunocompromised Host......Page 1101
17.06- Hospital Acquired Infections Nosocomial Infections......Page 1103
17.07- Prevention of Health Care Associated Infections......Page 1106
17.08- Hospital Infection Control......Page 1110
17.09- Staphylococcal Infections......Page 1112
17.10- Streptococcal Infections......Page 1115
17.11- Pneumococcal Infections......Page 1117
17.12- Meningococcal Infections......Page 1120
17.13- Gonococcal Infections......Page 1123
17.14- Typhoid Fever (Enteric Fever)......Page 1126
17.15- Bacillary Dysentery......Page 1129
17.16- Cholera......Page 1131
17.17- Diseases Caused by Gram-Negative Enteric Bacilli......Page 1133
17.18- Haemophilus Influenzae Infections......Page 1137
17.19- Legionnaires Disease......Page 1140
17.20- Plague and Other Yersinia Infections......Page 1142
17.21- Clostridial Infections......Page 1145
17.22- Diphtheria......Page 1150
17.23- Pertusis-Whooping Cough......Page 1152
17.24- Syphilis......Page 1154
17.25- Non-Syphilitic Treponematoses......Page 1158
17.26- Leptospirosis......Page 1160
17.27- Lyme Disease, Rat Bite Fever, and Other Spirochaetal Infections......Page 1163
17.28- Anaerobic Infections......Page 1165
17.29- Atypical Mycobacteria......Page 1167
17.30- Brucellosis......Page 1168
17.31- Donovanosis......Page 1170
17.32- Actinomycosis and Nocardiosis......Page 1172
17.33- Bartonella Infections......Page 1175
17.34- Melioidosis......Page 1177
17.35- Rickettsial Infections......Page 1178
17.36- Chlamydial Infections......Page 1181
17.37- Mycoplasma Infections......Page 1184
17.38- Basic Considerations of Viral Diseases......Page 1186
17.39- Herpes Virus Infections......Page 1191
17.40- Human Papilloma Virus and Parvovirus Infections......Page 1194
17.41- Bird Flu and Swine Flu......Page 1198
17.42- Dengue......Page 1201
17.43- Ebola and Marburg Infections......Page 1204
17.44- Japanese Encephalitis......Page 1206
17.45- Rabies......Page 1209
17.46- Viral Gastroenteritis......Page 1213
17.47- Mumps......Page 1214
17.48- Measles (Rubeola)......Page 1215
17.49- Smallpox......Page 1217
17.50- Lymphocytic Choriomeningitis and Other Arena Virus Infections......Page 1218
17.51- Prion Diseases......Page 1219
17.52- Malaria......Page 1220
17.53- Amoebiasis and Giardiasis......Page 1228
17.54- Leishmaniasis......Page 1231
17.55- Toxoplasmosis......Page 1235
17.56- Trypanosomiasis......Page 1238
17.57- Cryptosporidiosis, Trichomoniasis, Balantidiasis and Isosporiasis......Page 1241
17.58- Ankylostomiasis, Ascariasis and Other Nematodal Infestations......Page 1243
17.59- Tapeworm and Hydatid Diseases......Page 1250
17.60- Filariasis and Other Related Infestations......Page 1254
17.61- Schistosomiasis Bilharziasis......Page 1259
17.62- Systemic Fungal Infections......Page 1261
17.63- Pneumocystis Jirovecii Infections......Page 1267
18.01- Basic Considerations of Metabolism......Page 1270
18.02- Inborn Errors of Carbohydrate Metabolism......Page 1272
18.03- Lipids and Lipoprotein Metabolism......Page 1275
18.04- Disorders of Purine and Pyrimidine Metabolism......Page 1283
18.05- Iron Metabolism and Iron Overload Syndrome......Page 1286
18.06- The Porphyrias......Page 1296
18.07- Wilsons Disease......Page 1300
18.08- Lysosomal Storage Disorders......Page 1306
18.09- Inherited Disorders of Membrane Transport......Page 1309
18.10- Amyloidosis......Page 1314
18.11- Disorders of Adipose Tissue and Obesity......Page 1318
18.12- Metabolic Syndrome......Page 1322
19.01- Kidney-Structure and Functions......Page 1324
19.02- Kidney Disease-A Clinical Approach......Page 1329
19.03- Acute Kidney Injury......Page 1334
19.04- Chronic Kidney Disease......Page 1338
19.05- Primary Glomerular Diseases......Page 1345
19.06- Secondary Glomerular Diseases......Page 1353
19.07- Urinary Tract Infections......Page 1359
19.08- Nephrolithiasis and Urinary Tract Obstruction......Page 1362
19.09- Vascular Injury to Kidney......Page 1366
19.10- Polycystic Kidney Disease and Inherited Tubular Disorders......Page 1370
19.11- Dialysis for Chronic Renal Failure......Page 1376
19.12- Renal Transplantation......Page 1382
20.01- Basic Considerations in Neurology......Page 1386
20.02- Neurological Disorders-A Clinical Approach......Page 1394
20.03- Clinical Neurophysiology......Page 1400
20.04- Neuroimaging......Page 1407
20.05- Epilepsy......Page 1414
20.06- Disorders of Speech......Page 1426
20.07- Disorders of Cranial Nerves......Page 1433
20.08- Ischaemic Cerebrovascular Diseases......Page 1444
20.09- Haemorrhagic Cerebrovascular Diseases......Page 1454
20.10- Cerebrovenous Thrombotic Disorder......Page 1461
20.11- Bacterial Meningitis and Brain Abscess......Page 1465
20.12- Neurotuberculosis......Page 1471
20.13- Neurosyphilis......Page 1477
20.14- Acute Viral Infections of Central Nervous System......Page 1480
20.15- Slow Virus Infections and Prion Diseases......Page 1486
20.16- Fungal and Parasitic Diseases of Nervous System......Page 1489
20.17- Raised Intra-Cranial Pressure and Hydrocephalus......Page 1494
20.18- Dementia......Page 1497
20.19- Extrapyramidal Disorders......Page 1502
20.20- Hyperkinetic Movement Disorders......Page 1507
20.21- Cerebellar Disorders......Page 1511
20.22- Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases......Page 1520
20.23- Demyelinating Diseases of Nervous System......Page 1525
20.24- Nutritional and Toxic Disorders of the Nervous System......Page 1533
20.25- Metabolic Disorders of Nervous System......Page 1539
20.26- Intra-Cranial Space Occupying Lesions......Page 1548
20.27- Head Injury......Page 1554
20.28- Myelopathies......Page 1561
20.29- Peripheral Neuropathy......Page 1572
20.30- Disorders of Autonomic Nervous System......Page 1583
20.31- Myasthenia Gravis......Page 1586
20.32- Diseases of Muscles......Page 1589
21.01- Basic Considerations of Oncology......Page 1598
21.02- Principles of Cancer Biology and Pathology......Page 1604
21.03- Cancer Screening and Prevention......Page 1608
21.04- Principles of Drug Treatment of Cancer......Page 1611
21.05- Principles of Radiotherapy......Page 1619
21.06- Head and Neck Cancers......Page 1622
21.07- Breast Cancer......Page 1624
21.08- Tracheobronchial and Lung Cancers......Page 1629
21.09- Tumours of the Gastrointestinal Tract (Stomach and Oesophagus)......Page 1637
21.10- Colorectal Cancer......Page 1641
21.11- Genitourinary Cancers......Page 1644
21.12- Gynaecological Malignancies......Page 1649
21.13- Soft Tissue Sarcomas......Page 1656
21.14- Cancer of Unknown Primary Site......Page 1659
21.15- Paraneoplastic Syndromes......Page 1665
21.16- Cancers in the Predisposed Host......Page 1669
21.17- Oncological Emergencies......Page 1672
21.18- Supportive Care in Cancer......Page 1675
22.01- Basic Considerations in Psychiatry......Page 1678
22.02- Anxiety Disorders......Page 1683
22.03- Bipolar Mood Disorders......Page 1688
22.04- Somatoform Disorders......Page 1692
22.05- Psychotic Disorders and Schizophrenia......Page 1695
22.06- Delirium, Dementia and Other Cognitive Disorders......Page 1700
22.07- Substance Related Disorders......Page 1704
22.08- Psychiatric Emergencies......Page 1713
22.09- Psychotherapy......Page 1717
22.10- Biological and Somatic Treatments of Psychiatric Disorders......Page 1721
23.01- Respiratory System-Structure and Functions......Page 1728
23.02- Pulmonary Disorders-A Clinical Approach......Page 1733
23.03- Pulmonary Disorders-Diagnostic Procedures......Page 1738
23.04- Upper Respiratory Tract Infections......Page 1744
23.05- Bronchial Asthma......Page 1747
23.06- Chronic Obstructive Pulmonary Disease......Page 1754
23.07- Pneumonia......Page 1762
23.08- Suppurative Pleuro-Pulmonary Diseases......Page 1769
23.09- Pulmonary Tuberculosis......Page 1777
23.10- Fungal Infections of Lungs......Page 1783
23.11- Diffuse Interstitial Lung Disease......Page 1788
23.12- Eosinophilic Lung Disease and Tropical Pulmonary Eosinophilia......Page 1794
23.13- Occupational and Environmental Lung Diseases......Page 1797
23.14- Sarcoidosis......Page 1801
23.15- Sleep Related Breathing Disorders......Page 1807
23.16- Pulmonary Embolism and Deep Vein Thrombosis......Page 1810
23.17- Diseases of Pleura, Mediastinum, Diaphragm and Chest Wall......Page 1817
23.18- Atelectasis and Pulmonary Fibrosis......Page 1827
23.19- Benign and Malignant Tracheobronchial Tumours......Page 1833
23.20- Cor Pulmonale......Page 1841
24.01- Basic Considerations of Rheumatology......Page 1846
24.02- Soft Tissue Rheumatism and Regional Rheumatic Pain Syndromes......Page 1851
24.03- Low Backache......Page 1856
24.04- Osteoarthritis......Page 1861
24.05- Gout and Other Crystal Arthritides......Page 1865
24.06- Rheumatoid Arthritis......Page 1872
24.07- Spondarthritides......Page 1887
24.08- Sjogrens Syndrome......Page 1894
24.09- Systemic Lupus Erythematosus......Page 1896
24.10- Antiphospholipid Syndrome......Page 1903
24.11- Systemic Sclerosis......Page 1906
24.12- The Vasculitides......Page 1910
24.13- Mixed Connective Tissue Disease and Overlap Syndromes......Page 1919
24.14- Inflammatory Muscle Diseases......Page 1922
24.15- Rheumatic Manifestations of Systemic Diseases......Page 1926
24.16- Miscellaneous Rheumatic Disorders......Page 1929
24.17- Emergencies in Rheumatology......Page 1934
25.01- Nutrition-Basic Considerations......Page 1938
25.02- Assessment of Nutritional Status......Page 1943
25.03- Protein Energy Malnutrition......Page 1947
25.04- Water Soluble Vitamins......Page 1952
25.05- Fat Soluble Vitamins......Page 1956
25.06- Minerals, Trace Elements and Antioxidants......Page 1960
25.07- Food Allergy and Food Intolerance......Page 1965
25.08- Eating Disorders......Page 1967
25.09- Enteral and Parenteral Nutrition......Page 1970
26.01- Poisoning-Basic Considerations and Epidemiology......Page 1976
26.02- Aluminium Phosphide Poisoning......Page 1979
26.03- Organophosphorous Poisoning......Page 1982
26.04- Corrosive Poisoning......Page 1984
26.05- Alcohol Poisoning......Page 1987
26.06- Plant Poisoning......Page 1990
26.07- Drug Overdose......Page 1993
26.08- Snake Bite Poisoning......Page 1998
26.09- Scorpion Sting......Page 2003
26.10- Fluorosis......Page 2008
26.11- Lathyrism......Page 2013
26.12- Epidemic Dropsy......Page 2015
26.13- Heavy Metal Poisoning......Page 2017
26.14- Miscellaneous Poisoning......Page 2026
27.01- Basic Considerations of Environmental and Occupational Diseases......Page 2032
27.02- Climate Change-Health and Disease......Page 2036
27.03- Environmental Pollution......Page 2041
27.04- Air-Borne Pollutants and Smoke-Related Hazards......Page 2044
27.05- Drowning, Near-Drowning and Submersion Injury......Page 2049
27.06- Electric Shock and Lightning Injury......Page 2051
27.07- Effects of Extremes of Temperature......Page 2054
27.08- High Altitude Medicine......Page 2060
27.09- Aviation Medicine......Page 2067
27.10- Radiation Hazards......Page 2071
27.11- Environmental Disasters......Page 2077
28.01- Geriatric Medicine......Page 2080
28.02- Sexual Medicine......Page 2085
28.03- Sports Medicine......Page 2089
28.04- Diet in Medical Diseases......Page 2093
28.05- Care of Terminally Ill......Page 2101
28.06- Exercise and Yoga in Health and Disease......Page 2104
28.07- Adult Immunisation......Page 2106
28.08- Perioperative Management......Page 2112
28.09- Law and Medicine......Page 2116
28.10- Travel Medicine......Page 2120
28.11- Nanotechnology and Nanomedicine......Page 2124
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I......Page 2146
L......Page 2148
M......Page 2149
N......Page 2152
O......Page 2153
P......Page 2154
R......Page 2157
S......Page 2159
T......Page 2162
V......Page 2164
Z......Page 2165

Citation preview

API Textbook of Medicine


Yash Pal Munjal




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

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API Textbook of Medicine Ninth Edition EDITOR-IN-CHIEF


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

Surendra K. Sharma MD, PhD

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

R.K. Singal



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

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

Pritam Gupta MD (Medicine)

Shyam Sundar

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


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

Sandhya A. Kamath MD, FICP

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

Subhash Varma MD, FICP

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

Milind Y. Nadkar MD, FICP

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

Anupam Prakash


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

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

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


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

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


Late Dr. R.J. Vakil

Late Dr. K.K. Datey

Late Dr. Shantilal J. Shah

1st and 2nd Edition

3rd Edition

4th Edition

Dr. G.S. Sainani

Dr. Siddharth N. Shah

5th and 6th Edition

7th and 8th Edition

Dr. Y.P. Munjal 9th Edition

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

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

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

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

Dr YP Munjal and the Editorial Board



Assisted By




J.S. Guleria

Randeep Guleria


Section 3 DIAGNOSTIC IMAGING Positron Emission Tomography

Shamim Ahmed Shamim

Rakesh Kumar


Section 8 BONE DISORDERS Rickets and Osteomalacia

Gaurav Aggarwal

Bindu Kulshreshtha

09 10 19 28

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

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

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


Section 14 HEPATOLOGY Non-Alcoholic Fatty Liver Disease

Harshal Rajekar

Yogesh K. Chawla


Section 15 HAEMATOLOGY Splenomegaly—A Clinical Approach

Brijesh Arora

Lalit Kumar


Section 16 HIV AND AIDS Pathophysiology and Clinical Features

Sonali Sanghavi

U.L. Wagholikar


Section 19 NEPHROLOGY Secondary Glomerular Diseases

Sonal Sharma Amit K. Dinda

O.P. Kalra

10 16

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

D. Nagaraja Ashok Panagariya


Demyelinating Diseases of Nervous System

Rita Christopher Parul Dubey Vipin Satija Prachi Mehndiratta


Section 21 ONCOLOGY Principles of Drug Treatment of Cancer

Ankur Behl

Lalit Kumar


Section 23 PULMONARY MEDICINE Pulmonary Disorders—Diagnostic Procedures

Archana Ahluwalia

Gautam Ahluwalia


Section 28 MISCELLANEOUS Adult Immunisation

Surendra K. Sharma

R.K. Singal

Man Mohan Mehndiratta






Yash Pal Munjal



Clinical Approach to Key Manifestations

A.K. Agarwal



Diagnostic Imaging

Raju Sharma



Clinical Pharmacology

B.B. Thakur




Sita Naik



Medical Genetics

Shyam Swarup Agarwal



Critical Care Medicine

Surendra K. Sharma



Bone Disorders

S.N.A. Rizvi



Diabetes Mellitus

Anil Bhansali




Nikhil Tandon




Vibhu Mendiratta




Gurpreet Singh Wander




Rakesh Tandon




Rajesh Upadhyay and S.K. Sarin




Rajat Kumar




Alaka Deshpande and B.B. Rewari


VOLUME 2 17.

Infectious Diseases

Shyam Sundar and Subhasish Kamal Guha



Disorders of Metabolism

B.K. Sahay




Vinay Sakhuja




M.V. Padma Srivastava




S.K. Bichile



Psychiatric Medicine

Yash Pal Munjal



Pulmonary Medicine

Surendra K. Sharma




Rohini Handa




S.V. Madhu



Poisoning and Toxicology

N.P. Singh



Environmental Medicine

Randeep Guleria




R.K. Singal


API Textbook of Medicine

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


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

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

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

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

Ashutosh Nath Aggarwal MD (Medicine)

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

DM (Pulmonary Medicine)

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

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

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

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

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

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

Jamal Ahmad MD (General Medicine) DM (Endocrinology)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Ragavendra Baliga MD MBA FRCP

DNB (Cardiology)


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

FICA (USA) ADHA (Hosp Adm)

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


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


API Textbook of Medicine

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

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


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

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

Dhruva Chaudhry MD DNB DM (Pulmonary and Critical Care)

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

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

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

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

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

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

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

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

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


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

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

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


API Textbook of Medicine

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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


API Textbook of Medicine

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

Gurudas Khilnani MD (General Medicine)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


MD (Pharmacology) DHRM

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

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

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

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

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

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

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

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

Consultant Physician Maiya Multispeciality Hospital, Bengaluru Karnataka, India

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

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

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

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

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


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

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


API Textbook of Medicine

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

Shubha R. Phadke MD (Paediatrics)

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

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

DM (Medical Genetics)

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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


API Textbook of Medicine

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

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

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

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

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

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

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


Prema Ramachandran Director Nutrition Foundation of India New Delhi, India

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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


API Textbook of Medicine

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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


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

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



The Practice of Medicine Yash Pal Munjal


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

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

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

SECTION 3: DIAGNOSTIC IMAGING 3.1 3.2 3.3 3.4 3.5 3.6

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

64 78 84 91 100 113 xxv

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SECTION 4: CLINICAL PHARMACOLOGY 4.1 4.2 4.3 4.4 4.5 4.6

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

120 123 125 128 133 135

SECTION 5: IMMUNOLOGY 5.1 5.2 5.3 5.4 5.5 5.6 5.7

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

138 146 149 151 155 159 164

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

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

170 173 180 189 193 201 206 209 215 217

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

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


Contents Contributors

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

SECTION 8: BONE DISORDERS 8.1 8.2 8.3 8.4 8.5 8.6

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

294 299 305 309 313 316

SECTION 9: DIABETES MELLITUS 9.1 9.2 9.3 9.4 9.5

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

321 324 327 331 336 xxvii

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

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

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

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

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

398 403 407 410 417 419 430 433 442 446 452

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

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


Contents Contributors

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

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

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

557 561 570 580 585 595 605 610 xxix

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

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

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


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

770 774

13.4 13.5 13.6 13.7 13.8 13.9 13.10 13.11 13.12 13.13 13.14

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

777 782 787

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791 799 806 813 819 823 829 834 837

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

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

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

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14.16 14.17 14.18 14.19 14.20

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

899 901 905 908 911

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


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

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

16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8

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


Contents Contributors

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

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

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

1042 1044 1048 1051 1058 1060 1063 1067

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

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

1069 1072 1074 1077 1080 1083 1086 1088 xxxiii

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17.17 17.18 17.19 17.20 17.21 17.22 17.23

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

D. 17.35 17.36 17.37

E. 17.38 17.39 17.40 17.41 17.42 17.43 xxxiv

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

1090 1094 1097 1099 1102 1107 1109

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

1111 1115 1117 1120 1122 1124 1125 1127 1129 1132 1134

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

1135 1138 1141

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

1143 1148 1151 1155 1158 1161

17.45 17.46 17.47 17.48 17.49 17.50 17.51

F. 17.52 17.53 17.54 17.55 17.56 17.57

G. 17.58 17.59 17.60 17.61

H. 17.62 17.63

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

1163 1166 1170

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1171 1172 1174 1175 1176

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

1177 1185 1188 1192 1195 1198

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

1200 1207 1211 1216

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

1218 1224

SECTION 18: DISORDERS OF METABOLISM 18.1 18.2 18.3 18.4 18.5

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

1228 1229 1232 1240 1243 xxxv

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18.6 18.7 18.8 18.9 18.10 18.11 18.12

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

1253 1257 1263 1266 1271 1275 1279

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

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

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

SECTION 20: NEUROLOGY 20.1 20.2 20.3 20.4 20.5


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

1345 1351 1357 1364 1371

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

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

1383 1390 1401

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


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

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

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

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

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

1636 1640 1645 1649 1652 1657 1661 1670


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

1674 1678

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

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

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

SECTION 24: RHEUMATOLOGY 24.1 24.2 24.3

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

1804 1808 1813 xxxix

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

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

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

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

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

SECTION 26: POISONING 26.1 26.2 xl


1896 1900 1904 1909 1913 1917 1922 1924 1927


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

1934 1936

26.4 26.5 26.6 26.7 26.8 26.9 26.10 26.11 26.12 26.13 26.14

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

1939 1941 1944

Contents Contributors


1947 1950 1955 1960 1965 1970 1972 1974 1983

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

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

1990 1993 1998 2001 2006 2008 2011 2017 2024 2028 2034


Geriatric Medicine Vinod Kumar Sexual Medicine Prakash Kothari

2038 2042 xli

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28.3 28.4 28.5 28.6 28.7 28.8 28.9 28.10 28.11 Index


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

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



Introduction The Practice of Medicine Yash Pal Munjal

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


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

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

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

Figure 1: Hippocrates (460–380 BC).

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

The Practice of Medicine

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

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


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

A 4


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

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

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

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

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

The Practice of Medicine

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

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


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


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

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

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

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

The Practice of Medicine

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

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

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

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

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


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


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

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


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


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



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

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


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

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

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

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

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

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

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

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

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

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

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

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

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


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


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


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

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

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

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

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


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

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

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

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


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

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

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

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

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

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


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

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

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

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


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

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

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


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


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


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



Chest Pain Sanjay Tyagi, Amit Mittal

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


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

Pulmonary embolism Pneumothorax Pneumonia Pleurisy

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

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

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


Pleural disorders

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


Acute coronary syndromes

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


Suggestive findings

Diagnostic approach

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

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

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


Gastrointestinal Oesophageal reflux (GERD) Peptic ulcer


Pulmonary Pulmonary embolism Pneumonia

Pneumothorax Pleuritis

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

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

Chest Pain

Table 2: Causes of Chest Pain

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

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

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

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

Clinical evaluation

Chest X-ray Usually clinical evaluation

Clinical evaluation

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


Diagnostic Category Gastrointestinal


Predisposing factors

Smoking Alcohol use

Physically active New activity Overuse Repeated activity

Onset Duration Character

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

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

Relieved by

Rest, sublingual nitrate

Food, antacids

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

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

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

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

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


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


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

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

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

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

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

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

Chest Pain

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

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

 

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

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

Renal function tests blood sugar

Liver function test (Cholecystitis) and amylase (pancreatitis)

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

Endoscopy for gastrointestinal causes of chest pain.

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



Acute Abdomen—Non-Surgical Causes

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

Sumeet Singla, AK Agarwal –

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

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

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



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

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

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

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

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

Acute Abdomen—Non-Surgical Causes

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

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

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

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

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

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

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

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

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

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


  

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

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

Table 1: Differential Diagnosis of Medical Causes of Abdominal Pain


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

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

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

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

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

Acute Abdomen—Non-Surgical Causes

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


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


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

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


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


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


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


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


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


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


Cough Suman Kirti

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

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

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

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

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

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

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

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

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


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

Clinical Features

Transient airway hyper-responsiveness

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

Rhinosinus infection/inflammation

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

Asthma Cough-variant asthma

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

Non-asthmatic eosinophilic bronchitis

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

Chronic obstructive pulmonary disease

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

Gastro-oesophageal reflux

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

Pulmonary tuberculosis

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


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

Tropical pulmonary eosinophilia

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

Bronchial carcinoma Less Common Causes

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

Repeated bronchial aspiration

Oesophageal disorders, neurological swallowing disorders

Pulmonary fibrosis

Patient is breathless; cough ‘dry’

Aspirated foreign body

May have no history of aspiration

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

Sometimes positional

Drug-induced cough

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

Pneumocystis jiroveci

Immune deficient patients with persistent cough


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

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

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

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

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


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


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


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


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


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


Haemoptysis Randeep Guleria, Jaya Kumar

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

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

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

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

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

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

Table 1: Causes of Haemoptysis

Table 2: Differences Between Haemoptysis and Haematemesis

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



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

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

Cough, breathlessness chest pain present

Nausea vomiting, abdominal pain

Malaena rare Examination shows macrophages or neutrophils

Malaena may be present Mixed with ingested food particles

Alkaline pH

Acidic pH

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


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

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

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

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


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

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

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


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


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

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

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

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

Aparna Agrawal 

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

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

Viral hepatitis.

Alcohol-induced liver disease.

Drug induced liver disease.

Infections involving the liver including liver abscess and sepsis.

Chronic hepatitis (all causes).

Gall stones and their complications.


Carcinoma of the pancreas.

Haemolytic anaemia.



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

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

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

History suggestive of acute viral hepatitis 

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

Change in taste and smell of food.

Contact with individuals with jaundice.

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

Some Practice Points

Blood or blood product transfusions.

Intravenous drug abuse.

Health care professionals.

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

History of sexually transmitted disease.

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

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

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



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




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

Basic Laboratory Abnormalities


Table 1: Classification and Causes of Jaundice

Unconjugated ↑ SBR Normal STA + ALP

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

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

Conjugated ↑ SBR Normal STA+ALP

Mixed ↑ SBR (↑ SBR + ↑ STA ± ↑ ALP)

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

↑ SBR + ↑ STA + ↑ ALP

Conjugated ↑ SBR + Normal STA + ↑↑ ALP


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


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

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

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

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

Figure 1: Clinical signs in jaundice.

 

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



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

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

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

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

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 

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


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

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


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

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

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

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

Haemolytic Jaundice

Hepatocellular Jaundice

Extrahepatic Cholestatic Jaundice

Colour of urine Colour of stools Pruritus Jaundice Antecedent history

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


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

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

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

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

Upper Gastrointestinal Bleeding

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

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

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


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


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


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


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


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


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

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


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

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

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

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

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

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

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

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

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


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

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

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

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


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

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

MRI in Medicine



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

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

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

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

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


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


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

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

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

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


Half-life (T½)

Type of Emission

Energy (Kev) (Photon)

6.01 hours 13.2 hours 27.7 days 2.8 days

IT EC γ EC, γ


73 hours



3.26 days

EC, γ

110 min 75 sec

β+ β+

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

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




Fluorine-18 Rubidium-82


F 82 Rb

MRI in Medicine

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

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

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





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

Half-life (T½)

Type of Emission

Energy (Kev) (Photon)

5.24 days

γ and β–

13 sec 6.01 hours


81 346 β– 190 140

6.01 hours



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

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


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

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

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

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

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


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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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


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

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


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

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

MRI in Medicine

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

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

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

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

Inborn Errors of Metabolism

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

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


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



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


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


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


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


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


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


Molecular Genetics, Human Genome Project and Genomic Medicine Girisha KM

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

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

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


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

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


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

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

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

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

Molecular Genetics, Human Genome Project and Genomic Medicine

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

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


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


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

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

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

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

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

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

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

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

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

Molecular Genetics, Human Genome Project and Genomic Medicine

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

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

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


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


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

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

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

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

Gene Therapy

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

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


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


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

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


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


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


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


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


Genetic Counselling and Prenatal Diagnosis

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

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

2. 3.

4. 5.


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

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


Figure 1: Karyotype showing free trisomy 21.

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

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

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

Carrier Father

Carrier Mother

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

15% 15% 100%

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

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

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

Genetic Counselling and Prenatal Diagnosis

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

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


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

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

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

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

Genetic Counselling and Prenatal Diagnosis

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

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

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

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


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

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


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


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


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

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


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


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


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

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


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

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

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


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


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

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


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


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


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


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

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

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

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


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

Tumour Suppressor Gene

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

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



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

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

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

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


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

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

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

Genetic Syndrome

Malignancy (Lifetime Risk of a Cancer)

Phenotypic/Tumour Features

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

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

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

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

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

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

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

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

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

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

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

Fluid and Electrolyte Balance in Health and Disease

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

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

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


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


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

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

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

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

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

Fluid and Electrolyte Balance in Health and Disease

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

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


Table 7: Causes of Hypermagnesemia

Table 8: Causes of Hypomagnesemia

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

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

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


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

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


Acid Base Disorders Alladi Mohan, Surendra K Sharma

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

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

[H+] (nmol/L)

6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8

158 125 100 79 63 50 40 31 25 20 15

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

Carbonic anhydrase ⎯⎯⎯⎯ → H2CO3–

→ ⎯ ⎯ ⎯⎯

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


log K’


log K’

[H+] [HCO3–] log [H2CO3]

pH = – log [H ]

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


Taking logarithm on both sides, we have


The pH is a ‘dimensionless representation’ of the H + concentration, it has no units and is just a number. There are several advantages of the expression pH compared to H+. Measured by the pH electrode, pH is related to the logarithm of H+ ‘activity’ rather than ‘concentration’ of H+ and this seems physiologically more appropriate. The relationship between pH and H+ is shown in Table 1. For each 0.1 pH unit increment, H+ falls by 20%; by remembering this relationship, the intermediate values can be derived accurately.

= [H2CO3 ]

Therefore, log [H+] + log

[HCO3–] [H2CO3]

and +

log [H ] =

[HCO3–] log K’ – log [H2CO3]

By changing signs on both sides of the equation, we have – log [H+] = – log K’ + log

[H2CO3–] [H2CO3]


Since – log [H ] is called pH and – log K’ is called pK, the equation can be re-written as [HCO3–] pH = pK + log [H2CO3 ] This has been called the ‘Henderson-Hasselbalch’ equation.


The pK represents the pH at which maximum buffering capacity can be achieved for that reaction. Since the carbonic acid concentration is dependent on the amount of dissolved CO2 which in turn is dependent on its solubility and the partial pressure of carbon dioxide (PaCO 2) in the arterial blood. Therefore, in this equation, H2CO3 can be substituted by s x PaCO2, where, s = solubility coefficient. In the clinical setting, pK = 6.1; s = 0.0301. Therefore, [HCO3–] pH = 6.1 + log 0.0301 × PaCO2 The body responds to the perturbations in the acid-base balance by buffering, which is the immediate response followed by respiratory (alteration in ventilation) and renal (alteration in bicarbonate excretion) responses. The major buffer system in the ECF is the CO2-bicarbonate buffer system. Other buffer systems that play a role in buffering are protein and phosphate buffer systems. In the blood, concentration of phosphate is very low and it is quantitatively unimportant. Protein buffers in blood include haemoglobin and plasma proteins. Haemoglobin is an important blood buffer particularly for buffering CO 2. According to the ‘isohydric principle’, at a given moment, all buffer systems which participate in defense of acid-base changes are in equilibrium with each other. It is important to remember that the carbonate and phosphate salts in bone act as a long-term supply of buffer, especially during prolonged metabolic acidosis. NOMENCLATURE FOR CLINICAL INTERPRETATION OF ARTERIAL BLOOD GAS MEASUREMENTS The nomenclature for clinical interpretation of ABG measurements are listed in Table 2. Normal laboratory values and acceptable therapeutic ranges for pH and PaCO2 are shown

in Table 3. The typical alterations in the ABG results and the expected compensatory mechanisms in simple acid-base disorders are listed in Tables 4A and B. Table 2: Nomenclature for Clinical Interpretation of ABG Measurements: Acid-Base Status Acidosis is an abnormal process or condition which would lower arterial pH if there were no secondary changes in response to the primary aetiological factor Alkalosis is an abnormal process or condition which would raise arterial pH if there were no secondary changes in response to the primary aetiological factor Acidaemia = Arterial pH < 7.36 Alkalaemia = Arterial pH > 7.44 Simple acid-base disorders are those in which there is a single primary aetiological acid-base disorder Mixed acid-base disorders are those in which two or more primary aetiological disorders are present simultaneously Respiratory disorders are caused by abnormal processes which tend to alter pH because of a primary change in PaCO2 levels Metabolic disorders are caused by abnormal processes which tend to alter pH because of a primary change in HCO3– ABG = Arterial blood gas; PaCO2 = Partial pressure of carbon dioxide; HCO3– = Bicarbonate

Table 3: Normal Laboratory Values and Acceptable Therapeutic Ranges for pH and PaCO2 Variable




Acceptable Therapeutic Range






PaCO2 (mmHg)





SD = Standard deviation; PaCO2 = Partial pressure of carbon dioxide

Table 4A: Expected Compensatory Mechanisms in Respiratory Acid-Base Disorders Acid-base Disorder

Initial Change

Compensatory Response

Respiratory acidosis



Equations for Expected Range of Compensation


For every 10 mmHg↑ in PaCO2, pH decreases by 0.08 units Expected pH = 7.4 – [0.008 × (PaCO2 – 40)]


For every 10 mmHg↑ in PaCO2, pH decreases by 0.03 units Expected pH = 7.4 – [0.003 × (PaCO2 – 40)]

Respiratory alkalosis




For every 10 mmHg↓ in PaCO2, pH increases by 0.08 units Expected pH = 7.4 + [0.008 × (40 – PaCO2)]


For every 10 mmHg↓ in PaCO2, pH increases by 0.03 units Expected pH = 7.4 + [0.003 × (40 – PaCO2)]

Table 4B: Expected Compensatory Mechanisms in Metabolic Acid-Base Disorders


Acid-base Disorder

Initial Change

Compensatory Response

Equations for Expected Range of Compensation

Metabolic acidosis



↓PaCO2 = 1.2 ×  (HCO3–) Expected PaCO2 = [1.5 × (HCO3–) + 8] ± 2 (Winter’s formula)

Metabolic alkalosis



↑PaCO2 = 0.7 ×  (HCO3–) Expected PaCO2 = [0.7 × (HCO3–) + 21] ± 2

Calculating PaCO2 Variance First, the PaCO2 variance is determined by calculating the difference between the measured PaCO2 and 40; then, the decimal point is shifted two places to the left. Example: pH 7.06, PaCO2 = 74 74 – 40 = 34 PaCO2 variance = 0.34 pH 7.48, PaCO2 = 20 40 – 20 = 20 PaCO2 variance = 0.20 Calculating Predicted pH Predicted respiratory pH is calculated as follows. If the PaCO2 is greater than 40, half the PaCO2 variance is subtracted from 7.40. If PaCO2 is less than 40, the PaCO2 variance is added to 7.40. Examples: 1. pH 7.06, PaCO2 = 74 74 – 40 = 34 PaCO2 variance = 0.34 0.34 × ½ = 0.17 Predicted respiratory pH = 7.40 – 0.17 = 7.23 2. pH 7.48, PaCO2 = 20 40 – 20 = 20 PaCO2 variance = 0.20 Predicted respiratory pH = 7.40 + 0.20 = 7.60 Estimate of Base Excess/Deficit The difference between the predicted respiratory pH and the measured pH reflects the metabolic pH change. Normally, a 10 mEq/L variance from normal buffer baseline represents a pH change of 0.15. If the pH decimal point is moved two places to the right, a 10 (10 mEq/L) to 15 (0.15) relationship will be evident and this has been expressed as “ 2/3 relationship”. By determining the difference between the measured pH and the predicted respiratory pH, moving the decimal point two places to the right and multiplying by 2/3, base excess/deficit can be calculated. When the measured pH is greater than the predicted pH, it is termed as base excess. When the measured pH is less than the predicted pH, it is termed as base deficit.

Examples: 1. pH 7.06, PaCO2 = 74, predicted pH = 7.23 Difference between predicted and measured pH = 7.23 – 7.06 = 0.17 Applying 2/3 rule, 0.17 × 2/3 = 0.11 Base deficit = 11 mEq/L

Acid Base Disorders

Indices for Acid-Base Balance Indices for acid-base balance include PaCO2, actual bicarbonate, standard bicarbonate and buffer base. Standard bicarbonate is the measurement made in the clinical laboratory after the blood has been equilibrated at 37oC with a PaCO2 of 40 mmHg. Actual bicarbonate is calculated from PaCO2 and pH using HendersonHasselbalch equation. Base excess is defined as the number of mEq of acid or base needed to titrate 1 L of blood to a pH of 7.40 at 37oC while PaCO2 is held constant. For quick bed-side calculation, it can be assumed that at PaCO2 held constant at 40 mmHg, 7 mEq of acid or base are required to change pH by 1 unit (0.10). Base excess (or deficit), which is a true reflection of non-respiratory component of acid-base balance, is an estimate and not an actual measurement. Therefore, it will be reliable only if the measurements used to derive it, the pH and PaCO2 are estimated accurately. Base excess is determined as follows:

2. pH 7.48, PaCO2 = 20, predicted pH = 7.60 Difference between predicted and measured pH = 7.6 – 7.48 = 0.12 Applying 2/3 rule, 0.12 × 2/3 = 0.08 Base deficit = 8 mEq/L 3. pH 7.20, PaCO2 = 90 90 – 40 = 50 PaCO2 variance = 0.50 0.50 × ½ = 0.25 Predicted respiratory pH = 7.40 – 0.25 = 7.15 Difference between predicted and measured pH = 7.20 – 7.15 = 0.05 Applying 2/3 rule, 0.05 × 2/3 = 0.033 Base excess = 3 mEq/L Base excess/deficit calculation serves as a useful guide for bicarbonate administration. Anion Gap Anion gap (AG) represents the concentration of all the unmeasured anions in the plasma (Table 5) and is calculated by the following formula: AG = [Na+] – [Cl–] + [HCO3–] Normal AG is 12 ± 4 mEq/L. Conditions resulting in metabolic acidosis other than hydrochloric acidosis usually lead to a decrease in the serum bicarbonate concentration without a concomitant rise in serum chloride thereby increasing the AG. Table 5: Unmeasured Anions and Cations Contributing to the Anion Gap Unmeasured Anions

Unmeasured Cations

Serum proteins, mostly serum albumin (15 mEq/L) Organic acids (5 mEq/L) Phosphates (2 mEq/L) Sulphates (1 mEq/L) Total = 23 mEq/L

Calcium (5 mEq/L) Potassium (4.5 mEq/L) Magnesium (1.5 mEq/L) Total = 11 mEq/L

Delta Ratio Delta ratio is related to the AG and buffering, and is defined as: Delta ratio = increase in AG/decrease in bicarbonate A high delta ratio can occur when the bicarbonate levels are already elevated at the onset of the metabolic acidosis either due to a pre-existing metabolic alkalosis, or as a compensation for pre-existing respiratory acidosis. A low delta ratio occurs with hyperchloraemic normal AG acidosis (Table 6). DIAGNOSIS OF ACID-BASE DISORDERS Clinical Assessment Patients with acid-base disturbances (Tables 7A and B) may present with symptoms due to the aetiological causes that


Table 6: Utility of Delta Ratio when Assessing Metabolic AcidBase Disorders Delta Ratio


10 mOsm/L is considered abnormal when calculated using this formula. Conditions causing increased osmolar gap metabolic acidosis include ethanol, ethylene glycol, methanol, acetone and propylene glycol poisoning. While a high AG, high osmolar gap metabolic acidosis is seen in methanol and ethylene glycol poisoning, normal AG, high osmolar gap metabolic acidosis is seen in isopropyl alcohol poisoning. Step 6: Determining whether other metabolic disturbances co-exist with an elevated anion gap acidosis A normal AG acidosis or a metabolic alkalosis may exist concurrently with an elevated AG acidosis. In this situation, corrected bicarbonate should be calculated as follows: Corrected HCO3– = measured HCO3– + (AG – 12) where, AG = anion gap If the corrected HCO3– is greater than 24, a metabolic alkalosis co-exists; if it is less than 24, then a normal AG metabolic acidosis co-exists.


Step 7: Assessing the normal compensation by the respiratory system for a metabolic disturbance In simple metabolic acidosis, the measured PaCO2 will fall within the range predicted by Winter’s formula (Table 4B). If a

concurrent respiratory disturbance is also concurrently present, it would be defined by the direction the PaCO2 varies beyond the range predicted by Winter’s formula rather than the PaCO2 variation from the normal value of 40. In metabolic alkalosis, the magnitude of respiratory compensatory response is not easily predictable because degree of PaCO2 increase does not exhibit an exactly linear relationship with the HCO3-. However, for practical purposes, the following equation has been found to be useful to calculate the expected: PaCO2 = [0.7 × (HCO3–) + 21] ± 2 In compensated metabolic alkalosis, the measured PaCO2 is equivalent to the expected PaCO2. If the measured PaCO2 is higher than the expected PaCO2, the respiratory compensation is not adequate, and the condition is termed as a primary metabolic alkalosis with a superimposed respiratory acidosis. In primary metabolic alkalosis with a superimposed respiratory alkalosis, the PaCO2 is lower than the expected. TREATMENT The aetiological causes responsible for acid-base disturbances largely determine the status and prognosis in patients with acidbase disorders. Therefore, it is essential to recognise the underlying cause responsible for the disturbance so that specific treatment can be instituted. Metabolic Acidosis Metabolic acidosis may induce a wide range of adverse clinical effects, some of which may be life-threatening. In lifethreatening metabolic acidosis, exogeneous alkali therapy aims to prevent or reverse the detrimental consequences of severe acidaemia affecting the cerebral, respiratory, metabolic and cardiovascular systems. Intravenous sodium bicarbonate is the mainstay of alkali therapy and should be given judiciously in amounts that will return blood pH to a safer level of about 7.20. The distribution of HCO3– being 40% of the body weight, the amount of HCO3– required to return the serum concentration to normal can be calculated as follows: HCO3– deficit = Body weight (kg) × 0.4 × (desired HCO3– – measured HCO3–) Except in situations of extreme acidaemia, sodium bicarbonate should be administered as an infusion rather than a bolus; about 30 minutes must elapse following the completion of the infusion before its clinical effect can be judged. One-half of the calculated deficit can be replaced in 3 to 4 hours, if severe heart failure is not present. Subsequently, monitoring of the patient’s acid-base status will determine additional alkali requirements. Alterations in respiratory function, dyselectrolytaemia (especially hypokalaemia) and hypo-tension must be recognised and treated. Specific therapy is required in the setting of poisoning and overdosage. Chronic metabolic acidosis (e.g. chronic kidney disease) is treated with oral sodium bicarbonate. Metabolic Alkalosis Metabolic alkalosis is usually mild; when severe (pH >7.6) or rapidly developing it may be life-threatening. The chlorideresponsive metabolic alkalosis can be treated with intravenous

Respiratory Acidosis Treatment of respiratory acidosis is directed at improving ventilation using non-invasive or invasive ventilatory strategies; administration of bicarbonate can be harmful and should be avoided. Respiratory Alkalosis Treatment of respiratory alkalosis should be directed towards the underlying cause, identification and correction of electrolyte abnormalities that usually co-exist. Usually, reassurance, re-breathing from a bag or treating the underlying psychological stress is enough to alleviate respiratory alkalosis. Controlling fever, seizure activity and sepsis will also help. RECOMMENDED READINGS 1.

Adrogué HJ, Madias NE. Management of life-threatening acid-base disorders. First of two parts. N Engl J Med 1998; 338: 26-34.


Adrogué HJ, Madias NE. Management of life-threatening acid-base disorders. Second of two parts. N Engl J Med 1998; 338: 107-11.


Driscoll P, Brown T, Gwinnutt C,Wardle T. A Simple Guide to Blood Gas Analysis. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2002.


Fall PJ. A stepwise approach to acid-base disorders. Practical patient evaluation for metabolic acidosis and other conditions. Postgrad Med 2000; 107: 249-50, 253-4, 257-8 passim. 5. Laski ME, Kurtzman NA. Acid-base disorders in medicine. Dis Mon 1996; 42: 51-125. 6. Mohan A, Sharma SK. An approach to interpret arterial blood gases. In Agarwal AK, editor Clinical Medicine Update 2006; Vol. IX. A publication of Indian Association of Clinical Medicine. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2006; pp 73-81. 7. Mohan A, Sharma SK. How to interpret blood gas data. In: Singal RK, editor Medicine Update. Mumbai: Association of Physicians of India; 2007:pp (17): 145-51. 8. Morganroth ML. An analytic approach to diagnosing acid-base disorders. J Crit Ill 1990; 5: 138-50. 9. Morganroth ML. Six steps to acid-base analysis: clinical applications. J Crit Ill 1990; 5: 460-9. 10. Narins RG, Emmett M. Simple and mixed acid-base disorders: a practical approach. Medicine (Baltimore) 1980; 59: 161-87.

Acid Base Disorders

saline administration. When alkalosis is severe, or there is a risk of volume overload, 1N hydrochloric acid administration may be required. Chloride-unresponsive alkaloses are more difficult to treat and treatment is directed at the underlying cause.



Enteral and Parenteral Nutrition in Critically Ill Patients

Feeding is not considered medical therapy under ordinary circumstances. But when patients are critically ill and cannot eat themselves food takes the form of medical therapy. The incidence of hospitalised malnutrition is well documented, especially in critically ill patients. Despite the advances in medicine, definitive indications for the use of nutritional support are unclear. Use of enteral and parenteral therapies should be widespread for various reasons: 1. Protein calorie malnutrition is common in a variety of hospitalised patients. 2. Documented association between malnutrition and increased morbidity and mortality. 3. It seems intuitive that well-nourished patients would respond more favourably to therapeutic interventions than malnourished patients. 4. Nutritional support can be provided safely to a wide variety of patients. 5. Several randomised prospective clinical trials showed that nutritional support benefits the patients. Therefore, there is a clear-cut evidence base for the role of enteral and parenteral therapies in hospitalised as well as critically ill patients. Nutritional support is a delivery of formulated enteral or parenteral nutrients to appropriate patients for the purpose of maintaining/restoring nutritional status. ENTERAL NUTRITION By definition, enteral nutrition means ‘within or by the way of gastrointestinal (GI) tract’. In practice, enteral nutrition is generally considered tube feeding. The consensus of nutritional experts is that the GI tract is more physiologically and metabolically effective than the intravenous route for nutrient utilisation. Any disease process that adversely affects oral intake may ultimately lead to significant nutritional deprivation and depletion. Patients who cannot eat, will not eat, or should not eat, yet who have adequate function of the GI tract, are candidates for enteral tube feeding.


Once the patient has been assessed and found to be a good candidate for enteral nutrition, the clinician selects the appropriate tube and route of access for tube placement. Enteral access selection depends on several factors as given below: 1. Anticipated length of time for which enteral feeding will be required 2. Degree of risk for aspiration or tube displacement 3. Presence or absence of normal digestion and absorption 4. Whether or not there is a planned surgical intervention 5. Administration issues such as formula viscosity and volume.

Shilpa S Joshi Advantages of Enteral Feeding Various advantages of enteral feeding are: (i) it is a preferred route of nutrition support as it is more physiologic, (ii) costeffective, (iii) safe, (iv) fewer side-effects as compared to parenteral nutrition, (v) maintenance of GI immune barrier, (vi) avoidance of central catheter related complications. The indications for enteral feeding are listed in Table 1. Table 1: Indications of Enteral Feeding Oral intake inadequate or contraindicated

Increased nutritional requirements Digestive and absorptive disorders

Metabolic and excretory disorders

Mechanical: stroke, central nervous system Disorders, coma, oropharyngeal and oesophageal disorders, partial or complete oesophageal or gastric obstruction Poor appetite: chemotherapy, radiation therapy, drug effect, nausea Transitional feeding: advance from parenteral to oral intake Psychological: anorexia nervosa, depression, Alzheimer’s disease Burns, trauma, sepsis, surgical or medical stress Inflammatory bowel disease, short bowel syndrome, pancreatitis, irradiated bowel, proximal and distal intestinal fistulae, immunocompromised syndromes Glycogen storage disease, hepatic encephalopathy, renal disease

Contraindications of Enteral Feeding Enteral feeding is contraindicated in patients with peritonitis, distal intestinal obstruction, intractable vomiting or severe diarrhoea. ASSESSMENT OF NUTRITIONAL NEEDS OF A PATIENT Before initiation of feedings, assessment of nutritional status of every patient is fundamental and includes some key components: nutritional history, anthropometric procedure, clinical examination, biochemical data, evaluation of weight loss and previous nutrient intake before admission, level of disease severity, co-morbid conditions, and function of the GI tract. Assessment of these parameters will help to document presence of malnutrition and will help clinician to select best method for providing nutrients and allows objective monitoring of nutritional efforts. These assessment are also needed to estimate caloric protein, micronutrient requirement and also help to select/make right kind of formula. FORMULA COMPOSITION Energy The target goal of enteral nutrition (defined by energy requirements) should be determined and clearly identified at

Males (kJ/day): REE = 278 + 58 (Wt) + 21 (H) -28.5 (Af) x SF Females (kJ/day): REE = 2734 + 40 (Wt) + 7.7 (H) -19.7 (Af) x SF where, kJ = Kilo Joules; REE = Required energy requirement; Wt = Weight in kilograms; H = Height in meters, Af = Activity factor, and SF = Stress factor Values for activity factor and stress factor for various diseases to be considered as standard are given below: Activity factor (AF) Stress factor (SF) Bed rest = 1.0 Post-operative with complication = 1.24 Ambulatory = 1.1 Skeletal trauma = 1.1-1.3 Active = 1.2-1.3 Sepsis = 1.3-1.6 Cancer = 1.2 where, 1 calorie is about 4.185 kJ. Efforts to provide more than 50% to 65% of goal calories should be made to achieve the clinical benefit of enteral nutrition over the first week of hospitalisation. Studies suggest that more than 50% to 65% of goal calories may be required to prevent increases in intestinal permeability in burn and bone-marrow transplant patients, to promote faster return of cognitive function in head injury patients and to improve outcome from immune modulating enteral formulations in critically ill patients. If unable to meet energy requirements (100% of target goal calories) after 7 to 10 days by the enteral route alone, consider initiating supplemental parenteral nutrition. Initiating supplemental parenteral nutrition before this 7 to 10 days period in the patients already on enteral nutrition does not improve outcome and may be detrimental to the patient. Proteins Proteins in the diet serve as a source of amino acids that body cannot make (essential amino acids) and provide nitrogen for the synthesis of other amino acid (non-essential amino acids). Insufficient protein intake can potentially affect all aspects of a patient’s care, for example, it can lead to muscle atrophy and can make it difficult to wean off the patient from ventilator. In addition to the importance of adequate amounts of protein is the quality of protein. Proteins can be modified in various ways in enteral formulation, for example intact protein, hydrolysed protein, amino acids. Intact proteins and protein isolates requires normal pancreatic enzymes to catabolise them into small polypeptides and free amino acids. Hydrolysed protein formulas can be directly absorbed into the blood stream. These feeds can be administered when the feeds are administered via jejunum and where only absorption of proteins takes place. IMMUNOMODULATORY AGENTS Glutamine and Branched Chain Amino Acids Glutamine and branched chain amino acids are amino acids found in skeletal muscles. These have been identified as key amino acids in preserving nitrogen balance during stress and injury. Numerous studies have indicated that glutamine is necessary to maintain integrity of intestinal mucosa, immune

function of lymphocytes to preserve muscle glutamine pool and to improve overall nitrogen balance. Arginine Arginine is a conditionally essential amino acid, i.e. it can be conditionally essential after injury. Human and animal studies have shown that increased intake of arginine after trauma decreases nitrogen losses and accelerate wound healing. Standard formulas contain arginine in the amount of 1 g and 2 g/L. Arginine enriched formulas contain 14 to 15 g/L. Nucleotides Nucleotides are added to some formulas as immunity enhancers. In animals, dietary supplementation of nucleotides has shown to facilitate growth and maturation of developing gut. Agents such as ribonucleic acid (RNA) nucleotides increase total lymphocyte count, lymphocyte proliferation and thymus function. Taurine Taurine is conditionally essential nutrient since it can be synthesised by dietary cysteine or methionine.

Enteral and Parenteral Nutrition in Critically Ill Patients

the time of initiation of nutritional support therapy. Energy requirements may be calculated by Harris Benedict equation, which is as follows:

EPA-DHA Omega-3 fatty acids eicosapentaenoic acid and docosohexaenoic acid displace omega-6 fatty acids from the cell membranes of immune cells. This effect reduces systemic inflammation through the production of alternative biologically less active prostaglandins and leukotrienes. Patients with acute respiratory distress syndrome and severe acute lung injury should be placed on an enteral formulation characterised by an anti-inflammatory lipid profile (i.e. omega3 fish oils, borage oil) and antioxidants. High Nitrogen Products These have increased proportions of branched chain amino acids. These products are used for patients with catabolic stress. Most of formulas contain a non-protein kcal: nitrogen ratio of 150:1 (with ranges between 100:1–200:1) which is thought to be optimal for patients. Most of the enteral formulations offer high nitrogen products. Patients who do not need high nitrogen formulas are likely to use amino acids for energy and increase urea production. As a result this formula should be given carefully to renal patients. Carbohydrates Carbohydrates (CHO) provide 30% to 90% of total calories of enteral formulas and in most of the formulas these are the principle source of energy. The main difference among the formulas is the form and composition of CHO. In general, the longer carbohydrate molecule are less osmotic, taste less sweet are require more digestion than the shorter ones. Lactase deficiency is most prevalent disaccharide deficiency and hence, most of the enteral formulas are lactose free. Fibre Enteral formulas containing fibre may have potentially clinical applications including ameliorating constipation and tube feeding-associated diarrhoea, improving mucosal healing in inflammatory bowel disease, supporting gut barrier of critical ill patient and increasing intestinal adaptation in short bowel


syndrome. Predominant source of fibre of enteral formula is soya derived polysaccharides. Soluble fibre may be beneficial for the fully resuscitated, haemodynamically stable critically ill patient receiving enteral nutrition who develops diarrhoea. Insoluble fibre should be avoided in all critically ill patients. Both soluble and insoluble fibre should be avoided in patients at high-risk for bowel ischaemia or severe dysmotility. Lipids Fat is a dense source of energy and also serves as a vehicle for fat soluble vitamins and essential fatty acids. Most of the enteral formulas contain vegetable oil as primary source of fat. Vegetable oil is also a good source of essential fatty acids. Fat does not contribute to osmolality of enteral formula. Long Chain Triglycerides Vegetable oils are predominant source of fat in enteral formulas. Long chain triglycerides are slowly cleared from blood stream and require carnitine for its absorption. Medium Chain Triglycerides (MCTs) MCTs are 6 to 12 carbon long and are usually prepared from palm kernel or coconut oil. They offer many advantages over long chain triglycerides, as they are absorbed intact without appreciable pancreatic or biliary function and are subjected to more rapid clearance from blood stream. They are transported to the liver principally via portal venous system where they cross mitochondrial membrane and can be oxidised independent of carnitine. These should not be used in patients who are prone to high ketone levels as they produce ketone. Vitamins, Minerals and Trace Elements A combination of antioxidant vitamins and trace minerals should be provided to all critically ill patients receiving specialised nutritional therapy. Supplemental vitamins and minerals should be given when quantity of formula does not fulfil the requirement. Water Fluid balance in patients receiving enteral nutrition should be monitored. The daily water requirement for a healthy adult is 1 mL/kcal taken for approximately 30 to 32 mL/kg. Minimum of 30 mL of water every 6 hours is recommended as a flush for tube patency alone. Probiotics Administration of probiotic agents has been shown to improve outcome (most consistently by decreasing infection) in specific critically ill patient populations involving transplantation, major abdominal surgery, and severe trauma. No recommendations can currently be made for use of probiotics in the general intensive care unit population because of a lack of consistent outcome effect.


PHYSICAL CHARACTERISTICS OF A FORMULA Osmolality Osmolality is a physical phenomenon of net permeability resulting in equilibrium across the cell membrane. It is a measure of concentration of free particles, molecule or ions in a given

solution in water. These particles include electrolytes, minerals, carbohydrates, proteins or amino acids and are expressed in milli osmoles per kilogram of water. All nutrients and dietary components except water contribute to osmolality solution. It has been widely thought that isotonic formulas (osmolality ranging from 280 to 320 milli osmoles/kg) are tolerated well than hyper or hypotonic formulas. Renal Solute Load Renal solute load refers to the constituents in the formula that must be excreted by the kidneys. Protein, sodium, potassium, and chloride are the major constituents of enteral formulas that contribute to the renal solute load. It is important, as there is obligatory water loss with each unit of solute. Nutritional Formulations A wide variety of commercially prepared formulas with variable sources and concentrations of protein, carbohydrate and fat are currently available. Polymeric Formulas Polymeric formulas are composed of intact proteins, disaccharides and polysaccharides and variable amount of fat. The osmolality of polymeric formula is usually lower than that of elemental formulas. These formulas require a functioning GI tract for digestion and absorption of nutrients. Polymeric formulas can be further subdivided into hypercaloric formulas, normocaloric formulas, etc. Pre-Digested Formulas Pre-digested formulas are composed of low molecular nutrients, have minimal residue and are thought to lead less stimulations of pancreatic and GI secretion and are less allergic than other formulas. These formulas have greater osmolalities than the polymeric formulas because of the small molecule weight of nutrients. Modular Products Individual macro-nutrients modules, such as glucose polymers, proteins, and lipids, are available as additives to foods and enteral formulas to change overall fuel composition. Disease Specific Formulas These products are designed for patients who have specific medical conditions that may require nutrient modifications. Formula Selections Selection of appropriate formulas is based on patient’s medical and nutritional status, digestive and absorptive capabilities indicate whether pre-digested or polymeric formulas can be used. Administration of Tube Feeding Proper administration of enteral formulas ensures safe delivery of desired nutrients, enhanced patient tolerance and optimal nutritional support. There are various methods of feeding the patients. Choice of technique depends upon GI function, feeding site, and ultimately patient’s response. 1. Bolus feeding Bolus feeding is rapid administration of large volumes of formula over a short period of time usually by syringe. This form of feeding is least cumbersome but is associated with

2. Continuous feeding Continuous infusion is controlled delivery of prescribed volume of formula at a constant rate over a continuous period of time using infusion pumps or gravity assisted sets. This method is considered advantageous since gastric cooling is minimised and few GI tract side effects are experienced. Continuous infusion into jejunum is more analogous to normal gastric emptying. 3. Intermediate infusions In intermediate feeding, total quantity of formula needed for 24 hours is divided into equal portions and required fractions are administered in 3 to 6 feedings. Each feeding is administered over 30 to 90 minutes period. Techniques of Feeding 1. Selection of appropriate formulas. 2. Elevate the head of the patient’s bed to at least 30 degree to horizontal levels before feeding begins. 3. Aspirate through nasogastric or gastrostomy tube before initiating feeding to determine whether retained gastric secretions are present. 4. Begin feeding schedule of 100 to 150 mL of isotonic or slightly hypertonic formulas every 4 hours. 5. Increase formula amount by 50 mL every 1 or 2 feeding up to 450 mL every 4 hours. 6. Flush the tube at least with 30 mL of water after feeding and every 4 hours to maintain patency. Complications of enteral feeding are shown in Table 2. Table 2: Complications of Enteral Feeding Mechanical complications

Blockage of tube Dislocation of tube Aspiration pneumonia

Gastrointestinal complications

Delayed gastric emptying Constipation Malabsorption

PARENTERAL NUTRITION Parenteral nutrition is a form of intravenous therapy that provides opportunity to replenish or maintain nutritional status. Parenteral nutritional was originally developed to nourish those whose GI tract was not capable of digesting and absorbing nutrients. Central parenteral nutrition is delivery of nutrients through the large diameter vein usually subclavian or superior vena cava. Peripheral parenteral nutrition is usually delivered through small veins usually in the forearm. Central parenteral nutrition is indicated when volume and concentration of solution preclude peripheral administration and when anticipated duration of therapy is greater than 7 days to 2 weeks and when substantial depletion of body fat and protein has occurred. Peripheral parenteral nutrition is preferred when solution concentration is less than 1000 mOsm/L and duration of therapy is less than 10 days.

RATIONAL OF PARENTERAL NUTRITION 1. The patient is well nourished before admission but after 7 days of hospitalisation enteral nutrition has not been feasible or target goal calories have not been met consistently by enteral alone. 2. On admission, the patient is malnourished and enteral nutrition is not feasible. A major surgical procedure is planned, the pre-operative assessment indicates that enteral nutrition is not feasible through the peri-operative period and the patient is malnourished. 3. Indications: The basic indications for the use of parenteral nutrition are required for nutrition when the GI tract is either not working or not available or not appropriate (Table 3). Table 3: Indications for Parenteral Nutrition Non functioning gut, e.g. paralytic ileus Malnourished patients after major abdominal surgery

Enteral and Parenteral Nutrition in Critically Ill Patients

increased possibility of aspiration, regurgitation and GI sideeffect. A rate of 30 mL/min or a volume of 500 to 750 mL per feed appears to mark physical tolerance limit.

Severe mucositis systemic chemotherapy, upper gastrointestinal strictures or fistulae and acute pancreatitis Patients with major resections of the small intestine (short bowel syndrome) before compensatory adaptation occurs Patients in the intensive care unit with systemic inflammatory response syndrome or multiple organ dysfunction syndromes.

PARENTERAL MACRONUTRIENTS Proteins/Amino Acids The primary function of protein in parenteral nutrition is to maintain nitrogen balance, thus, preventing skeletal muscle from being degraded from gluconeogenesis. Protein requirement can be very high during intensely catabolic state. A positive nitrogen balance may not be feasible during the first few days of the catabolic stress. A positive caloric balance is necessary to establish a positive nitrogen balance. For delivered amino acids to be incorporated into new protein rather than catabolise the ratio of non-protein calories to gram of nitrogen should approach 150:1. This ratio is based on the fact that 10% to 15% or more of required calories during catabolism are derived from protein breakdown. Commercial amino acids are available. Dilute solutions are most often used for peripheral administration. Amino acid profiles of parenteral solutions are based on Food and Agriculture Organisation – World Health Organisation (FAO-WHO) recommendations for optimal proportion of essential amino acids. Carbohydrates Primary function of parenteral carbohydrate is to serve as energy source. Optimum carbohydrate is an amount adequate to spare protein without exacerbating hyperglycaemia. Commercial carbohydrates consist of N-hydrate, dextrose monohydrate in sterile water. Fats Parenteral lipids provide as a source of essential fatty acids and calories. These can be substituted for dextrose calories for patients with glucose intolerance or used as concentrated caloric source for patients who require volume restriction. Fats


have lower respiratory quotient than carbohydrates, which is a rational for use of lipids to provide large proportion of nonprotein calories in patients with respiratory failure. Because fat emulsions are isotonic, these can be administered through peripheral vein. Alternatively these may be directly added to parenteral nutritional solution. Electrolytes Electrolytes requirement for patients receiving total parenteral nutrition may vary depending on body weight, presence of malnutrition or catabolism, the degree of electrolyte depletion, change in organ function, ongoing electrolyte losses and disease process. Vitamins Vitamin requirements during parenteral nutrition therapy are uncertain because these are not based on balanced studies. Recommendations for parenteral nutritional therapy have been made by American Medical Association—Nutrition Advisory Group. Water Water requirements vary depending on the capacity of patient to excrete an osmotic load. Usually requirements are 30 ml/kg in normal adult or approximately 1 ml/kcal delivered. An additional 360 ml per day is recommended for each centigrade of temperature elevation. Also 300 to 400 ml of water per day may be necessary for new intra-celluloid fluid, if anabolism is being induced. Restriction of water is necessary during volume overload and presence of hyponatraemia. Patients who become hyperosmotic may need additional free water on daily basis. Trace Elements Trace elements are those nutrients that make-up less than 4 g or 0.01% of total body content. Individual trace elements may be supplemented in appropriate dose as specific patients deficiency dictates. Osmolality and Osmolarity While osmolality is most often used in reference to enteral feeding, osmolarity is preferred term for parenteral solutions.


Body maintains serum osmolality between 280-300 mOsm/kL. To avoid the irritation to veins, solutions with osmolarity greater than 900 mOsm/L are not usually administered peripherally. Initiation of Parenteral Nutrition Prior to initiation of parenteral nutrition, a baseline biochemistry profile should be checked and fluid and electrolyte abnormalities should be corrected. Monitoring During the first week of parenteral nutrition (and subsequently if patient is unstable with respect to fluid and electrolyte or metabolic issues) the patient should be monitored intensively. Reintroduction of Diet Diet should be reintroduced in a graded fashion. COMPLICATIONS The complications of parenteral therapy can be divided into three categories: (i) technical—pneumothorax, malposition, subclavian artery puncture, air embolism etc; (ii) septic— catheter related sepsis, septic thrombosis; and (iii) metabolic – hyperglycaemia, hypoglycaemia, hyperkalaemia, hypophosphataemia, etc. With proper patient monitoring, most of these complications can be minimised. RECOMMENDED READINGS 1.

Barr J, Hecht M, Flavin KE et al. Outcomes in critically ill patients before and after the implementation of an evidence-based nutritional management protocol. Chest 2004; 125: 1446-57.


Calo L, Bianconi L, Colivicchi F, et al. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: A randomised, controlled trial. J Am Coll Cardiol 2005; 45: 1723-8.


Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition. Crit Care Med 2009; 37: 1-30.


Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med 2006; 34: 2325-33.


Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006; 34: 1033-8.


Acute Respiratory Failure Ashit M Bhagwati


Table 1: Aetiology of Type 1 Respiratory Failure

Respiratory system is responsible for gas exchange in the human body. Inability to maintain a normal state of gas exchange leads to respiratory failure. Disorders involving the respiratory centre in the brain, peripheral nerves, respiratory muscles, airways, pleura, lung parenchyma and the chest wall can lead to compromise of gas exchange; thereby leading to a clinical scenario of acute respiratory failure (ARF). ARF is one of the most common life-threatening disorders encountered in the intensive care unit (ICU) and is associated with poor prognosis.

Respiratory System Airway disease: Asthma, COPD Parenchymal: Airspace: Pneumonia (bacterial, viral, mycoplasmal, fungal), atelectasis, bronchiectasis, and tumours Vascular: Pulmonary embolism, fat embolism, pulmonary arterial hypertension Pleura: Pneumothorax Chest Wall: Flail chest

DEFINITION Clinically, respiratory failure occurs when hypoxaemia (PaO2 is less than 60 mmHg), i.e. inadequate oxygenation of the blood or hypercarbia (arterial PCO2 is >50 mmHg), i.e. excess content of circulating carbon dioxide; or frequently, a combination of both types of gas exchange abnormalities occur. CLASSIFICATION ARF is classified as hypoxaemic respiratory failure (type 1), hypercapnic respiratory failure (type 2), post-operative/peri-operative respiratory failure (type 3) and shock-related respiratory failure (type 4). Respiratory failure is also classified as per its onset; acute or chronic respiratory failure. ARF refers to disorders of recent onset (hours to days). It suggests that respiratory failure has developed too rapidly for physiologic compensation to occur; therefore, pH is less than 7.3. Chronic respiratory failure develops overmonths to years, allowing compensatory mechanisms to improve oxygen transport and to buffer respiratory acidaemia; therefore the pH is slightly decreased. Sometimes, ARF may be superimposed on chronic respiratory failure. HYPOXAEMIC (TYPE 1) RESPIRATORY FAILURE Hypoxaemic respiratory failure (type 1) is defined as a condition in which the respiratory system exhibits a failure in its gas exchange function of oxygenation, PaO2/FiO2 35 breaths/min and with active use of accessory muscles of respiration. It is also associated with a normal or low PaCO2. The underlying physiologic aberration results from a disease process that involves the lung itself such as a ventilation-perfusion (V/Q) mismatch, shunting or diffusion impairment. The classic example of acute hypoxaemic respiratory failure is acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Aetiology Type 1 ARF is usually seen in diseases of the lung parenchyma, cardiovascular system and lower airways. The causes are due to low inspired concentration of oxygen (alveolar hypoventilation), impairment of diffusion, VA/Q mismatch, intrapulmonary shunting and low mixed venous oxygen content (Table 1).

Cardiovascular System Pulmonary oedema (cardiac failure), cyanotic congenital heart disease Miscellaneous: Obesity

Physiology The process of gas exchange has two components: the flow of gas between the atmosphere and the terminal airways; and the diffusion of gases between the terminal lung regions and the pulmonary capillary blood. The efficiency of gas exchange can be evaluated clinically by measuring the PAO2, PaCO2 and the alveolar-arterial (A-a) PO 2 gradient. Thus, patients with hypoxaemia may be divided into those with a normal gradient and those with an increased gradient (Table 2). The alveolar PO2 can be calculated from the alveolar air equation: PAO2 = (PB – PH2O) FiO2 – (PaCO2 /R) here, PAO2 is alveolar PO2; FiO2 is fraction of inspired oxygen; PB is barometric pressure (760 mmHg at sea level), PH2O is water vapour pressure (47 mmHg at sea level), and R is respiratory exchange ratio (assumed to be 0.8). Ventilation-perfusion mismatch and intrapulmonary shunting are the clinically important causes of hypoxaemia in ARF. Ventilation-Perfusion Mismatch In the presence of disease, the V/Q units vary. The low V/Q units contribute to hypoxaemia and hypercapnia as compared to high units where wastage of ventilation may occur without affecting the blood gases unless quite severe. If the patient is given 100% oxygen to breathe, there is a dramatic increase in the PaO2 as it eliminates low V/Q units, thereby correcting the hypoxaemia. Intrapulmonary Shunts Normally in health some degree of intrapulmonary shunting does occur, i.e. referred to as anatomical shunt accounting for 2% of the shunt. In addition, cyanotic congenital heart diseases or A-V malformations in the lungs cause right-to-left shunt. When the deoxygenated blood bypasses the ventilated alveoli and mixes with the oxygenated blood that has perfused the ventilated alveoli, reduction in the arterial content of oxygen occurs, i.e. hypoxaemia (PaO2 level decreases). Such situation


occurs in conditions such as pneumonia, atelectasis and severe pulmonary oedema of either cardiac or non-cardiac origin. Hypercapnia occurs when the shunt exceeds > 60%. In low V/Q mismatch and intrapulmonary shunting, the decreased PaO2 is always associated with an elevated P (A-a) oxygen gradient. In patients with low V/Q mismatch, the PaO2 has a dramatic rise in response to 100% oxygen, whereas in patients with intrapulmonary shunting, it shows a much smaller response. Differentiating between these causes of hypoxaemia is important clinically (Table 2). Table 2: Physiological Conditions Causing Type 1 Respiratory Failure

Criteria for Diagnosis of Acute Respiratory Distress Syndrome (ARDS) 1. Predisposing factors for ARDS, viz. sepsis, burns, pancreatitis, aspiration, malaria, leptospira, etc. 2. Tachypnoea, breathlessness, tachycardia, crackles on auscultation. 3. Progressive infiltrates in both the lung fields.

Pathophysiology of Hypoxaemia

P (A-a) O2 Gradient


4. Normal pulmonary capillary wedge pressure.

Low partial pressure of inspired oxygen Low ventilation-perfusion mismatch Right-to-left shunt Diffusion impairment


Normal or decreased

5. Refractory hypoxaemia with PAO2/FiO2 ≤200.


Normal or decreased

Increased Increased

Normal or decreased Normal or decreased

6. Decreased lung compliance ≤40 mL/cm water.

ARDS is the classic example of severe hypoxaemic respiratory failure. The European American Consensus Conference on ARDS defined ALI and ARDS. ALI is a syndrome of inflammation and increased permeability that is associated with a constellation of clinical, radiologic and physiologic abnormalities that cannot be explained by, but may co-exist with, left atrial or pulmonary capillary hypertension. The clinical criteria for ALI include: (i) acute onset of pulmonary failure, (ii) hypoxia with a PaO2/FiO2 ratio ≤300 mmHg, (iii) bilateral chest infiltrates visible on chest radiograph, and (iv) a pulmonary artery occlusion pressure ≤18 mmHg or no clinical evidence of increased left atrial pressure on the basis of chest radiograph and other clinical data. On the other hand, ARDS is defined as a more severe form of ALI with a PaO2/FiO2 ≤200, regardless of the level of positive end-expiratory pressure (PEEP) used on the ventilator. Clinical Manifestations Manifestations of hypoxaemic respiratory failure are due to a combination of features of arterial hypoxaemia and tissue hypoxia. Arterial hypoxaemia causes hyperventilation due to stimulation of carotid body chemoreceptors, leading to dyspnoea, tachypnoea and hyperpnoea. There may be cyanosis; degree of cyanosis depends on the concentration of the haemoglobin and the patient’s perfusion. Other features include generation of lactic acid due to anaerobic metabolism. Increased blood lactate levels may further stimulate ventilation. Mild hypoxia may also lead to impaired mental performance. With the progression of hypoxia alteration in the sensorium, somnolence, coma, seizures can occur leading to permanent brain damage.


Chest radiograph may be normal initially but later on (in established cases) may show bilateral infiltration (interstitial, airspace or both). Arterial blood gas analysis is central to diagnosis and reveals hypoxaemia with normal, but usually a low PCO2.

Patient develops tachycardia, diaphoresis, and systemic vasoconstriction leading to hypertension. Severe hypoxia can lead to bradycardia, vasodilation, hypotension, myocardial ischaemia, infarction, arrhythmias and cardiac failure. The manifestations of hypoxia are further amplified in the presence of tissue hypoxia. Symptoms and signs also reflect not just acute hypoxaemia, but also the underlying cause of respiratory failure.

HYPERCAPNIC (TYPE 2) RESPIRATORY FAILURE Aetiology Type 2 respiratory failure can result from abnormalities in any one component of the respiratory system including the brain, spinal cord, neuromuscular system, thorax, pleura and upper airways. Diseases of the lower airways (alveoli) or circulatory system are rare causes of type 2 respiratory failure (Table 3). Table 3: Aetiology of Type 2 Respiratory Failure Brain Drugs: narcotics, barbiturates, sedatives, poisons, general anaesthetics Metabolic: hyponatraemia, hypocalcaemia, hypercapnia, severe alkalosis, myxoedema Infections: meningitis, encephalitis, bulbar polio, cerebral abscess Neoplasms Trauma Central alveolar hypoventilation, obstructive sleep apnoea Occult status epilepticus Spinal Cord Traumatic transection, compressive tumours, poliomyelitis Neuromuscular Drugs: neuromuscular blockers, aminoglycosides Metabolic: hypokalaemia, hypophosphataemia, hypomagnesemia Infections: tetanus, Guillain-Barré syndrome, sepsis Trauma Neoplasm Myasthenia gravis Others: critical illness neuropathy, muscular dystrophies, respiratory muscle fatigue Upper Airways Upper airway mass: adenoid hyperplasia, goiter, polyps, malignant tumours Infections: epiglottitis, laryngotracheitis Trauma Others: bilateral vocal cord palsy, tracheomalacia, laryngeal oedema Chest Wall Trauma: Flail chest Others: kyphoscoliosis, scleroderma and massive pneumothorax or pleural effusion

Reduction in minute ventilation can be affected by processes affecting the central nervous system, peripheral nervous system, neuromuscular junction, respiratory muscles, chest wall abnormalities, metabolic and electrolyte abnormalities, and upper airway obstruction. In these disorders alveolar-arterial oxygen pressure difference (A-aDO2) is usually normal unless lung disease is present. Excessive CO2 production is usually due to fever, burns, sepsis, high carbohydrate diet, burns and hyperthyroidism. Agitation, myoclonus, or other causes of muscle activity can increase VCO2 and contribute to type 2 respiratory failure. Increase in the respiratory quotient, which is normally 0.8-2.0 doubles VCO2. Reduced CO2 elimination also occurs due to decreased alveolar ventilation. Alveolar hypoventilation may result from VA/Q mismatch (high VA/Q, increased physiological dead-space and wasted ventilation) as in pulmonary embolic diseases, intrinsic lung diseases (e.g. emphysema, asthma, cystic fibrosis or pulmonary fibrosis) and in chest wall disorders (e.g., scoliosis). Hypoventilation is characterised by hypercapnia and hypoxaemia. As minute ventilation reduces to less than 4 L/min, the PaCO2 rises dramatically. Usually these patients have normal A-aDO2 gradients. Patients at risk of hypercapnic respiratory failure may also be divided into two major categories: those with normal lungs (e.g., sedative overdose, neuromuscular disorders or chest wall abnormalities) and those with intrinsic lung disease (e.g., emphysema, chronic bronchitis or asthma) where maldistribution of ventilation and perfusion results in an increase in dead space. The final result is inadequate CO 2 clearance despite normal or increased minute ventilation. Clinical Manifestations Patients with acute hypercapnic respiratory failure largely present with central nervous system (CNS) disturbances. Hypercapnia is a CNS depressant leading to lethargy, somnolence, coma, asterixis, restlessness, tremors, slurred speech, headache and papilloedema. Symptoms of hypercapnia may overlap those of hypoxaemia. Basically, hypercapnic patients may have either decreased or increased minute ventilation depending on the primary disorder. As a result these patients have dyspnoea, tachypnoea, hyperpnoea with tachycardia and uncompensated respiratory acidosis. Diagnosis History is most important in diagnosis of ARF. It should aim at eliciting relevant information about possible predisposing factors, co-morbid conditions and identifying processes that affect prognosis. The clinical signs and symptoms of ARF reflect the underlying disease process and the associated hypoxaemia and hypercapnia. Diagnosis of respiratory failure requires

arterial blood gas study, not only to determine the presence and severity of respiratory failure but also to differentiate between type 1 and type 2 respiratory failure. POST-OPERATIVE/PERI-OPERATIVE (TYPE 3) RESPIRATORY FAILURE Post-operative/peri-operative respiratory failure can be defined as the need for intubation and mechanical ventilation (MV) within the 48 hours after surgery. In the post-operative/perioperative period, surgical patients following general anaesthesia often develop reduction in functional residual capacity leading to atelectasis in the dependent lung units. This leads to respiratory failure referred to as post-operative/perioperative respiratory failure (Table 4). To avoid this situation, a proper pre-operative assessment is mandatory to identify the patients who are at increased risk after non-thoracic and thoracic surgery. These subgroup of patients are best managed with frequent change of posture, chest physiotherapy, adequate analgesia for post-operative pain relief. Non-invasive ventilation (NIV) also may be used to tide over the crises. However, evidence-based studies on the usefulness of respiratory physiotherapy, incentive spirometry and NIV to prevent respiratory complications are lacking.

Acute Respiratory Failure

Physiology The hallmark of acute hypercapnic respiratory failure is an elevated PaCO2. Three processes, alone or in combination, can produce acute hypercapnic respiratory failure: a reduction in minute ventilation, an increase in CO2 production and alveolar hypoventilation.

Table 4: Aetiology of Type 3 Respiratory Failure Intra-pulmonary Causes Atelectasis, aspiration, pneumonia Acute lung injury/acute respiratory distress syndrome Volume overload/congestive heart failure Pulmonary embolism Asthma/Chronic obstructive pulmonary disease Pneumothorax Extra-pulmonary Causes Upper airway obstruction Obstructive sleep apnoea syndrome Diaphragmatic dysfunction/phrenic nerve injury

SHOCK-RELATED (TYPE 4) RESPIRATORY FAILURE Respiratory muscles consume less than 5% of the total cardiac output and oxygen delivery. Shock leads to increase in deadspace ventilation and pulmonary inflammation. The increase in dead-space ventilation is an early accompaniment of shock. It leads to hypoperfusion of the respiratory muscles, leading to respiratory muscle fatigue, causing a combined metabolic (lactic acidosis) and respiratory acidosis. Under this situation, more than 40% of the cardiac output is distributed to the respiratory muscles. Intubation and MV help redistribution of the cardiac output to the vital organs while shock is being treated. MANAGEMENT The general principles of support are similar regardless of the type of respiratory failure. The priorities in the management of ARF vary according to the aetiology. However, the primary aim in all the cases are the same: (i) to maintain a patent airway and ensure adequate ventilation and oxygenation; and (ii) to treat, if possible, the primary condition. This includes removal of excessive secretions to maintain clear airway, use of aerosolised bronchodilators, antibiotics, viz. aminoglycoside (tobramycin),


colistin according to sensitivity pattern and effective systemic antimicrobials for the treatment of infections. Hypoxaemic Respiratory Failure (Type 1) Patients with acute hypoxaemic respiratory failure are best managed in the ICU. The management of these patients involves both supportive and specific strategies that are generally performed simultaneously. Supportive therapy is aimed at stabilising the clinical condition of the patient by improving gas exchange and includes airway management and correction of hypoxaemia. Hypoxaemia is corrected by oxygen administration and use of ventilatory support (non-invasive and invasive mechanical ventilatory support). Measures are also directed towards specific therapy for identifying and reversing the underlying pathophysiologic mechanisms. Specific therapy varies depending on the underlying disease (e.g. use of antibiotics to treat patients with pneumonia and diuretics for pulmonary oedema). Oxygen therapy Oxygen supplementation is the most important therapy for hypoxaemic respiratory failure. After the airway is secured, attention is directed to the management of hypoxaemia. The treatment goal is to provide adequate oxygen delivery to the tissues (SaO2 >90% and PaO 2 ≥60 mmHg). Oxygen can be delivered by different means (nasal cannula for flow rates ≤ 5 L/min, face mask for flow rates ≥6 L/min or use of air entrainment devices, (i.e. venturi masks for higher flow rates). If the patient’s condition does not improve with high-flow oxygen: MV, either invasive or non-invasive, should be considered. Non-invasive ventilation In last few years, substantial data has emerged on the use of NIV in patients with acute hypoxaemic respiratory failure to avoid endotracheal intubation and ventilator-associated pneumonia, thereby reducing mortality. However, despite emerging studies regarding NIV as an adjunct in the management of hypoxaemic respiratory failure, its safety and efficiency remains unanswered. This is mainly due to varied aetiologies in subgroups of patients causing respiratory failure. Recently, a few studies have focused on some of the individual diagnoses within the large category. It has been found to be very effective in cardiogenic pulmonary oedema. NIV may also be useful when some components or degree of cardiac decompensation participates in the clinical feature, even if it is not the main or only cause of episode of respiratory failure.


It should be noted that patients with hypoxaemic respiratory failure should preferably be ventilated with a full face mask during acute phase and may be shifted to nasal mask, once the condition stabilises. Mechanical ventilation The two major goals of therapy are to maintain alveolar ventilation and correct hypoxaemia. In cases where NIV fails to correct hypoxaemia, invasive MV is used. Patients with severe ARF and a large intrapulmonary shunting may require high FiO2 while on the ventilator. MV increases alveolar ventilation, eliminates CO2 and corrects acidaemia. Due to the danger of oxygen toxicity, patients should be treated with the lowest concentration of oxygen that provides adequate oxygenation.

Hypercapnic Respiratory Failure (Type 2) Oxygen therapy Hypoxaemia secondary to hypoventilation can be easily treated with by supplemental oxygen (increasing FiO2). Failure of PaO2 to improve should alert to the possibility of an unsuspected concomitant lung disease producing a shunt effect (e.g. pneumonia, atelectasis). In many patients with chronic ventilatory failure, especially chronic obstructive pulmonary disease (COPD), oxygen therapy can cause acute worsening of hypercapnia. Three mechanisms have been proposed to explain this phenomenon. These patients may have a ‘blunted’ CO2 drive to breathe and the hypoxaemic drive is suppressed by supplemental oxygen. Oxygen may increase V/Q inequality by inhibition of hypoxic pulmonary vasoconstriction or by changing bronchomotor tone. Finally, haemoglobin affinity for CO2 decreases with increasing oxygen saturation (Haldane effect), which may further contribute to hypercapnia. Therefore, supplemental oxygen therapy for ventilatory failure aims at maintenance of PaO2 in a ‘safe’ range that does not compromise systemic oxygen delivery but minimises the possibility of worsening hypercapnia (SaO2 of 90% to 92%). Air entrainment oxygen masks (venturi masks) can be used to deliver precise doses of oxygen. If venturi masks are unavailable or are not feasible, a nasal cannula at flow rates of 0.5-2.0 L/min may be used to treat hypoxaemia (low-flow oxygen therapy). However, despite therapy, progressive hypercapnia and acidosis may develop in some patients and lead to confusion, stupor or coma, even when the FiO2 is increased only moderately. Such patients may require tracheal intubation and MV. Therapy in patients with asthma or COPD consists of oxygenation, hydration and aggressive treatment of the underlying aggravating factor with bronchodilators (theophyllin, anticholinergics and beta-agonists) and corticosteroids. Infection needs to be treated with appropriate antibiotics and any electrolyte abnormality must be corrected. In patients who progress to respiratory muscle fatigue, elective intubation and MV may be necessary to prevent respiratory arrest. Non-invasive ventilation (NIV) NIV is most commonly applied in acute hypercapnic respiratory failure commonly associated with COPD, where the ventilatory response to raised PaCO2 is decreased. Administration of NIV in patients with COPD with respiratory failure helps to increase the neural output to the diaphragm and other respiratory muscles, and thus, resets the respiratory control centre making it more responsive to an increased PaCO2. These patients are then able to maintain a normal PaCO2 throughout the daylight hours without the need for MV. The use of NIV in patients with acute exacerbations of COPD is considered the ventilatory mode of choice. It helps by reducing the rate of endotracheal intubation. It also improves the vital signs, gas exchange, thereby reducing dyspnoea. There is also reduction in the in-hospital mortality, with reduction in the complications like nosocomial pneumonia. NIV may also be used in patients with acute exacerbations of bronchial asthma. Uncontrolled studies have reported improvements in gas exchange and low rates of intubation after

Although the use of NIV in asthma is inconclusive, a trial of NIV in selected patients is justified, particularly in patients who fail to respond promptly to medical treatment and have no contraindications. It has also been suggested that aerosolised medicines may be delivered more effectively by NIV. However, NIV is not recommended for routine use in patient with asthma exacerbation. Mechanical ventilation Some patients with ventilatory failure may respond to early and aggressive management of the primary disorder. Others, with progressive pathology or whose loads are not rapidly reduced may require MV. Although no PaCO2 absolutely mandates MV, if the pH is < 7.20 and if rapid reversal with therapy is not expected, or failure of NIV occurs or NIV is contraindicated, then prompt MV is initiated. Delayed MV in these patients increases the risk of circulatory collapse and other complications. A common error in MV of a patient with acute on chronic respiratory failure is to reduce the PaCO2 to normal (40 mmHg),

which leads to a compensatory reduction in bicarbonate. On resumption of spontaneous breathing, patients who are chronically hypercapnic will retain CO2 rapidly (to their previous pre-morbid level). As the kidneys require more time (24 to 48 hours) to compensate, an acute respiratory acidosis may ensue and impede liberation from MV. Accordingly, the ventilatory goal in patients with acute on chronic respiratory failure is not a normal PaCO2 but rather a PaCO2 approximating their baseline value when they are not acutely decompensated, at which the pH is normal range.

Acute Respiratory Failure

the initiation of NIV in patients with severe asthma. In another randomised trial, no benefit of NIV in asthma was demonstrated.


Burns KE, Sinuff T, Adhikari NK, et al. Bilevel non-invasive positive pressure ventilation for acute respiratory failure: survey of Ontario practice. Crit Care Medicine 2005; 33: 1477-83.


Ferreyra G, Ranieri MV. Non-invasive ventilation in hypoxaemic respiratory insufficiency controversies in intensive care medicine. ESICM Year book 2008; pp 3-7.


Hemmila MR, Napolitano LM. Severe respiratory failure: advance treatment options. Crit Care Med 2006; 34 (9 Suppl): S278-90.


Lichtenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure. Chest 2008;134:117-25.


Martin Tobin. Principles and Practice of Mechanical Ventilation; 2nd Ed. New York: McGraw-Hill Professional Publishers;2006: pp 129-54.


7.7 SEPSIS Sepsis (derived from the Greek word sepo meaning “decay or putrefaction”), severe sepsis (acute organ dysfunction secondary to infection) and septic shock (derived from the French word choquer meaning ‘to collide with’), are major health care problems world over. The incidence of sepsis and related syndromes is increasing and the conditions affect millions of individuals around each year. DEFINITION OF SEPSIS AND RELATED SYNDROMES Though the existence of sepsis and related disorders were known since time immemorial, formal definitions for the same were laid by the American College of Chest Physicians (ACCP) and Society of Critical Care Medicine (SCCM) Consensus Conference in 1991. With advances in the understanding of the pathophysiological aspects of septic shock and the dissatisfaction in several quarters regarding these definitions, a Consensus Sepsis Definitions Conference was convened in 2001 under the auspices of ACCP, SCCM, the European Society of Intensive Care Medicine, and the Surgical Infection Societies to re-visit the definitions of sepsis and related conditions. The key change was regarding the definition of systemic inflammatory response syndrome (SIRS) [manifested by (but not limited to) 2 or more of the following conditions: temperature > 38 °C or, < 36 °C; heart rate > 90 beats/min; respiratory rate > 20/min or (PaCO2) < 32 mmHg; white blood cell count >12.0 × 109/L, < 4:0 × 109/L, or > 10% immature (band) forms] which was expanded to include longer list of possible signs of sepsis (Table 1). As per the new guidelines, sepsis is defined as infection plus systemic manifestations of infection (Table 1). Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion (Table 1). Septic shock is defined as sepsisinduced hypotension persisting despite adequate fluid resuscitation. Staging System for Sepsis Since the definitions of sepsis and related syndromes does not allow for precise characterisation and staging of patients with this condition, staging systems have been proposed to stratify these patients by both their baseline risk of an adverse outcome and their potential to respond to therapy. In line with the tumour, node, metastasis in vogue for cancer, a classification scheme for sepsis that will stratify patients basing on their predisposing conditions, the nature and extent of the infection, the nature and magnitude of the host response, and the degree of concomitant organ dysfunction, termed PIRO staging system has been described (Table 2). Several attempts are underway to apply the PIRO system clinically with promising results.


Aetiology Gram-negative bacterial infection is the most common cause of sepsis and related syndromes. However, septic shock can be

Sepsis and Acute Respiratory Distress Syndrome Alladi Mohan, Surendra K Sharma caused by Gram-positive bacteria and fungi also. Polymicrobial aetiology of sepsis has also been described. In India, septic shock can occur due to falciparum malaria, enteric fever, dengue fever and other infections. Pathogenesis The pathophysiological hallmark of sepsis and related syndromes is the mismatch of the host response to the intensity of the pathogenic stimuli, ultimately leading to organ injury or Table 1: Diagnostic Criteria for Sepsis in Patients with Documented or Suspected Infection General variables Fever (core temperature >38.3°C) Hypothermia (core temperature 90/min or >2 SD above the normal value for age Tachypnoea Altered mental status Significant oedema or positive fluid balance (>20 mL/kg over 24 hours) Hyperglycaemia (plasma glucose >120 mg/dL) in the absence of diabetes Inflammatory variables Leukocytosis (WBC count >12,000 /mL) Leukopaenia (WBC count 10% immature forms Plasma C-reactive protein >2 SD above the normal value Plasma procalcitonin >2 SD above the normal value Haemodynamic variables Arterial hypotension (SBP 3.5 L/min/m2 Organ dysfunction variables Arterial hypoxaemia (PaO2/FiO2 1.5 or aPTT >60 sec) Ileus (absent bowel sounds) Thrombocytopaenia (platelet count 4 mg/dL) Tissue perfusion variables Hyperlactatemia (>1 mmol/L) Decreased capillary refill or mottling SD = Standard deviation; WBC = White blood cell; SvO2 = Central venous oxygen saturation; INR = International normalisation ratio; MAP = Mean arterial pressure; SBP = Systolic blood pressure; PaO2 = Partial pressure of arterial oxygen; FiO2 = Fraction of inspired oxygen; aPTT = Activated partial thromboplastin time Adapted from: Crit Care Med 2003; 31: 1250-6.


Clinical Parameters

Laboratory Parameters

Predisposing conditions

Age, co-morbid conditions (e.g. alcoholism, diabetes, cirrhosis of liver), gender, corticosteroid use, immunosuppressive state, religious and cultural beliefs Site of infection (e.g. pneumonia, peritonitis, catheter), Type of infection (hospital acquired versus community acquired) SIRS, other signs of sepsis, shock, CRP

Genetic polymorphisms in components of inflammatory response (e.g. TLR, TNF, IL-1, CD14)


Response Organ dysfunction

Blood pressure, urine output, Glasgow coma scale, organ dysfunction as number of failing organs or composite score (e.g. MODS, SOFA, LODS)

Virulence of the infecting organism, antimicrobial sensitivity, assay of microbial products (e.g. LPS, bacterial DNA), gene transcript profiles White blood cell count, prothrombin time, APTT, blood lactate levels, biomarkers (e.g. CRP, PCT) PaO2/FiO2, serum creatinine, serum bilirubin, platelet count

TLR = Toll-like receptor; TNF = Tumour necrosis factor; IL-1 = Interleukin-1; LPS = Lipopolysaccharide; DNA = Deoxyribonucleic acid; SIRS = Systemic inflammatory response syndrome; APTT = Augmented partial thormboplastin time; CRP = C-reactive protein; PCT = Procalcitonin; PaO2 = Partial pressure of arterial oxygen; FiO2 = Fraction of inspired oxygen; MODS = Multiple organ dysfunction syndrome; SOFA = Sepsis-related organ failure assessment; LODS = Logistic organ dysfunction system. Adapted from: Crit Care Med 2003; 31: 1250-6.

Sepsis and Acute Respiratory Distress Syndrome

Table 2: Some Clinical and Laboratory Variables Being Evaluated for the PIRO Staging System for Sepsis in Adults

dysfunction with or without hypotension. This results in a predominantly proinflammatory (SIRS), mixed [mixed antagonistic response syndrome (MARS)], or predominantly anti-inflammatory compensatory anti-inflammatory syndrome. The current concepts underlying the molecular pathogenesis of sepsis are shown in Figure 1. The major complications of septic shock are listed in Table 3. Table 3: Major Complications of Sepsis Cardiopulmonary Acute lung injury, acute respiratory distress syndrome Depression of myocardial function Renal Acute kidney injury Drug-induced renal damage Disseminated intravascular coagulation Neurological Critical illness polyneuropathy Multiorgan dysfunction syndrome

Clinical Manifestations The clinical manifestations of sepsis result as a consequence of the complex interplay among the immune, coagulation, and neuroendocrine systems in response to severe infection. These manifestations overlap the signs and symptoms due to the underlying medical conditions and primary site of infection. Septic shock should be suspected whenever, a patient with fever or hypothermia, tachycardia and tachypnoea and evidence of decreased organ perfusion develops hypotension. It is not strictly necessary that tachycardia, tachypnoea or fever be present to make the diagnosis. Generally, there is predisposition to infections such as a patient on cytotoxic or immuno-suppressive drugs, chronic debilitating disease such as diabetes mellitus, cirrhosis of liver, etc. Haemtogenous seeding of the skin or underlying soft tissue can manifest as cellulitis, pustules, bullae, or haemorrhagic lesions. Other features that help in pointing towards a diagnosis of septic shock include evidence of impaired organ perfusion, altered mental status, jaundice, gastrointestinal bleed due to stress ulceration, disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). Acrocyanosis and ischaemic necrosis of

Figure 1: Overview of the molecular pathogenesis of sepsis.


peripheral tissues, usually digits, may be evident due to hypotension and DIC. Principles of Management The basic principles of initial resuscitation (fluid therapy, vasopressors, inotropic support, infection issues (source identification and control, appropriate antibiotic therapy), blood product administration and haemodynamic support described in the updated Surviving Sepsis Campaign guidelines for the management of severe sepsis and septic shock 2008 must be followed meticulously (Figure 2). Broad-spectrum, site-specific appropriate intravenous antibiotics (monotherapy or combination therapy as appropriate) should be started as early as possible, and always within the first hour of recognising severe sepsis and septic shock. The antimicrobial regimen must be assessed daily to optimise efficacy, prevent resistance, avoid toxicity and minimise costs. The antibiotic therapy must be administered for 7 to 10 days. The duration may be longer if the response is slow, the foci of infection are undrainable, or if immunodeficiency is present. Low doses of corticosteroids and recombinant human activated protein C may be considered as useful adjunctive therapies in selected sub-groups of patients. The optimal timing for initiating these modalities of treatments appears to be 6 to 24 hours from onset of shock. Patients receiving these treatments should systematically be monitored for superinfection and serious bleeding complications. Principles of mechanical ventilation (MV) are described under ARDS. Factors indicating poor prognosis in septic shock are shown in Table 4. Table 4: Factors Indicating Poor Prognosis in Septic Shock Pre-existing factors Old age Nature of co-existing illness (e.g. leukaemia) Number of failed organs Cardiovascular Lack of ventricular dilatation Persistence of tachycardia and raised cardiac output Others Delay in institution of treatment Acute respiratory distress syndrome Disseminated intravascular coagulation Hypothermia Leucopaenia Hyperglycaemia Metabolic acidosis Renal failure Polymicrobial infection

ACUTE RESPIRATORY DISTRESS SYNDROME ARDS is defined as an acute lung injury (ALI) resulting in extensive bilateral pulmonary infiltrates, severe refractory arterial hypoxaemia and stiff lungs. It is a common cause of ICU admission world over.


Aetiology Bacterial sepsis is the single most important cause of ARDS in hospitalised patients. Other common causes of ARDS are listed in Table 5.

Figure 2: Initial resuscitation with goal-directed therapy in severe sepsis and septic shock. CVP = Central venous pressure; MAP = Mean arterial pressure; SvO2 = Central venous oxygen saturation; SBP = Systolic blood pressure; CI = Cardiac index.

Definition The American-European Consensus Conference definitions of ALI and ARDS are simple to apply in the clinical setting and also recognise that the severity of clinical lung injury varies according to the severity of arterial hypoxaemia. Recently, pulse oximetric saturation (SpO2) to fraction of inspired oxygen (FiO 2) ratio (S/F ratio) has been found to correspond to the arterial oxygen tension (PaO2) to FiO2 ratio (P/F) (Table 6). These non-invasive substitutes for assessing oxygenation can

Common Causes Infections Gram-negative and Gram-positive bacterial sepsis Pneumonia (bacterial, viral, mycoplasma, pneumocystis) Pancreatitis Burns Gastric aspiration Bilateral lung contusion Cardiopulmonary bypass Uncommon Causes Multiple blood transfusions Inhalational injuries (ammonia, chlorine, nitrogen dioxide, phosgene, smoke, sulphur dioxide) Fat embolism Raised intracranial pressure Infections (pulmonary and miliary tuberculosis, falciparum malaria, enteric fever, leptospirosis) Drugs (e.g. thiazides, methadone, barbiturates, narcotics, lidocaine, cytosine arabinoside, phenytoin, salicylates) Heat stroke High altitude pulmonary oedema

Table 6: Definitions of Acute Lung Injury and Acute Respiratory Distress Syndrome Acute lung injury Acute onset PaO2/FiO2 ≤300* SpO2/FiO2 ≤315*† Bilateral infiltrates on the frontal chest radiograph PCWP ≤18 mmHg, or no clinical evidence of left atrial hypertension

Acute respiratory distress syndrome Acute onset PaO2/FiO2 ≤200* SpO2/FiO2 ≤235‡ Bilateral infiltrates on the frontal chest radiograph PCWP ≤18 mmHg, or no clinical evidence of left atrial hypertension

* Irrespective of level of positive end-expiratory pressure; † The sensitivity of 91% and specificity of 56% for identifying acute lung injury; ‡ The sensitivity of 85% and specificity of 85% for identifying acute respiratory distress syndrome. Adapted from: Am J Respir Crit Care Med 1994; 149: 818-24; Chest 2007; 132: 410-7.

be useful in the settings where arterial blood gas (ABG) analysis is not available and facilitate the monitoring of the course of the disease. Clinicopathological Stages of ARDS Irrespective of the precipitating factors ARDS usually evolves along a stereotypic common pathway with characteristic clinical, pathological and radiological changes as exudative phase, proliferative phase, fibrotic phase and phase of healing and repair. These changes are usually described by the term diffuse alveolar damage. Clinical Features ARDS is acute and rapid onset of respiratory failure, dyspnoea, dry cough, disorientation and agitation that usually develops 24 to 72 hours after the precipitating event marking the exudative

phase. Tachypnoea, tachycardia, cyanosis, crepitations and rhonchi may also be present. Arterial hypoxaemia that is refractory to treatment with supplemental oxygen which may eventually warrant tracheal intubation and assisted MV is a characteristic feature of ARDS. Diagnostic Work-up The patient should be carefully evaluated for an underlying cause keeping in mind the possibility of treatable infections, such as sepsis, pneumonia, tuberculosis (TB), malaria among others. Other useful investigations include: Arterial blood gas analysis The ABG analysis usually reveals severe refractory hypoxaemia, hypocapnia and alkalosis if the patient is breathing spontaneously. Hypercapnia usually does not occur unless chronic lung disease co-exists. Chest radiograph In patients with ARDS, the radiographic changes become evident by about 12 hours after the clinical onset of respiratory failure. Initially, patchy, ill-defined opacities may become apparent through out the lungs. They rapidly coalesce and diffuse massive air-space consolidation becomes evident. In contrast to cardiogenic pulmonary oedema of cardiogenic origin, air-bronchogram is frequently visible. After about a week, the lungs remain diffusely abnormal, but the pattern gradually becomes ‘reticular’ or ‘bubbly’ suggestive of a diffuse interstitial and air-space fibrosis.

Sepsis and Acute Respiratory Distress Syndrome

Table 5: Causes of Acute Respiratory Distress Syndrome

Computed tomography Computed tomography (CT) of the chest also facilitates the identification of some causes of ARDS, such as, pneumonia and lung abscess. The CT of the chest reveals diffusely distributed, non-uniform, ground-glass opacification or consolidation which may not conform to the gravity distribution early in the exudative phase. Susbequently in the exudative phase, the consolidation becomes more homogeneous and gravity dependent. As the proliferative and fibrotic stages evolve, there is a decrease in the overall lung density and the appearance of an interstitial reticular pattern. Complications of ARDS, such as pneumothorax, pneumomediastinum and interstitial emphysema may also be evident on CT of the chest. Echocardiography Echocardiography is useful in differentiating ARDS from cardiogenic pulmonary oedema. Swan-Ganz catheterisation Swan-Ganz catheterisation facilitates measurement of pulmonary capillary wedge pressure (PCWP). A PCWP less than 18 mmHg and cardiac index more than 2.1 L/min/m2 is altered in ARDS. Fibreoptic bronchoscopy and bronchoalveolar lavage Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) are employed to exclude infectious causes of ARDS. Most prominent finding on BAL in patients with ARDS (though nonspecific) include increased number of polymorphonuclear leukocytes (making up to nearly 80% of the total cell population; normal value 18 mmHg), and echocardiographic abnormalities may be evident. Once PCWP is brought to normal, infiltrates on the chest radiograph may clear. Diffuse alveolar haemorrhage The initial clinical presentation of diffuse alveolar haemorrhage may resemble ARDS and is accompanied by a dramatic fall in the haematocrit, occurrence of haemoptysis, and the presence of frothy red fluid on bronchoscopy. Haemosiderinladen macrophages may be demonstrable in the BAL fluid. Idiopathic acute eosinophilic pneumonia Patients with idiopathic acute eosinophilic pneumoia may be previously healthy and present with cough, dyspnoea, fever, and occasionally chest pain. Peripheral blood and BAL fluid eosinophilia is present. This condition rapidly responds to corticosteroid treatment, usually within 48 hours. Metastatic malignancy When malignancy presents as ARDS it is uniformly fatal. Cytologic examination of blood drawn from pulmonary circulation through the Swan-Ganz catheter keeping the balloon inflated, or BAL fluid is usually helpful in confirming the diagnosis. More invasive procedures such as transbronchial lung biopsy, open lung biopsy may have to be undertaken at times to ascertain the diagnosis. These procedures are, however, associated with increased risk of complications. Management In the appropriate clinical setting, a high index of clinical suspicion is necessary to diagnose ARDS early. Efforts directed at establishing the cause of ARDS must be actively pursued to facilitate institution of specific treatment. General therapeutic measures Patients with ARDS should be admitted in an ICU equipped with facilities for invasive monitoring and providing assisted MV. Ideally, pulmonary and systemic arterial lines should be inserted for haemodynamic monitoring and rational fluid replacement therapy. SpO2 monitoring by pulse oximetry, periodic ABG analysis must also be done. Adequate nutrition should be ensured; enteral route is preferred to the parenteral route as it does not cause the serious risk of catheter induced sepsis. If sepsis is presumed to be the cause of ARDS, empirical antibiotic treatment may be started in the early phase of the disease as detailed above. Haemodynamic stabilisation The fundamental principles remain same as in Figure 2.


Ventilatory support While some patients with ARDS can be managed with conservative measures and non-invasive ventilation, tracheal intubation and assisted MV are required in a majority of the

patients. Aim of MV is to maintain gas exchange with minimal complications. Initially, spontaneous ventilation using a face mask with a high flow gas delivery system can be used to deliver a FiO2 of up to 0.5 to 0.6. Continuous positive airway pressure (CPAP) may be added to improve PaO2 without increasing FiO2. If a FiO2 of more than 0.6 and CPAP of more than 10 cm H2O are needed to achieve a PaO2 of more than 60 mmHg, tracheal intubation and MV must be considered. The maximal clinical benefit is likely to occur if MV is initiated early, i.e. within 96 hours of the onset of ARDS, a time when alveolar recruitment potential is the greatest. Recent evidence suggests that, whatever mode of ventilation is used, tidal volume should be set in the region of 6 mL/kg (‘lung protective ventilation’) and the peak pressure should be limited to 30 to 35 cm H2O to prevent lung overdistension. Presently, in the absence of routine static pressure-volume curve measurement, positive end expiratory pressure (PEEP) is set at a relatively high level such as 15 cm H2O in patients with ARDS. It is also a common practice to increase the I:E ratio to 1:1 or 2:1 (inverse ratio ventilation) with close monitoring of intrinsic PEEP and haemodynamics during pressure control ventilation (Table 7). The usefulness of recruitment manoeuvres such as the high function where intermittent breaths of larger tidal volume are administered either via the mechanical ventilators or by hand, sustained inflation or CPAP aimed at increasing alveolar recruitment are also being studied. Other ventilatory strategies Other alternative approaches to conventional MV include prone positioning of the patient, high frequency ventilation (HFV, rate Table 7: Protective Lung Ventilation Protocol from the ‘ARDSNet Study’ Variable


Ventilator mode Tidal volume (initial)

Volume assist-control 6 mL/kg of predicted body weight* initially < 30 cm H2O 6 – 35 breaths/min

Plateau pressure Rate of respiration Ratio of the duration of inspiration to the duration of expiration Oxygenation target PaO2 SaO2 FiO2 and PEEP†

1:1 – 1:3 7.3 – 10.7 kPa (55 – 80 mmHg) 88 – 95 (%) FiO2 PEEP 0.3 5 0.4 5–8 0.5 8 – 10 0.6 10 0.7 10 – 14 0.8 14 0.9 14 – 18 1.0 18 – 24

* Predicted body weight of male patients = 50 + 0.91 [height (cm) – 152.4]; predicted body weight of female patients = 45.5 + 0.91 [height (cm) – 152.4] † Set according to pre-determined combinations (PEEP range 5 – 24 cm H2O) PEEP = Positive end-expiratory pressure; FiO2 = Fraction of inspired oxygen

Sepsis and Acute Respiratory Distress Syndrome

> 60/min) techniques such as high frequency jet ventilation (HFJV) and high frequency oscillatory ventilation (HFOV), and liquid ventilation, among others. The relative merits of these alternative methods of MV must be critically weighed against the potential side-effects in every setting. Extracorporeal respiratory support In extracorporeal membrane oxygenation (ECMO), venous blood is removed via a cannula in the inferior vena cava or right atrium, passed through a heart/lung machine, and is returned to either the right atrium (veno-venous bypass) or aorta (veno-arterial bypass). Extracorporeal carbon dioxide (CO2) removal (ECCOR) involves use of an extracorporeal venovenous circuit with lower blood flow and oxygenation still occurring via the patient’s lungs. These modalities may be useful in selected patients and, studies with a large sample size are required to clarify their role in the management of ARDS. Pharmacological therapies Though various pharmacological therapies are directed at the pathophysiologic mechanisms of ARDS. These include neuromuscular blockade, inhaled nitric oxide, vasoactive agents (intravenous phenylephrine, inhaled prostacyclins, almitrine, among others. The therapeutic potential of these strategies needs further study. Corticosteroids The role of corticosteroid treatment in the management of ARDS is controversial. The studies published in the 1980s had employed high-dose corticosteroids (1 to 8 doses of 30 mg/kg methylprednisolone) for short durations (< 48 hours). Compared with placebo, corticosteroid treatment resulted in either no difference or increased the incidence of ARDS. In more recent studies, low-to-moderate doses of corticosteroids (methylprednisolone 1 to 2 mg/kg per day to start) for longer duration (mean 25 to 32 days), with gradual tapering has been evaluated. Presently, corticosteroid therapy is not considered to be beneficial before the onset of ARDS or early in its course. A difference of opinion exists among experts regarding the efficacy of corticosteroids for late-stage ARDS. Even though lowdose corticosteroid therapy improves lung function and shortens the duration of MV in persistent ARDS, the impact on long-term mortality is unclear. More data are required from clinical trials before they can be recommended for routine use in patients with unresolved ARDS. Nutritional supplementation Enteral feeding with omega-3 fatty acids, such as, eicosapentanoic acid, γ-linolenic acid, and antioxidants was shown to facilitate improvement in oxygenation and reduction in mortality in earlier trials. However, this benefit has not been replicated in more recent clinical trials. Figure 3 outline algorithm for the management of ARDS. ARDS in the Tropics Infectious causes such as pulmonary and miliary tuberculosis TB, falciparum malaria, enteric fever, and leptospirosis are rare but treatable causes of ARDS. When the cause of ARDS is not clear, especially in endemic areas, these aetiological causes should be kept in mind and active efforts directed at

Figure 3: Treatment algorithm for the management of ARDS. FiO2 = Fraction of inspired oxygen; SaO2 = Arterial oxygen saturation

establishing this diagnosis must be pursued to facilitate early institution of specific therapy. Outcome Interestingly, initial indices of oxygenation and ventilation have not been found to be useful in predicting the outcome in ARDS. Majority of deaths in patients with ARDS are attributable to sepsis or multi-organ dysfunction rather than primary respiratory disease. Certain prognostic factors have been identified to predict risk of death at the time of diagnosis of ARDS (Table 8). Table 8: Predictors of Mortality in Patients with ARDS Advanced age Chronic liver disease Non-pulmonary organ dysfunction Sepsis Organ transplantation Human immunodeficiency virus infection Active malignancy Failure of pulmonary function to improve during the first week of treatment 261

Prevention No form of therapy is known to prevent the occurrence of ARDS. Corticosteroid therapy, routine administration of antibiotics in the absence of evidence of infection, and use of prophylactic PEEP have not been shown to prevent ARDS in patients at risk.


Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Int Care Med 2008; 34:17-60.


Esan A, Hess DR, Raoof S, et al. Severe hypoxemic respiratory failure. Part 1: Ventilatory strategies. Chest 2010; 137: 1203-16.


Levy MM, Fink MP, Marshall JC, et al. SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-6.


Raoof S, Goulet K, Esan A, et al. Severe hypoxemic respiratory failure. Part 2: Nonventilatory strategies. Chest 2010;137:1437-48.



Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med 2009; 37: 291-304.

7.8 Mechanical ventilation (MV) of the lungs is defined as assisting or substituting spontaneous respiration of the patient with artificial respiration with a lung ventilator or manual resuscitator bag. Application of positive airway pressure overcomes the increased airway resistance (asthma, chronic obstructive pulmonary disease [COPD]) and inflates less compliant alveoli (acute respiratory distress syndrome [ARDS], pneumonias), improves functional residual capacity (FRC) and improves oxygenation by recruitment of atelactic lung units. Positive pressure counteracts the hydrostatic pressure in capillaries and redistributes (decreases) extracellular lung water. However, MV is associated with a number of complications which are discussed briefly in the following sections. COMMONLY USED TERMS It is important to know the jargon of terms used in context to ventilation for better understanding of this subject. The commonly used terms are as under: Cycling The mechanism used to terminate inspiration and switch over to exhalation is called cycling. It is also used to classify ventilators. Pressure Cycling Inspiration is terminated after desired airway pressure (PAW) is achieved. The tidal volume (VT) is directly proportional to PAW and inversely proportional to airway resistance, e.g. in bronchospasm. Volume Cycling Inspiration stops after delivering the set VT. Airway pressure increases with airway resistance (bronchospasm) or low compliance (pulmonary oedema). Flow Cycling Inspiration is terminated after the flow rate falls to a particular level e.g. 25% of peak flow rate. Time Cycling Inspiration is terminated after the set inspiratory time. Modern ventilators use a combination of these cycling mechanisms. Trigger Trigger is the signal used to start ventilator breaths. Ventilator itself triggers breaths at a set respiratory rate (RR). Alternatively, ventilator senses patient’s inspiratory pressure (pressure trigger) or inspiratory flow (Flow trigger) for triggering breaths. Recently, electrophysiological activity of diaphragm is being used as trigger (see NAVA). Breathing Circuit The arrangement of corrugated tubings designed to deliver gas to the patient is called breathing circuit. It requires periodical and between-patients cleaning and sterilisation. Most

Mechanical Ventilation Surender Kashyap, Surinder Singh components are re-usable, expensive and include corrugated tubings, humidifier or (HME), flow sensor, Y-piece, water traps and exhalation valve. Gas Flow Flow of the air (enriched with oxygen) in the breathing circuit is called gas flow. A number of ventilators use a continuous basal flow of 5 to 10 L which is used for sensing patient’s effort and is called basal flow or bias flow. Diagnostic Functions Newer ventilators can measure changes in compliance, resistance, positive end-expiratory pressure (PEEP) and air trapping, etc. Auto-PEEP is measured by ‘end-exipratory hold’ or occlusion for 5 to 10 seconds whereas similar manoeuvre after end-inspiration ‘inspiratory hold’ depicts plateau/alveolar pressure (PPLAT/ALV). These diagnostic functions are helpful in making rational ventilator adjustments. Nebulisation Some of the ventilators have programmable nebulisers to allow aerosol therapy without interruption, or modification of ventilation. MODES OF VENTILATION Mode of ventilation specifies the method and type of ventilatory assistance being provided by the ventilator. Commonly used modes for ventilating the lungs are as under: Manual Ventilation It refers to the hand delivered ventilation using ambu bag-mask or bag-tracheal tube technique with or without oxygen supplementation. Manual ventilation is quite effective, and controlled or assisted ventilation can be given until a ventilator becomes available. Spontaneous Mode Ventilator does not give breaths, but delivers the set fraction of inspired oxygen (FIO2), continous positive airway pressure (CPAP) and pressure support. Controlled Mechanical Ventilation (CMV) The ventilator is set to deliver fixed breath rate and VT (CMV-V) or inspiratory pressure (CMV-P). Spontaneous respiration is abolished with deep sedation or neuromuscular blocking drugs. CMV is used in initial phase of ventilation. Assist-Control Respiratory rate, VT and trigger sensitivity level are set in this mode and the patient triggered breaths are assisted by the ventilator, otherwise it works CMV mode. Common assisted modes are as follows: Synchronised Intermittent Mandatory Ventilation (SIMV) Ventilator delivers the set breath rate and V T (SIMV-V) or inspiratory pressure (SIMV-P) using patient trigger. SIMV


improves patient comfort and allows spontaneous breathing between synchronised ventilator breaths. Pressure Support Ventilation (PSV) Inspiratory efforts of the patient trigger the ventilator to augment gas flow to achieve the desired airway pressure. PSV helps the patient to overcome increased airway resistance and decreased compliance and thus it “off loads” the inspiratory muscles. Proportionate Assisted Ventilation (PAV) Proportion of assisted ventilation is directly proportional to the effort of the patient. The proportion to be assisted is set as percentage, but the assistance decreases with decreasing patient’s effort (exhaustion) and hypoventilation can occur. Adaptive Support Ventilation (ASV) The clinician determines minute ventilation and ventilator algorithm manages the RR/VT relationship with changing lung dynamics. If the patient fails to trigger, controlled breaths are delivered automatically to avoid hypoventilation. Neurally Adjusted Ventilatory Assistance (NAVA) This under-investigation mode senses the electrical activity of diaphragm (through oesophageal electrode) to trigger ventilator-assisted breaths and aims at enhanced patient comfort by neuro-ventilatory coupling. The mode is not yet available in most of the available ventilators. Positive End-Expiratory Pressure (PEEP) PEEP is achieved by adding resistance to the exhalation. It prevents complete emptying of alveoli, airway closure and increases the duration for gas exchange. Application of PEEP in ARDS protects the alveoli from shearing stress due to repeated collapse and expansion. However, inap-propriately high PEEP increases the risk of barotrauma and hypotension. Continuous Positive Airway Pressure PEEP during spontaneous respiration is called CPAP. In addition to the effects of PEEP, it decreases the inspiratory work required for opening up of closed airways. Biphasic Positive Airway Pressure (BiPAP) Two distinct phases of positive pressure are applied during inspiration and expiration. Inspiratory PAP (iPAP) resembles PSV whereas expiratory PAP (ePAP) resembles CPAP. Apart from intensive care unit (ICU) ventilators, separate BiPAP machines are also available. S-PAP and DuoPAP are equivalents of BiPAP. Volume Assured Pressure Support; Volume Support; Variable Pressure Support; and Pressure Augmentation In addition to ventilator support, e.g. PSV, these modes ensure delivery of the desired VT in spontaneously breathing patient. Ventilator monitors the inspiratory flow and if the patient is unlikely to inhale desired VT, the ventilator augments the gas flow and delivers the set VT.


Inverse Ratio Ventilation (IRV) IRV is sometimes used in severe cases of ARDS by setting an inspiration longer than exhalation during CMV. It can improve oxygenation with increased risk of cardiopulmonary complications.

Airway Pressure Release Ventilation (APRV) APRV has been tried in place of IRV with mixed results. The lungs are kept continuously inflated with brief periods of relief for exhalation without formal breath cycles. Spontaneous breathing is possible with considerable effort. Airway pressures and circulatory effects are less pronounced than IRV. Apnoea Back-up Ventilation It is a safeguard CMV mode and starts automatically in case patient stops breathing or triggering breaths. Parameters for back-up ventilation should be adjusted for individual patient while starting the ventilation. TYPES OF VENTILATORS Different types of mechanical ventilators are available for use in the hospitals (ICU ventilators), for transport of the patient (transport ventilators), for use at home (domiciliary ventilators) and (anaesthesia ventilators) for anaesthetic applications. A simple but effective form of multi-purpose ventilator is manual resuscitator bag (Ambu bag). INDICATIONS FOR MECHANICAL VENTILATION Main indications for MV include respiratory failure associated with hypoxia, hypercapnoea or both, compromised circulatory status and pulmonary oedema. Clinical Indications Clinical indications include ARDS, acute severe asthma, COPD with acute exacerbation, Landre Guillain Barré syndrome, poliomyelitis, head injury with diffuse brain oedema, pulmonary oedema and after major surgical operations. Severe tetanus (opisthotonus) and recently bird flu and swine flu have become indications for mechanical ventilation. Only those patients who are likely to recover completely from underlying disease are selected for ventilation. Brain dead patients may require ventilation until organ harvesting. Objective indications for mechanical ventilation are given in Table 1. Table 1: Objective Indications for Mechanical Ventilation Blood gas values

PaO2 50 mmHg HCO3 is also raised and pH 400 mmHg on 100% oxygen

Bedside measurements

Respiration rate >35 breaths/min; Rapid shallow breathing index, i.e. RR/ VT (L) >100

Spirometric values

Tidal volume 10 L/min Vital capacity –25 cm H2O or 0 to 24 cm H2O

PaO2 = Arterial oxygen tension; PaCO2 = Arterial CO2 tension; HCO3 = Plasma bicarbonate Note: All these parameters may not be available in every patient; hence, clinical judgement is important.

PROCESS OF MECHANICAL VENTILATION Initiation of Mechanical Ventilation Initiating MV has inherent risks and requires meticulous preparation, which should be based on ABCDE. A = Airway:

Management of Ventilation Airway is secured with oral or nasal tracheal tube and ventilation of both the lungs is ensured with careful auscultation. Orotracheal tubes require deeper levels of sedation and cause excessive salivation whereas nasotracheal tubes are tolerated better, require less sedation, but there is increased risk of epistaxis, bacteraemia and sinusitis. The VT, RR and airway pressure should be appropriate for the size of the patient and lung pathology. It is safe to use 100% oxygen during first few minutes followed by gradual reduction to a level necessary to maintain pulse oximetric saturation (SpO2) more than 90%. Humidification of inhaled gases is essential for optimal mucociliary function and is achieved with a heated humidifier (e.g. Fischer Paykel humidifier) or a disposable heat and moisture exchanger (HME). Blood gas analysis should be done 1 to 2 hours after starting ventilation make further adjustments in ventilation. Lung physiotherapy with chest wall percussion, postural drainage of lungs and tracheobronchial suctioning is done through tracheal tube intermittently. CARE OF THE PATIENTS ON MECHANICAL VENTILATION General Care The patients on ventilator are totally dependant on nursing staff and meticulous maintenance of hygiene is essential for control of infection and optimal outcome of the patients. General measures include dressing of hair, cleaning of eyes and use of lubricant eye ointment, oral hygiene with brush or small pea-nut gauge soaked in chlorhexidine 2% and oral suctioning, catheterisation of bladder, and diapers for prevention of soiling with faecal matter. Skin is kept clean with daily sponge bath, change of wet clothing or linen, talcum powder and wrinkle free sheets. Use of pneumatic mattresses combined with change of posture every 2 hours reduces the risk of bedsores. These patients are susceptible to stress induced gastrointestinal bleeding and an H2 blocker, proton pump inhibitor or mucosal barrier like sucralfate should be administered regularly. Sedation and Analgesia In the initial phase of ventilation, sedation with narcotics, midazolam or propofol, etc. is required to suppress respiratory efforts of the patient and fighting with ventilator. In postoperative, traumatised and other painful conditions, adequate analgesia is required. Muscle relaxants may cause myopathy, complicate weaning and are avoided, except in neurosurgical patients. Sedatives and muscle relaxants interfere with neurological assessment of the patient. Sedation is reduced

gradually as the patient recovers and weaning from the ventilator is started. The sedatives may be with held in the morning to allow the patients to wake up (daily sedation vacation). Nutrition Maintenance of proper nutrition with sufficient calorie content is mandatory in patients on MV. ESPEN 2004 guidelines state that enternal nutrition should be started within 24 hours in hemodynamically stable patient’s. Enteral feeding is preferred because it is natural, emotionally satisfying and prevents sepsis by maintaining integrity of gut mucosa. Diet should be adequate in calorific value which should be maintained at 2530k cal/kg body weight per day for the patients. These calories are distributed as 50% carbohydrate, protein at 1g/kg per day and rest comprises of fat. Excessive carbohydrates increase carbon dioxide production and respiratory workload which may be harmful in COPD patients. Dietary composition in diabetics and hepatorenal disease requires additional considerations. Patients on ventilator start tolerating Ryle’s nasogastric tube (RT) feed after 24 to 48 hours and require insertion of RT. RT feed is started at 3 to 4 hourly intervals with volumes of 4-5 ml/kg. RT feeds are not available in a number of hospitals in our country (especially, after H1N 1 epidemic, ventilators have been installed in district hospitals), and therefore, relatives may have to be trained to prepare RT feed using common ingredients.

Mechanical Ventilation

Maintenance of patient airway and tracheal intubation is necessary. B = Breathing: Patient requires ventilation with oxygen and bag mask technique during tracheal intubation. C = Cardiovascular instability or even cardiac arrest may occur in sick patients. An intravenous line must be secured with 18G or 16G cannula and normal saline or Ringers’ lactate should be running unless contraindicated. D = A number of drugs are needed; midazolam, or anaesthetic like thiopentone, muscle relaxants usually succinylcholine are used to calm and relax the patient for tracheal intubation. Adrenaline and atropine should be ready for immediate use. E = Equipment must be checked in advance and includes laryngoscopes, oropharyngeal airways, tracheal tubes, manual resuscitator (Ambu bag), ventilator and a patient monitor.

Communication with Patient Most patients undergoing MV are conscious, they should be re-assured and informed about their progress, explained about the procedures to be done on them and taught to co-operate, especially during weaning. Intubated patients cannot speak and often use tapping of bed rails or may sometimes write. Their calls should always be attended with sympathetic and reassuring attitude. Monitoring of Vital Signs Continuous monitoring of vital signs like, electrocardiogram (ECG), SpO2, and non-invasive blood pressure is required. Arterial blood gas analysis and electrolyte status is needed in metabolic disorders, like diabetes. Unstable patients require monitoring of intra-arterial pressure, central venous pressure and cardiac output. Non-invasive technology has largely replaced pulmonary artery catheterisation. Neurological patients may require monitoring of electroencephalogram or intracranial pressure. Urine output is recorded at hourly intervals in case of renal dysfunction otherwise at 3 to 4 hourly intervals. Monitoring of Ventilation Most of the modern ventilators monitor and display parameters like exhaled VT, minute volume, waveforms breath rate and peak airway pressure and display simple pressure/time or volume/ time waveforms on screen (Figure 1). Small variations (± 10%; read user manual of ventilator) from set values are acceptable and, therefore, alarms limits should be set accordingly. Sophisticated ventilators display real time pressure, volume and flow graphics in the form of waveforms or as loops, which are utilised for diagnosing changes in resistance (resistive load, e.g. in asthma), compliance (elastance load, e.g. ARDS, pulmonary oedema), air trapping and auto-PEEP (e.g. COPD). Basic waveforms (open and loop) illustrating important findings are shown in Figures 2A and B.


Figure 1: Airway pressure waveforms with different modes of ventilation left panel, right panel shows waveforms with 5 cm PEEP/CPAP. VA = Assisted breath; S = Spontaneous breath

Hysteresis The pressure and volume curves are not linear due to variable resistive and elastic properties of the lungs and chest wall. As a result inspiratory curve assumes sigmoid shape and the lung volume is always higher during expiratory phase at any given pressure.


Upper inflection point (UIP) Over filling of alveoli leads to abrupt rise in pressure and the upper part of inspiratory pressure curve deviates the curve to the right (pressure axis). The upper part of pressure volume curve assumes a ‘duck-bill’ shape. UIP is an abnormal finding and VT needs to be decreased so that the shape of the curve/ loop becomes normal.

Lower inflection point (LIP) Pressure volume curve deviates towards pressure axis due to resistance of closed airways and after opening up of airways the curve becomes steep owing to the compliance of alveoli. This shift creates a distinct point on the axis of airway pressure called LIP or initial point of inflection (iPI). It denotes excessive airway closure and requires application of external PEEP (ePEEP). It has been recommended earlier that ePEEP value should be 2 to 3 cm more than the airway pressure corresponding to LIP, but recognition of air trapping has led to recommendation of lower value of ePEEP based on detection of airway closure or autoPEEP on expiratory curve.

Mechanical Ventilation

Figures 2A and B: (A) Typical flow and pressure waveforms. (B) Loops showing points of inflection. Insp = Inspiration; PIP = Peak inspiratory pressure; LIP = Lower inflection point; PEEP = Positive end-expiratory pressure

Titration of applied PEEP or ePEEP There is no fixed method to determine the value of ‘best PEEP or optimal PEEP’ which would provide maximum gas exchange without side effects, like air trapping and haemodynamic compromise. Airway closure and iPEEP, both occur during expiration and the fact, that lung volume (at corresponding point on expiratory curve) at any given value of pressure on inspiratory curve is much higher. Application of PEEP/ CPAP the basis of LIP may lead to the worsening of air-trapping (iPEEP) particularly in COPD patients. The recent trend is to set ePEEP value up to 7085% of iPEEP. A number of methods like monitoring of oesophageal pressure,monitoring airway pressure and expiratory flow/ volumes, haemodyanamic status, computed tomography and transthoracic-electric impedance and values of PaO2, FiO2/PaO2 ratio etc are being used with reasonable success. Transthoracic impedance is directly proportional to the lung volume and its monitoring is somewhat similar to ECG monitoring. This noninvasive method may become a useful tool for monitoring and real time display of resting lung volume in future. Pressure and flow volume loops Advanced ventilators display these curves in the form of pressure/volume or flow/volume loops, which are very useful in diagnosing various problems. Schedule for Investigations or Tests A bi-weekly or as per protocols of the hospital, schedule for clinical tests like haemogram, cell counts, cultures and

radiography, etc. should be followed. Appearance of new signs and invasive procedures should be appropriately investigated. WEANING FROM MECHANICAL VENTILATION The process of discontinuation of lung ventilation is called ‘weaning from ventilation’ and can take several hours to days. The patient should have substantially recovered from respiratory distress, underlying disease and haemodynamically stable with minimal cardio-respiratory support. Objective assessment of readiness for weaning a patient from ventilator is based on a number of criteria given in Table 2. Common methods used for weaning from ventilation are as under: Table 2: Criteria to Assess Readiness for Weaning a Patient from Mechanical Ventilation Clinical parameters

RR: ≤35 per minute with RSBI: 2 blood cultures in the absence of a primary focus (Staphylococcus aureus, enterococci, Streptococcus viridans, Streptococcus bovis, HACEK)


Definite 2 Major 1 Major and 3 minor 5 Minor Pathologic/histologic findings

Persistently positive blood culture drawn more than 12 hour apart or all ¾ drawn at least 1 hour apart between first and last Evidence of endocardial involvement Positive echocardiogram (TEE) Oscillating intracardiac mass on valve, implanted material or supporting structures in path of regurgitant jets Abscess New partial dehiscence of prosthetic valve New valvular regurgitation

Heart condition Drug abuse Fever >38°C Vascular phenomena Major arterial emboli Janeway’s lesions Septic pulmonary infarcts Immunologic phenomena Osler’s nodes Roth’s spots Rheumatoid factor Glomerulonephritis Microbiologic evidence Positive blood culture Positive serologic finding Echocardiographic evidence consistent with infective endocarditis but not meeting the major criteria


Possible Findings fell short of the definite but not rejected categories Rejected Alternate diagnosis Resolution of the infection with antibiotic therapy for less than 4 days No pathologic evidence after antibiotic therapy

Major criteria: consider the following as major criteria Staphylococcal bacteraemia (irrespective of community or nosocomially acquired, or with or without a focus) Positive serology for coxiella, chlamydia, bartonella Positive molecular diagnosis for specific gene targets of bacteria and fungi Minor criteria: add the following as minor criteria Raised CRP (>100 mg/L), Raised ESR (>30 for 50 for older) Newly diagnosed clubbing Splinter haemorrhages Microscopic haematuria Splenomegaly Petechiae, or purpura Delete the following from minor criteria Echocardiogram consistent with IE but not meeting major criteria Diagnosis Possible IE can be diagnosed either with one major and one minor, or three minor criteria alone

TREATMENT The treatment of IE entails long course of bactericidal antibiotics intravenously, monitoring for response, decision for surgical treatment if required, attention to portal of entry if possible, and ancillary measures for patients well-being including anticipatory guidance for preventing recurrence. Recommended antibiotic treatment charts are available in all standard texts, the principles of drug therapy are summarised. 1. Therapy has to be of sufficient dose and duration to eradicate bacteria, prevent mortality, and relapse. Usually 4 weeks therapy is required. All patients should be hospitalised for at least 2 weeks initially. 2. Longer-term treatment (6 to 8 weeks) is recommended if the symptoms have been present for >3 months, if IE is complicated by embolism, poor response, likely resistant bacteria, atypical organisms, or for prosthetic valve endocarditis (8 weeks). 3. In penicillin sensitive organism, penicillin is better than vancomycin. The dose of penicillin to be used in a patient (12-24 million units in 4-6 divided doses) depends on the available or perceived sensitivity of the organism, or clinical IE. 4. Intermittent bolus or continuous infusion are probably equally effective, boluses are usually preferred. Attention to planning of veins to be used, changing intravenous lines 48 hourly, use of central lines and aseptic precautions are customary details. 5. Therapy for staphylococcal sp. is based on methicillin sensitivity and not coagulase status. Almost all Staphylococcus are penicillin resistant, methicillin sensitive strain respond better to methicillin congeners. 6. Rifampicin is utilised in patients with prosthetic valves, or foreign materials and staphylococcal IE. 7. Fluoroquinolones can be substituted for Staphylococcus resistant to aminoglycosides as additional therapy. 8. Aminoglycosides are added carefully and therapy is only for few days in Staphylococcus, or for 2 weeks. In some


10. 11. 12.

13. 14.

organism, 4 weeks duration is required with careful attention to renal and vestibular functions. Enterococci do not respond to methicillin, cephalosporin and often have resistance to aminoglycosides as well. Combination therapy is preferred. Linezolid, daptomycin are increasingly used for vancomycin resistant enterococci or Staphylococcus aureus, and others. A consultation from infectious disease specialist should be obtained in difficult circumstances. Culture negative endocarditis can be treated with vancomycin, ceftriaxone and gentamicin pending further insight into the possible organism (some prefer only vancomycin and gentamicin). Ideally trough drug levels should be measured, but is not possible in most circumstances. Surgery should be considered early, rather than late, in some situations.

Infective Endocarditis

Table 4B: Suggested Modifications of Duke‘s Criteria

Treatment of common organisms is shown in the Table 5. Therapy of atypical organisms need special considerations and consultations with infectious disease specialists. Therapy for brucella include doxycycline with streptomycin, (with or without rifampicin), and in children trimethoprim-sulphamethoxazole and rifampicin, Q fever needs doxycycline with hydroxychloroquine (possibly with fluoroquinolones), bartonella can be treated with amoxicillin with gentamicin or tetracyclines/macrolides antibiotics. These are not detailed here. Surgery for Infective Endocarditis Surgical treatment during IE may be required because of (1) severe congestive heart failure from mechanical complications, (2) uncontrolled infection, and (3) repeated embolism. While complications of surgery is higher during IE than without IE, but the mortality without surgery in such patients is very high and surgery is preferred and should be done early without waiting for infection to subside. Although, mortality despite operation in these circumstances may be as high as 20% to 40%, mortality without operation is in the range of 60% to 90%. The chances of postoperative IE in the replaced valves are not higher than 2% to 3%. Early prosthetic valve endocarditis, paravalvular leak, annular abscesses, fungal endocarditis, persistent fever >2 weeks despite antibiotics in the absence of other causes, and embolisms are typical indications for consideration of operative treatment. Various types of operative procedures may be required. Thorough debridement, patch repairs, vegetectomy and valve repair may be done, usually valve replacement is needed. The choice of valve is individual preference and outcomes are not different between mechanical or biological valves. Some may prefer homografts. If the patient has suffered a CNS event, it is better to postpone surgery, if possible. Open heart surgery should be postponed by 3 to 4 weeks after a haemorrhage in the brain and at least a few days to weeks after an infarct because of the use of anticoagulation during open heart surgery and the risks of adverse neurological outcomes. Anticoagulation in Infective Endocarditis Anticoagulation increase the chances of CNS bleed and should be avoided. In a patient with mechanical prosthetic valve, careful titration of minimal possible anticoagulation should be used. It is preferable to stop oral anticoagulant and rely on heparin for the duration of therapy.


Table 5: Treatment of Infective Endocarditis (Common Organisms) Microorganism


Streptococcus viridans Penicillin G Streptococcus bovis Amoxicillin or Ceftriaxone If penicillin allergy-vancomycin Enterococcus Amoxicillin or ampicillin with gentamicin If penicillin allergic vancomycin with gentamicin3 Staphylococcus Flucloxacillin or oxacillin If penicillin – allergic vancomycin Optional gentamicin Prosthetic valve IE Vancomycin with Or MRSA rifampicin with gentamicin Fungal endocarditis Amphotericin Flucytosine or fluconazole (second line only) Culture negative


Vancomycin with Gentamicin and Ceftrioxone5 Ceftriaxone or Ampicillin-sulbactam If allergic, ciprofloxacillin

Dose (Per Day)

Duration 1

12 to 24 MU/6 doses 100 to 200 mg/kg 2g in (100 mg/Kg) single dose 30 mg/kg in 2 doses 200 mg/kg in 4 to 6 dosage 3 mg/kg in 2 to 3 doses 30 mg/kg in 2 to 3 doses 12 g/d in 4 to 6 doses 30 mg/kg in 2 doses 3 mg/kg 30 mg/kg in 2 dose 1,200 mg in 2 dose 3 mg/kg in 2 dose 1 to 1.5 mg/kg4 100 to 150 mg/kg in 4 doses 600 to 800 mg or 10 to 12 mg/kg oral or IV in 2 doses 30 mg/kg in 2 dose 3 mg/kg in 2 dose 2 g in single dose 2g single dose 12 gm (2 g Ampicillin and 1 g Sulbactam) in 4 doses or 300 mg/kg ampicillin 6 hourly, 800 mg IV or 1,000 mg oral in 2 doses

4 weeks2 4 weeks2 4 weeks2 4 weeks2 4 to 6 weeks

4 to 6 weeks 4 to 6 weeks 5 days ≥ 6 weeks ≥ 6 weeks 2 weeks 6 to 8 week or more

4 to 6 weeks

4 to 6 weeks

1 = Dose of penicillin depends on the MIC for the organism, in the absence of that data, empirically decided; 2 = The duration of therapy should be 6 weeks if the symptoms have lasted for more than 3 months. For uncomplicated and responsive endocarditis, some authors have reported cure with 2 weeks therapy of ceftriaxone; 3 = for uncommon vancomycin resistant or multidrug resistant enterococci, Linezolid 600 mg IV or oral BD has been used; 4 = Amphotericin has to be built up slowly to this dose after initial test dosages, lipid soluble formulations may be better tolerated. Newer antifungals like caspofungin and newer azoles are being tried; 5 = Treatment of culture negative endocarditis varies with the clinical background. Some authors recommend adding ceftriaxone to cover Gram-negative organisms.

Monitoring During Therapy Monitoring the patient during long course of treatment is vitally important. Most patients start showing clinical improvement and become afebrile within a week. Some may respond slowly. The diagnosis is doubted if the patient becomes afebrile in less than 4 days of therapy. Appetite, body weight, sense of well

being should be evaluated routinely and thorough physical examination daily is mandatory. Echocardiography should be repeated weekly. Blood cultures, haemogram, ESR, chest radiographs, renal parameters, are monitored frequently. Recurrence of fever after initial response may occur (Table 6) due to several reasons. Drug fever may occur without rash and

Table 6: Fever During the Treatment Cause



Uncontrolled infection Annular abscess

Continuing ill-health, metastatic foci, extension of infection in heart Conduction disturbance on ECG, pericarditis suggest the diagnosis, often missed, TEE useful Renal, pulmonary or spleen, may become infected Splenic common, ultrasound/CT required Common in CNS, may cause cerebral haemorrhage, not routinely searched Minor phlebitis more often incriminated as cause than actual, may miss more serious cause Common with penicillin after 3rd week, rash, eosinophilia may not be present Patient appear less toxic despite high fever May be nosocomial fungal or Gram-negative infection

Review choice or dosages of antibiotics Consider change in antibiotics, surgery

Organ infarcts Mycotic aneurysms Thrombophlebitis Drug fever

Super infection

Immunologic phenomenon Wrong diagnosis or double disease 658

Reflects poor hospital practices, broad index of suspicious required For example, a patient with glomerulonephritis, or immune mediated phenomena in otherwise responding patient SLE, lymphoma, tuberculosis may masquerade, double disease diagnosis is against the law parsimony (i.e. diagnose one condition in a patient), but very rarely does occur

Splenic abscess may need precutaneous drainage or splenectomy Aneurysm can decrease with antibiotics, surgery may be required Change IV lines frequently, if peripheral Require to change antibiotics, total duration of treatment should count Addition of appropriate therapy required Glomerulonephritis may remit after surgical removal of infection Treat according to the diagnosis

Infective Endocarditis

can be high grade. Other investigations like abdominal ultrasound and CT are utilised as required. Splenic infarct or abscess can be diagnosed with both. Mycotic aneurysms are not routinely searched in the absence of symptoms. MR angiography can detect CNS aneurysms if suspected. SPECIAL SITUATIONS Prosthetic Valve Endocarditis IE in patients with prosthetic valve occurs nearly in 1% in the first year and 0.5% per year afterwards. Early prosthetic valve endocarditis (PVE) occurring within 2 months of operation results from contamination in the operative or post-operative period and carry very high mortality. Organisms like coagulase negative Staphylococcus or S. aureus, Pseudomonas, Candida predominate. Some authors consider early PVE till 1 year period. Surgical treatment is the rule for early PVE and antibiotics are required for 6 to 8 weeks. IE later is due to the usual organisms but carries a higher-risk. PVE is essentially an annular infection, and therefore, chances of annular abscess are higher.

Figure 2: Echocardiogram in four chamber view showing vegetations (arrow) on tricuspid valve in a patient of small ventricle septal defect (not seen). LV = Left ventricle; RV = Right ventricle.

Culture Negative Endocarditis Culture negative endocarditis, although thought of as a group, actually encompass different entities. Culture could be negative because of (1) prior antibiotic therapy in otherwise a usual endocarditis, the commonest cause, (2) poor culture techniques, inadequate sample, media, transport, etc., (3) fastidious organisms needing special media like abiotrophia, HACEK, etc., and (4) organism that do not grow in blood culture like aspergillus, tropheryma whipplei, coxiella. The approach to these groups should be different. As discussed above, serological tests are useful in the diagnosis of brucella, Q fever, etc., and PCR is being utilised for many bacteria and improves the positive yield. In the absence of any clinical clues, suggested broad-spectrum cover include vancomycin with gentamicin and ampicillin or ceftriaxone. Infective Endocarditis in Children IE is uncommon before 2 years of age, except as nosocomial infection in neonates in presence of intravenous cannula and central lines. Staphylococcus aureus and candida dominate. Tricuspid valve endocarditis may present with unexplained dyspnoea due to unanticipated pulmonary embolism. Most other IE in children occur in the presence of a CHD or RHD. IE in the VSD or tetralogy of Fallot patients occurs as right-sided endocarditis (Figures 2 and 3). Systemic embolism does not occur unless there is a right to left shunt or IE occur in the leftsided structures also. Pulmonary complications like infiltrate, infarct, abscess, pulmonary artery pseudo-aneurysm occur. Response to therapy can be satisfactory. Surgery might have to be resorted to in the presence of active infection in unsatisfactory responders. Ligation of ductus arteriosus is frequently followed by response to therapy in patients with ductus arteriosus and pulmonary valve endocarditis. Infective Endocarditis in Drug Addicts IE in drug addicts usually affects normal tricuspid valve, but may also occur on aortic, and mitral valves. Right-sided IE responds well to therapy. Some may have HIV, but IE in them also responds well, unless CD4 counts drop low. Polymicrobial IE or IE due to unusual organisms like bartonella may occur. Addicts using

Figure 3: Chest radiograph of a patient of tetralogy of Fallot having right-sided infective endocarditis. Note the shadow in right lower chest from a pulmonary infarct.

pentazocine have high chances of pseudomonas, and heroine addicts injecting brown heroine in lemon juice frequently have candida. In Elderly IE in elderly is increasingly seen and is more common in males.The underlying predisposing lesion often is mitral valve prolapse with mitral regurgitation or degenerative valvular aortic stenosis. Co-morbidities decide the clinical course. Drug therapy will need extra care and dose adjustments with attention to renal and hepatic functions. MORTALITY Without treatment IE is invariably fatal. Rare case reports of recovery in the pre-antibiotic era may be misdiagnosis. Antibiotics reduced the mortality but IE has a mortality of 20%


Table 7: Prevention of Infective Endocarditis Underlying Lesions



Rheumatic heart disease Dental procedure Prosthetic valves Involving periapical region of Previous infective endocarditis teeth or perforation of the oral Congenital heart disease mucosa or gingival tissues Unrepaired cyanotic CHD including Respiratory procedures palliative shunts and conduits Respiratory tract that involves incision Within 6 months of repair, devices or biopsy of the respiratory mucosa, such Residual lesions near patches, or prosthesis as tonsillectomy and adenoidectomy, Valve disease after cardiac transplant (none for bronchoscopy) Skin and soft tissue Surgical procedure that involves infected skin, skin structure, or musculoskeletal tissue Genitourinary or Gastrointestinal procedures None

to 40% even in current era. Further reduction in mortality is expected with more frequent surgical treatment. Mortality rates depend on several factors, but large size vegetations, heart failure portends poorer prognosis. Some subsets have particularly high mortality. Prosthetic valve IE has a mortality of 30% to 55% with surgery and 60% to 90% without surgery. The mortality in fungal IE is 60% to 90% despite treatment. With concerted efforts, protocol driven management and teamwork of cardiologist, microbiologists, surgeons and infectious disease specialist, the mortality of Streptococcus viridans IE can be as low as 7% to 10%, but enterococci and Staphylococcus mortality remains about 10% and 10% to 20% respectively. Right sided IE in drug addicts have a better response and lower mortality. PREVENTION In experimental settings, antibiotics administration before inoculating bacteria prevented colonisation and IE, and hence for years, elaborate recommendations were made for drugs to be given before procedures expected to cause bacteraemia. With time, it became clear that bacteraemia occur in daily living activities (like brushing, chewing, etc.) far more frequently than procedure induced, and that very few episodes of IE, if at all, could be prevented by such administration as previously advised. Further, costs and adverse effects of antibiotics use (including development of resistance) are not negligible. Therefore, it is prudent to advise all patients on maintaining good oral health and routine dental visits. Such is not the routine in India, but that can help reducing IE burden more than any antibiotic prophylaxis. Antibiotics before procedures are recommended only to patients in whom risks of occurrence and consequences of IE (if it occurs) are considered high (Table 7). No IE prophylaxis is recommended for gastrointestinal or genitourinary procedures in the American Heart Association recommendations. Dental procedures which may cause gum bleeding or apical tissue handling would cause bacteraemia are specified. Only single dose 2 gm amoxicillin is recommended where required.


There have been no new data about RHD, and these patients could have poor oral hygiene. Individual judgement should still be used in advising prophylaxis. No prophylaxis is required for vaginal delivery, tattooing, ear piercing, or TEE.

Oral amoxicillin 2 g (50 mg/kg), or Intravenous/intramuscularly ampicillin 2 g, cefazolin, ceftriaxone 1 g (50 mg/kg) In allergic to penicillin: Oral cephalexin 2 g (50 mg/kg), or azithromycin/clarithromycin 500 mg (15 mg/kg), or intravenous clindamycin 600 mg

CONCLUSIONS The following parameters recapitulate important aspects of management of infective endocarditis. Do’s and Don‘ts of Infective Endocarditis 1. Prevent IE by anticipatory guidance on oral hygiene in RHD, CHD and other at risk patients. 2. Think of IE in all susceptible patients with fever, anaemia, weight loss, or heart failure. 3. Do not rely overly on any test including echocardiogram as false positive and false negatives are not uncommon. 4. Think of plausible portal of entry/organism before deciding on therapy. 5. Do not jump to the latest antibiotics, nor slavishly follow the regimens, think critically. 6. Monitor trends carefully, anticipate the complications but do not change antibiotics frequently with any minor alterations including 1 to 2 days fever. 7. Keep the surgeon in the loop for decision regarding early surgery, if required. 8. Prevent recurrence, relapse by appropriate advice and management. RECOMMENDED READINGS 1.

Anderson JL, Sande MA, Kartalija M, et al. Infective endocarditis. In: Fuster V, et al, editors, Hurst‘s the Heart; 11th Ed. McGraw Hill Publication; 2004: pp 2001-36.


Mylonakis EM, Calderwood SB. Infective endocarditis in adults. N Engl J Med 2001;345:1318-30.


Prevention of infective endocarditis. Guidelines from the American Heart Association: A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:1736-54.


The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009); Eur Heart J 2009; 30: 2369-413.


Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK micro-organisms. American Heart Association. JAMA 1995; 274: 1706-13.


Atherosclerosis KK Sethi, S Lahiri

INTRODUCTION Atherosclerosis is multi-focal, multi-factorial smouldering inflammatory disease that affects the intima of medium sized and large arteries, resulting in intimal thickening that may lead to luminal narrowing and inadequate blood supply. Atherosclerosis derives its name from the Greek word ‘adhere’—means gruel or porridge, and ‘sclerosis’ means hardening, i.e. hardening of gruel-like material inside the blood vessels. According to the original concept, atherosclerosis was thought to be just a bland proliferative process. The advent of cell biology era of atherosclerosis modified the earlier view and implicated inflammatory mechanism in disease development. According to that concept, endothelial denudation resulted in platelet aggregation and release of platelet-derived growth factor (PDGF) which led to the proliferation of smooth muscle cells in the arterial intima. Current evidence integrates inflammation as a key regulatory process with multiple other risk factors in atherosclerosis. PATHOGENESIS Early Atherosclerotic Lesions The earliest lesions of atherosclerosis, i.e. fatty streaks, are present in the aorta from early childhood and may even begin to develop early in foetal life.They are highly cellular inflammatory lesions consisting of macrophage foam cells (intracellular lipid) and T-lymphocytes (immune reaction). Fatty streaks do not protrude into the lumen and hence are not symptomatic. Fatty streaks develop under an intact but activated, dysfunctioning endothelium particularly atherosclerosis prone areas with preexisting intimal thickening. Hypercholesterolaemia is associated with increased endothelial permeability, increased transcytosis and intimal retention of lipoproteins and endothelial activation with focal expression of vascular cell adhesion molecule 1 (VCAM-1) leading to monocyte and T-lymphocyte adhesion. It is thought that inflammatory cells are recruited by adhesion molecules and chemokines such as monocyte chemoattractant protein-1 (M-CSF) and activated in the intima by factors such as oxidised lipids and cytokines. Within the intima, the monocyte-derived macrophages engulf the blood derived low-density lipoprotein (LDL), possibly through their scavenger receptors after oxidative modification and become lipid-filled foam cells. These inflammatory cells constitute the major part of the early fatty streak lesions (Figure 1). Fate of Fatty Streaks Fatty streaks can progress to more advanced lesions because they occur at the same anatomic sites. A smaller fraction of fatty streaks appears to progress to more advanced symptomatic lesions. Advanced Atherosclerotic Lesions When lipids begin to accumulate, extracellular atherogenesis has passed beyond the fatty streak stage.Two different processes

Figure 1: Formation of fatty streak. Source: Weissberg, Heart 2000; 83: 247-52.

are responsible for the extracellular accumulation of lipids. Blood-derived atherogenic lipoprotein particles may be trapped directly within the proteoglycan-rich extracellular matrix and/or lipid may be released from the macrophage foam cells after their death by apoptosis. Within a lipid-rich core, erythrocytes and their lipid-rich membranes may contribute to the expansion of the core (plaque rupture and haemorrhage). There is accumulation of smooth muscle cells which gives rise to a heterogeneous spectrum of plaques ranging from fibro-fatty plaques (abundant smooth muscle cells) to thincap fibroatheroma (scanty smooth muscle cells with rich lipid core). With the passage of time endothelial denudation takes place and adherent platelets can be seen over mature plaques. Growth factors released from the adherent platelets and micro thrombi may stimulate the smooth muscle cells within the plaque to produce more connective tissue matrix. Neovascularisation Neovascularisation is frequently present at the base of advanced atherosclerotic plaques and is thought to be derived from vasa vasorum derived new vessels. Vasa vasorum developing from the adventitial layer of vessel wall also serve the purpose of transit of leukocytes and other growth factors inside the plaque. Vulnerable Plaque and Plaque Instability Pathological studies indicate that certain plaques are more prone to develop acute myocardial infarction (MI) than others. These are called vulnerable plaques, i.e. plaques which are at high risk of for disruption or thrombosis leading to symptomatic cascade of acute coronary events. Vulnerable plaques are characterised by the following:  A thin fibrous cap (thin cap fibroatheroma or TCFA),  A large lipid pool of cholesterol esters,  Heightened inflammation,  Positive remodelling of the vessel (outward expansion of the opposite wall of the vessel), and  Extensive neovascularisation.


Vulnerable plaque ruptures due to uneven thinning of the fibrous cap. Rupture usually occurs often at the shoulders of the lesion where macrophages enter, accumulate and are activated. Degradation of the fibrous cap results from elaboration of matrix metalloproteinases such as collagenases, elastases and stromelysins. The metalloproteinases are stimulated by activated T-cells which promote plaque instability and rupture (Figure 2).

Figure 2: Vulnerable (instable) plaque formation. VSMC = Vascular smooth muscle cell; INF-γ = Interferon-gamma. Source: Weissberg, Heart 2000; 83: 247-52.


Role of Innate and Adaptive Immunity Innate immunity is the primitive arm of inflammation and constitutes immune response that is elicited without ‘education’ of the immune system. This response is very rapid and combats perceived foreign invaders. Natural antibodies, certain complement proteins and families of cell surface receptors recognise microbial products and provide primordial host defence responses. These receptors include scavenger receptors which cause uptake of modified lipoproteins, and are toll-like receptors (TLR) that recognise microbial structures and products. These receptors trigger a complex intracellular signalling cascade that stimulates the production of pro-inflammatory cytokines and other inflammatory mediators. The cellular recruitment seen very early in atherosclerosis is an example of innate immunity. The mononuclear phagocytes get attached to activated endothelial cells by leucocyte adhesion molecules. Maturation of monocytes into macrophages, their multiplication and production of mediators ensues. Recent evidence suggests that mononuclear recruitment is a continuous process which is also seen in established lesions and could be a therapeutic target for targeting monocytes for treatment. In the presence of hyperlipidaemia, there is an enrichment of proinflammatory subset of monocytes. Apart from monocytes, there is now firm evidence that mast cells release vasoactive small molecules such as histamine and leukotrienes, serine proteinases and heparin — a cofactor in growth factor action and angiogenesis. Certain pharmacological agents can modulate mast cell function and this can have therapeutic implications. There are links between lipoproteins and innate immunity. Modified lipoproteins such as oxidised lipoproteins and oxidised phospholipids may drive inflammation. A lipoprotein-associated phospholipase-A2 (Lp-PLA2) currently targeted in clinical trials may generate proinflammatory derivatives of oxidatively modified lipoproteins (apolipoproteins).

Recent data suggest that CIII, a constituent of certain triglyceriderich lipoproteins incites inflammation by binding to TLR2. The activation of platelets results in secretions of proinflammatory cytokines such as CD40-ligand and also myeloid-related protein (MRP) 8/14. The MRP serves as a biomarker for adverse cardiovascular events and can promote endothelial cell apoptosis, a process thought to be vital in plaque thrombosis. Adaptive immunity requires antigen presenting cells, such as dendritic cells. The dendritic cells populate atherosclerotic plaques and present antigens to T-lymphocytes, thus forming the key limb of adaptive immunity. These antigens in relation to atherosclerosis are heat shock proteins (HSP), components of plasma proteins and some microbial structures. T-cells proliferate and produce cytokines that amplify inflammation. There are several types of T-cells. Helper T-cells (Th1) response appears to aggravate atherosclerosis as it amplifies proinflammatory pathway by gamma interferon production. The Th2 cells produce cytokines that modulate inflammation. These cytokines such as interleukin (IL)-4 can promote humoral immunity. Regulatory T-cells can, however, dampen atherosclerotic response. There is also a role of CD8 marker T-cells or cytotoxic T-cells or CD8 cells. CD8 T-cells are capable of killing smooth muscle cells and macrophages and cause lesion growth and complications. Humoral immunity is mediated by B-lymphocytes. B-lymphocytes secrete antibodies which attenuate rather than aggravate atherosclerosis. Splenectomy aggravates athero-sclerosis by eliminating some population of B-cells. Humoral immunity against oxidised LDL might protect against atherosclerosis and may be a potential target of vaccine therapy. RISK FACTORS FOR ATHEROSCLEROSIS Classic risk factors of atherosclerosis are also known as traditional risk factors.These risk factors can predict atherosclerotic coronary events to a certain extent.The NCEP ATP- III is based on traditional (old) risk factors of age, sex, total cholesterol, HDL cholesterol, systolic BP and smoking. In a more recent scoring system (PROCAM), eight risk variables are identified: age, LDL cholesterol, diabetes, smoking, HDL cholesterol, triglycerides (TG), systolic BP, family history of premature coronary artery disease. Table 1 presents risk factors for atherosclerosis. Hypertension Hypertension is considered to be one of the traditional risk factors of atherosclerosis. Concentrations of angiotensin-II, the principal product of renin-angiotensin system are often elevated in patients with hypertension. Angiotensin-II is a potent vasoconstrictor. In addition to cause hypertension, it can contribute to atherogenesis by stimulating the growth of smooth muscle cells. Angiotensin binds to specific receptors in smooth muscle cells resulting in activation of phospholipase C, which can lead to increase in intracellular calcium and smooth muscle contractions, increased protein synthesis and smooth muscle hypertrophy. It also increases smooth muscle lipooxygenase activity which can increase inflammation and oxidation of LDL. Hypertension also has proinflammatory actions such as increasing the formation of hydrogen peroxides and free radicals such as superoxide anions and hydroxyl radicals in plasma. These substances reduce the formation of nitric oxide (NO) by endothelium, increase leucocyte adhesion and increase peripheral resistance.




Sex (men > women)

High-normal blood pressure

Apolipoprotein B; Apolipoprotein A-1


Metabolic syndrome

Triglycerides; triglyceride-rich lipoprotein remnants

Family history of Diabetes premature cardiovas- mellitus; cular disease impaired glucose tolerance; impaired fasting glucose

Small, dense LDL; oxidised LDL; antibodies against oxidised LDL

Total cholesterol; LDL cholesterol; HDL cholesterol (negative risk factor)


Hypertension Smoking

Homocysteine High-sensitivity C-reactive protein

Overweight/obesity LDL = Low-density lipoprotein; HDL = High-density lipoprotein.

Smoking Smoking increases the risk of atherosclerosis by several mechanisms. Cigarette smoking is associated with increased levels of lipoproteins and the effects of oxidants in cigarette smoke renders LDL more susceptible to peroxidative modification by cellular elements such as macrophages and vascular smooth muscle cells. The inflammatory cells recruited in the atherosclerotic plaques are increased in smokers. Nicotine activates the complement system as well, which causes increased inflammation in the vessel wall. Certain chemicals in tobacco smoke tend to activate factor XII and favour thrombus formation. The risk associated with smoking diminishes slowly after smoking cessation and equals to non-smokers after 3 years of cessation. Diabetes Mellitus In the first 20 years of the Framingham Heart Study, the incidence of cardiovascular disease among men with diabetes mellitus was twice than that among men without diabetes. Among women with diabetes, the incidence of cardiovascular disease was three times than that among women without diabetes. Microalbuminuria and silent myocardial ischaemia at baseline has predictive value for future coronary heart disease (CHD) in asymptomatic patients with type II diabetes. Subjects with impaired glucose tolerance and those with insulin resistance are more likely to have subclinical atherosclerosis (Framingham Offspring Study) and it is no wonder that NCEP considers diabetes as a CHD risk equivalent. Type II diabetes is associated with insulin resistance. Insulin resistance reduces the ability of adipose tissue to clear/store circulating lipids, in part because of reduced lipoprotein lipase activity. This results in paradoxical elevation in serum TG and free fatty acids (FFA). There is also elevation in the apoB due to increased lipogenesis by the liver. Insulin resistance is characterised by the formation of more atherogenic (small dense) LDL. It can also stimulate inflammation. The secretion of proinflammatory mediators initiated by systemic insulin resistance stimulates several intracellular cascades of nuclear factor kappa beta pathway.

Metabolic Syndrome Metabolic syndrome encompasses a range of cardiovascular risk factors such as elevated TG (> 150 mg/dL), low HDL cholesterol (men < 40 mg/dL; women < 50 mg/dL), impaired fasting glucose (≥ 110 mg/dL), high blood pressure (≥ 130/85 mm Hg) and increased waist circumference (men > 90 cm, women > 80 cm in Asians) is believed to increase the risk for CHD at any level of LDL cholesterol. Further, the presence of metabolic syndrome has a greater impact on the incidence of CHD in women than men. Leptin is a protein that plays a role in fat metabolism and closely correlates with insulin resistance and is an independent risk factor for CHD.


Table 1: Old, Old/New, and New Risk Factors for Atherosclerosis

Lipid Risk Factors Triglycerides and triglyceride-rich remnant lipoproteins Though there was some initial debate on the role of hypertriglyceridaemia as an independent CHD risk factor, data from the PROCAM study showed a significant relation between hypertriglyceridaemia and CHD risk independent of LDL cholesterol and/or HDL cholesterol. Triglyceride-rich lipoproteins comprise a great variety of nascent and metabolically modified lipoprotein particles. The capacity to enter the subintimal area of the vasculature is inversely related to the size of the lipid particles. Whereas chylomicrons and large very low-density lipoprotein (VLDL) particles are unable to pass through the endothelial layers, smaller VLDL, IDL and LDL particles can enter the suboptimal space. In the Framingham Offspring Study, both remnant lipoprotein (RLP)-cholesterol and RLP-TG were significantly increased in diabetic men and women compared to non-diabetes. Remnant lipoproteins were independent risk factors for atherosclerosis. Lipoprotein (a) [Lp (a)] is formed by joining a lipoprotein that is structurally similar to LDL in protein and lipid composition to a carbohydrate-rich hydrophilic protein Apo (a). The Lp (a) particles contain Apo (a) and Apo (B) in a 1: 1 molar ratio. Most of the data on Lp (a) comes from retrospective studies. Prospective studies, however, have mixed results. However, plasma Lp (a) is indeed an independent risk factor for CHD in both men and women. The Lp (a) levels above 33 mg/dL and high LDL cholesterol (>163 mg/dL was associated with increased cardiovascular risk compared with Lp (a) levels below 33 mg/dL. Homocysteine Homocysteine is formed during demethylation of methionine, whereas its degradation takes place via remethylation and/or trans-sulphuration). Impaired homocysteine metabolism has been implicated as a risk factor in atherosclerosis, cerebrovascular disease and peripheral vascular disease. Hyperhomocysteinaemia results from genetic cause (enzyme deficiencies), vitamin deficiency (folic acid, B12, B6), use of certain medications and impaired renal function. Direct relations between homocysteine, cigarette smoking, diabetes, obesity and hypertension have been suggested. The exact mechanism by which hyperhomocysteinaemia may translate into increased CHD and/or thrombotic risk remains speculative. Both direct toxic effects on endothelial cells, in part due to oxidative stress as well as more indirect mechanisms have been postulated. However, treating hyerhomocysteinaemia with vitamins has not shown to be beneficial in large studies both in terms of stroke and cardiovascular event reduction.


Thrombogenic/Haemostatic Factors Elevated plasma fibrinogen and factor VII are potential risk factors for CHD. Other thrombogenic/haemostatic factors that have been investigated in their potential role in atherogenesis and/or thrombosis include von Willebrand factor and plasminogen activator inhibitor-1. High-Sensitivity C-Reactive Protein and Other Inflammatory Markers Since atherosclerosis represents a chronic inflammatory state, inflammatory parameters (e.g. IL-6, tumour necrosis factor-alpha) have predictive value for future cardiovascular events. Data shows that CRP has additive value for predicting CHD risk on top of traditional risk factors. hs-CRP is associated with subclinical pericardial coronary calcification in men and women and is significantly elevated in patients suddenly dying of severe coronary artery disease. Elevated hs-CRP constitutes an independent predictor of advanced plaques in dyslipidaemic subjects and early onset carotid atherosclerosis with increased intima-media thickness and elevated serum levels of inflammatory markers. Matrix-metalloproteinase 9 concentration has been identified as a novel predictor of cardiovascular mortality in patients with coronary artery disease. Elevated IL-10 has a more favourable prognosis in patients with acute coronary syndrome (ACS) and elevated CRP levels. Though there is no definite hard evidence of a causal relation between infection and atherosclerosis, studies are accumulating that indicate a possible role of infection. Viral agents such as cytomegalovirus (CMV), enterovirus, influenza virus, human parvovirus B19, herpes simplex viruses and bacterial agents such as Chlamydia have been studied extensively. Other potential agents such as Helicobacter pylori and periodontitis have been implicated. In a recent meta-analysis, it has been shown that influenza vaccination in patients with CHD can lower the risk of acute myocardial infarction. Periodontitis is associated with atherosclerotic cardiovascular disease, though direct causal relation is not yet established. The incidence of atherosclerotic cardiovascular events increase in patients with chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and psoriasis.


Biomarkers such as hs-CRP, IL- 6, IL- 8, soluble CD40 ligand are all markers of widespread inflammatory process in the vessel wall and can be identified by laboratory assays to detect subclinical atherosclerosis. There was an association between CRP and carotid atherosclerosis as assessed by ultrasono-graphy among 3,173 men and women enrolled in the Framingham Offspring Study. Overall, they found that increasing levels of CRP were predictive of carotid artery disease. Elevated levels of CRP may reflect the presence of vulnerable plaque that is at highrisk of rupture, as opposed to solely reflecting the burden of atherosclerosis. Emerging data, however, suggest that CRP may be a mediator as well as marker of atherosclerosis. CRP induces expression of cellular adhesion molecules, IL-6 and endothelin1 by endothelial cells. Recently, interest has focused on the measurement of a circulating soluble form CD40 L (sCD40) for risk stratification of patients with or at risk of developing coronary artery disease. However, in a large multiethnic population-based sample, sCD40L was not associated with most atherosclerotic risk factors or subclinical atherosclerosis.

Technology has now made it possible to image atherosclerosis and the day is not far when it will be routinely used in identifying vulnerable plaques which are prone to rupture. It is yet unproven that therapies directed at sealing such plaques are beneficial. Techniques to image “vulnerable” plaque is given in Table 2. Table 2: Techniques to Image “Vulnerable Plaque” Angioscopy Intravascular ultrasound Palpography Virtual histology Near-infrared/Raman spectroscopy Ocular coherence tomography/ocular frequency domain imaging Thermography Vasa vasorum imaging Magnetic resonance imaging (invasive and non-invasive) Positron emission tomography/computed tomography Molecular imaging

TREATMENT/PREVENTION Systemic pharmacotherapy is the cornerstone of plaque stabilisation, with reductions in lipid content, inflammation and vasa vasorum neovascularisation. Statin therapy in high-dose has been documented to be beneficial in atherosclerotic plaque regression. In the A study to evaluate the effect of Ultrasound rosuvastatin an Intravascular derived coronary Atheroma Burden trial, rosuvastatin 40 mg per day led to an absolute regression in atheroma volume. Increasing HDL levels have been found to be antiatherogenic. However, even with the best combination consisting of high dose statins, ACE-inhibitors and aspirin, there is still a 22% recurrent coronary event rate in 2 years. Regional therapy such as photodynamic therapy and cryotherapy as intravascular treatment of coronary segments may be beneficial in near future. Plaque sealing with balloon expandable stents may tackle the vulnerable plaque. Vaccine development for atherosclerosis Historically, vaccines have been proven to be safe and efficient for protection against infectious diseases. Several antigen targets have been proposed for vaccine design, implementation and efficacy for atherosclerosis. Ideal vaccines for atherosclerosis should provide protective immunity against infection-derived pro-atherogenic antigens and also immune tolerance for auto-immunogenic selfantigens. LDL was the earliest target for vaccine therapy as it is a major mediator of atherosclerosis. Studies focusing on a knockdown of Ox-LDL showed a decrease in atherosclerotic lesion size. Immunisation with phosphatidylcholine (PC) containing Streptococcus pneumoniae generated vaccine which showed reduced atherosclerosis. However, the major problem with Ox-LDL is the chance of cross-reactivity. For greater OX-LDL specificity, more recent studies have targeted ApoB-100 peptide fragments. Studies to target the potential antigenicity of heat shock protein (HSP) mycobacterial HSP 65 elicit a pro-atherogenic response. Immunisation of patients with HSP 70 also showed decreased atherosclerosis. Following the idea that molecular mimicry is the mechanism responsible for cross-reactivity with foreign HSP, vaccination against infectious agents like influenza virus has been examined in the context of atherosclerosis. Vaccines


Fruchart JC, Niermann MC, Stroes ESG, et al. New risk factors for atherosclerosis and patient risk assessment. Circulation 2004;109: 15-9.


Fuster V, Topol EJ, Nabel EJ. Atherothrombosis and Coronary Artery Disease. 2005; 2: 15-1575.


Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med 2005; 352: 1685-95.


Libby P, Ridker MP, Hansson GK. Inflammation in atherosclerosis: From physiology to practice. J Am Coll Cardiol 2009; 54: 2129-38.


McGill HC, McMahon CA, Gidding SS. Preventing heart disease in the 21st century: Implications of the pathological determinants of atherosclerosis in the youth (PDAY) study. Circulation 2008; 117: 1216-27.


Moreno PR. Vulnerable plaque: Definition, diagnosis and treatment. Cardiol Clin 2010; 28:1-30.


against more risk factors and proteins like nicotine, angiotensin1, gherkin and periodontitis have also been examined with some interesting results. Thus, vaccine development for atherosclerosis is already underway and showing promising results.



Ischaemic Heart Disease Inder S Anand, Shibba Takkar Chhabra

Ischaemic heart disease (IHD) is characterised by myocardial impairment due to imbalance between coronary blood flow and myocardial requirement. The commonest cause of IHD is atherosclerotic coronary artery disease (CAD). Nonatherosclerotic causes of myocardial ischaemia are rare and include coronary spasm (Prinzmetal’s angina), coronary artery embolism, coronary arteritis (polyarteritis nodosa, Takayasu’s disease, systemic lupus erythematosus), cocaine abuse or spontaneous dissection of coronary arteries. CORONARY CIRCULATION The left main and right coronary arteries arise from the left and right coronary sinuses of the aortic root, distal to the aortic valve. Within 2.5 cm of its origin, the left main coronary artery divides into the left anterior descending artery (LAD), which runs in the anterior interventricular groove, and the left circumflex artery (LCX), which runs in the atrioventricular groove. The LAD gives branches to supply the anterior part of the septum (septal perforators) and the anterior, lateral and apical walls of the left ventricle (diagonals). The LCX gives obtuse marginal branches that supply the lateral, posterior and inferior segments of the left ventricular (LV). The right coronary artery (RCA), runs in the right atrioventricular groove, giving acute marginal branches that supply the RA, RV and inferoposterior aspects of the LV. The posterior descending artery runs in the posterior interventricular groove and supplies the inferior part of the interventricular septum. It arises from the RCA in approximately 85% of people (dominant right system) and from the LCX in the remainder (dominant left system). The coronary anatomy varies greatly from person to person and there are many normal variants. The RCA supplies the sino-atrial (SA) node in about 60% of individuals and in the remaining 40% SA node is supplied by LCX. The AV node is supplied by a small AV nodal artery which arises from the dominant coronary artery (RCA in 85%) (Figure 1). Proximal occlusion of the RCA, therefore, often results in sinus bradycardia and may also cause AV nodal block. Abrupt occlusions in the RCA, due to coronary thrombosis, result in infarction of the inferior part of the LV and often the RV. Abrupt occlusion of the LAD leads to anterior wall or anteroseptal myocardial infarction (MI). LCX causes infarction in the anterolateral territory of the LV. Acute occlusion of the left main coronary artery is usually fatal.


PHYSIOLOGY The myocardium relies almost exclusively on oxidative metabolism for its energy needs. Even at rest the transmyocardial oxygen extraction is near maximal with a coronary venous O 2 saturation that is lowest in the body (25% to 35%). Any increase in myocardial O2 demand can only be met by proportional increase in myocardial blood flow, chiefly

Figure 1: The coronary arteries of the heart. Diagram of the anterior view.

mediated by reduction in coronary arteriolar resistance. The left coronary artery fills only in diastole while the RCA shows both systolic and diastolic coronary flow. MAGNITUDE OF THE PROBLEM Cardiovascular disease accounts for approximately 12 million deaths annually and is the commonest cause of death globally. Previously considered a disease of the affluent, the past three decades have seen considerable decline in the incidence and prevalence of atherosclerotic CAD in the industrialised western world; whereas at the same time, this problem is assuming epidemic proportions in the developing world. Asian Indians, whether living in their own country or elsewhere, have much higher incidence of CAD as compared to all other ethnic groups. While the incidence of coronary artery disease has reduced by 50% in the west, in India it has doubled in the last 25 years. The prevalence of coronary artery disease in the years 1960, 1980, 1990 and 2000 progressively increased (2%, 4% to 6%, 9.5% and 10% to 15% respectively). In the rural India, the CAD prevalence increased two-fold from 2% to 4%. In urban India, the increase was three-fold from 3.45% to 9.45%. In 1990, 25% deaths in India were attributable to cardiovascular disease compared to 9% due to diarrhoeal disease, 12% due to respiratory infections and 5% due to tuberculosis. RISK FACTORS The National Heart Lung and Blood Institute of USA initiated the Framingham Heart Study in 1949 and by 1961, the concept of risk factors for CHD was established with hypertension and hypercholesterolaemia being identified for intervention.

Table 1: Risk Factors for Clinical Atherosclerosis Non-Modifiable


Age Male gender Family history of CHD Presence of CHD Menopause Physical inactivity

Dyslipidaemia Hypertension Diabetes Abdominal obesity Smoking Diet

Asian Indians have the highest ethnic risk of CAD despite lower rates of smoking, hypertension, obesity and higher vegetarianism. The insulin resistance syndrome (metabolic syndrome X), lipoprotein(a), atherogenic dyslipidaemic phenotype and some newer emerging risk factors [homocysteine, tissue plasminogen activaetor (tPA), plasminogen activator inhibitor (PAI-1), fibrinogen, infections and inflammation] may be more relevant as underlying genetic susceptibility associated with a modest abnormality in lipid and lifestyle factors makes CAD assume an aggressive course in Asian Indians. Important risk factors in Asian Indians have been listed in Table 2.The INTERHEART study (2004) on 25,000 myocardial infarction patients confirmed nine risk factors attributing to CAD—ApoB/ApoA-1, smoking, diabetes, hypertension, abdominal obesity, psychosocial, fruits and vegetable intake, exercise and alcohol. Of these ApoB/ ApoA-1 and smoking were especially associated with increased incidence of myocardial infarction in younger patients. Table 2: Coronary Risk Factors for Asian Indians Fixed Male age >35 years Female age >45 years Family history of premature CAD (at age 23 Homocysteine >10 mmol/L High PAI – 1

sudden cardiac death (Table 3). The understanding of the conversion of a stable atherosclerotic lesion to a plaque rupture with thrombosis has provoked a unifying hypothesis for the aetiology of acute coronary syndromes. Table 3: Nomenclature of Myocardial Ischaemia Old


Asymptomatic Stable effort angina Unstable angina

Asymptomatic Stable effort angina Acute coronary syndromes, unstable angina without necrosis Non-ST elevation MI (NSTEMI) (evidence of myocardial necrosis) ST elevation MI (STEMI) Sudden death Ischaemic cardiomyopathy

Non-Q wave MI Q wave MI Sudden death Silent ischaemia

Ischaemic Heart Disease

The classically defined eight risk factors for CAD are hypertension, dyslipidaemia, diabetes, physical in activity and sedentary lifestyle, central obesity, stress and type A personality, family history of CAD and smoking. Of these, smoking, diabetes, hypertension and family history of premature CAD are particularly important. Table 1 enlists the modifiable and non-modifiable risk factors for CAD.

CLINICAL PRESENTATION Symptoms The typical clinical presentation of angina refers to poorly localised retrosternal discomfort with radiation to neck, shoulders, arms, jaws, epigastrium or back; usually, not above the jaw and not below the umbilicus. Angina is typically triggered by physical activity, emotional stress, exposure to cold, consuming a heavy meal or smoking. Pain is poorly localised, vague chest discomfort which may be described as squeezing, burning, tightness, choking, heaviness, hot or cold sensation, dyspnoea, fatigue, weakness, lightheadedness, nausea, diaphoresis, altered sensorium and syncope. These symptoms have been called angina equivalents. Pain lasts for 2 to 8 minutes. Ischaemia seldom lasts more than 30 minutes without causing acute myocardial infarction (AMI). Pain is relieved with rest or sublingual nitroglycerine in 2 to 5 minutes. It is less likely to be angina if it is localised (finger pointing), less than 30 s, or more than 30 min without AMI, exclusively at rest (except unstable/Prinzmetal), pricking or jabbing and changing sites of pain (Figure 2).

Modifiable: Lipid Total cholesterol >150 mg/dL Triglycerides >150 mg/dL LDL cholesterol >100 mg/dL ApoA lipoproteins 10 mm Hg in systolic pressure during inspiration.


Investigations for Pericardial Effusion and Cardiac Tamponade General investigations for pericardial effusion and cardiac tamponade include routine blood counts and ESR. There may be leucocytosis and neutrophilia and the sedimentation rate may be high. Electrocardiography ECG can be normal or non-specific ST-T-wave changes are seen, total electrical alternans is seen in large effusions and tamponade (Figure 3). Bradycardia and electromechanical dissociation are diagnostic of end-stage tamponades.

seen posteriorly. Pericardial effusions large enough to produce cardiac tamponade are almost always circumferential (both anteriorly and posteriorly). Echocardiography reveals the size of effusions: 1. Small (echo-free space in diastole 10 mm posteriorly) 3. Large (>20 mm) 4. Very large (>20 mm with compression of the heart) In cases of gross effusion, the heart assumes a ‘swinging’ effect, wherein the heart seems to oscillate within the pericardial sac. Echocardiography also provides information on the significance of the pericardial effusion. In the presence of cardiac tamponade, there is diastolic collapse of the free walls of the right atrium and/or right ventricle (Figures 5 and 6). The collapse is exaggerated during expiration when right heart filling is reduced. Right atrial collapse is more sensitive for tamponade, but right ventricular collapse lasting more than one-third of diastole is a more specific finding for cardiac tamponade. On echo Doppler study, there can be marked reciprocal respiratory variation in mitral and tricuspid flow velocities reflecting the enhanced ventricular interdependence that is the mechanism of the paradoxical pulse.

Figure 3: Total electrical alternans seen in large pericardial effusion and cardiac tamponade.

X-ray In pericardial effusion, the cardiac silhouette will be increased in size. Enlarged cardiac silhouette with clear lungs on chest radiograph is very characteristic of large pericardial effusion (Money Bag appearance) (Figure 4). The individual chamber and blood vessel contours are lost. Echocardiography Echocardiography is an important part of the evaluation in patients with pericardial effusion and cardiac tamponade. The most important finding is the separation of the two pericardial layers by an ‘echo-free’ space. Small pericardial effusions are only

Figure 5: Echocardiography showing circumferential pericardial effusion with RA collapse (White or red arrow).


Figure 4: Enlarged cardiac silhouette with clear lung field in large pericardial effusion.

Diagnostic and Therapeutic Pericardiocentesis Aspiration of the pericardial fluid will not only confirm the diagnosis but also help in detection of the aetiology. The aspirated fluid should be analysed and sent for bacteriological culture and sensitivity tests. If there is no haemodynamic compromise and the diagnosis can be established by other means, pericardiocentesis may not be necessary but it is generally advisable in patients with very large pericardial effusions (>20 mm on echocardiography), even in the absence of tamponade. It must be recognised that pericardiocentesis will not yield a diagnosis in most patients and, therefore, the reason for draining large effusions is to avoid potential progression to tamponade.

The feasibility of pericardiocentesis is high (>93%) in patients with anterior effusion more than 10 mm, while the rate of success is only 58% with small, posteriorly located effusions. The most serious, but rare, complications are lacerations/ perforations of the myocardium and the coronary vessels. In addition, patients can experience air embolism, pneumothorax, arrhythmias (usually bradycardia), and puncture of the peritoneal cavity or abdominal viscera.

Diseases of the Pericardium

mammary arteries. It is prudent to drain the fluid in stepped amounts of less than 1 litre at a time to avoid acute right ventricular dilatation.

If the fluid withdrawn is found to be purulent or there is large effusion then an indwelling pigtail catheter is left in pericardial cavity for drainage of residual or reoccurring effusion later on. Along with this, appropriate antibiotic therapy should be instituted.

Figure 6: Echocardiography showing large posterior pericardial effusion (Red arrow).

Other Investigative Procedures Computerised axial tomography and magnetic resonance imaging also help, especially when echocardiography does not reveal good images due to pulmonary disease. Prognosis This depends on the aetiological factor. Tuberculous pericardial effusion very often results in chronic constrictive pericarditis. Pericardial effusion in uraemia and neoplasms are harbingers of death. Purulent pericardial effusion, if not treated vigorously, may prove fatal.

SPECIAL FORMS OF PERICARDITIS 1. Idiopathic Pericarditis As the name suggests, the cause of this type of pericarditis is not known, though it is presumed to be viral. It affects all age groups and presents with fever, bodyache and chest pain. Pericardial effusion develops in about 75% of the cases. Treatment consists essentially of rest and analgesics. If pain is very severe and the effusion does not subside, then corticosteroids may be given. Very rarely, constrictive pericarditis may ensue. 2. Rheumatic Pericarditis This is seen in cases of acute rheumatic fever and is characterised by tachycardia, chest pain and fleeting joint pains. Usually, it is dry pericarditis (‘bread and butter’ pericarditis) but pericardial effusion may occur. There is complete regression with treatment and no sequelae are seen.

Treatment The treatment of pericardial effusion is two-fold; treatment of the aetiological factor and treatment of the effusion.

3. Uraemic Pericarditis Two forms of pericarditis have been described in renal failure:

The treatment of cardiac tamponade is drainage of the pericardial effusion. Medical management is usually ineffective and should be used only while arrangements are being made for pericardial drainage. Fluid resuscitation may be of transient benefit if the patient is volume depleted. The use of inotropic agents is usually ineffective because there is already intense endogenous adrenergic stimulation.

(a) Uraemic pericarditis Fibrinous inflammation with adhesions between the thickened pericardial membranes (‘bread and butter’ appearance) caused by the high degree of azotemia in advanced renal failure before dialysis is started or shortly, thereafter. This is seen usually in the terminal stages of uraemia. The pericarditis is of the dry type.

PERICARDIOCENTESIS Pericardiocentesis is the aspiration of the pericardial fluid for therapeutic as well as for diagnostic purposes. Indications for pericardiocentesis are: cardiac tamponade, diagnosis of the aetiology of pericardial effusion and introduction of drugs into the pericardial cavity (when indicated). Procedure Pericardiocentesis can be performed either using fluoroscopic (cardiac catheterisation laboratory) or preferably in the intensive care unit, under echocardiographic guidance. There are various sites for aspiration but the two commonest sites used are the subxiphoid and the left fifth intercostal space. The subxiphoid approach is the much preferred route, as one can aspirate fluid even in the case of small effusions. This route is extrapleural and avoids the coronary, pericardial, and internal

(b) Dialysis-associated pericarditis Patients on maintenance haemodialysis, and occasionally with chronic peritoneal dialysis caused by inadequate dialysis and/or fluid overload. Most patients with uraemic pericarditis respond within 1 to 2 weeks to haemo or peritoneal dialysis, with resolution of chest pain and reduction of the pericardial effusion. To avoid intrapericardial haemorrhage, heparin-free haemodialysis should be used. 4. Post-Infarction Pericarditis Pericarditis may occur ‘early’ or be ‘delayed’ (Dressler’s syndrome) after myocardial infarction. Early pericarditis occurs in the first few days of a transmural myocardial infarction, although early thrombolytic treatment has decreased its incidence. Dressler’s syndrome occurs from


one week to several months after myocardial infarction and is considered to be an autoimmune phenomenon. Aspirin, up to 650 mg every four hours for 2 to 5 days, has been successfully used to treat post-infarction pericarditis. Other nonsteroidal agents risk thinning the infarction zone. Corticosteroid treatment is used for refractory symptoms but can delay infarction healing. 5. Tuberculous Pericarditis This is possibly the commonest cause of pericarditis and pericardial effusion in India. It is even more common after the advent of HIV infection and AIDS. Infection occurs through neighbouring structures, e.g. lungs, bronchi, lymph nodes or by blood-borne infection. The patient may have vague complaints of fever, malaise, evening rise in temperature, loss of weight, etc. There may be no cardiac manifestations initially but later on, chest pain, cough and dyspnoea may appear due to an increase in the size of the effusion. Aspiration of the fluid reveals either straw-coloured or bloodtinged exudative fluid. A systematic, multiple diagnostic approach is essential, e.g. sputum cultures, analyses of pericardial effusion by acid-fast staining, mycobacterial culture or radiometric growth detection (BACTEC-460), adenosine deaminase (ADA), pericardial lysozyme, and PCR for Mycobacterium tuberculosis. High ADA (>40 U/L) in pericardial effusion is diagnostic for tuberculous pericarditis (93% sensitivity, 97% specificity). The absolute criteria for diagnosis are the identification of Mycobacterium tuberculosis in the pericardial fluid or tissue, and/or the presence of caseous granulomas in the pericardium. However, pericarditis in proven extracardiac tuberculosis is strongly suggestive of a tuberculous aetiology. PCR is as sensitive (75% vs. 83%), but more specific (100% vs. 78%) for tuberculous pericarditis than ADA. Very often, even on a very close search, no evidence of tuberculosis may be found anywhere in the body. Tuberculous pericarditis should be promptly treated with a combination of antitubercular drugs according to standard protocols. Prednisone should be administered along with antituberculous drugs as it reduces the host reaction to mycobacterial infections, minimises exudation, fibrin deposition, and proliferation of tuberculomas and may decrease symptoms and signs. However, despite combination therapy, many patients develop constriction and if untreated, it is one of the commonest causes of constrictive pericarditis in India.


6. Purulent Pericarditis This is due to infection of the pericardium by organisms like the Staphylococcus, Streptococcus, Pneumococcus, Meningococcus and Haemophilus, etc. The infection may be either blood-borne, extension of an intrathoracic infection or from outside as in cases of stab wounds. Patient presents with high-grade fever and appears very toxic. If the effusion accumulates very rapidly it may result in cardiac tamponade. Pericardial fluid aspirate should undergo urgent Gram’s, acid-fast, and fungal staining followed by cultures for aerobes and anaerobes. Purulent effusions have significantly lower fluid glucose concentrations than non-infectious effusions.

Purulent pericarditis is an absolute indication for pericardial drainage and rinsing of the pericardial cavity, combined with high doses of systemic antibiotic treatment. A combination of antistaphylococcal antibiotic and aminoglycoside, followed by tailored antibiotic treatment according to the results of pericardial fluid and blood cultures, is mandatory. 7. Viral Pericarditis This is a common cause of pericarditis and is clinically difficult to differentiate from idiopathic pericarditis. Viral pericarditis can be caused by direct viral attack (enterovirus, adenovirus, cytomegalovirus (CMV), Ebstein-Barr virus, herpes simplex virus, influenza virus, parvo B19, hepatitis C virus, HIV, etc.), the immune response or both. Initial presentation is the syndrome of acute pericarditis, often resolving within two weeks but may progress to pericardial effusion which may be serous, suppurative, or haemorrhagic. The diagnosis depends on the demonstration of rising titers of specific antibodies in the serum. A four-fold rise in serum antiviral antibodies is suggestive but not diagnostic per se. In most patients, pericardial viral infection is self-limiting and no specific treatment is necessary. 8. Neoplastic pericarditis Neoplastic pericarditis is also an important specific diagnosis to rule out in patients with pericarditis. It is responsible for about 5% of unselected cases of acute pericarditis and may metastasise to the pericardium, with the most common being lung and breast cancer and lymphomas. Lung cancer is the commonest malignancy giving early invasion of lymph nodes and thus being easily responsible for pericardial effusion. Primary tumours of the pericardium are less common. 9. Haemopericardium Accumulation of blood in the pericardial cavity usually occurs after rupture of a cardiac chamber (after myocardial infarction), coronary artery or a dissecting aneurysm. Rarer causes include scurvy, neoplasms and leukaemia. Pericardial tamponade may occur and need drainage. 10. Pneumopericardium Air in the pericardial cavity may result from stab wounds, perforation of an air-containing organ into the pericardium, by gas-forming organism or by introduction of air into the pericardial cavity. An X-ray of the chest reveals the presence of gas in the pericardial cavity. This usually does not require treatment, but the underlying cause requires treatment. CHRONIC CONSTRICTIVE PERICARDITIS Chronic constrictive pericarditis (CCP) is defined as a dense and rigid thickening of one or both layers of the pericardium with adhesions resulting in compression of the heart with impairment in the diastolic filling. Aetiology The most common causes include:  Tuberculosis  Idiopathic and viral pericarditis  Chest irradiation  Collagen vascular disease

Post-cardiotomy Malignancy

In developing countries with high prevalence of tuberculosis, it is most common cause of CCP. In India, tuberculosis is responsible for nearly two-third of the cases of CCP. The aetiology of CCP in the western world has undergone a significant change, with tuberculosis reported in only 0% to 1% of cases. However, with emergence of the AIDS pandemic these numbers are likely to increase again. The leading identifiable causes of CCP in western world are following cardiac surgery and radiation therapy, besides viral pericarditis, but such cases are possibly missed in India. Pathophysiology The pericardium undergoes thickening and calcification (normal thickness of the pericardium is 3 to 5 mm). The thickened peri-

cardium forms an encasement of the heart and is unable to stretch during diastole. The unyielding pericardium impairs the diastolic relaxation of the heart and thereby diminishes venous filling of the right ventricle. However, there is no interference with systole. The pathophysiological hallmark of pericardial constriction is equalisation of the end-diastolic pressures in all four cardiac chambers. This occurs because the filling is determined by the limited pericardial volume, not the compliance of the chambers themselves. Initial ventricular filling occurs rapidly in early diastole as blood moves from the atria to the ventricles without much change in the total cardiac volume. However, once the pericardial constraining volume is reached, diastolic filling stops abruptly. This results in the characteristic dip and plateau of ventricular diastolic pressures. The stiff pericardium also isolates the cardiac chambers from respiratory changes in intrathoracic pressures, resulting in Kussmaul’s sign (Figures 7 and Figures 8A and B).

Diseases of the Pericardium

Figure 7: Schematic representation of transvalvular and central venous flow velocities in constrictive pericarditis. During inspiration, the decrease in left ventricular filling results in a leftward septal shift, allowing augmented flow into the right ventricle. The opposite occurs during expiration. EA = Mitral inflow; LA = Left atrium; LV = Left ventricle; RA = Right atrium; RV = Right ventricle.

Figures 8A and B: Pressure recordings in a patient with constrictive pericarditis. (A) Simultaneous right ventricular (RV) and left ventricular (LV) pressure tracings with equalisation of diastolic pressure, as well as ‘dip and plateau’ morphology. (B) Simultaneous right atrial (RA) and LV pressure with equalisation of RA and LV diastolic pressure. The y-descent is prominent.


Due to the reduction in venous filling, the stroke output falls and to compensate for decreased cardiac output the heart rate rises. The systemic pressure rises because of the limited cardiac filling. The liver and spleen are enlarged and the capsule is thickened as a consequence of chronic congestion. Haemodynamics in cardiac tamponade and constrictive pericarditis are compared in Table 4.

calcification of the pericardium.This is best seen in the left lateral or oblique views and is present in about two-thirds of the cases. In the lateral view, if the calcification is seen in the entire pericardium (i.e. anteriorly, inferiorly and posteriorly) the appearance is termed as ‘egg-shell pericardial calcification’ (Figure 9). The lung fields remain clear. Severe venous engorgement may lead to pleural effusions.

Symptoms and Signs The commonest complaint is the distension of the abdomen due to ascites and swelling of the feet. The next common complaint is dyspnoea and fatigue. On inspection, the neck veins are engorged, even in the standing position. A deep ‘y’ descent (Frederick’s sign) is seen. JVP is raised and increases/fails to decrease during deep inspiration (Kussmaul’s sign).The arterial pulse is of a low volume and the rhythm may be irregular indicating the presence of atrial fibrillation. Table 4: Haemodynamics in Cardiac Tamponade and Constrictive Pericarditis Tamponade Paradoxical pulse Equal left/right filling pressures Systemic venous wave morphology

Usually present Present Absent y descent

Inspiratory change in systemic venous pressure

Decrease (normal)

‘Square root’ sign in ventricular pressure


Constriction Present in ≈ 1/3 Present Prominent ‘y’ descent (M or W shape) Increase or no change (Kussmaul’s sign) Present

Inspection of the praecordium reveals a ‘quiet’ heart and prominent veins may be observed all over the chest. A systolic retraction at the apex may be observed. On palpation, a diastolic ‘tap’ or ‘shock’ may be palpated. It is due to the rapid filling of the right ventricle. The characteristic finding on auscultation is the ‘pericardial knock’.This is a sound due to rapid filling of the ventricle in the early rapid filling phase. It occurs about 0.08 to 0.12 second after the second sound in contrast to the normal third sound, which occurs a little later (0.13 to 0.16 s). The heart sounds are normal and usually no murmur is heard. Examination of the abdomen reveals an enlarged, smooth and tender liver. The chief finding in the abdomen, however, is the presence of ascites which is massive and out of proportion to the oedema on the legs (which may be minimal). It tends to refill very rapidly after aspiration. Investigations Electrocardiography The ECG findings are not characteristic but include low voltage of the QRS complexes, flattening or inversion of the T-waves and occasionally atrial fibrillation. X-ray 744

The heart size is usually normal or slightly smaller. The characteristic finding of constrictive pericarditis, however, is the

Figure 9: Chest radiograph showing marked pericardial calcifications in a patient with constrictive pericarditis.

Echocardiography This is perhaps the most useful investigation to diagnose constrictive pericarditis. The presence of thickened and/or calcified pericardium clinches the diagnosis. However, increased pericardial thickness can be missed on a transthoracic echocardiogram. Transoesophageal echocardiography is more sensitive and accurate in determining pericardial thickness. Doppler echocardiography is important in the evaluation of patients with suspected pericardial constriction. Doppler echocardiography frequently demonstrates restricted filling of both ventricles with a rapid deceleration of the early diastolic mitral inflow velocity (E wave) and small or absent a wave. In addition, there is substantial (>25%) respiratory variation of the mitral inflow velocity (Figure 10). There are signs of systemic venous congestion such as dilation of hepatic veins and distension of the inferior vena cava with lack of inspiratory collapse (Figure 11). CT/MRI CT and MRI allow accurate measurement of pericardial thickness and some assessment of diastolic filling patterns. Ancillary diagnostic findings include conical narrowing of the ventricles, atrial dilation, and enlargement of the inferior vena cava, hepatomegaly, and ascites. Excellent overall sensitivity (88%), specificity (100%), and accuracy (93%) have been reported for MRI. Increased pericardial thickening may not always imply

Diagnosis The combination of pulsus paradoxus, neck vein signs, ascites and pericardial ‘knock’ should pose no difficulty in the diagnosis. However, similar clinical pictures may be seen in tricuspid valvular diseases, restrictive cardiomyopathies and cirrhosis of the liver. Tricuspid valvular defects have their characteristic murmurs, which increase in intensity on deep inspiration. Cardiomyopathies may be diagnosed on echocardiograms.

Figure 10: Doppler echocardiography showing respiratory variation of the mitral valve inflow velocity in a case of constrictive pericarditis.

Diseases of the Pericardium

relaxation of the ventricle during diastole and is usually more than one-third of the systolic pressure. The right atrial tracings show a ‘M’ or ‘W’ shaped pattern corresponding to the right ventricular pressures. It has been observed that the pulmonary wedge pressure, pulmonary artery diastolic pressure, right ventricular end-diastolic pressure, mean right atrial pressure and superior vena cava pressures tend to be equal or near-equal in constrictive pericarditis.

Prognosis Without surgery the prognosis is poor. Long-standing cases of constrictive pericarditis develop hypoproteinaemia due to a protein-losing enteropathy. They also develop a myocardial failure (probably due to fibrosis) which does not respond to digoxin, even after pericardiectomy. Treatment Medical management of constrictive pericarditis, especially in less severe cases, is aimed at relief of fluid overload with careful administration of diuretics and is at best, palliative. Surgical pericardiectomy remains the only definitive management and should be done before calcification and myocardial involvement progresses. However, if the cause is thought to be tuberculosis, then a few weeks on antituberculous drugs should precede the surgery. The results of surgery are very gratifying. Other aetiological causes should get their respective treatments.

Figure 11: M mode showing dilated IVC with minimal respiratory variation in a case of constrictive pericarditis.

constriction, and conversely, constrictive pericarditis can present with normal pericardial thickness on non-invasive imaging, histology, or a combination of these. Cardiac catheterisation Though a very valuable tool in the diagnosis of constrictive pericarditis in the past, it is no longer used routinely after the advent of echocardiography. Catheterisation reveals an elevation of the right ventricular end-diastolic pressure, characterised by an early diastolic ‘dip’ and a late diastolic ‘plateau’. The end-diastolic pressure is high due to incomplete

CONCLUSION Pericarditis remains a common disorder, particularly as a complication of modern treatments such as cardiac surgery, percutaneous interventions, and radiation therapy. Pericardial effusion and constrictive pericarditis are infrequent sequelae that can be diagnosed accurately in most cases by use of modern imaging methods. Cardiac tamponade, a medical emergency should be promptly diagnosed and managed with urgent pericardiocentesis. Management of uncomplicated pericarditis rests largely on NSAIDs with the addition of colchicine for relapses. Pericardial effusion can be managed percutaneously in most cases, whereas definitive treatment for constriction remains surgery. RECOMMENDED READINGS 1.

Bernhard Maisch, Arsen D. Ristic. Practical aspects of the management of pericardial disease. Heart 2003; 89: 1096-1103.


Hoit BD. Management of effusive and constrictive pericardial heart disease. Circulation 2002; 105 (25): 2939-42.


Imazio M, Spodick DH, Brucato A, et al. Controversial issues in the management of pericardial diseases . Circulation 2010; 121: 916-28.


LeWinter MM, Kabbani S. Pericardial diseases. In: Braunwald E, et al. editors, Heart Disease: A Textbook of Cardiovascular Medicine, 7th Ed. Philadelphia: Saunders; 2004: pp. 1757-79.



Surgical Management of Heart Disease

INTRODUCTION The era of cardiac surgery was ushered more than a century ago when Ludwig Rehn of Frankfurt operated to relieve cardiac tamponade and sutured a stab wound to the right ventricle in September 1896. However, ‘open-heart surgery’ as we know it today began a little over fifty years ago with the development of an artificial ‘heart-lung machine’ by John H. Gibbon, Jr. On May 6, 1953, the Gibbons-IBM oxygenator was successfully used for total substitution of the heart and lungs for 26 minutes, enabling correction of an atrial septal defect, and thereby the world’s first successful open heart surgery. Since then, technological advances and myocardial protection techniques evolving continuously over the last six decades have enabled routine conduction of successful and complex cardiac surgery, totally bypassing the vital function of lungs and heart for hours to days. Cardiac surgery broadly encompasses: surgery for congenital heart disease; surgery for valvular heart disease; surgery for ischaemic heart disease and cardiac transplantation and related heart failure surgery. SURGERY FOR CONGENITAL HEART DISEASE Congenital heart disease (CHD) has an overall incidence of 0.8%. The patient population is diverse. Defects, presentation, diagnosis, treatment and outcome differ widely according to age of presentation and complexity of lesions. These can be broadly classified into acyanotic and cyanotic heart defects. A. Acyanotic 

Increased pulmonary blood flow (Left to Right shunt) Atrial septal defect Ventricular septal defect Patent ductus arteriosus Partial anomalous pulmonary venous connection

All these patients must be operated upon before schoolgoing age, unless progressive pulmonary arterial hypertension supervenes, in which case, early surgery is indicated to prevent the development of Eisenmenger complex. 

Normal pulmonary blood flow Aortic stenosis/bicuspid aortic valve Mitral regurgitation Coarctation of aorta Mitral stenosis

B. Cyanotic (Right to Left shunt) 


Increased pulmonary blood flow Truncus arteriosus Single ventricle Transposition of great arteries Total anomalous pulmonary venous connection Hypoplastic left ventricle

Muhammad Abid Geelani, Nikhil Prakash Patil 

Decreased pulmonary blood flow Tetralogy of Fallot Pulmonary atresia Tricuspid atresia with pulmonary stenosis Total transposition of great arteries with pulmonary stenosis Ebstein malformation

All blue babies must be closely observed for cyanotic spells. Severe and frequent spells constitute an indication for urgent operation. Early surgery is preferred as there is always a risk of paradoxical embolism with its complications. Surgery may be classified into: 

Palliative, e.g. Blalock-Taussig shunt (BT shunt), cavopulmonary shunt (Bi-directional Glenn shunt), pulmonary artery banding. Corrective, e.g. atrial/ventricular septal defect repair, ligation of patent ductus arteriosus, arterial switch for simple transposition of great arteries.

Conditions such as patent ductus arteriosus, coarctation of the aorta, atrial septal defect, partial atrioventricular canal and tetralogy of Fallot can now have corrective surgery with hospital mortality ranging from 0% to 5% depending upon the age at surgery and the complexity of the condition. Many complex conditions such as pulmonary atresia, transposition of the great arteries, tricuspid atresia and many other conditions previously considered inoperable are now being successfully treated with acceptable mortality and satisfactory long-term results. SURGERY FOR VALVULAR HEART DISEASE Acquired disease of heart valves can be treated by repair procedures or by replacement with an artificial prosthesis (Figures 1 to 3). The valves commonly affected are the aortic, mitral and tricuspid valves; the commonest pathologies are rheumatic and degenerative disease. Rheumatic heart disease, which has been practically eradicated from Western countries, continues to be a problem in South Asian countries. Rheumatic mitral stenosis (MS) without mitral regurgitation (MR) may initially be treated by balloon mitral valvuloplasty (BMV) or rarely with closed mitral valvotomy when BMV is not possible because of difficulty in percutaneous access to mitral valve, e.g. in inferior vena cava obstruction or inability to puncture the interatrial septum. But when echocardiography suggests unfavourable anatomy (Wilkins score > 8)* or when a left atrial clot is present, it is best to do as an open-heart procedure and * A scoring system exists to grade the morphological changes in the mitral valve during assessment with echocardiography. This takes into account 4 characteristics; leaflet mobility, leaflet thickening, valve calcification and involvement of the subvalvular apparatus. The involvement is graded from 0-4. A total score of more than 8 is predictive of a low success post percutaneous mitral valvuloplasty.

Mitral regurgitation may be caused by degenerative changes in the leaflet, prolapse of the leaflets, rupture of chordae tendineae or due to annular dilatation or tethering of the subvalvular apparatus secondary to ventricular dilatation. In such cases, a repair procedure may be considered. This is usually combined with implantation of a flexible or rigid annuloplasty ring to support the repair. All patients in NYHA class II and above, having orthopnoea, severe pulmonary hypertension, gradually dilating left ventricle and falling ejection fraction (LVEF), must be referred for early surgical procedure for better outcome.

Figure 1: Tilting disc mechanical valve (TTK Chitra valve).

Figure 2: Bileaflet mechanical valve.

Figure 3: Bioprosthetic valve (Pericardial).

repair/replacement of the valve may be indicated. Nowadays, BMV is done even in presence of left atrial appendage clot after giving anticoagulation therapy for 6 weeks. All patients in New York Heart Association (NYHA) functional class II or above, having dyspnoea, orthopnoea, severe pulmonary hypertension,

If a repair is not possible and mitral valve replacement is indicated, there is a wide choice of prosthetic and bioprosthetic valves available. Mechanical heart valves have evolved from a ball and cage design to the tilting disc valve to the bi-leaflet prosthesis. Currently, the bi-leaflet pyrolytic carbon low profile mechanical prosthesis is the most commonly used prosthesis as it has the advantage of central flow and excellent long-term results. The preservation of posterior leaflet with/without anterior chordal apparatus provides better long-term result as it maintains left ventricular geometry. Lifelong anticoagulation is mandatory for all mechanical heart valves to prevent thromboembolic complications. In spite of this, the incidence of thromboembolic complications is 1.5% to 2% per patient year. The alternative to the use of mechanical prosthesis is the use of bioprosthetic valves, which have a biological origin. These are generally stent-mounted porcine valves or pericardium treated with buffered glutaraldehyde to promote cross linkages between the collagen bundles. Anticoagulation is not essential for recipients of bioprosthetic valves after 6 weeks of surgery unless they are in atrial fibrillation. The main disadvantage of bioprosthetic valves is their limited durability; many of them degenerate and even calcify in 10 to 15 years time. The longterm durability of these prostheses have been improved by the use of proprietary anti-calcification treatment and by the development of valves constructed from glutaraldehydetreated bovine pericardium mounted within a specially designed stent. The hospital mortality for mitral valve replacement for primary non-ischaemic mitral valve disease is between 2% and 7%. The survival rate following surgery is 65% to 80% at 5 years, 50% to 60% at 10 years, and 30% to 40% at 15 years from several reported series. Most patients who need replacement of the aortic valve are in the older age group and have calcific aortic stenosis. Aortic regurgitation is either due to rheumatic heart disease causing fibrosis and shrinkage of the leaflets or due to annular dilation as in cystic medial necrosis or in aortic aneurysms and dissections. Aortic valve replacement has better early and late survivals than mitral valve replacement because of afterload reduction and low thrombogenicity in a high flow area. Small aortic root and patient-prosthetic mismatch is still a concern which leads to higher gradient across aortic valve and poor exercise tolerance. It is better to use stentless valves in the aortic position (autografts as in the Ross operation, homografts or xenografts) or root enlargement techniques in such situations. Enlarging left ventricle, syncope or angina in aortic valve disease warrant early surgery.

Surgical Management of Heart Disease

left atrial clot, must be referred for percutaneous/surgical intervention.


The tricuspid valve is generally treated with repair procedures and the implantation of annuloplasty rings rather than valve replacement as prosthetic valves do not function well in this relatively low pressure area. If the patients are offered surgery during late stages of the disease, the results of valve replacement are adversely affected because of left ventricular dilatation, pulmonary hypertension and congestive heart failure with hepatic and renal dysfunction. Surgery for valvular heart disease is now standardised in Indian centres but problems of late referrals, cost, maintenance of optimal anticoagulation and proper follow-up are the limiting factors. SURGERY FOR ISCHAEMIC HEART DISEASE Coronary artery bypass grafting (CABG) is one of the procedures with the highest impact in the history of medicine. CABG is based on the underlying principle that the symptoms and clinical events of coronary artery disease (CAD) are related to stenotic coronary lesions that can be identified by angiography, and if those lesions are bypassed, then those symptoms and clinical events become less common. Surgical attempts at increasing blood flow to the ischaemic myocardium originated a century ago when Alexis Carrel anastomosed a carotid artery segment between the descending aorta and the left coronary artery in a dog, for which he was later awarded the Nobel prize. Three decades later, Arthur Vineberg started implanting the left internal mammary artery (LIMA) into the anterior myocardial territory of patients with CAD in order to increase arterial inflow and relieve angina, with some experiencing prolonged symptomatic improvement. Surgery on the coronary arteries was introduced clinically in 1958 by William Longmire, who reported on the use of endarterectomy in five patients operated without cardiopulmonary bypass (CPB). The first reported successful CABG operation took place in 1964 in Leningrad, where Vasilii Kolesov grafted a LIMA to the left anterior descending (LAD) artery without CPB. The world’s first CABG program started 3 years later in Cleveland, as Favaloro began to routinely use reversed saphenous veins for aortocoronary grafting. CABG today constitutes the keystone of adult cardiac surgery, but novel surgical, percutaneous, and medical alternatives loom large on the horizon. Yet CABG is constantly evolving and remains the most durable means of revascularisation for patients with CAD. Although CAD is largely diagnosed by conventional coronary angiography, evolving less invasive techniques like cardiac CT angiography may become the diagnostic modality of choice in the future.


or two-vessel disease not involving the proximal LAD and with only a small area of viable myocardium or no objective evidence of ischaemia on non-invasive testing. Several studies have shown that emergent surgery for relentless unstable angina or non-Q wave MI in the context of failed or unfeasible percutaneous coronary intervention (PCI) is associated with an increase in peri-operative mortality compared with semi-urgent CABG, although surgical revascularisation may still be preferable to a conservative strategy. Consequently, an attempt should be made at stabilising these patients with maximal medical therapy (and in some cases the temporary use of an intra-aortic balloon pump) to allow surgery to be performed on a non-emergent basis with a lower operative risk. Intravenous thrombolytic therapy and primary PCI have supplanted CABG as the first line of therapy for patients in the acute period of ST segment elevation MI. As a result, residual ongoing ischaemia and cardiogenic shock despite maximal non-surgical therapy now constitute the main indication for emergent CABG in acute MI patients. Other acute indications include failed thrombolysis and demonstration of a large myocardial territory at risk in combination with an unsuitable anatomy for PCI, a left main coronary stenosis, an LV failure with severe coronary stenosis outside the initial infarct area, significant valve disease, or a mechanical complication of MI. PCI may occasionally result in intractable coronary dissection or plaque haemorrhage, threatened proximal occlusion with a large myocardial area at risk, loss of a foreign body in a crucial anatomical position, or coronary rupture. These complications are indications for immediate surgical intervention, but inhospital mortality is high in these patients (10% to 14%) because of unfavourable selection factors such as haemodynamic compromise and severe impairment of the coagulation system. CABG should NOT be attempted on an emergency basis in stable patients in whom PCI has failed because of unsuitable anatomy or no-reflow state. Conduit Selection The choice of conduit is determined by the quality of available conduit, the suitability of the target vessels and the age and co-morbidity of the patient.

CABG is indicated in patients with chronic stable angina and left main coronary artery stenosis ≥ 50%, left main equivalent (i.e. proximal stenosis of at least 70% of the proximal LAD and circumflex), three-vessel disease [especially if left ventricular ejection fraction (LVEF) is less than 0.50], and one- or two-vessel disease with either a large myocardial area at risk on noninvasive testing or depressed LVEF.

Internal mammary artery grafts The internal mammary artery (IMA) is the best conduit available for CABG and provides short- and long-term survival benefits in all patients subgroups, including those 75 years of age or older. Use of the LIMA to graft the LAD (or a main target vessel on the left coronary circulation if the LAD is free of disease) should be performed except in exceptional circumstances such as pre-existing or iatrogenic damage to the LIMA, poor flow from severe spasm, injury, or dissection, involvement of the LIMA in providing collateral supply to the lower extremity, mediastinal irradiation (if other arterial conduits are available), and emergency CABG with cardiogenic shock.

CABG may also be indicated for symptomatic improvement in low-risk patients with significant CAD who do not fulfil the above criteria but experience disabling myocardial ischaemia or unacceptable lifestyle restrictions on maximal medical therapy. CABG is not preferred over PTCA in patients with one-

The use of bilateral IMAs should be considered over single IMA grafting whenever, possible in young patients, as they may lead to lower reoperation rates, decreased late PCI rates, and longterm survival benefits. Relative contraindications to the use of bilateral IMAs include emergency operation, advanced age,

Radial artery grafts The radial artery likely constitutes, after the left and right IMA, the next best conduit for CABG. Radial artery harvest is contraindicated in the presence of insufficient collateral supply to the hand or Raynaud’s syndrome, in patients with high manual demands such as professional musicians, in the very elderly (who have a high prevalence of radial arteriosclerosis), during emergency operations, and in patients who are likely to require postoperative vasopressors such as those with very poor LV function. Saphenous vein grafts Saphenous veins are known not to be the conduit of choice for CABG due to proven lower short- and long-term patency than IMAs. Nevertheless, the long saphenous veins are still used in the majority of CABG operations by a large number of surgeons for practical reasons. They are also particularly useful for specific situations. They constitute the most readily available CABG conduit, provide immediate and reliable coronary flow with a low propensity for spasm or flow compromise during lowoutput states, and provide a time-honoured means of coronary revascularisation during emergency procedures or in patients with severe co-morbidity and limited life expectancy in whom procedural simplicity, expeditiousness, and reliability are most desirable. Other conduits The gastroepiploic artery, short saphenous vein and inferior epigastric artery constitute additional available conduits that are rarely needed for primary revascularisation, but which may be useful as a last resort in patients with severe conduit shortage, e.g. redo surgeries. Off-pump: CABG versus CPB CABG can be carried out with CPB (on-pump) or without (offpump: OPCABG). Many surgeons elect to perform CABG on pump, until recently, the advantages of a still, clear operating field, myocardial protection and haemodynamic and respiratory control, appeared to outweigh the disadvantages of CPB. However, recent improvements in methods of stabilising the heart have led to some institutions adopting OPCABG expecting to see lower morbidity and mortality. OPCABG appears to offer favourable outcomes, leading to reductions in postoperative atrial fibrillation, transfusion requirements, inotrope requirements, ventilation times, length of hospital and intensive care unit stay, and cost compared to on-pump coronary artery surgery. But, till date, no randomised trial has been sufficiently powered to detect the widely expected difference in death or stroke at 30 days or one year. Nevertheless, OPCABG is a suitable alternative to CPB in experienced centres. It should probably be the technique of choice in patients with porcelain (calcified) aorta, poor LV function, renal dysfunction, pulmonary dysfunction and advanced age or other co-morbidity.

SURGERY FOR HEART FAILURE Heart Transplantation Dr. Christiaan Barnard performed the world’s first human heart transplant operation on 3 December 1967. The patient, Louis Washkansky, was a 54-year-old grocer, suffering from diabetes and incurable heart disease. Washkansky survived the operation and lived for eighteen days. However, he succumbed to pneumonia induced by the immunosuppressive drugs he was taking. Barnard later wrote, ‘For a dying man it is not a difficult decision because he knows he is at the end. If a lion chases you to the bank of a river filled with crocodiles, you will leap into the water, convinced you have a chance to swim to the other side.’ Though the first patient with the heart of another human being survived for only a little more than two weeks, Barnard had passed a milestone in a new field of life-extending surgery. Since then, nearly 60,000 of these operations have been done worldwide, including over a hundred in Indian centres. The main limiting factor is the availability of suitable donors and the logistics of the procedure. The prognosis for heart transplant patients has greatly increased over the past 20 years. With the current immunosuppressive therapy using anti-thymocyte globulin, corticosteroids and azathioprine or mycophenolate survival is now 80% at 1 year, 70% at 5 years and 50% at 10 years. After the 20% mortality during the first year, the yearly mortality is approximately 4% per year. These results can be achieved only if the patients are carefully followed-up and monitored with percutaneous myocardial biopsy at appropriate time depending upon the clinical progress and modification of the immunosuppressive therapy based on the results of myocardial biopsy. Tony Huesman was the world’s longest living heart transplant recipient, having survived for 31 years with a transplanted heart (he died on August 10, 2009 of cancer)— the operation was performed in 1978 at Stanford University by American heart transplant pioneer Dr. Norman Shumway.

Surgical Management of Heart Disease

diabetes mellitus, obesity, and severe COPD for which the patient requires systemic steroid therapy.

In patients with severe pulmonary vascular disease heart-lung transplantation may be indicated but this operation is technically more difficult to perform and to manage post-operatively, and carries significantly lower survival rates. Cardiomyoplasty using latissimus dorsi muscle is not used anymore but Myosplint and its modification, which prevent dilatation of LV, are currently undergoing clinical trials. The artificial heart, which is essentially a ‘bridge to transplantation’, at present holds a very promising future as externally rechargeable energy sources are in the final stages of clinical trials. RECOMMENDED READINGS 1.

David D Yuh, Luca A Vricella, William A Baumgartner. The Johns Hopkins Manual of Cardiothoracic Surgery; 1st Ed. McGraw-Hill Professional; 2007.


Frank W Sellke, Pedro J del Nido, Scott J Swanson. Sabiston and Spencer’s Surgery of the Chest; 7th Ed. Elsevier Saunders; 2004.


Nicholas T Kouchoukos, Eugene H Blackstone, Donald B Doty, et al. Kirklin/ Barratt-Boyes Cardiac Surgery; 3rd Ed. Churchill Livingstone; 2003.


Stephen Westaby, Cecil Bosher. Landmarks in Cardiac Surgery; 1st Ed. Informa Healthcare; 1998.



Diseases of the Aorta Manotosh Panja

INTRODUCTION The aorta is composed of a thin intima, a thick media and a thin adventitia. The media is composed of laminated but intertwining sheets of elastic tissue in a spiral manner that gives it not only tensile strength but also distensibility and elasticity. The aorta is divided anatomically into thoracic and abdominal segments. The thoracic aorta is further divided into ascending, arch and descending segments, while the abdominal aorta consists of suprarenal and infrarenal segments. Aortic isthmus is the point where aortic arch joins the descending aorta. This is especially vulnerable to trauma as it is the junction of the mobile ascending aorta and arch and relatively fixed descending aorta.This is also the site for coarctation of the aorta. Other aortic anomalies could be right-sided aortic arch, double aortic arches and cystic medial degeneration as in Marfan’s syndrome and acquired degeneration of the aortic wall secondary to ageing, arteriosclerosis, hypertension and specific inflammatory, infectious or autoimmune diseases. AORTIC ANEURYSMS Aortic aneurysm is a localised dilatation of the aorta having a diameter at least 1.5 times that of the expected normal diameter of that given aortic segment. A true aneurysm involves all the three layers of the aortic wall. It is produced by the progressive distension of the aortic wall that is weakened by the degeneration of the tunica media. Sometimes, there may be a pseudoaneurysm or false aneurysm, which is actually a welldefined collection of blood and connective tissue outside the vessel wall as a consequence of a contained rupture of the aortic wall. Morphologically, an aneurysm is either fusiform or saccular. Fusiform aneurysm is more common. It is a symmetrical dilatation of the full circumference of the aortic wall. Saccular aneurysm on the other hand involves more localised dilation appearing as an outpouching of only a portion of the aortic wall. Incidence The post-mortem incidence of aortic aneurysm is 1% to 3%. There has been a gradual decline in the incidence of syphilitic aneurysms, but this has been offset by an increase in the atherosclerotic variety. ABDOMINAL AORTIC ANEURYSMS Abdominal aortic aneurysms (Figure 1) are far more common than thoracic aneurysms. They are 8 to 10 times more frequent in men than in women. Their incidence shows a rapid rise after 55 years in men and 70 years in women.


Aetiopathogenesis These aneurysms are usually atherosclerotic. Very rarely they may be traumatic, congenital or myxomatous. Most are

Figure 1: Post-mortem specimen of abdominal aortic aneurysm. Bilateral renal artery stenosis with infrarenal aortic involvement.

infrarenal and fusiform, varying in size from a few millimetre to ten centimetre. Only 2% to 5% are suprarenal. Absence of vasa vasorum in the infrarenal aorta coupled with atherosclerotic thickening of intima may jeopardise nutrient and oxygen supply to the media of this segment. This may hasten degeneration of tunica media in genetically predisposed subjects due to increased elastolytic activity and lead to aneurysm formation. Surprisingly, diabetes mellitus patients are not prone to development of abdominal aortic aneurysm. Clinical Features Symptoms Backache, abdominal pain, limb oedema and venous congestion are common. Acute pain and hypotension secondary to rupture may occur. Signs There is palpable pulsatile mass in the abdomen, presence of peripheral vascular disease, signs of distal embolisation, and haemodynamic collapse. Majority of the cases are asymptomatic and are detected on incidental examinations like abdominal X-ray or ultrasound.

The major risk of abdominal aortic aneurysm is its rupture. Expansion or impending rupture are heralded by sudden onset of new or worsening pain that is characteristically constant, severe, localised to back or lower abdomen and sometimes radiating to the groin, buttocks and legs. The pulsatile abdominal mass, if present already, may become tender on palpation. Abrupt onset of back pain and abdominal pain with tenderness, and hypotension characterises actual rupture, but this pathognomonic sign is present in only one-third cases. In 80% of the cases rupture occurs in the left retroperitoneum and is signalled by haematomas in the flanks and groin. Most of the remainder rupture into the peritoneal cavity, causing uncontrolled haemorrhage and result in abdominal distension. Rupture into the duodenum presents as massive gastrointestinal haemorrhage. Rarely, it may rupture into inferior vena cava, iliac or renal vein producing haemodynamic collapse and acute high-output cardiac failure. Rupture is associated with high mortality; 60% die before any medical intervention and 50% of those survive after operative correction. Diagnosis and Size Estimation Aneurysm may be detected and their size estimated by physical examination, routine roentgenography, abdominal crosssectional ultrasonography, digital subtraction angiography, abdominal aortic angiography, CT scan and MRI. In about 70% of cases, plain X-rays show a curvilinear or linear rim corresponding to the aneurysm wall. In fact aneurysm usually presents as a paravertebral soft tissue mass.With rupture, there is distortion of the psoas muscle shadow and absence of gas in the bowel over the aneurysm. Abdominal ultrasound is the most easily available and inexpensive way of detecting an aneurysm and assessing its size, wall thickness and presence of thrombus. Aortography is a risky procedure and is used in selective pre-operative cases to assess suprarenal extent of the aneurysm, any associated iliofemoral disease and for defining renal and mesenteric arterial anatomy. It may underestimate aneurysmal size in the presence of non-opacified mural thrombus lining its wall. CT scan is an extremely accurate method for both diagnosing and sizing the abdominal aortic aneurysms. MR angiography is also a highly effective method in delineating aneurysm anatomy pre-operatively and it is safe alternative to aortography. Pre-operative aortography is largely replaced by CT scan and MRI now-a-days considering their noninvasive nature and high sensitivity and specificity. Treatment Medical therapy with beta-blockers slows the expansion of aneurysm although its efficacy is less in aneurysm of bigger size. Aneurysmectomy and replacement by a synthetic

prosthesis, usually Dacron, is advised for all abdominal aortic aneurysms 6 cm in diameter or wider since three-fourth of them will rupture. Operative mortality is 4% to 6% in elective repair. The benefit of surgery for asymptomatic aneurysms 4 to 5 cm in size is not yet established. Complications of surgery include stenosis or occlusion of the prosthetic graft, false aneurysm formation, infection and rupture. Endovascular treatment in the form of percutaneously implanted expanding endovascular stents are new interventional options for the treatment of abdominal aortic aneurysms not suitable for surgery (older patients, patients at higher risk for surgery). Endoleaks (persistent residual flow in aneurysmal sac) are a major disadvantage with this option.

Diseases of the Aorta

Younger patients (50 years old or less) are more likely to be symptomatic. The most frequent complaint is a steady, gnawing pain in the hypogastrium or lower back, lasting for several hours or days at a time and not affected by movement. A pulsatile mass extending variably from the xiphoid process to the umbilicus may be felt. Stagnation of blood in the aneurysmal sac forms mural thrombus which may embolise to distal arteries leading to absence of femoral and lower limb pulses and bruits over affected arteries. Rarely, an expending aneurysm can compress inferior vena cava or one of the iliac veins to produce lower limb oedema and venous congestion.

THORACIC AORTIC ANEURYSMS Thoracic aortic aneurysms are divided according to anatomical location into ascending arch and descending aortic aneurysms, each differing in aetiology, natural history and therapy. Ascending aorta aneurysms most often result from cystic medial necrosis. Other causes are Marfan’s syndrome, syphilis, mycotic aneurysm secondary to aortic bacterial endarteritis and rarely atherosclerosis. Aortic arch aneurysms may be due to atherosclerosis, cystic degeneration, syphilis or other infections while descending aortic aneurysms are predominantly atherosclerotic. The basic pathogenetic mechanism is progressive dilatation of the aortic wall weakened by tunica media degeneration. Clinical Manifestations Forty per cent of the patients are asymptomatic and are diagnosed on incidental physical examination or X-ray. Symptoms reflect either a vascular consequence of the aneurysm or a local mass effect. Vascular consequences are aortic regurgitation and secondary congestive heart failure due to aortic root dilatation, myocardial ischaemia due to coronary artery compression by enlarged sinuses of Valsalva, rupture of sinus of Valsalva into the right heart producing continuous murmur with congestive heart failure and thromboembolism causing stroke, lower extremity ischaemia, renal infarction or mesenteric ischaemia. Local mass-effects depend on anatomical location. Ascending aortic aneurysm may cause superior vena cava syndrome due to compression of the superior vena cava. Arch aneurysms cause superior vena cava syndrome; tracheal or main stem bronchus obstruction leading to wheeze, cough, dyspnoea (may be positional), haemoptysis and recurrent pneumonitis. Descending aortic aneurysms may cause trachea or main stem bronchus compression, oesophageal compression producing dysphagia or recurrent laryngeal nerve compression producing hoarseness. Steady, deep, boring and sometimes excruciating chest or back pain develop due to compression of intrathoracic structures or due to erosion of adjacent bone. Aneurysms eroding through the chest wall are visible as pulsating masses. The most serious consequence of thoracic aneurysm is rupture that is heralded by sudden increase in the intensity of pain. Rupture most commonly occurs into the left intrapleural space or the intrapericardial space and presents as hypotension. Next common site is the oesophagus that presents as life-threatening haematemesis. Thoracic aneurysm may also develop aortic dissection.


Diagnosis Many thoracic aneurysms, except for smaller ones, are evident on chest X-ray. Transthoracic Echocardiography (TTE) is useful in the imaging of aortic valve and proximal aortic root. Transoesophageal Echocardiography ( TEE) can help in assessment of aneurysm of ascending and descending aorta but it cannot visualise aneurysm of the arch. Contrast CT-scan and MR angiography are very accurate in detecting and sizing aneurysms. Aortography was a preferred pre-operative modality to define the anatomy of the aneurysm. However, as in the case of abdominal aorta, CT and MR angiogram are now often sufficient in most of the cases to define aortic and branch vessel anatomy. MR angiography is preferable to CT scanning when the aortic root is involved. Treatment Medical therapy is directed towards risk factor reduction and control of blood pressure. Aneurysmectomy and replacement by a prosthetic sleeve or composite graft-valve (in case of ascending aorta) is indicated for aneurysms 6 cm or larger; however, in case of Marfan’s syndrome, bicuspid aortic valve or rapidly growing aneurysms, early surgery is indicated. Propranolol may be used to delay the surgery in smaller aneurysms. Surgical repair of arch aneurysms is particularly challenging with high incidence of stroke. Descending thoracic aneurysmectomy may produce post-operative paraplegia due to interruption of spinal cord blood supply. Transluminally placed endovascular stent grafts is an alternative approach for treating descending aneurysms in patients with higher risk for surgery. DISSECTION OF THE AORTA Aetiopathogenesis Aortic dissection is initiated by entry of blood through an intimal tear into a degenerated tunica media of the thoracic aorta. The medial degeneration may occur due to classical cystic medial necrosis or connective tissue disorders like Marfan’s or EhlersDanlos syndrome. The blood jet divides the media into two producing a false lumen.The inner portion of the dissected wall forms an intimal flap. The intimal flap may be pushed into the true lumen, by the false lumen distended with blood, or it may be torn open by the blood jet producing an exit site. Old age (50 to 70 years), female sex, pregnancy, hypertension, bicuspid or unicuspid aortic valve, giant cell arteritis, Noonan and Turner syndromes and cocaine abuse may predispose to dissection. Aortic dissection occurs at a rate of 5 to 10 cases per million population per year. Classification (Figure 2) DeBakey classification Type I: Begins in the ascending aorta and extends to the descending aorta and arch. Type II: Confined to the ascending aorta. Type III: Originates in the descending aorta and extends distally or rarely, retrograde into arch and ascending aorta.


Stanford classification Type A: All dissections involving the ascending aorta, regardless of the site of origin. Type B: All dissections not involving the ascending aorta.

Figure 2: Schematic diagram of classification of aortic dissection.

Descriptive classification Proximal: DeBakey types I and II or Stanford type A. Distal: DeBakey type III or Stanford type B. Proximal dissections are twice more common and more lethal than distal dissections. Clinical Picture A tearing, ripping or severe stabbing pain, from its initiation and with a tendency to migrate from its point of origin to other sites following the course of dissection is typically present in majority of cases except for those with chronic dissections. Severe pain from onset differentiates it from myocardial infarction. Anterior chest pain or neck, throat, jaw or face pain usually signifies ascending aorta involvement and interscapular or back, abdomen or lower limb pain that of descending thoracic aorta. Obstruction of the branches by compression of the true lumen by the distended false lumen or by obstruction of the vessels orifices by a mobile intimal flap may produce pulse deficits, pseudohypotension, syncope, cerebrovascular accident, cardiac arrest or sudden cardiac death, ischaemic peripheral neuropathy and paraplegia. Pulse deficits and neurological manifestations are more common in proximal dissection. Hypertension is seen in 80% to 90% of distal dissection and hypotension is more common in proximal dissection. Aortic regurgitation due to dilatation of aortic root and annulus, detachment of aortic leaflet or prolapse of a mobile intimal flap through aortic orifice is the characteristic of proximal dissection and results in congestive cardiac failure. The murmur has a musical quality and radiates along the right sternal border. Syncope without a focal neurological sign heralds rupture of a proximal dissection into pericardial sac producing cardiac tamponade or that of distal dissection into the intrapleural space. Investigations Anaemia may develop from significant haemorrhage or sequestration of blood in the false channel. A mild-tomoderate polymorphonuclear leucocytosis (10,000-14,000/ mm3) is common. Lactate dehydrogenase (LDH) and bilirubin levels are sometimes elevated. Serum glutamic oxaloacetic transaminase (SGOT) and CK-MB are usually normal, unless associated myocardial infarction develops along with

TTE is a useful tool for the diagnosis of ascending aortic dissections. However, it is limited by its inability to show the distal extent. TEE is highly sensitive and specific for evaluating proximal aortic dissection. Development of helical CT with multiplanar and 3D reconstruction and CT angiography has made CT scan a highly sensitive (83% to 94%) and specific (87% to 100%) mode for diagnosis of aortic dissection. It is fast replacing the conventional angiography (Figures 3A and B and Figure 4) as a standard diagnostic test in many centres. MRI although highly sensitive and specific it is used preferably for chronic aortic dissection and post surgical follow-up. Treatment Therapy is aimed at halting the progression of the dissecting haematoma. Without treatment 25% of the patients die within

Figures 3A and B: Aortogram showing aortic dissection. (A) pre-stenting and (B) post-stenting.

24 hours, more than 50% within the first week, 75% within one month, and more than 90% within one year. Early emergency treatment All patients should be admitted immediately to an intensive care unit. Initial therapeutic goals are the elimination of pain and reduction of systolic blood pressure to 100 to 120 mm Hg with a potent vasodilator like sodium nitroprusside. Nitroprusside when used alone can cause increase in the dp/dt so it should be used with a beta-blocker.

Diseases of the Aorta

dissection. ECG abnormalities are particularly common in Stanford type A aortic dissections. ST depression is most common abnormality. Sometimes, patients present with inferior wall MI due to involvement of right coronary sinus. Chest X-ray may reveal widening of the aortic arch in 40% to 50% of cases, change in configuration of the aorta on successive X-ray, obliteration of the aortic knob with displacement of the trachea to the right, localised hump on the aortic arch and an increase in distance from intimal calcification to the outer edge of the aortic shadow of > 1 cm (calcium sign).

Propranolol is used in incremental doses of 1 mg intravenous every five minutes until there is an evidence of satisfactory betablockade, usually indicated by a pulse rate of 60 to 80 beats/ min. Labetalol and esmolol can also be used in this setting. Patients who have contraindication for beta-blocker therapy should be put on cardioselective calcium channel blockers. In chronic stable dissection propranolol is given orally in dose of 20 to 40 mg six hourly. Definitive subsequent therapy Results of surgical therapy is superior to medical therapy in acute (< 2 weeks) proximal dissection and, conversely medical therapy offers a relative advantage over surgery in most cases of uncomplicated acute distal dissection (Table 1). Table 1: Indications for Definitive Therapy in Aortic Dissection Surgical Treatment of choice for acute proximal dissection Treatment of choice for acute distal dissection complicated by progression with vital organ compromise Rupture or impending rupture Aortic regurgitation (rare) Retrograde extension to the ascending aorta Dissection in Marfan’s syndrome Medical Treatment of choice for uncomplicated distal dissection Treatment for stable, isolated arch dissection Treatment of choice for stable chronic dissection (uncomplicated dissection presenting two weeks or later after onset)

Long-term medical therapy to control hypertension and reduce dp/dt is indicated for all patients regardless of whether they have received definitive surgical or medical therapy. Follow-up of patients should include repeated physical examinations, periodic chest X-rays, CT scans or digital substraction angiograms (DSA) for evidence of localised aneurysm formation. MRI also promises to be a valuable tool for follow-up. INTRAMURAL HAEMATOMA It is an acute aortic syndrome which is typically characterised by haemorrhage within medial layer of aortic wall, but unlike classic aortic dissection, there is no evident tear in intimal layer. It is proposed that it results from the rupture of vasa vasorum within aortic wall although some believe that it results from intimal tear which is too small to be visualised. The risk factors, signs and symptoms resemble classic aortic dissection. Among the various available diagnostic modalities CT scan is the most preferred diagnostic tool to visualise the intramural haematomas.

Figure 4: Aortogram showing dissection of aorta.

The natural history of intramural haematoma is debatable but they can proceed in four possible ways absorption of


haematoma, persistence of haematoma, development of aortic aneurysm, and conversion to classic aortic dissection. Treatment of this aortic syndrome is similar to classic aortic dissection in the sense that proximal aortic intramural haematoma should be operated while distal intramural haematoma should be managed medically. AORTO ARTERITIS (TAKAYASU’S ARTERITIS) Takayasu’s arteritis (TA) is a chronic inflammatory disease of the aorta and its major branches. Though the disease was named after him,Takayasu was not the first to describe this disease entity. ‘Pulseless’ disease was reported by Adams way back in 1827. In 1908, Takayasu described a peculiar ‘wreath-like’ appearance of arteriovenous anastomosis around the optic papilla. The disease has a worldwide distribution, though the majority of cases are seen in Japan, India, South Africa, Mexico and parts of South America. Mongoloid races are affected the most, followed by the Indo-Aryan. The disease predominantly affects young females. The female: male ratio being 7:1 in Japan, 5:1 in Mexico and 3:1 in India. Aetiopathogenesis The specific cause of the disease is not known, though the bulk of evidence favours an autoimmune aetiology. Association with rheumatic fever, streptococcal infection, rheumatoid arthritis, other collagen vascular disease and tuberculosis were described. The disease has two stages. The early active phase, there is non-specific granulomatous panarteritis involving all the layers of the wall of the aorta and its branches but unlike other forms of the aortitis, pulmonary artery may be involved in this disease. The disease progresses variably to a chronic sclerotic phase, characterised by intimal hyperplasia leading to purely stenotic lesion in 85% of the patients, purely dilatative in 2% and mixed lesion in 13% of the patients. Classification Lupi-Herrera et al in 1977, described four varieties of disease based on predominant site of involvement:Type I (Shimizu-Sano) aortic arch and its branches (Figure 5); Type II (Kimoto) thoracoabdominal aorta and its branches; Type III (Inada) combinesfeatures of both Type I and Type II; and Type IV (Oata) pulmonary artery (Figure 6). Another variety of arteritis is proposed as Type V aorto-arteritis associated coronary artery (Panja et al) (Figure 7). Criteria of American College of Rheumatology for the Classification of Takayasu Arteritis (1990) are given in Table 2.

Figure 5: Aortogram showing involvement of aortic arch with both common carotid arteries with aorto-arteritis.

Figure 6: Pulmonary artery involvement in a patient with aorto-arteritis.

Clinical Manifestations The disease affects teenagers in three-fourths of cases, though no age is immune to this disease. More than half of the patients present with features of active disease viz. fever, anorexia, malaise, weight loss, night sweats, arthralgias, pleuritic pain and fatigue. Localised pain and tenderness may be noted over the affected arteries. Occasionally, it may present as fever of unknown origin. In the sclerotic phase, the manifestations include diminished or absent pulses in 96%, bruits in 94%, hypertension in 74% and heart failure in 28% patients. Retinopathy leading to retinal detachment and loss of vision is seen in 25% of the cases. 754

Patients with types I and III disease present as ‘reverse coarctation’ manifested by absent or diminished pulse and

Figure 7: Severe coronary artery involvement in a patient of aorto-arteritis.

Hypertension, a major complication of this disease, arises due to renal artery stenosis (35.85%) (Figure 8), involvement of baroreceptors by aortitis, loss of elasticity of aorta and coarctation like lesion. Congestive heart failure occurs due to hypertension, dilated cardiomyopathy or more rarely aortic regurgitation. Coronary artery involvement may cause angina, myocardial infarction. Pulmonary artery involvement may result in a clinical picture similar to primary pulmonary hypertension. Investigations During the systemic phase, elevated ESR, low-grade leucocytosis and mild anaemia of chronic disease are frequent. IgG or IgM values are elevated in more than half of the patients. C-reactive protein may be elevated with increased anti-streptolysin titre, rheumatoid factor, anti-endothelial antibodies and elevated fibrogen levels. Chest X-ray is usually unrevealing although a rim of calcification is sometimes seen in the walls of the affected arteries. Arteriography reveals irregular intimal surface with stenosis of the aorta or its branches, post-stenotic dilatation, saccular aneurysm and even complete occlusion of vessels. The affected thoracic aorta has been described as having a rat-tail appearance. Arterial biopsy may be positive in 20% to 35% of the cases. Gallium-67 radionuclide scan may demonstrate uptake in aorta and its branches. High resolution ultrasono-graphy is useful in monitoring disease of common carotid and subclavian arteries. MRI, MR angiography and CT scan are useful for serial examination and diagnosis in early phase of Takayasu arteritis.

Use of contrast may reveal inflammatory lesion prior to development of stenosis. Ishikawa and American College of Rheumatology have proposed criteria for the diagnosis of Takayasu arteritis (Table 2). Table 2: 1990 Criteria of American College of Rheumatology for the Classification of Takayasu Arteritis Criteria


Diseases of the Aorta

blood pressure in the upper limbs, bruits over diseased arteries and syncope. Type II disease is manifested by abdominal angina, claudication of limbs and hypertension due to renal artery involvement.

Age of onset

Development of symptoms or findings related to Takayasu arteritis at age 10 mm Hg in systolic pressure between arms Bruit Bruit audible on auscultation over one or both subclavian arteries or abdominal aorta Arteriogram Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibro-muscular dysplasia, or similar causes: changes usually focal or segmental

For purposes of classification, a patient shall be said to have Takayasu’s arteritis if at least three of these six criteria are present. The presence of any three or more criteria yields a sensitivity of 90.5% and a specificity of 97.8%. Natural History The disease is basically progressive, though the rate of progression varies considerably. The cause of death is usually heart failure, encephalopathy, renal failure, rupture of aneurysms and cerebral haemorrhage.

Figure 8: Bilateral renal artery involvement with left common iliac artery involvement in patient with aorto-arteritis.

Treatment Medical treatment is recommended for those suffering from active and early lesions, those in whom surgery is not possible or considered too risky because of extensive and multifocal involvement of the arterial tree and where surgery is contraindicated due to uncontrollable congestive cardiac failure or progressive renal failure. Steroids are often effective in relieving the constitutional symptoms. Cyclophosphamide, cyclosporine, mycophenolate mofetil and methotrexate can be tried in cases which fail to respond to steroids. Etanercept and infliximab may be used for inducing clinical remission in steroid-dependent patients. Anticoagulant anti-platelet and drugs like warfarin, aspirin and dipyridamole are recommended to treat transient ischaemic symptoms and to prevent progression. Aggressive treatment of hypertension is important. Surgical treatment for late complications includes endarterectomy, bypass of obstructed arteries especially renal arteries, resection of localised coarctation, excision of saccular aneurysms and rarely aortic valve replacement.


Percutaneous transluminal coronary angioplasty (PTCA) with or without stenting has emerged as a useful effective and less invasive therapeutic option for Takayasu’s disease. This option is especially effective for discrete lesions. CARDIOVASCULAR SYPHILIS It is very rare as a result of aggressive antibiotic treatment of syphilis in its early stages. Cardiovascular complications occur in approximately 10% of cases of untreated syphilis. The latent period may extend from 5 to 40 years, with a usual time of 10 to 25 years. During the secondary phase of the disease the bacteria directly invade the aortic media. The direct infection and subsequent inflammatory response cause destruction of muscular and elastic media followed by its fibrosis. Clinical Manifestation In the absence of’ aortic regurgitation an aneurysm may undergo significant enlargement without producing symptoms. Eventually it may expand to compress and erode contiguous structure, particularly the sternum and the anterior right thoracic cage. This causes pain at the point of involvement. Ascending aortic aneurysms and those involving the arch may cause a tracheal tug, stridor and dysphagia. There may be hoarseness due to compression of the left recurrent laryngeal nerve and cough from pressure against the left main stem bronchus. Patients may have anginal symptoms due to associated stenosis of the coronary ostia. Diagnosis There is a history of syphilis and other manifestations of tertiary syphilis in 10% to 30% of cases. About 15% to 30% of patients have negative routine serological tests for syphilis (Wassermann, Kahn and VDRL). Serological tests directed against a specific treponemal antigen are almost invariably positive. The chest Xray may show calcification in the ascending aorta proximal to the brachiocephalic vessels. Angiography may delineate the aneurysm and help to quantify the severity of aortic regurgitation. In patients suspected to have coronary ostial stenosis and in patients where surgical correction is contemplated, the coronary artery anatomy, and particularly the ostia, should be visualised by coronary angiography. CT and MRI are quite helpful in evaluating the aneurysm. Treatment All patients who are seen one year or more after the initial contact should be given a course of antibiotic therapy, i.e. injection benzathine penicillin 2.4 million units IM weekly for three weeks. For patients allergic to penicillin, tetracycline 500 mg four times daily for 30 days is recommended. GIANT CELL ARTERITIS This disease is found predominantly in elderly people and characteristically involves medium-sized arteries. The aorta and its branches are affected in about 15% cases. The aetiology of giant cell arteritis is unknown. However, the possibility of an


autoimmune or infectious origin has been considered. The typical pathological lesion is granulomatous inflammation of the media of small-to-medium calibre arteries about the size of the temporal artery, with a special predilection for the vessels of the head and the neck. Clinical Manifestations It typically affects patients over the age of 50 years and occurs predominantly in females. The typical presentation consists of fever, malaise and headache. Other constitutional symptoms include anorexia, weight loss, myalgias, night sweats and lassitude. Headaches are often intense and unbearable and occur over the involved arteries, usually the temporal arteries, but occasionally over the occipital region. Blindness may occur due to involvement of the ophthalmic artery. The syndrome of polymyalgia rheumatica is seen in nearly 40% of these patients. Physical examination reveals the patient to be febrile. The involved vessels are thickened and tender, pulse may be lost and bruits may be heard over the sites of arterial occlusion. Investigations A high erythrocyte sedimentation rate (ESR) is virtually inevitable, normocytic, normochromic anaemia may be present. Antinuclear antibody and rheumatoid factor are not found. The diagnosis is usually confirmed by biopsy of the temporal artery (TA). Colour duplex ultrasonography of TA is a promising alternative for temporal artery biopsy. Angiography may help to confirm the diagnosis in cases of larger vessel and aortic involvement. CT, MRI are used as second-line diagnostic procedure. Treatment Treatment consists of prednisolone 60 to 80 mg per day for 1 to 2 years. With ESR as guide, steroid may be tapered to a maintenance dose of 5 to 15 mg per day for 1 to 2 years. Cyclosporine and azathioprine or cyclosporine and methotrexate are used in steroid-resistant cases. The overall prognosis with treatment is good. OTHER ARTERITIS SYNDROMES These may be seen in association with ankylosing spondylitis, psoriatic arthritis, ulcerative colitis, and Reiter’s syndrome. AORTIC TRAUMA Aortic injuries may occur with severe blunt trauma as in motor vehicle accident, blast injuries, crush injuries and severe falls. The most common site of tear is the aortic isthmus just distal to the origin of the left subclavian artery. Other sites include the supravalvular portion of the ascending aorta, the aortic arch, the innominate artery, abdominal aorta and combinations of these. RECOMMENDED READINGS 1.

Jonathen L Halperin, Jeffery W Olin. Diseases of Aorta. In: Valentine F, Alexander WR, Robert A; editors. Hurst’s The Heart 11th Ed. McGraw Hill Publication House; 2004; 230:1-22.


Isselbacher ME. Diseases of Aorta. In: Zipes DR, Libby P, Bonow 0R, Braunwald E; editors. Braunwald’s Heart Disease. 7th Ed. Elsevier Saunders; 2005: 1403-36.


Vascular Disorders of the Extremities

INTRODUCTION Vascular disorders of the extremities can involve the arterial, venous or the lymphatic systems. These are generally more common in the lower limbs than in the upper limbs. These disorders can have an acute onset or may develop chronically. The diagnosis is made in most cases by a thorough clinical, ultrasonographic and Doppler evaluation. These abnormalities can be primary in origin or they may be manifestations of a systemic disorder. ARTERIAL DISORDERS Vascular occlusion, acute or chronic, is the major arterial disorder of the extremities. Table 1 outlines the arterial disorders. Table 1: Classification of Arterial Disorders Occlusive Acute occlusion (embolic, thrombotic, traumatic) Chronic occlusion (Atherosclerotic, Takayasu’s arteritis) Gangrene Wet (due to acute occlusion) Dry (due to chronic occlusion) Aneurysm Arteriovenous fistula Thromboangiitis obliterans (Buerger’s disease) Vasospastic disorders Raynaud’s disease Livedo reticularis Acrocyanosis

Chronic Arterial Occlusion It presents less dramatically than acute occlusion and is much more common. Atherosclerotic peripheral arterial disease (PAD) affects the leg eight times more often than the arm. The pathophysiology of PAD is similar to coronary artery disease. The most important risk factors are smoking, diabetes, hyperlipidaemia and hypertension. The clinical manifestations depend on the anatomical site, the presence or absence of collateral supply, the rapidity of onset and the occurrence of external trauma. Takayasu’s arteritis (pulseless disease) is another common cause of chronic PAD involving the aorta and its major arteries. Most commonly upper limb vessels are affected. Its prevalence is high in young women of Indian, Japanese and Mexican descent. There is a panarteritis in the acute stage, culminating in fibrotic occlusion in the chronic stage. No definitive therapy is available for this disease. However, in acute stage steroids are of some use. Vascular interventions (balloon angioplasty and metallic stents) are often used with variable results. In Indian subcontinent, diabetics form the largest group of patients with atherosclerotic PAD. The occlusive disease in diabetics is more extensive and complicated due to associated

Gurpreet Singh Wander, Bishav Mohan neuropathy and increased risk of infection. Most patients with chronic PAD have bad prognosis due to associated coronary and cerebral atherosclerosis. Diabetic foot is one of the dreaded complication with high rate of amputation. This can be managed with combined approach of preventive measures (education, foot care, special shoes) and treatment strategies (angioplasty ± stents). These have reduced the below knee amputation rate. Patients often present with intermittent claudication when the limb ischaemia is less critical. This is a cramp-like pain felt in the calf muscles, brought on by walking and relieved on standing still. The distance walked is called ‘claudication distance’ and is relatively constant for a patient. Patients with critical limb ischaemia (CLI) are defined as those with rest pain that is felt in the foot at rest and made worse by lying down or elevation of the foot. Characteristically, the pain is worse at night and relieved by hanging the foot out of the bed. Other changes include coldness, numbness, paraesthesias and colour change (ischaemic limbs become blanched on elevation and develop a purple discolouration on dependence). Severe arterial insufficiency can result in painful superficial erosions between the toes, on the dorsum of feet and around the malleoli. Later, this can progress to ulceration and frank gangrene (Figure 1). A severely ischaemic foot is frequently paralysed and cold but may feel warmer as it takes on the temperature of its surroundings. In the upper limb, atheromatous occlusive disease can involve subclavian artery and may cause claudication and rarely frank ischaemia of an arm.The subclavian lesion may also cause distal embolisation and consequent loss of digits. Subclavian steal syndrome may occur if the first part of the subclavian artery is obstructed and the vertebral artery provides a collateral circulation into the arm by reversing its direction of blood flow. The classic syndrome of syncopal attack and visual disturbance associated with arm exercise and a diminished blood pressure in the affected limb is rare. Asymptomatic reversal of flow in the vertebral artery recognised by duplex scanning or angiography is much more common. Relevant investigations include tests for diabetes mellitus, lipid abnormalities and anaemia. Doppler ultrasound is a very sensitive type of stethoscope that can be used in conjunction with a sphygmomanometer to assess the systolic pressure in relatively small vessels. Ankle: brachial pressure index (ABPI) is the ratio of systolic pressure in the ankle to that in the arm. Values under 0.9 indicate mild ischaemia whereas < 0.5 indicate severe ischaemia. Duplex imaging combines B-mode ultrasound with Doppler ultrasound to give detailed knowledge about vessel-wall thickness, blood flow and turbulence. The ‘gold standard’ for arterial occlusive disease is angiography, which involves the injection of radio-opaque dye in the vessels


performed by inserting a balloon catheter into an artery and inflating it within a narrowed or blocked area. In certain cases, a metallic stent may need to be inserted to keep the lumen patent (Figures 2Ato C, and Figures 3A and B). In feasible cases, a surgical vascular bypass may be performed around the occluded part of the vessel to permit distal perfusion.The long-term results of reconstructive aortoiliac surgery are good and they are usually only marred by a progressive disease producing femoro-popliteal occlusions at a later stage. Stem cell therapy (therapeutic angiogenesis) has generated a lot of interest. However, the results need to be documented in large randomised control trials.

Figures 2A to C: (A) Bilateral common iliac stenosis, (B) Stents placed in both common iliac arteries, (C) Post-stenting angiogram showing normal flow.

Figure 1: Patient with chronic arterial occlusion of left lower limb showing discolouration of left foot, thinning of ankle and foot, and dry gangrene of distal digits.

and then using a real time or single shot X-ray to detect the status of the vessels. Digital subtraction angiography (DSA) helps in better delineation of the vessels by subtracting the images of overlying tissues. More recently, ultra fast CTangiography done by injection of intravenous contrast helps in studying the arterial tree without the need for arterial injection as in conventional angiography. Renal function test should be done before sending the patient for contrast imaging. Magnetic resonance angiography (MRA) provides multiplanar imaging without the need of ionising radiation.


Arterial occlusive disorders can be managed conservatively in most cases. Encouraging exercise within the limits of disability is a good way of increasing exercise capacity. Spontaneous improvement occurs after a few months due to formation of collaterals. Drugs that have a role in occlusive arterial disorders include those for underlying diabetes, hypertension and lipid abnormalities. Antiplatelet agents like aspirin (75 to150 mg od) or clopidogrel can be used. Cilostazol, a phosphodiesterase inhibitor with vasodilator and antiplatelet properties has been shown to improve claudication distance. Naftidrofuryl oxalate may alter tissue metabolism, thus increasing claudication distance. Pentoxifylline improves RBC rheology (flexibility) and has some blood thinning capacity, thus helping to improve circulation. Prostacyclins may have some minor role in the management of the critically ischaemic limb. Lumbar sympathectomy has been used for pain relief. In vessels with localised blocks, transluminal angioplasty and stenting may be

Figures 3A and B: (A) Angiogram showing stenosis in the peroneal artery, (B) Post-angioplasty angiogram showing normal flow.

Acute Arterial Occlusion Sudden occlusion of an artery may be due to emboli from a remote site, thrombus formation on a pre-existing atheroma or trauma (Figures 4A and B). The emboli can arise from an atrial source as in atrial fibrillation or left ventricular mural thrombus following myocardial infarction. These tend to lodge at vessel bifurcation. Acute occlusion is an emergency and threatens limb viability. It needs immediate diagnosis and early management since delay can compromise limb viability.

Figures 4A and B: This patient presented with a tibial fracture and absent distal pulses: (A) Angiogram showing sudden cut-off of arterial blood flow at the level of the fracture; (B) After stabilisation of the fracture, injection of local vasodilators and ballooning of the blocked segment, flow is restored.

Vascular Disorders of the Extremities

The classical signs in the lower limb are the 6 P’s – pain, pallor, paresis, pulselessness, paraesthesia and poikilothermia. The limb is cold and, almost immediately, the toes cannot be moved. Sensation to touch is soon lost and distal pulses become impalpable. B-mode ultrasound imaging shows lack of pulsation in arteries and Doppler confirms the diagnosis by showing lack of blood flow. Appropriate treatment is the immediate intravenous administration of heparin. This can halt the extension of the thrombus and maintain patency in the surrounding vessels. Pain relief is essential because pain is severe and constant. Surgical embolectomy for larger vessels till the popliteal artery is the treatment of choice when done within 12 hours of ischaemia. Thrombolysis using streptokinase or urokinase is preferred for distal vessels. This has to be done within 6 to 12 hours to preserve limb viability. Patients presenting late often go on to develop gangrene of the distal toes and the feet. Gangrene The combination of rest pain, colour changes and hyperaesthesias with or without ischaemic ulceration is frequently referred to as pre-gangrene. Gangrene implies death of macroscopic portions of tissue. It is commonly seen affecting the distal part of the limb. A gangrenous part lacks arterial pulsation, venous return, capillary response to pressure (colour return), sensation, warmth and function. The colour changes from pale through dusky-gray to mottled until finally taking on the characteristic dark brown, green-black or black appearance. Dry gangrene This occurs when the tissues are desiccated by gradual occlusion of the vessels. It is typically due to atheromatous occlusion of the arteries. The affected part becomes dry and wrinkled, discoloured and greasy to touch. Wet gangrene This occurs when the artery is suddenly occluded and there is venous obstruction as well. Infection and putrefaction are present and the affected part becomes swollen and discoloured and the epidermis may be raised in blebs. Crepitus may also be palpated (Figure 5). Treatment includes general measures like hydration, pain control and control of infection. Once gangrene has set in, the reestablishment of blood flow by percutaneous intervention or surgery does not help. Unviable portions of tissue need to be amputated to relieve pain and prevent the spread of infection and gangrene. Aneurysm An aneurysm is a localised dilatation of a segment of the arterial system. Aneurysms can be true (involving the vascular intima, media and adventitia) or false (with a fibrous wall). In appearance, they may be fusiform, saccular or dissecting. Aetiology can be atheromatous, traumatic, syphilitic or due to collagen disease. These can present due to expansion, thrombosis or embolisation. Intrinsically, a pulsatile swelling is present along the course of an artery, which diminishes on application of proximal pressure. The sac is usually compressible unless thrombosed. A thrill may be felt and a systemic bruit auscultated.

Figure 5: Wet gangrene of both lower limbs due to acute arterial occlusion with blebs, denuded skin and blackish discolouration of both feet.

Extrinsically, pressure on veins or nerves may cause distal oedema or altered sensation. Arteriovenous Fistula This is a communication between an artery and vein. This may be congenital or acquired due to surgical trauma and catheter access. AV fistulas may also be created in the upper limb to facilitate haemodialysis. Haemodynamically significant fistulas may lead to a wide pulse pressure and a thrill is present. A continuous bruit can be heard over the fistula. Pressure on the artery proximal to the fistula may cause the swelling to diminish, the thrill and bruit to cease and the pulse rate to fall (Nicoladoni’s or Branham’s sign) and the pulse pressure to return to normal. Embolisation by autologous material (fat/muscle) or gelatine sponges, silicon spheres can obliterate the fistula. Large, painful or bleeding AV fistula can be managed surgically or with endovascular grafts/stents. Thromboangiitis Obliterans This involves occlusive disease of the small and medium sized arteries, thrombophlebitis of superficial and deep veins, and Raynaud’s phenomenon. It is also known as Buerger’s disease. It is most common in Asian males under the age of 30, generally smokers. Treatment is primarily cessation of smoking. This helps halt the progression of the disease but does not lead to reversal of the established occlusion. Sympathectomy for pain relief is also done. Stem cell therapy has also been tried. Vasospastic Disorders Raynaud’s disease It predominantly affects the upper limbs in young women. The peripheral pulses are normal. Due to an abnormal response to


cold temperature, the vessels constrict and then dilate. This produces a classic triphasic colour change; pallor, cyanosis followed by redness of the digits. This is often accompanied by pain. Raynaud’s syndrome shares the clinical features of Raynaud’s disease but is much more severe. It is generally a manifestation of collagen vascular disease. It may also follow the use of vibrating tools and is then known as ‘vibration white finger’. Treatment is primarily directed at the underlying condition. Calcium channel blockers may have a role in management. Livedo reticularis This involves purplish mottling of the skin due to spasm of dermal arterioles in lower extremities, especially on cold exposure. Acrocyanosis It is an uncommon condition seen in females and is characterised by bluish discolouration in hands and fingers. No specific therapy is required. VENOUS DISORDERS Blood returns from the limbs via the deep and superficial veins. In the upper limb, the superficial veins are more important. The superficial veins in the leg are the long and short saphenous veins, and they carry only 10% of the blood from the lower limbs. There is a foot-pump that ejects blood from the plantar veins as pressure is placed on the foot during walking. On exercise, the thigh and calf muscles contract compressing the veins and ejecting blood towards the heart. Venous valves control the direction of flow of blood in the veins. During muscle relaxation phase, the pressure within the calf falls to a low level and blood from superficial veins flows through the perforating veins into the deep veins. Venous diseases are of two main types; venous thrombosis and venous incompetence.

thrombosis in young patients. Common acquired thrombophilic states are previous surgery (especially orthopaedic like joint replacement), trauma, pregnancy, certain malignancies, stroke, heart failure, prolonged immobilisation and drugs such as oral contraceptives and hormone replacement therapy (Table 2). Long haul air travel has been associated with an increased incidence of DVT due to the immobilisation. Table 2: Predisposing Causes for Venous Thrombosis Hypercoagulable states Mutations of factor V (Leiden), prothrombin gene Deficiency of protein C, protein S, antithrombin III Antiphospholipid antibody Disseminated intravascular coagulation Surgery Orthopaedic, thoracic, abdominal Neoplasia Pancreas, lung, ovary, testes, breast Trauma Fractures, spinal injuries Immobilisation (any cause) Hormonal Pregnancy, oral contraceptives

The most significant clinical findings are tenderness in the calf and ankle oedema. Pain in the calf on dorsiflexion of the ankle (Homan’s sign) is rare and often misleading. Other signs and symptoms are swelling, pain, redness, dilated superficial veins and low-grade pyrexia (Figure 6). Some

Venous Thrombosis Venous thrombosis of the deep veins involves the lower limbs more frequently than the upper limbs. In most cases, deep vein thrombosis (DVT) is asymptomatic and resolves without sequelae. However, often patients are left with a postthrombotic limb that is persistently swollen, often complicated by venous ulceration. During the acute phase, DVT needs to be taken seriously since the thrombi can dislodge and embolise to the pulmonary circulation. A clot from the lower limb veins detaches from its site and passes via the inferior vena cava and right heart to the pulmonary arteries. It may totally occlude the perfusion to a part or all of one or both lungs. In 10% patients who die in the hospital, the cause of death is pulmonary embolism following a DVT.


The main causative factors are part of the Virchow’s triad; stasis (slowing of the blood flow), hypercoagulability (increased tendency to clot) and vessel wall damage (which releases thrombogenic substances). The term ‘thrombophilia’ implies an increased tendency for clotting, often for prolonged periods of time. This can be inherited or acquired. The common genetic causes responsible for venous thromboembolism are mutations involving factor V Leiden (20% to 40%) and prothrombin (6%) genes. Inherited deficiency of protein C (3%), protein S (3%) and antithrombin III (1%) have also been shown to lead to venous

Figure 6: Superficial and deep vein thrombosis of right leg showing oedema and calf swelling due to DVT. There is an accompanying superficial vein thrombosis as evidenced by the linear redness and swelling.

For diagnosis, a quantitative D-dimer analysis is done to measure the levels of fibrin degradation products. It is recommended to rule-out DVT in clinically suspicious patients. It is, however, not very specific and hence the value of a positive test is limited. The best method for diagnosis is B-mode and Doppler ultrasound in which we look for flow in the veins and augmentation on calf compression. Ascending phlebography is rarely done. Immobilisation is usually needed only for first 24 hours. Treatment involves anticoagulation after the diagnosis is made. Standard treatment involves unfractionated intravenous heparin (UFH) with dose adjusted according to activated partial thromboplastin time (aPTT). The onset of action is rapid and it is given for about 5 days. The aim is to minimise the risk of pulmonary embolism and to encourage the resolution of the thrombus. Subcutaneous injections of low molecular weight heparin (LMWH) are an alternative method and have been found to produce reliable anticoagulation.These are given twice daily and are easier to administer. They also do not require aPTT monitoring. Many LMWHs are now commercially available and are preferred over UFH nowadays. At the same time, the patient should be started on oral anticoagulants (e.g. warfarin, acenocoumarol) to reduce risk of recurrence of DVT. Duration of treatment is usually for 6 to 12 months. Patients who have inherited thrombophilia require lifelong anticoagulation. The effect of warfarin is monitored by measuring the international normalised ratio (INR), which should be prolonged to 2.0 to 3.0 times the control values. Inferior vena cava (IVC) filters are implanted in patients with contraindication to oral anti-coagulants (GI bleed), recurrent DVT and high risk DVT. Retrievable filters are preferred over permanent ones. Prevention of DVT can be done by both mechanical and pharmacological methods. Graduated elastic compression stockings have been shown to reduce the incidence of deep vein thrombosis. Intermittent pneumatic compression devices are used only peri-operatively. Pharmacological methods include UFH and LMWH. LMWHs are generally preferred. These are considered in all immobilised patients especially those with orthopaedic surgery, congestive cardiac failure and occlusive strokes. Prevention of thrombosis during long distance air travel requires the use of graduated compression stockings, exercise during the flight and avoidance of alcohol and sleeping tablets. Superficial Vein Thrombosis This is a frequent complication of varicose veins and may also follow cannulation of a vein for intravenous infusion. Spontaneous superficial thrombophlebitis may occur in the presence of polycythaemia, polyarteritis and Buerger’s disease and may also herald the presence of a visceral cancer. This condition does not carry the risks of deep vein thrombosis and is normally treated symptomatically with simple analgesics and anti-inflammatory drugs.

Axillary Vein Thrombosis This may occur following excessive exercise or as a complication of thoracic outlet syndrome. It is occasionally associated with a cervical rib. The arm becomes swollen and the superficial veins become distended. Early treatment with anticoagulants may result in rapid resolution. In severe cases, the use of fibrinolytic therapy, streptokinase or TPA may be considered. Definite treatment of thoracic outlet syndrome by surgical decompression of the subclavian may be needed, e.g. by resection of the first rib. Venous Incompetence Unidirectional venous flow requires the competence of the valves in the superficial and deep veins as well as the venous perforators. Dysfunction of these valves leads to venous incompetence and varicose veins. The incidence of varicose veins in developing countries is lower than in the western nations due to genetic, lifestyle and dietary differences. Varicose veins develop more frequently in people who stand during their work and during pregnancy under the influence of oestrogen and progesterone.

Vascular Disorders of the Extremities

patients with DVT may have no symptoms in the leg but initially present with sudden onset dyspnoea due to pulmonary embolism.

Symptoms include tiredness, aching, tingling, ankle swelling and a cramping sensation in the legs, which progressively worsen towards the end of the day and are relieved by elevating the leg. Patients with more severe venous disease may notice skin changes. Some patients may be asymptomatic and may present for cosmetic reasons. On examination, there is an increase in size of the calf muscles, ankle oedema, and skin complications like brown pigmentation, eczema and severe ulcerations. Later on, lipodermatosclerosis may develop. Contraction of the skin and subcutaneous tissue is seen and the ankle becomes narrow. A combination of narrow ankle and prominent calf is often referred to as a champagne bottle leg. Venous ulceration may also develop in these areas. Diagnosis can be made by a thorough clinical examination and Doppler ultrasound evaluation. The treatment depends on the size of the varices, their extent and the symptoms they produce. Compression stockings are used in early stages of disease. Injection sclerotherapy involves the injection of an irritant solution, sodium tetradecyl. Surgical treatment involves the ligation of the source of reflux (usually the saphenopopliteal or saphenofemoral junction) and removal of the incompetent saphenous trunks and the associated varices. Endovenous radio frequency and laser ablation have been used in patients with persistent symptoms and/or who develop ulceration. LYMPHATICS DISORDERS Lymphatic system is composed of interstitial fluid that bathes tissues of the body, lymphatic capillaries that collect interstitial fluid, transporting vessels and the lymph nodes. The lymphatic capillaries absorb interstitial fluid and empty into transporting vessels, which traverse the extremities and join with the visceral channels to form the cisterna chyli adjacent to the upper abdominal aorta.These pass through the diaphragm to become the thoracic duct. The thoracic duct empties into the left 761

subclavian vein. A separate smaller right lymphatic duct drains the right upper extremity and neck, and enters the right subclavian vein. Normally between 2 litres and 4 litres of interstitial fluid is filtered each day and returned to the vascular system by the lymphatic system. Diseases of the lymphatics include lymphoedema due to lymphatic obstruction, lymphangiomas and tumours. Lymphoedema Lymphoedema is caused by excessive accumulation of interstitial fluid in the extravascular, extracellular fluid compartment due to defects in the lymphatic transport system. Inadequate removal of the interstitial fluid by the lymphatic system may be the result of absent hypoplastic or obstructed lymphatic vessels. In the limb, interstitial fluid accumulates mainly in the cutaneous tissues and presents as a swollen extremity. In the early stages, the oedema is pitting but later it typically becomes non-pitting. The skin becomes thickened, hypertrophic and hyperkeratotic. It should be distinguished from other causes of unilateral leg swelling such as DVT (Table 3). Lymphoedema may be primary or secondary (Table 4).

‘Lymphoedema precox’ presents at about the time of puberty and is the most common form of primary lymphoedema accounting for >80% of the cases. ‘Lymphoedema tarda’ refers to lymphoedema that appears at about the third or fourth decade of life. Secondary lymphoedema It is usually due to acquired lymphatic obstruction. The causes of obstructive lymphoedema are infiltration of regional lymph nodes by tumour, surgical excision of regional lymph nodes in the treatment of malignancy, repeated infections, inflammatory processes causing fibrosis and irradiation. In tropical and subtropical countries infestation by filarial parasites is the most frequent cause of secondary lymph-oedema. Eight filarial species infect humans out of which only two; Wuchereria bancrofti and Brugia malayi are found in India and South-East Asia. W. bancrofti is the most widely distributed human filarial parasite. In India, the disease is rampant in Uttar Pradesh, Bihar, Andhra Pradesh, Orissa,Tamil Nadu, coastal Kerala and Gujarat.Tuberculous lymphangitis may also cause lymphoedema. In Western countries lymphoedema occurs most commonly in the arm after surgical excision of lymph nodes for carcinoma of the breast.

Table 3: Differences Between Swelling of the Extremity Due to Lymphatic and Venous Obstruction Lymphatic Obstruction

Venous Obstruction

Swelling typically involves the distal aspect of the extremity and characteristically involves the dorsum of the feet and toes

Swelling is present distal to the site of obstruction and uniformly involves the extremity uniformly

Swelling is usually painless. Pain and redness occur only if there is associated cellulitis

There is pain, redness and dilated superficial veins in the affected extremity

Oedema is pitting in nature and responds to limb elevation, however later on it characteristically becomes non-pitting and does not respond to limb elevation

Oedema is pitting in nature in the initial phase and responds to limb elevation

Due to lymphoedema, skin becomes thickened, hypertrophic and then hyper-keratotic

Due to increase in foot vein pressure, skin around the ankle becomes pigmented due to leakage of blood and fibrin into the surrounding tissues. With passage of time, the skin becomes eczematous and ulcerated

Table 4: Types of Lymphoedema Primary Lymphoedema congenita Lymphoedema precox Lymphoedema tarda Secondary Filariasis Tuberculosis Neoplasia Recurrent lymphangitis Surgery Radiotherapy

Primary lymphoedema This is relatively uncommon and often associated with inherited disorders like Turner’s and Klinefelter’s syndromes. ‘Lymphoedema congenita’ is a severe form of lymphoedema that is usually apparent at birth or during early infancy. Familial cases are termed as Milroy’s disease. These patients have associated lymphatic abnormalities such as intestinal and pulmonary lymphangiectasia. 762

Lymphangiography is used to diagnose lymphoedema and to demonstrate the nature of lymphatic abnormality. However, as this procedure is invasive and because of the risk of oil embolism, it is being replaced by isotope lymphangiography. MRI imaging has also been employed to investigate the lymphatic system. Treatment includes prolonged bed rest, limb elevation, elastic stockings, meticulous skin hygiene, avoidance of local injury and prompt treatment with antibiotics if cellulitis occurs. Surgery is reserved for those with severe disabling lymphoedema. It includes the excision of hypertrophic tissue, pedicle transfer of normal lymphatic bearing tissue and microvascular bypass. Lymphangiomas Lymphangiomas are benign overgrowths of lymphatic vessels. It is not certain whether these are congenital malformations, hamartomas or true neoplasms. Capillary lymphangiomas are small, circumscribed, pale-white to pink lesions composed of network of endotheliumlined, thin-walled lymphatic spaces separated by lymphoid

Cavernous lymphangiomas are more common than the capillary variety. They are slow growing, congenital lesions and are composed of numerous dilated lymphatic channels filled with lymph and often surrounded by a fibrous capsule. Lymphangiosarcoma It is a rare malignant lesion that develops in a lymphoedematous/ extremity. Malignant transformation is more frequent in cases of secondary lymphoedema. It appears as purple-red nodules in the skin. It is an aggressive and rapidly fatal tumour.


Creager MA, et al (eds): Vascular Medicine. Philadelphia, Saunders Elsevier, 2006.


Faxon DP, et al. Atherosclerotic Vascular Disease Conference: Executive summary: Atherosclerotic Vascular Disease Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2004; 109:p2595.


Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Eng J Med 2001; 344:p1608.


Parakh R, Kakkar VV, Kakkar AK. For Venous Thromboembolism (VTE) Core Group. Management of Venous Thromboembolism. JAPI 2000; 55: 49-70.


Rockson SG. Lymphoedema. Current Treat Options Cardiovasc Med 2006; 8: p129.

Vascular Disorders of the Extremities

aggregates. These mainly involve skin or mucous membranes of the head and neck.


12.33 INTRODUCTION Management of pregnancy in patients with heart disease continues to pose a challenge to the clinicians. Heart disease is the third leading cause of death in 25 to 44-year-old women. Because it is relatively common in women of childbearing age, heart disease of varying severity complicates about one per cent of pregnancies. Rheumatic heart disease accounts for most of the cases and mitral stenosis being the commonest lesion, in India. NORMAL PHYSIOLOGIC CHANGES IN PREGNANCY There is an increase in blood volume, by about 50%, and relatively haemoglobin concentration falls, causing the physiological anaemia of pregnancy. Cardiac output increases as early as 5 weeks after the last menstrual period and rises to 45% above baseline at 24 weeks’ gestation. Increased cardiac output is achieved by an increase in heart rate, which rises progressively until 32 weeks’ gestation, and in stroke volume, which begins to increase by 8 weeks and peaks as early as 20 weeks. Twin pregnancies result in an additional 15% rise in cardiac output in mothers. The cardiovascular system is taxed further by stage one of labour, which is associated with an additional 12% increase in demand for cardiac output. This demand increases to a mean of 34% above the already increased baseline value as labour progresses to its final stages. After delivery stroke volume decreases by 2 weeks post-partum, but a small further reduction occurs up to 6 months after delivery. The stroke volume remains at pregnancy levels for the first 2 days post-partum and then falls dramatically. Heart rate remains elevated for 2 days post-partum and returns to the baseline by 10 days after delivery. Cardiac output similarly decreases from pregnancy levels to normal levels between 24 hours and 10 days post-partum. Systemic vascular resistance and diastolic blood pressure decrease as a result of changes in aortic compliance and arterial venous shunting in the uterus.


Pregnancy and Heart Disease Amal Kumar Banerjee

Table 1: Physical Findings During Normal Pregnancy Mild jugular venous distension Lower-extremity oedema Decreased breath sounds at bases Upward and leftward deviation of point of maximal impulse Volume-loaded ventricle (active praecordium) Increased valve closure sounds ‘Flow’ murmurs (pulmonic and aortic) Mammary soufflé (left sternal border) Wide pulse pressure Increased heart rate Table 2: Some Clinical Indicators of Heart Disease During Pregnancy Symptoms Progressive dyspnoea or orthopnoea Nocturnal cough Haemoptysis Syncope Chest pain Clinical Findings Cyanosis Clubbing of fingers Persistent neck vein distension Systolic murmur grade 3/6 or greater Diastolic murmur Cardiomegaly Persistent arrhythmia Persistent split-second sound Criteria for pulmonary hypertension Table 3: Changes in Non-invasive Test Results That Occur During Pregnancy

DIAGNOSIS OF HEART DISEASE Many of the physiological changes of normal pregnancy tend to make the diagnosis of heart disease more difficult due to alterations in the physical examination of the pregnant patient (Table 1). Symptoms and clinical findings that may indicate heart disease (Table 2), should be carefully recognised. Pregnant women who have none of these findings, rarely have serious heart disease.




Leftward axis deviation Increased ventricular voltage Increased rate Repolarisation changes

Chest X-ray film

Upward diaphragm displacement Horizontal heart placement Enlarged pulmonary silhouette

Diagnostic Studies The physiologic changes associated with pregnancy may also alter the results of non-invasive evaluations of the heart (Table 3).


Increased left ventricular diastolic dimension Increased left ventricular wall thickness Mild increase in contractility

In most cases,conventional testing including electrocardiography, Doppler echocardiography and chest radiography will provide necessary data. If indicated, right-heart catheterisation can be performed with limited X-ray fluoroscopy. All X-ray procedures should generally be avoided, particularly early in pregnancy.

GENERAL MANAGEMENT Poor maternal functional class, cyanosis, myocardial dysfunction, left-heart obstructive lesions, prior arrhythmia, and prior cardiac events are prognostic of complications during pregnancy. The

A three tiered risk classification of maternal mortality (Table 4), has been developed. This will help in counselling the woman regarding advisability of conception or continuation of pregnancy. Most current management recommendations have been based on expert opinion and/or retrospective series. To date, there has been only one large multicenter study to prospectively ascertain maternal and foetal outcomes in women with cardiac disease. This Canadian study also derived and validated a risk index for the prediction of maternal cardiac complications during pregnancy (Table 5). Women with heart disease who are at intermediate or highrisk for complications should be managed in a high-risk pregnancy unit by a multidisciplinary team from obstetrics, cardiology, anaesthesia, and paediatrics. Table 4: Risks for Maternal Mortality Caused by Various Heart Disease Cardiac Disorder

Mortality (%)

Group 1 – Minimal Risk Atrial septal defect Ventricular septal defect Patent ductus arteriosus Pulmonary or tricuspid disease Tetralogy of Fallot, corrected Bioprosthetic valve Mitral stenosis, NYHA classes I and II

0 to 1

Group 2 – Moderate Risk 5 to 15 2A: Mitral stenosis, NYHA classes III and IV Aortic stenosis Aortic coarctation without valvular involvement Tetralogy of Fallot, uncorrected Previous myocardial infarction Marfan’s syndrome, normal aorta 2B: Mitral stenosis with atrial fibrillation Artificial valve Group 3 – Major Risk Pulmonary hypertension Aortic coarctation with valvular involvement Marfan’s syndrome with aortic involvement

25 to 30

NYHA = New York Heart Association.

Table 5: Risk Factors for Maternal Cardiac Adverse Events During Pregnancy Adverse Maternal Cardiac Event

Risk Factor

Pulmonary oedema Arrhythmia Stroke Death

General NYHA functional class III or IV or cyanosis Systemic ventricular EF < 40% Mitral valve area < 2 sq cm, aortic valve area < 1.5 sq cm, peak left ventricular outflow gradient > 30 mmHg Cardiac event ( arrhythmia, stroke, pulmonary oedema ) prior to pregnancy

The general risk factors can be used to create a maternal risk index for adverse cardiac events related to pregnancy: 0 risk factors < 5% risk, 1 risk factor = 27% risk, ≥ 2 risk factors = 75% risk.

Congestive Heart Failure Management of congestive heart failure (CHF) during pregnancy, is not much different from that at other times. Salt restriction and limitation of activity to a level below that, which causes symptoms are appropriate. In a woman with significant symptoms or pulmonary oedema, standard therapy can be used with the exception of ACE-inhibitors. Congestive heart failure is one situation, where maintaining a woman in supine position may be beneficial by causing preload reduction with obstruction of return of blood from the inferior vena cava to the heart. Low-Cardiac-Output Syndrome A low cardiac output is an ominous sign in pregnancy with heart disease. Although potentially treatable causes such as tamponade or severe valvular stenosis should be considered, it is most often due to intravascular volume depletion. This should be prevented when possible and corrected when recognised.

Pregnancy and Heart Disease

likelihood of cardiac complications during pregnancy is 3%, 30% and 66% when none, one or more than one of these are present.

Thromboembolic Complications The risk of venous thromboemboli increases five-fold during and immediately after pregnancy, and there is an increase in arterial emboli as well. Prevention is optimal, and prophylactic full-dose heparin or low-molecular-weight heparin is indicated in those at high-risk of a thromboembolic complication. If a thrombus or embolus is identified, 5 to 10 days of intravenous heparin therapy followed by full-dose subcutaneous heparin is recommended. If a thromboembolus is life-threatening, like a massive pulmonary embolus or a thrombosed prosthetic valve, thrombolytic therapy can be used. Pulmonary Hypertension Pulmonary hypertension, whether primary or secondary, is associated with 30% to 70% maternal mortality and even with maternal survival, foetal loss exceeds 40%. The mother is most vulnerable during labour and in the first post-partum week. If detected early in pregnancy, interruption is advised. When detected late in pregnancy, close follow-up is necessary. Intravascular volume depletion should be promptly corrected, since it puts these patients at greatest risk. Systemic vascular resistance and pressure must be maintained in patients with pulmonary hypertension who have a right-to-left shunt, and meticulous attention is necessary to avoid air or thrombus emboli from intravenous catheters, which may lead to systemic emboli. At the time of labour and delivery, a central venous line allows adequate fluid administration, and a radial artery catheter makes determinations of blood pressure and oxygen saturation easier. These lines should be continued for 48 to 72 hours post-delivery. Arrhythmias The rules for the treatment are the same as in the non-pregnant patient, with the possible exception that a rhythm causing haemodynamic instability should be treated more promptly and aggressively because of the concern about diversion of blood flow away from the uterus. Complete heart block, which in this age group is most likely to be of congenital origin, is consistent with a successful pregnancy. If required, a permanent pacemaker can be implanted. Endocarditis Infective endocarditis is uncommon during pregnancy and the puerperium. The clinical presentation and management of endocarditis during pregnancy is the same as at other times.


SPECIFIC FORMS OF HEART DISEASE Rheumatic Heart Disease Rheumatic mitral valve disease continues to be the most prevalent heart disease encountered in pregnant women in India. Women with rheumatic valvular heart disease (VHD), have high rate of clinical deterioration and a marked increase in morbid events during pregnancy, including CHF, arrhythmias and need to either initiate or increase cardiovascular drug therapy or to hospitalise patients during pregnancy. Pregnancy with VHD, may be associated with an increased incidence of intrauterine growth restriction (IUGR), preterm deliveries, and lower birth weight, especially in cases with moderate and severe stenosis of the mitral or aortic valve. Acute Rheumatic Fever This disease occurs only rarely during pregnancy and management is similar to that of non-pregnant patients. Mitral Stenosis This is the commonest VHD in pregnancy and represents a common health problem in our country. The increased preload of normal pregnancy, as well as other factors that require increased cardiac output, may cause ventricular failure with pulmonary oedema in these women with relatively fixed cardiac output. About 25% of women with mitral stenosis experience cardiac failure for the first time during pregnancy. In some cases, this may be confused with idiopathic peripartum cardiomyopathy. The most prominent complaint is dyspnoea due to pulmonary venous hypertension and pulmonary oedema. Other common symptoms are fatigue, palpitations, cough and haemoptysis. The therapeutic approach is to reduce the heart rate and decrease blood volume. Limited physical activity is generally recommended. Prophylactically beta-blocking agents can be used and digoxin may be considered in patients with AF. For chronic AF, anticoagulation with heparin is also indicated. If symptoms of pulmonary congestion develop, activity is restricted even more, dietary sodium is restricted and diuretic therapy is started. Labour and delivery are particularly stressful for women with tight stenosis. Epidural analgesia for labour, with strict attention to avoid intravenous fluid overload, is ideal. Vaginal delivery is preferable. In symptomatic patients with moderateto-severe stenosis (mitral valve area < 1.5 cm2), haemodynamic monitoring is indicated during labour and delivery with haemodynamic optimisation by diuretics, beta-blockers, digoxin or nitroglycerin. Intrapartum endocarditis prophylaxis is required. Closed mitral commissurotomy is associated with only minimal risk to the foetus and therefore, preferable to the open technique. It should be recommended only in centres where it is done routinely.


The safety and efficacy of percutaneous balloon mitral valvuloplasty (PBMV) has been reported by several investigators. Now, PBMV during pregnancy has been reported without foetal loss and should be the preferred modality of treatment in this subset of patients. Mitral valve repair or replacement during pregnancy should be considered only in cases with severe stenosis (mitral valve area < 1.0 cm2), refractory to optimal medical therapy, PBMV is not feasible or when close follow-up during pregnancy, labour and delivery is not possible. When valve replacement is indicated, selection of the type of

prosthesis should be based on its haemodynamic profile and durability and the need for anticoagulation. Mitral Regurgitation This condition is well tolerated in pregnancy. In symptomatic patients, diuretics are indicated, and digoxin may be beneficial in cases with impaired left ventricular systolic function. Aortic Stenosis Rheumatic aortic stenosis is unusual finding in pregnancy and may occur in conjunction with mitral valve disease in about 5% of pregnant patients with rheumatic valvular disease. Most patients with aortic stenosis (Valve area > 1.0 cm2), tolerate pregnancy well. But patients with more severe stenosis may experience clinical deterioration with exertional dyspnoea, near-syncope or syncope and pulmonary oedema. Serious symptoms during pregnancy, if resistant to medical treatment, may necessitate termination of pregnancy or repair of the valve either surgically (valve replacement) or by percutaneous balloon valvuloplasty. For women with critical aortic stenosis, intensive monitoring during labour is necessary and epidural analgesia seems ideal, thus avoiding potentially hazardous hypotension. Aortic Regurgitation This condition is well tolerated in pregnancy. Symptoms necessitate salt restriction, diuretics and digoxin. Prosthetic Valve Disease A prosthetic valve is a relative contraindication to pregnancy. Maternal mortality is 3% to 4% with mechanical valves and foetal, loss is common. The critical issue is anticoagulation in cases with mechanical prosthesis. Full anticoagulation throughout pregnancy is recommended with subcutaneous heparin, maintaining anticoagulation at the high therapeutic level by following levels of factor Xa. Just before delivery, heparin is stopped. Protamine sulphate may be used to counter excessive bleeding. Anticoagulant therapy with warfarin or heparin may be restarted 6 hours following vaginal delivery. But anticoagulation should be withheld for at least 24 hours, following caesarean delivery. Antibiotic prophylaxis is necessary during labour. Mitral Valve Prolapse Pregnant women with mitral valve prolapse, rarely have cardiac complications. For women who are symptomatic, beta-blockers are used. Antibiotic prophylaxis for labour and delivery in patients with mitral valve prolapse, accompanied by valve thickening and/or regurgitation, seems warranted. Congenital Heart Disease A good maternal outcome can be expected in most cases with acyanotic congenital heart disease. Maternal functional capacity and cyanosis determine foetal outcome. Foetal wastage is about 45% in cyanotic mothers compared with 20% in acyanotic mothers with congenital heart disease. Prematurity and IUGR are common in cyanotic mothers. Risk of congenital heart disease is increased for the offspring of mothers with congenital heart disease with a reported incidence of 4% to 8%. Elective induction of labour, when foetal maturity is confirmed, may be used in high-risk patients for better planning of haemodynamic monitoring. Vaginal delivery is preferred for

Antibiotic prophylaxis for vaginal delivery in all patients with congenital heart disease (except secundum type of ASD, 6 months or more after repair of septal defects or surgical ligation and division of patent ductus arteriosus), is necessary. Atrial Septal Defect Atrial septal defect is well tolerated in pregnancy. Pulmonary hypertension and atrial arrhythmias occur rarely and antibiotic prophylaxis is not indicated. Ventricular Septal Defect Isolated ventricular septal defect is usually well tolerated in pregnancy. The occasional congestive heart failure or arrhythmias, developing during pregnancy, can be managed in the usual manner. The incidence of ventricular septal defect in the offspring has been reported to be 4% to 11%. Volume depletion during or after delivery, may lead to shunt reversal, in patients with pulmonary hypertension. Prompt volume replacement is necessary to prevent further complications. Patent Ductus Arteriosus A patent ductus arteriosus is tolerated well during pregnancy. On occasion, congestive heart failure can occur, but standard treatment is effective. Antibiotic prophylaxis is recommended. Peripartum decrease in systemic blood pressure should be promptly corrected. Congenital Aortic Valve Disease Most patients with mild aortic stenosis have favourable outcome of pregnancy, provided that they are diagnosed early. Appropriate care, including haemodynamic monitoring during labour and delivery and appropriate anaesthesia are associated with favourable outcomes. Moderate and severe aortic stenosis may be associated with symptomatic deterioration during pregnancy and may lead to maternal morbidity and even mortality. Exertional dyspnoea, chest pain, light headedness, and syncope may develop in the second or third trimester. Increased incidence of cardiac defects has been reported in live born infants of mothers with left ventricular outflow obstruction. Optimal management strategies of a pregnant woman with severe aortic stenosis include early abortion followed by valve replacement and repeat pregnancy, and continuation of pregnancy and plan for percutaneous balloon valvuloplasty or surgical intervention who show clinical deterioration not controlled by medical therapy. These procedures have been performed successfully in pregnant women but are not free from complications. So, these interventions should be reserved for patients with severe disease, not manageable by medical therapy and should be avoided during first trimester. Coarctation of Aorta Both maternal and foetal outcome is usually favourable. In case of severe hypertension, congestive heart failure and aortic dissection may occur. To prevent aortic dissection and rupture of cerebral aneurysm, physical activity should be limited and

blood pressure must be adequately lowered. Surgical correction can be performed successfully in patients with severe, uncontrolled systolic hypertension or heart failure. Pulmonic Stenosis Isolated pulmonic stenosis is usually well tolerated in pregnancy. Occasionally, progressive right ventricular failure, symptoms related to stenotic valve or intracardiac shunt at either the atrial or ventricular level with cyanosis may develop. Percutaneous balloon valvotomy should be considered in such situations. Tetralogy of Fallot

Pregnancy and Heart Disease

most patients, and caesarean section is indicated in stable patients only for obstetric reasons. Oxygen should be given to hypoxaemic mother during labour. Haemodynamic and blood gas monitoring is necessary in patients with impaired functional capacity, cardiac dysfunction, pulmonary hypertension, and cyanotic malformations. Blood loss should be treated promptly.

Successful pregnancy can be achieved, but maternal mortality is high and foetal loss can exceed 50%. During labour and delivery, right to left shunt may increase. Maternal haematocrit above 60%, arterial oxygen saturation below 80% and syncopal episodes are poor prognostic signs. In cyanotic women, the rate of spontaneous abortion, premature deliveries and IUGR is high. Close monitoring of systemic blood pressure and blood gases during labour is necessary for cyanotic or symptomatic patients. Incidence of cardiac defects reported born to such mothers infants ranges between 3 and 17%. Patients who have significant residual defects after repair, such as residual ventricular septal defect, pulmonic stenosis or regurgitation, and ventricular dysfunction, are still at higher risk during pregnancy. Patients who had undergone shunt procedures to improve cyanosis, may develop pulmonary hypertension, which increases the risk of pregnancy. After surgical repair, maternal and foetal outcomes improve markedly. Eisenmenger’s Syndrome This condition leads to poor foetal outcome, with high incidence of foetal loss, prematurity, IUGR and perinatal death. Since there is a high-risk of maternal mortality, patients with Eisenmenger’s syndrome should be advised against pregnancy, and early abortion should be recommended for those who are already pregnant. In an overview of 125 pregnancies in patients with Eisenmenger’s syndrome, primary and secondary pulmonary hypertension, maternal mortality was uniformly high at 36%, 30% and 56% respectively. The overall neonatal mortality was 13%. Management of a patient who decides to proceed to term, must include close follow-up for early recognition of clinical deterioration. Anticoagulation is necessary in the third trimester and 4 weeks post-partum, to prevent peripartum thromboembolism. Since premature delivery is common, patients should be hospitalised for any sign of premature uterine activity. Early hospitalisation ensures restricted activity and close follow-up. Spontaneous delivery is preferred to induction, and should lower the chance of prematurity or the need for caesarean section. Blood pressure, ECG and blood gas monitoring are essential during labour and delivery to ensure early detection and correction of problems. High concentration of oxygen may be beneficial. Most patients with stable condition, tolerate vaginal delivery, but an attempt is to be made to shorten the second stage of labour by the use of forceps. A planned caesarean section is often preferred, to avoid risk of foetal distress during vaginal delivery and potential need for emergency caesarean section. Swan-Ganz catheter should be avoided.


Ebstein’s Anomaly Pregnancy with acyanotic Ebstein’s anomaly is well tolerated. But in cyanotic cases, pregnancy is associated with increased risk of maternal heart failure, prematurity and foetal loss. The management during labour and delivery in symptomatic or cyanotic cases, includes antibiotic prophylaxis, oxygen inhalation, haemodynamic and blood gas monitoring, and measures to prevent a fall in systemic blood pressure due to peripheral vasodilatation or blood loss. Complex Cyanotic Congenital Heart Disease In India, very few successful pregnancies have been reported in patients with partially corrected and uncorrected cyanotic heart disease, like pulmonary and tricuspid atresia, transposition of great vessels, truncus arteriosus, single ventricle, doubleoutlet right ventricle and double-inlet left ventricle. A report (outside India) has demonstrated complications like, heart failure, thromboembolic events, supraventricular tachycardia, peri-partum infective endocarditis, high incidence of foetal wastage, premature deliveries, IUGR and both cardiac and noncardiac congenital malformations, in such situations. Marfan’s Syndrome In this condition, pregnancy may be associated with cardiovascular complications and a high-risk of having a child who will inherit the condition. Cardiovascular complications include dilatation of ascending aorta, leading to aortic regurgitation and congestive heart failure, and proximal and distal dissections of aorta with occasional involvement of the iliac and coronary arteries. Patients with aortic diameter less than 40 mm, usually tolerate pregnancy well. Marfan’s syndrome may be associated with cervical incompetence, abnormal placental site and post-partum haemorrhagic complications. Women with Marfan’s syndrome should be advised to avoid pregnancy and if already pregnant, interruption is recommended. Preconception echocardiographic assessment of the aorta and periodic followup during pregnancy are necessary and transoesophageal echocardiography is preferred. During pregnancy, physical activity should be restricted and beta-blockers should be administered. Substantial dilatation of aorta, necessitates therapeutic abortion or surgical intervention. Caesarean section should be preferred to minimise, haemodynamic stresses of vaginal delivery. Hypertrophic Cardiomyopathy In this condition, pregnancy is associated with a favourable outcome in most cases but there may be increased morbidity and even mortality. If congestive heart failure or abnormal rhythms occur, standard therapy is appropriate. Hypovolaemia should be avoided. Beta-blockers or calcium channel blockers may be used if necessary. Vaginal delivery is safe and second stage of labour may be shortened by the use of forceps. Antibiotic prophylaxis is necessary during labour and delivery.


Peripartum Cardiomyopathy Symptoms usually occur during last trimester and is detected in the early peripartum period. The clinical presentation and haemodynamic changes are same as in other forms of dilated cardiomyopathy. The incidence is greater in elderly multiparous women with pre-eclampsia and twin pregnancies. There is relatively rapid recovery of cardiac size and function in large number of patients with recurrence of left ventricular

dysfunction in subsequent pregnancies. About 50% to 60% of the patients show complete or near complete recovery of clinical status and cardiac function, usually within first 6 months post-partum. Rest of the patients demonstrate either further clinical deterioration, leading to early death or persistent left ventricular dysfunction and chronic heart failure. Acute heart failure necessitates prompt treatment with oxygen, diuretics, digoxin and vasodilator agents. Anticoagulant therapy is necessary. The temporary use of an intra aortic balloon pump or left ventricular assist device may help stabilise the patient’s conditions pending improvement. Intravenous immune globulin use, has shown a favourable effect on recovery of left ventricular dysfunction. Subsequent pregnancies should be discouraged. CONCLUSION With important exceptions, most women with cardiac disease can be expected to do well during pregnancy with appropriate management based on systematic risk stratification. Pregnancies deemed to be at intermediate or high-risk should be managed and delivered in a tertiary care setting. More thorough pre-pregnancy cardiovascular evaluations, is likely to better identify patients who are capable of proceeding safely with pregnancy and delivery. Best outcome is based on the strong relationships between physicians in cardiology and in high-risk obstetrics. RECOMMENDED READINGS 1.

Bozkurt B, Villaneuva FS, Halubkov R, et al. Intravenous immune globulin in the therapy of peripartum cardiomyopathy. J Am Coll Cardiol 1999; 34: 177-80.


Caulin-Glaser T, Setaro JF. Pregnancy and cardiovascular disease. In: Burrow GN, Duffy TP editors: Medical Complications During Pregnancy, 5th Ed. Philadelphia: Saunders; 1999:p111.


Gupta A, Lokhandwala YY, Satoskar PR, et al. J Am Coll Surg 1998; 187: 409-15.


Jose AM, de Souza MD, Eulogio E, Martinez, Jr MD, et al. Percutaneous Balloon Mitral Valvuloplasty in Comparison with Open Mitral Valve Commissurotomy for Mitral Stenosis During Pregnancy. J Am Coll Cardial 2001; 37: 900-3.


Lock JE, Khalilullah M, Shrivastava S, et al. Percutaneous catheter commissurotomy in rheumatic mitral stenosis. N Engl J Med 1985; 313: 1515-8.


Mangione JA, Zuliani MF, Del Castilho JM, et al. Percutaneous double balloon mitral valvuloplasty in pregnant women. Am J Cardiol 1989; 64: 99-102.


Mishra S, Narang R, Sharma M, et al. Percutaneous Transseptal Mitral Commissurotomy in Pregnant Women with Critical Mitral Stenosis. Indian Heart J 2001; 53: 192-6.


Presbitero P, Somerville J, Stone S, et al. Pregnancy in cyanotic congenital heart disease: Outcome of mother and foetus. Circulation 1994; 89: 2673-6.


Rossiter JP, Repke JT, Marales AJ, et al. A prospective longitudinal evaluation of pregnancy in the Marfan’s syndrome. Am J Obstet Gynecol 1995; 173: 1599-606.

10. Siu SC, Sermer M, Colman JM,et al.Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001; 104: 515-21. 11. Siu SC, Colman JM, Sorensen S, et al. Adverse neonatal and cardiac outcomes are more common in pregnant women with cardiac disease. Circulation 2002; 105: 2179-84. 12. Weiss BM, Hess OM. Pulmonary vascular disease and pregnancy: Current controversies, management strategies, and perspectives. Eur Heart J 2000; 21: 104-15. 13. Warnes CA, Elkayam U. Congenital heart disease and pregnancy. In Elkayam U, Gleicher N, editors. Cardiac Problems in Pregnancy. 3rd Ed. New York: Wiley-Liss; 1998: pp 39-53. 14. Whittemore R, Wells JA, Castellsague X. A second-generation study of 427 probands with congenital heart defects and their 837 children. J Am Coll Cardiol 1994; 23: 1459-67.



Gastroenterology Section Editor: Rakesh Tandon 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 13.9 13.10 13.11 13.12 13.13 13.14

Clinical Approach—Gastrointestinal Disorders A.C. Anand Investigations—Gastrointestinal Disorders Ashok Chacko Endoscopy—Diagnostic and Therapeutic Utility Gourdas Choudhuri Diarrhoea and Malabsorption B.S. Ramakrishna Constipation—Diagnosis and Management Uday Chand Ghoshal Gastrointestinal Bleeding Rakesh Kochhar, Mohd. Talha Noor Oesophageal Disorders Shobna J. Bhatia, Praveen Mathew Diseases of the Stomach and Duodenum Pankaj Dhawan Diseases of the Pancreas V. Balakrishnan, G. Rajesh Functional Gastrointestinal Disorders Philip Abraham Abdominal Tuberculosis Govind K. Makharia Inflammatory Bowel Disease Ajit Sood, Vandana Midha Ischaemic Bowel Disorders Deepak Kumar Bhasin Gastrointestinal Symptoms in Systemic Diseases Rakesh Tandon, Sudeep Khanna

770 774 777 782 787 791 799 806 813 819 823 829 834 837



Clinical Approach—Gastrointestinal Disorders

Patients with gastrointestinal diseases can have varied presentations. Symptoms like dysphagia, heartburn, abdominal pain, nausea, vomiting and haematemesis point to diseases of the upper gastrointestinal tract, while constipation, diarrhoea and haematochezia are commonly due to disease of the lower gastrointestinal tract. Diagnosis from individual gastrointestinal symptom may however be difficult at times as symptoms may overlap in a variety of diseases. For example, even the classic symptoms of peptic ulcer such as relief of pain by antacids or food and nocturnal pain are commonly seen in functional dyspepsia. DYSPHAGIA, ODYNOPHAGIA AND HEARTBURN Dysphagia, odynophagia and heartburn point towards oesophageal diseases as a cause of the symptoms. Dysphagia is difficulty in passage of solids or liquids from the mouth to the stomach. It should be distinguished from odynophagia, which is pain on swallowing. Heartburn is a burning sensation behind the sternum. It is important to differentiate dysphagia into causes that mostly affect the pharynx or proximal oesophagus (high/


Figure 1: Approach to a case with dysphagia. * May be intermittent dysphagia in an oesophageal ring.

AC Anand oropharyngeal dysphagia) and low oesophageal dysphagia. Oropharyngeal (transfer) dysphagia is due to diseases of the neuromuscular mechanism of the pharynx and cricopharyngeus. The patient is unable to initiate and execute the swallow mechanism. There may be coughing or regurgitation of fluids from the nose while swallowing besides associated features of cranial nerve palsies in the form of dysarthria and hoarseness of voice. Low oesophageal dysphagia is due to diseases involving the body of the oesophagus and gastrooesophageal junction. The common causes of dysphagia are given in Table 1 and the approach to a patient with dysphagia is summarised in Figure 1. The diagnosis can be confirmed by barium swallow, upper GI endoscopy and oesophageal motility study as indicated. NAUSEA, RETCHING AND VOMITING Nausea is an unpleasant feeling of wanting to vomit; this may be associated with autonomic features like increased salivation and sweating. Retching is a strong involuntary effort at vomiting. Vomiting is associated with bringing out of gastric contents through the mouth.

Associated symptoms like abdominal pain and constipation point to a gastrointestinal aetiology. Vomitus may be projectile in raised intra-cranial tension. There may be stale food in vomitus in gastric outlet obstruction. The vomitus is bilious in obstruction distal to the duodenum. Vomiting of psychogenic aetiology occurs during or soon after a meal. Table 1: Causes of Dysphagia Oropharyngeal or high dysphagia


Anatomical or muscular

Low oesophageal dysphagia

Motility disorder

Mechanical obstruction

Cerebrovascular accident Motor neurone disease Parkinson’s disease Multiple sclerosis Myasthenia gravis Oropharyngeal malignancy (uncommon) Zenker’s diverticulum Retropharyngeal abscess Cervical osteophyte Achalasia Scleroderma Chagas disease Diffuse oesophageal spasms Webs Schatzki ring Neoplasm Strictures Dysphagia lusoria (due to aberrant subclavian artery)

DYSPEPSIA Dyspepsia comprises of a group of upper abdominal symptoms including bloating, pain, postprandial fullness, heartburn and belching. Dyspepsia is defined as chronic or recurrent pain or discomfort centred in the upper abdomen. The first step in assessment is to select patients who will require early endoscopy and/or investigations to rule out serious diseases such as malignancy. The warning signs and symptoms that should alert the physician to a possibility of malignant disease are shown in Table 2.

both sides of the spinal cord. Pain location corresponds to those dermatomes that match the innervation of the diseased organ. Generally, visceral pain from abdominal organs proximal to the ligament of Treitz is felt in the epigastrium; pain from organs between the ligament of Treitz and the hepatic flexure of the colon is felt in the periumbilical region; and that from organs beyond the hepatic flexure is perceived in the lower abdomen midline. Pain arising in hollow organs may wax and wane due to peristaltic waves. Parietal Pain Parietal pain is well localised and sharp and is due to peritoneal irritation by the inflamed organ, e.g. appendicitis. Referred Pain Referred pain may be seen, for example, as shoulder pain due to liver abscess causing diaphragmatic irritation. Assessment of cause of abdominal pain includes a careful history of onset, duration, progress, location, radiation, character and aggravating and relieving factors. Clinical examination starts with inspection, which may show scars, hernias, splinting of abdominal movements, and visible peristalsis. A patient with peritonitis would lie still and the abdomen would be tender and would appear rigid. In contrast, a patient with ureteric colic may be rolling in bed due to pain. Visible peristalsis may be seen in bowel obstruction. Palpation may show a lump or tenderness. Guarding or rebound tenderness may be seen in peritonitis. Percussion may show ascites or obliteration of hepatic dullness in bowel perforation. Auscultation may reveal hyperactive or absent bowel sounds, besides bruits. Rectal examination can reveal a rectal growth or a pelvic abscess. GASTROINTESTINAL BLEEDING Bleeding from the GI tract can present as melaena, haematochezia or haematemesis; patients with occult bleed may present only with anaemia. Melaena is black, tarry foul-smelling stool and usually signifies the presence of >50 mL of blood. It usually implies a proximal GI source. It takes about 12 hours of transit time for melaena to develop. It can rarely develop as a result of bleeding from right colonic sources.

Table 2: Alarm Symptoms in a Patient with Dyspepsia that Indicate High Risk for Serious Underlying Disease

Haematochezia (maroon bloody stools) can come from a proximal GI source if intestinal transit is rapid but usually signifies a lower GI source. Fresh red blood is commonly due to rectal or left colonic disease.

Anaemia Weight loss Gastrointestinal bleed Recent onset of progressive symptoms Age >45 years Dysphagia

Haematemesis is blood in vomitus. It may be fresh bright-red or older coffee-ground material and signifies an upper GI bleed. The presence of haematemesis or melaena signifies an upper GI source but patients with rapid upper GI bleed may present with haematochezia.

ABDOMINAL PAIN Abdominal pain can have three broad patterns: visceral, parietal, and referred. Visceral Pain Visceral pain is dull crampy and poorly localised. It is often in the midline because abdominal organs transmit afferents to

Clinical Approach—Gastrointestinal Disorders

Gastrointestinal disorders causing vomiting include infections, bowel obstruction, cholecystitis, pancreatitis, infectious hepatitis, appendicitis and peptic ulcer. Vomiting may also be due to drugs, motion sickness, raised intracranial tension, meningitis, azotaemia, pregnancy, systemic illness and psychogenic causes.

Preliminary clues to the site of haemorrhage include the presence of haematemesis, hyperactive bowel sounds, and increased blood urea nitrogen out of proportion to creatinine (upper GI), or fresh rectal bleeding (colonic). Insertion of a nasogastric tube and aspiration may help in localisation of bleeding. However, it may be negative in some cases of upper GI bleed.


In upper GI bleeding, from a management point of view, it is important to differentiate between variceal and non-variceal aetiology. The clinical evaluation of upper GI bleed is shown in Table 3. Gastrointestinal endoscopy is usually required to make a definitive diagnosis. In obscure GI bleeding, one may need an isotope scan, angiography, or capsule or doubleballoon enteroscopy to determine the source of bleeding. Table 3: Differentiating Variceal from Non-Variceal Bleed Variceal source suspected if GI bleeding is associated with Jaundice Ascites Splenomegaly Past history of treatment for liver disease Clinical stigmata of chronic liver disease (spider naevi, palmar erythema, testicular atrophy, gynaecomastia, etc.) Non-variceal source is suspected if bleeding is associated with Absence of the above History of epigastric pain Past history of peptic ulcer Recent NSAID intake Recurrent vomiting/retching (Mallory-Weiss tear)

CONSTIPATION Patients usually define constipation not only by infrequent stools (typically fewer than three per week), but also by associated symptoms which are equally important, and probably more important, such as: hard stools, the need for excessive straining, a sense of incomplete bowel evacuation, and excessive time spent on the toilet or in unsuccessful defaecation. Constipation is a common symptom, more so in the elderly. A number of commonly used drugs in the elderly often aggravate constipation, including calcium supplements, iron supplements, diuretics, calcium-channel blockers, etc. A history of recent onset of constipation and/or blood mixed with stool raises the possibility of a malignant colonic lesion. A thorough physical examination should be performed to exclude systemic or neurological illnesses that may cause constipation. Abdominal examination may reveal abdominal mass or palpable stools. Anorectal examination may reveal fissures, haemorrhoids, lack of anal sphincter tone or a rectal stricture. Stool for occult blood is a useful screening test, while colonoscopic examination would be required to rule out local diseases. DIARRHOEA Diarrhoea is defined as increase of volume, frequency or fluidity of stool. It could be acute or chronic. Acute diarrhoea (< 4 weeks) is usually due to infections and is often self-limited. It may be associated with fever, pain in abdomen or dehydration. Chronic diarrhoea (>4 weeks) may be associated with malabsorption and weight loss.


Evaluation of a case of chronic diarrhoea requires detailed clinical history. Malabsorption will be associated with semisolid (occasionally watery) stools that are bulky, float on water, and stick to the pan. The stools may be explosive in character and be associated with flatulence and borborygmi. It may contain undigested food particles, increase with lactose intake, and decrease on fasting. There may be mild periumbilical pain relieved by passage of flatus or stools. Small volume stools associated with blood, mucous and tenesmus are suggestive of large bowel diarrhoea. The clinical clues to aetiology of chronic diarrhoea are given in Table 4. The approach to chronic diarrhoea (>4 weeks) should follow the following steps: Table 4: Chronic Diarrhoea: Clinical Clues Clubbing: Immunoproliferative small intestinal disease, Crohn’s disease, coeliac disease Fever: Tuberculosis, lymphoma, Whipple’s disease, Crohn’s disease/ulcerative colitis Response to antibiotics: Bacterial overgrowth, giardiasis, tropical sprue, Whipple’s disease Response to steroids: Inflammatory bowel disease (IBD), microscopic colitis, eosinophilic gastroenteritis, Addison’s disease Arthritis: IBD, coeliac disease, Whipple’s disease, collagen disorder Lymphadenopathy: HIV,Whipple’s disease, tuberculosis, lymphoma Dermatitis herpetiformis: Coeliac disease Pyoderma gangrenosum: IBD Abdominal mass: Crohn’s disease, lymphoma, tuberculosis

Step 1: Rule-Out Irritable Bowel Syndrome Red flag symptoms that are against the diagnosis of irritable bowel syndrome are shown in Table 5. Table 5: Red Flag Symptoms that make the Diagnosis of Irritable Bowel Syndrome Unlikely Fever Weight loss Nocturnal diarrhoea Blood in stools ↓ Haemoglobin, ↓ albumin, ↑ ESR Recent symptoms in middle age/elderly

Step 2: Large Bowel versus Small Bowel (Table 6) Table 6: Large Bowel Diarrhoea versus Small Bowel Diarrhoea Large bowel diarrhoea

Small bowel diarrhoea

Presence of blood and mucous

Malodorous, floating, greasy, containing undigested food particles Large-volume stools

Rectal/anal symptoms such as tenesmus/dyschezia Small-volume jelly-like stools Associated hypogastric cramps

Mid-abdominal cramps with borborygmi

Features of carbohydrate malabsorption with lactose intolerance causing explosive stool with flatulence are suggestive of mucosal malabsorption. This can be confirmed by an abnormal d-xylose test. In chronic pancreatitis, classical history of pancreatic pain with radiation to back and imaging evidence of chronic pancreatitis are often clearly evident. The d-xylose test would be normal in chronic pancreatitis and faecal fat excretion is often more than 14 gm/day, much more than that seen in mucosal malabsorption. A clinical approach to chronic diarrhoea is shown in Figure 2. RECOMMENDED READINGS

Figure 2: Approach to chronic diarrhoea: Basic clinical segregation of patient into small bowel diarrhoea and large bowel diarrhoea is usually adequate in directing evaluation. A small subgroup of patients with watery diarrhoea, in whom evaluation for the above have been negative, require advanced evaluation.


Flasar MH, Goldberg E. Acute abdominal pain. Med Clin N Am 2006; 90: 481503.


Owen W. ABC of the upper gastrointestinal tract-dysphagia. Br Med J 2001; 323: 850-3.


Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005; 129:1756-80.


Thomas PD, Forbes A, Green J, et al. Guidelines for the investigation of chronic diarrhoea; 2nd Ed. Gut 2003; 52 (Suppl V): v1-v15.

Clinical Approach—Gastrointestinal Disorders

Step 3: Chronic Pancreatitis versus Mucosal Malabsorption



Investigations—Gastrointestinal Disorders Ashok Chacko

INTRODUCTION The gastrointestinal (GI) tract can be evaluated by examination of luminal contents, upper and lower GI endoscopy and various laboratory tests which may help in establishing diagnosis. In this chapter, author discusses about tests for luminal contents and laboratory tests while the endoscopy of GI tract has been covered in next chapter (see Chapter 3 Endoscopy—Diagnostic and Therapeutic Utility). STOOL EXAMINATION Stool examination must be performed in all patients with abdominal symptoms, especially diarrhoea. Stool inspection, often neglected, is important as it gives information regarding volume, consistency and presence of blood and mucous. Stool microscopy helps in detection of RBC and pus cells— suggesting bacillary dysentery and inflammatory bowel disease, parasitic ova/cysts, and fat in stools (Sudan stain) suggesting malabsorption. In immunocompromised patients with diarrhoea, stool evaluation for parasites like Cryptosporidium, Microsporidium, Isospora belli and Cyclospora should be performed. Stool culture is not done routinely except in persistent diarrhoea. Stool positive for occult blood suggests GI blood loss and warrants further evaluation. Acidic stools (pH 50 mOsm/kg is characteristic of osmotic diarrhoea whereas secretory diarrhoea has osmotic gap 15 mmol per hour suggest ZES (normal BAO 0.55 mmol/L false positive results Urine >20% of ingested xylose


72 h faecal fat

Quantification of stool fat while patient ingests 50 g fat/d Normal: 10% with equal ratio of both isotopes after antibiotics

Gastric disease: Free vitamin B12 absorption decreased Ileal disease: Free vitamin B12 and vitamin B12 - IF factor complex absorption decreased Bacterial overgrowth: vitamin B12 normal


Breath hydrogen

Measurement of breath hydrogen every 30 min for 2 hours after 50 g of lactose Hypolactasia >20 ppm

Early rise of breath H2 in small bowel bacterial overgrowth


Isotopic quantification of 7 days whole body retention of oral dose 75SeHCAT

Accurate and specific

Bile acids


SeHCAT test


Normal: >15%

Involves radiation

Abnormal: 12 ppm rise over baseline within 120 min. Time to first sustained response within 3-5 hours 20 ppm rise over baseline within 3 h. 14 CO2 > 0.3% at 2-3 h


Bacterial overgrowth 14 Bacterial CO2 > 0.3% overgrowth at 2-3 h Fat malabsorption Breath 14CO2 < 0.0005% 13/14 Confirm H. pylori CO2 > 5-fold eradication baseline at 20 min.


RADIOISOTOPE TESTS Radioisotope tests are shown in Table 4. Table 4: Radioisotope Tests Test



Gastric emptying



Tc pertechnetate In-DTPA 14 C/13C Urea

TUMOUR MARKERS CA 19:9 Pancreatic and biliary malignancy CEA Colonic malignancy Chromogranin Neuroendocrine tumour Molecular Tests


Urea breath test Meckel’s scan



51 Cr labelled Labelled red cell scan erythrocytes Labelled leucocyte 111In or 99mTc HMPAO scan labelled leucocytes

Albumin tagged scan


125 51

I-Albumin, Cr-Albumin

Confirm H. pylori eradication Meckel’s diverticulum in obscure GI bleed Obscure GI bleed Distribution of activity (extent) in inflammatory bowel disease Protein losing enteropathy


Gene Affected

Familial adenomatous polyposis Multiple endocrine neoplasia Hereditary non-polyposis colon cancer Peutz-Jegher syndrome

APC Menin hMSH 2, hMLH1 LKB1


Feldman M, Friedman LS, Sleisenger MH. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease; 8th Ed. Philadelphia: WB Saunders and Co; 2009: pp 81-2.


Endoscopy—Diagnostic and Therapeutic Utility

INTRODUCTION Advancement in endoscopy has revolutionised our approach to diagnosis and management of various gastrointestinal disorders. The word endoscopy is derived from Greek, ‘end’ meaning within and ‘skopein’ meaning to view or observe. In this chapter upper gastrointestinal endoscopy, colonoscopy and endoscopic retrograde cholangio-pancreatography (ERCP) will be discussed in brief.

Gourdas Choudhuri

Table 1: Indications for Upper Gastrointestinal Endoscopy Diagnostic

HISTORY The first attempt at looking into the body cavity was made by Adolf Kussmaul who devised the first gastroscope in 1868, made up of a rigid metal tube. Subsequently Rudolf Schindler (18881968) improved this instrument but it was Basil Hirschowitz who pioneered the use of fibre optics (glass fibre that conduct light) that greatly improved the flexibility and manoeuvrability of the instrument. In 1957 he himself swallowed the first fibre optic gastroscope. The use of electronic chips (charge couple devices or CCD) to transmit the image from the tip of the endoscope to a video screen resulted in the present generation of video endoscopes since the 1980s. UPPER GASTROINTESTINAL ENDOSCOPY (UGIE) Indications This largely depends on the suspected diagnosis, availability of facilities and expertise, and patient’s choice. The common diagnostic and therapeutic indications for UGIE are given in Table 1 and shown in Figures 1 to 6. Contraindications The absolute contraindications are given in Table 2. Apart from these conditions special precautions should be taken in patients with Zenker’s diverticulum, compromised cardiovascular and pulmonary reserve and coagulopathy. Taking biopsy should be avoided in patients with coagulopathy. Pregnancy is not a contraindication for UGIE, but should only be performed for pressing indications.

Figure 1: Upper gastrointestinal endoscopy showing large oesophageal varices with red colour signs.


Upper gastrointestinal bleeding: past or present Patients with splenomegaly or suspected chronic liver disease: for presence and grading of oesophago-gastric varices Upper abdominal distress that persists despite an appropriate trial of therapy Upper abdominal distress associated with symptoms or signs that suggest serious organic disease. Dysphagia or odynophagia Oesophageal reflux symptoms that are persistent or recurrent despite appropriate therapy Persistent nausea and vomiting of unknown cause Surveillance for malignancy Gastric or oesophageal ulcers Familial adenomatous polyposis Adenomatous gastric polyps Barrett’s oesophagus Occult gastrointestinal bleeding Small bowel biopsy Cirrhotic patients in whom prophylactic therapy is considered After caustic ingestion to assess for acute injury Treatment of bleeding lesions Sclerotherapy or banding of varices Removal of foreign bodies Removal of selected polypoid lesions or superficial neoplasms Placement of feeding or drainage tubes Dilation of stenotic lesions Palliative treatment of stenosing neoplasms Drainage of pancreatic pseudocysts

Table 2: Contraindications for Upper Gastrointestinal Endoscopy The risks to patient health or life are judged to outweigh the most favourable benefit of the procedure. Adequate patient cooperation cannot be obtained. A perforated viscus is known or suspected.

Figure 2: Upper gastrointestinal endoscopy showing polypoidal, ulcerated growth suggestive of oesophageal cancer.


Figure 3: Upper gastrointestinal endoscopy showing a benign gastric ulcer.

Figure 4: Oesophageal variceal sclerotherapy. Note the blue scleropathy needle.

Figure 5: Glue injection being done in a patient with large, bleeding fundal varices.

Figure 6: Oesophageal variceal band ligation. Note the blue ‘O’ ring on one of the varix.

Preparation and the Procedure The procedure is performed after anaesthetising the pharynx with lignocaine spray or gel. Tense and apprehensive patients may need intravenous sedation with midazolam or propofol. The procedure is performed with the patient lying in the left lateral position. The endoscope is inserted through the mouth, pharynx, oesophagus, stomach and then further down to the second part of the duodenum under vision.

as the most useful test for evaluation of the colon and terminal ileum.

Complications of UGIE Endoscopic examination of the upper gastrointestinal tract is a fairly safe procedure with overall complications being less than 1% and mortality rate 10 mmHg usually indicates a 20% or greater reduction in blood volume (Table 1). Concomitantly, the patient may have symptoms like light-headedness, syncope, nausea, diaphoresis and thirst. Shock frequently results when the blood loss is more than 25% of the blood volume. Patients may occasionally experience a vasovagal reaction with bradycardia during bleeding episodes. Haematocrit is used to assess the degree of blood loss. However, it does not fall immediately with haemorrhage because of proportionate reduction of plasma and red cell volumes and it reflects the true magnitude of bleed only after a period of 24 to 48 hours. Hence, during this

Patient’s haemodynamic status Resting hypotension Postural hypotension Normal

Blood loss % >26 10-20 3,000 mL). Fresh frozen plasma (FFP) or platelets may be required in patients with coagulopathy or severe thrombocytopaenia, and in patients who require ten or more units of blood. Differentiating Upper from Lower GI Bleeding After resuscitation, the source of bleeding must be localised to direct further management. A nasogastric lavage must be performed irrespective of the probable site of the bleed. A bloody or a coffee ground aspirate confirms an upper GI source but their absence does not rule it out. A clear aspirate may be seen in up to 10% to 20% of patients with bleeding from a duodenal source. However, the presence of bile in the clear aspirate rules out a duodenal source. Other clues to upper GI bleeding include hyperactive bowel sounds and an elevation in blood urea nitrogen (BUN); the latter results from volume depletion and breakdown of blood proteins in the gut. Patients with lower GI bleed are less likely to present with shock or orthostatic symptoms as compared to patients with upper GI bleed. They have higher haemoglobin levels at presentation and also lower transfusion requirements.


DIAGNOSTIC EVALUATION OF PATIENTS WITH GI BLEEDING Acute Upper Gastrointestinal Bleeding History and physical examination A history of prior episodes of bleeding, illnesses such as ulcers, cirrhosis, cancer or bleeding disorders, prior surgery (such as for peptic ulcer), consumption of excess of alcohol, and medications like nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-coagulants should be elicited. Oesophago-gastric variceal bleed is painless and massive. A bleeding episode preceded by abdominal pain usually indicates underlying peptic ulcer disease. A history of retching and vomiting prior to haematemesis may indicate Mallory-Weiss syndrome. Examination of the skin may reveal cutaneous stigmata of cirrhosis. Rarely, evidence of underlying cancer (e.g. acanthosis nigricans), tumours (e.g. neurofibromatosis, blue rubber bleb nevus). Henoch-Schönlein purpura or vascular anomalies may be found. Skin and musculoskeletal abnormalities of pseudoxanthoma elasticum or Ehlers-Danlos syndrome may be diagnostic. Further clues on systemic examination include lymphadenopathy or abdominal masses, malignancy, abdominal tenderness (peptic ulcers, pancreatitis) and splenomegaly with or without prominent abdominal wall veins (cirrhosis, portal/splenic vein thrombosis). INVESTIGATIONS Endoscopy plays a major role in diagnosing the cause of GI blood loss. Other tests that may help include USG abdomen, CT scan of the abdomen and angiography. Endoscopy Endoscopy should be performed only after the patient has been haemodynamically stabilised. However, if the patient is bleeding massively and responding to resuscitative measures, endoscopy can be performed at the bedside provided adequate support personnel and with resuscitative facilities. Repeated gastric lavage prior to urgent endoscopy helps in clearing the stomach of blood clots, thereby providing a better field of view. Intravenous erythromycin can help clear the stomach if given half an hour before endoscopy. There is no role of cold saline lavage in controlling gastrointestinal bleeding. At endoscopy, detailed evaluation of the oesophagus, stomach and duodenum is carried out.


A majority of the bleeds occur from peptic ulcers, varices and erosions (Table 2). If there is no evidence of any of these, other uncommon lesions, especially vascular malformations should be carefully looked for. Endoscopy is superior to barium studies as it detects more lesions, it permits mucosal biopsy of suspicious lesions; it may act as a therapeutic modality; presence of active bleeding or stigmata or recent haemorrhage can provide prognostic information; and results of endoscopy guides the decision on the level of hospital care, on when to resume feeding and on length of hospitalisation. Endoscopic Forrest classification of peptic ulcer is useful for stratifying patients into high and low risk of rebleeding. Patient with Forrest 1a (active bleeding) and Forrest 1b (oozing vessel) at the time of endoscopy have high risk of rebleeding. Patients with Forrest 2a (visible vessel), Forrest 2b (adherent clot) and Forrest 2c (pigmented base) have moderate risk of rebleeding. Patients with Forrest 3 (clean base) have low risk of rebleeding. Patients in Forrest class 1, 2a and 2b benefit from endotherapy.

Other Diagnostic Tests Ultrasound of the abdomen can provide evidence of portal hypertension in the form of coarsened liver echotexture, dilated splenoportal axis, presence of collaterals and splenomegaly, it should be carried out in all patients. Computed tomography (CT) of the abdomen is useful to look for any evidence of pancreatitis, tumour or haemosuccus pancreaticus, CT angiography is useful in the diagnosis of visceral aneurysms. AETIOLOGY AND MANAGEMENT OF UPPER GI BLEED The various causes of upper GI bleed and management are given in Table 2 and Figure 1. In India, most common aetiology is oesophageal variceal bleeding, other common causes are duodenal ulcer, gastric ulcer and gastritis. Table 2: Causes of Upper Gastrointestinal Bleeding Common causes Peptic ulcer disease Oesophageal and gastric varices Oesophagitis Gastric erosions Duodenitis Mallory-Weiss tear Gastrointestinal malignancies Uncommon causes Angiodysplasia Dieulafoy lesion Cameron ulcers Gastric antral vascular ectasia Portal hypertensive gastropathy Gastric polyps Aortoenteric fistula Haemobilia Haemosuccus pancreaticus Foreign bodies Iatrogenic-nasogastric tube erosions, endoscopic polypectomy, sphincterotomy

Acute Variceal Haemorrhage In India, non-cirrhotic portal hypertension (NCPF) account for up to 25% of portal hypertension, and they have a better prognosis than cirrhosis. Oesophageal varices are the site of bleeding in most patients. Bleeding from gastric varices can occur in patients with active as well as thrombosed oesophageal varices. Some patients may bleed from portal hypertensive gastropathy and gastric antral vascular ectasia. Treatment options for bleeding oesophageal varices include pharmacotherapy, balloon tamponade, endoscopic, transjugular intrahepatic portosystemic shunt and surgery. In the emergency room, if clinical suspicion of bleed being variceal is high, patients can be started on intravenous terlipressin 1 mg every 4 to 6 hourly or octreotide 50 to 100 µg bolus, followed by infusion at 50 µg/hour. Continuation of these drugs for 3 to 5 days after endoscopic treatment reduces chances of rebleeding. If the patient is bleeding actively and immediate endotherapy is not possible, an alternative of endoscopic therapy is balloon tamponade with Sengstaken Blakemore tube. It has two balloons, oesophageal and gastric, control of haemorrhage requires inflation of gastric balloon with 250 mL of air, oesophageal balloon is usually not inflated as it is associated with risk of oesophageal rupture. It is very effective in immediate controlling of bleeding in over 80%

Gastrointestinal Bleeding

Figure 1: Algorithm for managing acute upper GI bleeding. TIPSS = Transjugular intrahepatic porto-systemic shunt; APC = Argon plasma coagulation.

of patients. It is associated with 50% rebleeding after deflation of balloon. It is also associated with risk of oesophageal rupture, ulceration and aspiration pneumonia. Though associated with significant complications, balloon tamponade can be instituted even by primary physicians. Endoscopic treatment options for bleeding oesophageal varices are endoscopic variceal ligation (EVL) and endoscopic sclerotherapy (ES). Both have an efficacy of about 90%. Endoscopic sclerotherapy involves visualisation of the varix during endoscopy, followed by injection of a sclerosing agent into the varix or into the adjacent tissue. Various sclerosing agents include sodium tetradecyl sulphate, polidocanol, sodium morrhuate and ethanol. Variceal obliteration is usually achieved after 3 to 6 sclerotherapy sessions at periodic intervals. Complications associated with ES include retrosternal pain, oesophageal ulcers and oesophageal stricture. EVL was first reported in 1989. The technique involves the placement of rubber bands around a portion of the varix containing oesophageal mucosa. The varix is sucked into a hollow, clear plastic cylinder attached to the tip of the endoscope. Once suctioned into the sheath, a trigger device allows deployment of the band around the varix. The blood flow is completely interrupted, producing ischaemic necrosis of the mucosa and submucosa. Later granulation takes place with sloughing of the

rubber rings and necrotic tissue, leaving shallow mucosal ulcerations that heal in 14 to 21 days. Application of the bands is started at the gastroesophageal junction and progresses cephalad in a helical fashion. EVL sessions are repeated at approximately 2-week intervals until varices are obliterated, usually requiring 2 to 4 ligation sessions. Complications are less frequent than with endoscopic sclerotherapy. Transjugular intrahepatic porto-systemic shunt (TIPSS) is a procedure in which a self-expanding metal stent is placed radiologically between the portal and hepatic veins. It is highly effective in reducing portal pressures and rebleeding and in controlling acute variceal haemorrhage. TIPSS is, however, associated with a risk of encephalopathy and shunt stenosis, although the latter risk is reduced with the use of the newer polytetrafluoroethylene covered stents. Recently a removable self-expanding oesophageal metal stent has also been used effectively in patients with variceal bleeding refractory to other treatment modalities. Nowadays surgery is rarely needed for variceal bleeding. Surgical options include shunt and non-shunt procedures. The shunts are either total or selective. Total shunts include portacaval, mesocaval and central splenorenal, selective shunt include distal splenorenal shunt. Non-shunt operations are gastroesophageal devascularisation or disconnection procedures.


For bleeding gastric varices, injection of N-butyl-cyanoacrylate can be made into the varices with good results. This modality can be used in actively bleeding gastric varices as well as to prevent rebleeding; 1 to 2 mL of cyanoacrylate is injected into the varix using a 21 gauge sclerotherapy needle. In refractory cases TIPSS is an effective treatment modality; it controls acute gastric variceal bleeding in over 90% patients. Balloon-occluded retrograde transvenous obliteration (B-RTO) is a new technique; it is highly effective in controlling acute gastric variceal bleeding. Bleeding from portal hypertensive gastropathy and gastric antral vascular ectasia is not massive but difficult to treat. Treatment of portal hypertensive gastropathy is directed towards underlying portal hypertension. First line therapy for gastric antral vascular ectasia (GAVE) is argon plasma coagulation. Recently, endoscopic variceal ligation has also been used for its treatment successfully. Apart from the treatment mentioned above, broad spectrum of antibiotics for a week have been shown to improve survival of these patients. After control of initial haemorrhage, prevention of variceal rebleeding is an important aspect of the management of portal hypertension. Non-selective beta-blockers reduce cardiac output and cause splanchnic vasoconstriction, reducing portal venous pressure. Several randomised controlled trials comparing propranolol or nadolol with placebo have shown a reduction in rebleeding and mortality with beta blockers. Addition of isosorbide mono nitrate to beta-blockers enhances the efficacy of therapy but offers no survival advantage and reduces tolerance to therapy. Peptic Ulcer Disease (PUD) Most ulcer bleeds are from duodenal ulcers, though in patients on NSAIDs, bleeding from gastric ulcers is more common. An ulcer bleeds when it erodes into the lateral wall of a blood vessel. Ulcers located high on the lesser curve of stomach or on the posteroinferior wall of the duodenal bulb are most likely to bleed. Helicobacter pylori infection, NSAID use, and stress due to critical illness contribute to the development of ulcers. Up to 80% of duodenal ulcers are caused by Helicobacter pylori, whereas about 50% of gastric ulcers are associated with this infection. NSAIDs constitute the most important cause of PUD after H. pylori infection, all patients who have PUD should be carefully questioned about NSAIDs use. NSAIDs induced ulcers may be painless because analgesic properties of NSAIDs can mask the pain of ulcers. Concurrent aspirin and oral anti-coagulant use increase the risk of bleeding. Other risk factors are cardiovascular or cerebrovascular disease and hospitalisation. Bleeding stops spontaneously in 80% of instances. Patients with ongoing bleed, haemodynamic compromise, and high transfusion requirements mandate urgent endoscopic therapy, which can achieve haemostasis in more than 90% of cases. Surgical intervention is indicated in patients whose bleeding is refractory to endoscopic therapy.


Proton pump inhibitors (PPI) are the mainstay of pharmacological treatment. Proton pump inhibitors elevate the pH, thus, enhancing clot formation and platelet aggregation. PPI should preferably be given intravenously, though oral administration is also shown to be effective. High dose intravenous (IV) omeprazole or pantoprazole (80 mg IV bolus followed by 8 mg per hour for 72 hours) has been shown to

reduce rebleeding rate and the need for surgery. Lansoprazole and esomeprazole are the other PPIs available for intravenous use. After the patient’s condition stabilises, intravenous PPI therapy may be switched to oral PPI therapy. Endoscopic therapy is accepted as the most effective method for controlling acute ulcer bleeding and for preventing rebleeding. Depending on the endoscopic appearance of the ulcer, different endoscopic modalities are applied. High risk ulcers are those that are bleeding actively and those with a non-bleeding visible vessel. These patients are shown to benefit the most from endoscopic therapy. Management of ulcers with adherent clots was controversial earlier, but now it has been shown that endoscopic therapy is superior to medical therapy for preventing recurrent haemorrhage in patients with bleeding peptic ulcers with adherent clots. Ulcers with flat pigmented spots or those with clean base have no additional benefit from endotherapy. The most popular endoscopic therapy is injection therapy using epinephrine (1:10,000). Other injection therapies include use of sclerosants, including sodium tetradecyl sulphate, polidocanol or ethanol. Biologic agents like thrombin, fibrin sealant and cynoacrylate glue can also be utilised. The assistant projects the needle, originally designed for injection sclerotherapy, about 5 mm beyond the plastic sheath, injects the solution, multiple injections are given around the ulcer to provide tamponade effect. Thermal methods for controlling bleeding include laser, electrocoagulation and heater probe. These can be combined with injection therapy. Newer techniques include application of metal clips, band ligation, argon plasma coagulation and endoloops. In patients with rebleeding, repeat endoscopy appears to be useful. Presence of hypotension at admission and an ulcer size larger than 2 cm are independent predictors of failure of endoscopic therapy. Eradication of H. pylori and stopping NSAIDS are two factors shown to prevent recurrent bleeding. Relook endoscopy with retreatment in peptic ulcer bleeding significantly reduces the risk of recurrent bleeding, although it does not substantially reduce the need for subsequent surgery or mortality. In summary management of bleeding peptic ulcer include initial resuscitation, pharmacotherapy with proton pump inhibitors, endoscopic therapy and in refractory cases, surgery should be considered. Indications for surgery include failure of endoscopic therapy, large ulcer (>2 cm), massive bleeding and development of complications like perforation. Transcatheter arterial embolisation is reserved for patients who have exceptionally high risks for surgery (e.g. acute myocardial infarction). Erosive Gastropathy Erosive gastropathy refers to endoscopically visualised subepithelial haemorrhages and erosions that may account for upper GI bleeding in 15% to 25% of cases. Antacids, H2 receptor blockers, proton pump inhibitors and sucralfate decrease bleeding from gastric erosions. Endoscopic, argon plasma coagulation has been found to be useful in the treatment of severe bleeding. Mallory-Weiss Syndrome Recurrent vomiting or retching can lead to mucosal tears at the gastro-oesophageal junction causing haematemesis. Bleeding

Dieulafoy’s Lesion Dieulafoy’s lesions are prominent submucosal vessels, usually found in the proximal stomach with no surrounding ulceration. These lesions are difficult to identify if they are not bleeding actively during endoscopy. Standard endoscopic injection, thermocoagulation, haemoclip, argon plasma coagulation or band ligation can successfully achieve haemostasis. Gastrointestinal Malignancies Endoscopy is used for diagnosis and for taking biopsies but it is usually ineffective in controlling the bleed. ACUTE LOWER GASTROINTESTINAL BLEEDING History and Physical Examination Passage of drops of blood either separately or coating the stool may indicate bleeding from an anorectal source, especially haemorrhoids. Bloody diarrhoea with or without pain occurs in infective colitis or inflammatory bowel disease. Associated weight loss or recent change in bowel habits suggests colorectal cancer. A history of radiation therapy suggests radiation proctitis. The abdomen should be carefully examined to detect tenderness, organomegaly or a mass. A per rectal examination should always be performed to look for prolapsed haemorrhoids, mass polyp or ulcer.

AETIOLOGY AND MANAGEMENT OF SPECIFIC CAUSES OF LOWER GI BLEED The various causes and management of lower GI bleed are given in Table 3 and Figure 2. Table 3: Causes of Lower Gastrointestinal Bleeding Common causes

Relative frequency in India

Colonic sources Haemorrhoids Inflammatory bowel disease Neoplasms Arteriovenous malformation, angiodysplasia Diverticula Small bowel source Meckel’s diverticulum or other diverticula Vasculitis Ulcers, e.g. typhoid

70% to 90% 30% to 40% 30% to 40% 15% to 20% 2% to 5%

Less common causes Solitary rectal ulcer syndrome (SRUS) Infectious enterocolitis Ischaemic colitis Aortoenteric fistula Colonic varices in portal hypertension Radiation proctitis Lesions associated with use of NSAIDs

2% to 5%

Gastrointestinal Bleeding

is usually not massive and stops spontaneously. Occasionally injection therapy or haemoclips may be required to control the bleeding.

2% to 5% 10% to 20%

Proctoscopy and Sigmoidoscopy Patients with presumed lower GI bleeding must undergo early proctoscopy and sigmoidoscopy for the detection of obvious, low-lying lesions such as bleeding haemorrhoids, anal fissure, rectal ulcer, proctitis or rectal cancer. Colonoscopy If procto-sigmoidoscopy is not informative, colonoscopy is the next logical investigation. It is superior to barium enema since it can detect vascular lesions and allows biopsies to be taken. As 5% to 10% patients with upper GI lesions present with haematochezia, it is prudent to perform upper GI endoscopy before undertaking extensive investigations. Urgent colonoscopy in lower GI bleeding is safe with high likelihood of making a specific diagnosis (75% to 100%). Performance of colonoscopy requires preparation of the patient with purgatives, polyethylene glycol and sodium phosphate are the commonly used purgatives. Angiography Angiography is helpful in detecting the site of bleed in actively bleeding patients. Angiodysplasias are the commonest lesions detected by angiography. It may also show vascular malformations or tumours, even if extravasation of contrast material is not noted. Radionuclide Scanning It involves intravenous administration of 99mTechnetium tagged sulphur colloid or RBCs followed by imaging with an external gamma camera to detect intestinal extravasation of the substrate. It can detect bleeding even at a slower rate than that detected by angiography.

Figure 2: Algorithm for managing acute lower GI bleeding.

Anorectal Lesions Haemorrhoids are the most common cause of lower GI bleed. Treatment may be in the form of sclerotherapy, banding, and cryotherapy. Surgery is required for large and prolapsed haemorrhoids. Solitary rectal ulcer syndrome (SRUS) is a benign condition in young individuals, which presents as rectal


bleeding, tenesmus and mucous discharge. Sigmoidoscopy with biopsy is essential for diagnosis. Treatment consists of avoiding digital rectal manipulation, laxatives and sucralfate enemas. Inflammatory Bowel Disease (IBD) Patients with IBD have a history of recurrent episodes of bloody diarrhoea. Colonoscopy with biopsy is required to differentiate IBD from other forms of colitis. Steroids and 5-aminosalicylic acid usually control the disease. Colectomy is required for massive bleeding not responding to medical management. Polyps Adenomatous colonic polyps can present with occult or overt rectal bleeding (if they are larger than 1 cm). Juvenile polyps are hamartomas occurring in the first two decades of life. Colonoscopic polypectomy is the treatment of choice. Bleeding from malignant colonic polyps requires colectomy. Infectious Enterocolitis Various invasive organisms viz. Shigella, Salmonella, Campylobacter, enteroinvasive E. Coli,Clostridium difficile and Entamoeba histolytica present with bloody diarrhoea.Diagnosis is usually made by routine examinations and culture of the stool.Treatment is with antibiotics. Colonic Diverticula Colonic diverticula are less frequent in the Indian population as compared to the West. However, in elderly patients especially those with complications, diverticular disease should be considered and looked for. Bleeding is abrupt in onset, usually painless and often massive, but ceases spontaneously in 80% of patients. Colonoscopy is required for diagnosis. Vasopressin infusion controls bleed temporarily. Segmental surgical resection is indicated for ongoing bleed. Angiodysplasia Angiodysplasia or arteriovenous malformations are also less frequent in Indians as compared to Western population. Bleeding from angiodysplasia is painless, trivial to massive in amount, recurrent and usually resolves spontaneously. Colonoscopic diagnosis and treatment by endoscopic electrocoagulation are generally successful in identification and definitive management of these lesions. Ischaemic Colitis Ischaemic colitis usually occurs in the elderly due to occlusion of a major vessel or low cardiac output. It usually presents with sudden, crampy, left lower abdominal pain and passage of bright red or maroon blood mixed with the stool. Bleeding is usually moderate. The splenic flexure, descending colon and sigmoid colon are most commonly affected. Colonoscopy shows segmental haemorrhagic mucosa with or without ulcerations. CT angiography is a non-invasive test which helps in diagnosis. Colectomy is required only if there are signs of bowel infarction. Radiation Colitis Symptoms of radiation colitis may occur few months to many years after abdominopelvic radiation usually for cancer of the cervix or prostate. Treatment using laser, argon plasma coagulation or sucralfate enema is effective.


Rectal Varices Rectal varices are an uncommon cause of lower gastrointestinal bleeding, seen in patients with portal hypertension particularly

extrahepatic portal venous obstruction. They can be successfully treated by endoscopic variceal ligation. Postpolypectomy Bleeding Postpolypectomy bleeding is the most frequent complication of colonoscopy and is seen in 0.2% to 1.8% cases of colonoscopic polypectomy. Delayed bleeding may occur up to 14 days after polypectomy. Endoscopic clipping is an effective treatment modality. SMALL INTESTINAL BLEED Only 3% to 5% of all GI bleeding arises between the second portion of the duodenum and the ileocaecal valve. Bleeding from this site is difficult to diagnose, since the small bowel is relatively inaccessible. Patients present either with chronic occult blood loss or with recurrent episodes of melaena. Repeated endoscopies and barium studies are often negative. Various causes of small intestinal bleed are given in Table 4. Vascular ectasias are the commonest cause of small intestinal bleed. Benign small bowel tumours (usually leiomyomas) are the second most common cause. Meckel’s diverticulum is the cause of bleeding in two-third of males younger than 30 years presenting with small bowel bleeding. Bleeding is almost always brisk, resulting from ulceration within the diverticulum or the adjoining ileal mucosa. Table 4: Differential Diagnosis of Occult-GI Bleeding Mass lesions in colon or small intestine Carcinoma Adenoma Inflammation Erosive oesophagitis/gastritis Ulcer (any site) Coeliac disease Inflammatory bowel disease Colitis (non-specific) Worm infestation (hookworm, whipworm, strongyloidiasis, ascariasis) Tuberculous enterocolitis Amoebiasis Other causes Drug intake Haemosuccus pancreatitis Haemobilia Vascular disorders (haemangioma, Dieulafoy’s lesion)

GASTROINTESTINAL BLEEDING OF OBSCURE ORIGIN Obscure bleeding is defined as recurrent bouts of acute or chronic GI bleeding for which no definite source has been discovered by routine endoscopic and barium contrast studies. Obscure gastrointestinal bleeding can be overt or occult, depending upon the presence or absence of clinically evident bleeding. Causes of gastrointestinal bleeding that are commonly missed on upper gastrointestinal endoscopy are Cameron’s erosion, gastric varices, Dieulafoy’s lesion, angiodysplasia, oesophagitis, portal hypertensive gastropathy and gastric antral vascular ectasia. Therefore, upper gastrointestinal endoscopy should be repeated, if it is negative then a cause in the small bowel should be looked

Figure 3: Algorithm for managing obscure gastrointestinal bleeding.

Angiography is performed only if bleeding is likely to be beyond duodenum and is so massive that endoscopy cannot be safely or satisfactorily performed and surgery is contraindicated. Blood loss must be greater than 0.5 mL/min for angiography to detect the site of bleed. Selective mesenteric angiography usually localises the site of bleeding in about 75% of such patients. Radionuclide imaging studies are not useful in the evaluation of upper GI bleeding. Radionuclide scanning is a sensitive method for detecting gastrointestinal bleeding at a rate of 0.1 mL/min. This technique is more sensitive, but less specific than angiography. The major disadvantages are that nuclear imaging localises bleeding only to an area of the abdomen and the intraluminal blood is moved away by intestinal motility leading to false localisation. For proximal small bowel push enteroscopy permits inspection of the entire duodenum and part of the jejunum. Capsule endoscopy (CE) was launched at the beginning of this millennium and since then it has had a very important impact

on managing obscure gastrointestinal bleeding. Before the advent of CE, small bowel was an organ which was very difficult to explore with available endoscopic, radiological and nuclear medicine techniques. Wireless CE is simple, safe, non-invasive, reliable procedure, well accepted and tolerated by the patient. This technique evaluates with high resolution images, the whole small bowel, avoiding surgery or radiation exposure. In this technique a small capsule camera is swallowed by the patient (capsule enteroscopy). It takes up to 50,000 photographs of the entire small intestine and transmits the images to a data recorder externally, enabling visualisation of areas where the endoscope cannot reach.

Gastrointestinal Bleeding

for. The most common cause of obscure GI bleeding is vascular ectasia of the small bowel. Certain lesions are difficult to diagnose because of their rarity or their subtle appearance; and some lesions are detectable only if active bleeding is seen endoscopically (e.g. Dieulafoy’s lesion). Tubercular enteritis/colitis is another cause of obscure GI bleed in our country. Worm infestation, especially with hookworms, is a common cause of anaemia in India. With a heavy parasite load, some patients may have continuous ooze from the small intestine and may have positive stool occult blood. Stool examination is diagnostic. An approach to management of obscure gastrointestinal bleeding is given in Figure 3.

Double-balloon enteroscopy is another new technique that allows access to the whole of the small bowel with the added advantage of therapeutic option, like haemoclip application or polypectomy, etc. As inferred from its name, the two inflatable balloons are the crux of the double balloon system. An overtube is backloaded onto the endoscope before intubation. The distal ends of the overtube and of the endoscope are fitted with inflatable/deflatable air-filled latex balloons. When inflated to 45 mmHg, the balloons grip the intestinal lumen, providing traction against the wall without undue pressure. Exploratory laparotomy with intra-operative endoscopy is indicated in patients with severe recurrent or persistent bleeding in whom all other investigative modalities have proved unsuccessful. Scintigraphy and mesenteric angiography can also be done to guide the surgeon in patients prior to exploratory laparotomy. Faecal Occult Blood Various causes of occult gastrointestinal bleeding are given in Table 4. An important cause of chronic occult bleeding is NSAIDs intake. Other causes are polyps and carcinoma of the colon. Faecal occult blood loss in normal individuals varies from 0.5 to 1.5 mL per day. Faecal occult blood tests are to detect blood not visible overtly. The classic faecal occult blood tests are of guaiac based type. They are based on haemoglobin pseudoperoxidase activity, guaiac turns blue after oxidation by oxidants or peroxidases in the presence of an oxygen donor such as hydrogen peroxide. Various factors influence the result of guaiac test, presence of animal haemoglobin and dietary peroxidases leads to false positivity while presence of vitamin C results in false negativity. Immunological faecal occult blood tests detect human globin epitopes and are highly sensitive for detection of blood. They are more specific than guaiac based tests; their results are not affected by dietary factors. Haem-porphyrin based test relies on spectrofluorometric method to measure porphyrin derived from haem, they provide a highly accurate determination of total stool haemoglobin. Intraluminal degradation of haemoglobin or interfering peroxidase producing substances do not effect the haem-porphyrin assay, although myoglobin, a haem containing protein found in red meats interferes with its result. The initial investigation for evaluation of occult bleeding is colonoscopy which should be followed by an upper GI endoscopy to rule out gastroduodenal pathology. If these tests are unrevealing, small intestinal causes of bleed should be considered. 797

PROGNOSIS OF GASTROINTESTINAL BLEEDING Mortality of each episode of variceal bleed in cirrhotics is 30% to 50%. Variceal bleeding in non-cirrhotic causes of portal hypertension, however, carries a good prognosis. Mortality for ulcer bleed is much lower (3% to 10%). Lower GI bleed is usually less life-threatening than upper GI bleed. Risk factors for increased mortality are presentation with shock, active bleeding at presentation, advanced cirrhosis, old age, co-morbid medical illnesses, occurrence of rebleeding and failure of endoscopic methods to control bleed.

stimulating advancement. Development of endoscopic suturing devices to close gastrointestinal perforations is equally exciting. These techniques will be increasingly adapted to control gastrointestinal bleeding in future. RECOMMENDED READINGS 1.

Anand CS, Tandon BN, Nundy S. The causes, management and outcome of upper gastrointestinal haemorrhage in an Indian hospital. Br J Surg 1983; 70: 209-11.


Ferguson CB, Mitchell RM. Non-variceal upper gastrointestinal bleeding: standard and new treatment. Gastroenterol Clin N Am 2005; 34: 607-21.


Goenka MK, Kochhar R, Mehta SK. Spectrum of lower gastrointestinal haemorrhage: an endoscopic study of 166 patients. Indian J Gastroenterol 1993;12: 129-31.


Gupta R, Reddy DN. Capsule endoscopy: current status in obscure gastrointestinal bleeding. World J Gastroenterol 2007; 13: 4551-3.


Sass DA, Chopra KB. Portal hypertension and variceal haemorrhage. Med Clin North Am 2009; 93: 837-53.


Zaman A, Chalasani N. Bleeding caused by portal hypertension. Gastroenterol Clin N Am 2005; 34: 623-42.

FUTURE PROSPECTS Steady progress in engineering including microelectrical systems will affect the performance of capsule endoscopy. With the advent of robotic capsule in near future, it will be possible to perform drug delivery and tissue sampling, robotic capsule will be equipped with microelectrical system for directed therapy. Natural orifice transendoscopic surgery (NOTES) is a


13.7 SYMPTOMS Oesophageal disorders are one of the commonest disorder of the GI tract. The description is given in next chapters. The passage of food through the body of the oesophagus is not sensed by an individual in normal circumstances. The major symptoms of oesophageal diseases are heartburn, chest pain, regurgitation and dysphagia. Heartburn (pyrosis) is defined as retrosternal burning pain that travels cephalad. It is exacerbated by bending or lying down, and is worse after meals. It is relieved by upright posture, by swallowing of saliva or water, or more reliably by antacids or acid-inhibiting drugs. Heartburn is a characteristic symptom of gastro-oesophageal reflux (GOR), and may be associated with regurgitation. Regurgitation is described as effortless appearance of acid or a bitter taste in the mouth. It occurs in GOR, and may result in laryngeal aspiration with spells of coughing and choking which awaken the patient from sleep. It may also result in aspiration pneumonia. Regurgitation of bland food suggests that an obstruction exists in the lower oesophagus; in GOR, bland regurgitation occurs when acid secretion has been inhibited by drugs. Dysphagia, or difficulty in swallowing, is a sensation of obstruction to the passage of food through the mouth, pharynx or oesophagus due to a significant problem in the anatomy or motility of these organs. Dysphagia could be oropharyngeal (transfer) or oesophageal. Oropharyngeal dysphagia occurs due to neuromuscular or structural abnormalities of mouth, hypopharynx or upper oesophagus; these patients have difficulty in initiating the swallow. Oesophageal dysphagia is classified as mechanical or motor. Mechanical oesophageal dysphagia is initially to solids only. It could be intermittent (webs or Schatzki ring) or progressive from solid to blenderised food and finally to liquids (stricture, malignancy). The severity of dysphagia in mechanical obstruction varies with the degree of luminal narrowing, type of food bolus, and presence of associated oesophagitis. On the other hand, dysphagia due to motor disorders is equal for solids and liquids, may increase with intake of very cold foods and it could be slowly progressive (achalasia cardia) or intermittent (less specific motility disorder). Nonobstructive dysphagia occurs in patients with reflux disease who have oesophageal inflammation associated with a motility disorder. Odynophagia or painful swallowing is due to mucosal noninfectious inflammation. Causes could be infectious (candidiasis, herpes, cytomegalovirus, Epstein-Barr virus, etc.) or noninfectious like corrosive intake, pill oesophagitis, radiation oesophagitis, severe GOR disease and rarely osesophageal carcinoma.

Oesophageal Disorders Shobna J Bhatia, Praveen Mathew Chest pain of oesophageal origin described as squeezing or burning sensation, is similar to cardiac angina and may not be related to swallowing. Almost 90% of times it is associated with other oesophageal symptoms. More than 50% of cases of non-cardiac chest pain have GOR disease; other causes are oesophageal spasm, achalasia cardia, nutcracker oesophagus and sometimes panic disorders. Water brash is reflex salivary hypersecretion that occurs in response to GOR. It should not be confused with regurgitation. Globus sensation is a feeling of food stuck at the pharyngeal level, but occurs between meal times. MOTILITY DISORDERS Skeletal Muscle Disorders Pharyngeal paralysis may occur following neuromuscular diseases; laryngeal and orofacial muscles also may be involved. It is characterised by transfer dysphagia, laryngeal aspiration and nasal regurgitation. Barium swallow with cineradiography is the investigation of choice, and reveals poor contraction of pharyngeal constrictors, barium in the valleculae and pyriform sinuses, and nasal and tracheal aspiration. Oesophageal motility studies may reveal reduced amplitude of contraction wave in pharynx and proximal oesophagus, reduction in upper oesophageal sphincter (UOS) resting tone, and incoordination between the pharynx and oesophagus during a swallow. Patients who have pharyngeal paralysis due to myasthenia gravis or polymyositis respond to treatment of the primary disease. In other patients, swallowing exercises usually help. In patients with a cerebrovascular accident, the extent of impairment of swallowing and its subsequent recovery depend on the type and extent of lesion. In severe cases, a permanent feeding gastrostomy may be required. In patients with UOS spasm, botulinum toxin injection or cricopharyngeal myotomy may be helpful. Cricopharyngeal achalasia is a disorder of unknown cause, and occurs due to failed relaxation of the UOS and can be associated with Zenker’s diverticulum. Dysphagia and choking are the predominant symptoms. On radiography, a prominent bar representing the contracted UOS may be seen. Cricopharyngeal myotomy may be helpful in selected cases, but should not be done in patients with associated GOR, because of increased risk of pulmonary aspiration post-operatively. Smooth Muscle Disorders Achalasia cardia Achalasia cardia is a motor disorder of the oesophageal smooth muscle in which the oesophageal body is aperistaltic, the lower oesophageal sphincter (LOS) may be hypertensive and does not relax completely with swallowing. In addition, because of the non-relaxing LOS, the intra-oesophageal pressure is higher than the gastric pressure. The underlying abnormality is defective innervation of the smooth muscle portion of the oesophageal body and the LOS.


Classic achalasia shows a marked reduction in myenteric neurons. Secondary achalasia may be caused by gastric carcinoma infiltrating the oesophagus, lymphoma, Chagas disease, neuropathic chronic intestinal pseudo-obstruction syndrome, irradiation and certain toxins and drugs. Dysphagia, chest pain and regurgitation are the main symptoms of achalasia. Dysphagia occurs with both liquids and solids. Various manoeuvres designed to increase intra-oesophageal pressure, including the Valsalva, may help passage of the bolus into the stomach. Regurgitation and pulmonary aspiration occur because of retention of large volumes of saliva and ingested food in the oesophagus. The overall course is usually chronic over months to years. Chest X-ray may show absence of the gastric air bubble. In advanced cases, an air-fluid level in the mediastinum in the upright position represents retained food in the dilated oesophagus. Barium swallow shows oesophageal dilatation and a persistent beak-like narrowing, representing the non-relaxing LOS, in the lower oesophagus (Figure 1). Oesophageal manometry shows the defining feature of distal body aperistalsis and incomplete or absent swallow induced relaxation of LOS. Other features are hypertensive LOS and low amplitude simultaneous onset oesophageal body contractions. An increased intra-oesophageal basal pressure that exceeds intragastric pressure is commonly seen. High resolution oesophageal manometry with contour plot topographical analysis has found three variants of achalasia (Figures 2A and B), type 1—no significant oesophageal pressurisation; type 2— rapidly progressive compartmentalised pressurisation, either localised to distal oesophagus or throughout the whole oesophagus; and type 3—rapidly progressive pressurisation attributable to spastic contractions. This classification is also helpful in prognosticating outcomes with type 2 responding best to therapy; type 3 achalasia does not respond well, and type 1 has intermediate response to any form of treatment. Endoscopy is helpful in excluding the causes of secondary achalasia, particularly gastric fundal carcinoma.


Figure 1: Barium swallow showing dilated oesophagus with bird beak appearance at the lower end and fluid level in the oesophagus, suggestive of achalasia cardia.

Figures 2A and B: (A) High resolution manometry shows normal peristaltic wave after a swallow. (B) Manometry shows aperistalsis in oesophageal body after a swallow with elevated lower oesophageal sphincter pressure suggestive of achalasia.

Medical treatment using nitrates is usually unsatisfactory. Calcium-channel antagonists such as nifedipine have been used with some success; these need to be administered sublingually 15 to 30 min prior to a meal. The best available non-surgical therapy involves endoscopy-assisted balloon dilatation of the LOS; this reduces the basal LOS pressure by tearing muscle fibres. Endoscopic injection of botulinum toxin into the LOS is effective in the short term. Heller’s extra-mucosal myotomy of the LOS in which the circular muscle layer is incised, is equally effective. Reflux oesophagitis and peptic stricture may develop after successful treatment of achalasia; this complication is more frequent after surgery than with balloon dilation. Surgery is increasingly being performed laparoscopically; additionally, fundoplication is often done to prevent GOR. Spastic Disorders of Distal Oesophagus Other than Achalasia This section includes a spectrum of disorders ranging from diffuse oesophageal spasm, nutcracker oesophagus, nonspecific spastic disorders and hypertensive LOS. These are differentiated on the basis of manometry findings (Figure 3). They all are present with history of chest pain, occasional dysphagia and rarely regurgitation. Pain is very similar to angina, may occur at rest or after swallowing, and may radiate to the back or neck. These disorders are associated with other functional bowel disorders and have high association with anxiety

Systemic diseases like scleroderma and diabetes mellitus also cause motor disorders of the oesophagus. Scleroderma oesophagus is typically one with a low LOS pressure and aperistalsis. There is atrophy of the smooth muscle. The patient presents with severe gastro-oesophageal reflux disease with complications. Diabetes mellitus, when complicated by autonomic neuropathy, may have associated oesophageal dysmotility. The patients are rarely symptomatic, but may have occasional dysphagia and heartburn. Candidal infection should also be considered; if present, patients may have odynophagia.

Oesophageal Disorders

dilatation of LOS has been found to be beneficial in cases with associated LOS hypertension. In refractory cases, long oesophagomyotomy has been tried with some success.

GASTRO-OESOPHAGEAL REFLUX DISEASE Figure 3: High resolution manometry shows simultaneous and prolonged contraction of oesophageal body suggestive of diffuse oesophageal spasm.

disorders, depression and other psychological abnormalities. The pathogenesis of these disorders is not known, probably functional with no anatomic abnormalities found. Diffuse oesophageal spasm is characterised by non-peristaltic responses of normal amplitude after 30% or more of swallows with a normally relaxing LOS. Barium swallow may reveal intermittent areas of oesophageal spasm that produce an appearance of a corkscrew oesophagus (Figure 4). Treatment includes ruling out the possibility of ischaemic heart disease; smooth muscle relaxants like nitrates and calcium channel blockers are beneficial in a few cases. Anti-depressants like imipramine, trazodone and sertraline have been found to be useful in a number of patients with chest pain. Pneumatic

Gastro-oesophageal reflux (GOR) is defined as backward flow of gastric contents into the oesophagus. A small amount of GOR occurs in normal individuals. GORD (gastro-oesophageal reflux disease) is defined as a condition which develops when stomach contents cause troublesome symptoms or complications, and adversely affects an individual’s quality of life. The typical reflux syndrome is defined by presence of troublesome heartburn and/or regurgitation. GORD is the most common oesophageal disorder, accounting for nearly 75% of all patients with oesophageal disorders. In Western studies, 15% to 20% of the general population suffers from GORD. The prevalence of GORD in Asia is lower (2.3% to 8%), probably due to higher prevalence of Helicobacter pylori, lower body mass index, low fat consumption in diet and genetic diversity. Adenocarcinoma of the oesophagus is on the rise in the Western world. Barrett’s oesophagus, which is a recognised precursor to adenocarcinoma is strongly associated with GORD. Pathophysiology The normal anti-reflux barrier at the gastro-oesophageal junction is a zone whose functional integrity is maintained by the LOS pressure, extrinsic compression of the LOS by the crural diaphragm, the intra-abdominal location of the LOS, integrity of the phreno-oesophageal ligament, and maintenance of the acute angle of His. Transient LOS relaxation is one of the most important causes for GORD; it is not associated with a swallow. It is more harmful because it is longer in duration (>10 seconds) compared with swallow-induced LOS relaxation, accompanied by relaxation of crural diaphragm and not associated with peristalsis. It is usually stimulated by gastric distension due to food or gas, or rarely fat and stress. Small amount of reflux occurs during swallow induced LOS relaxation. The role of hypotensive LOS seems to be present only in patients with severe oesophagitis. Hiatus hernia is seen in 60% to 90% of patients with reflux oesophagitis, especially in patients with peptic stricture or Barrett’s oesophagus. Hiatus hernia breaches the anti-reflux barrier by displacing the LOS from crural diaphragm. Loss of the intra-abdominal segment of LOS increases transient LOS relaxation and impairs oesophageal acid clearance.

Figure 4: Barium swallow showing appearance of a corkscrew oesophagus.

Impaired oesophageal motor function resulting in inadequate volume clearance occurs in oesophagitis; peristaltic dysfunction increases with increasing severity of oesophagitis. The layer of mucous carpeting the mucosa and mucosal bicarbonate also constitute an important line of defence against acid injury.


If acid injury and cell necrosis occur, the rate of regeneration plays a role in determining the severity of lesions. There is no increase in gastric secretions in GORD patients, but there is a pocket of acid in the distal oesophagus which escapes the buffering action of food; hence the predilection for oesophagitis at this location. Animal and human studies have demonstrated that acid and pepsin are responsible for the mucosal injury. Other factors implicated are duodenogastric reflux, with conjugated bile acids and trypsin as possible culprits. Gastroparesis is found in 6% to 38% of patients with GORD. Helicobacter pylori infection is currently believed to lower the frequency of GORD. This is backed by epidemiological data of low prevalence of GORD in areas with high prevalence of H. pylori and vice versa. Prevalence of more virulent strains of H. pylori in developing countries results in corpus or pangastritis, thus reducing gastric acid secretion and resulting in decreased symptoms of GORD. Pathology Grossly, the spectrum of oesophageal mucosal appearances varies from normal appearing mucosa (40% to 80%) to mucosal injuries of varying severity-erosions to ulcerations. The earliest finding, seen on electron microscopy, is dilated intercellular spaces, at least three times greater than controls; this is reversible on administering proton pump inhibitors. Light microscopy shows papillary height more than half, and basal zone thickness more than 1/6th of total mucosal thickness. Acute inflammation with neutrophils and eosinophils is seen in up to 40% of cases but is not specific for GORD. Development of columnar-lined mucosa, with specialised intestinal metaplasia is the defining feature of Barrett’s oesophagus, visible on endoscopy when normal squamous mucosa is replaced by salmon pink columnar mucosa. This can progress from low grade to high grade dysplasia, and later to adenocarcinoma of the oesophagus. Clinical Features Symptom complex of GORD has been divided into oesophageal and extra-oesophageal syndromes. Oesophageal syndromes include the typical reflux syndrome and reflux chest pain syndromes. Typical reflux symptoms are heartburn, a burning sensation in the retrosternum and regurgitation—a perception of flow of gastric contents into the mouth or hypopharynx.The prevalence of these is 75% to 98% and 48% to 91%, respectively. GORD can be diagnosed by these two symptoms without the need for endoscopy. Reflux chest pain can be indistinguishable from pain of ischaemic heart disease, but is usually associated with other symptoms of GORD. GORD is the most common oesophageal cause of chest pain. Sleep disturbance is often associated with GORD. In patients with minimal symptoms, exercise has been found to worsen symptoms of GORD.


Dysphagia in a patient with GORD could be a marker of peptic stricture or development of malignancy. Dysphagia may also occur because of reflux oesophagitis and motor functional abnormalities. Barrett’s oesophagus is an endoscopic diagnosis (Figure 5) confirmed on histology showing specialised intestinal

Figure 5: Endoscopy shows evidence of Barrett’s metaplasia in the oesophagus. The normal squamous mucosa of the oesophagus is replaced by columnar gastric mucosa.

metaplasia. There are no symptoms which herald the development of Barrett’s oesophagus. Increasing age, male gender, long duration of GORD symptoms, obesity and smoking are risk factors for Barrett’s oesophagus. Adenocarcinoma may develop in patients with Barrett’s oesophagus especially high grade dysplasia. Extra-oesophageal syndromes are classified as those with established associations and those with proposed associations. Established associations include reflux cough, reflux laryngitis, reflux asthma and reflux dental erosions. These syndromes usually occur with the concomitant manifestation of typical reflux oesophageal symptoms and rarely in their absence. Reflux is rarely the only cause for these extra-oesophageal symptoms. They have been found to respond to treatment of GORD. Other symptoms with proposed associations are sinusitis, pulmonary fibrosis, recurrent otitis media and pharyngitis. The degree of evidence for this last group is minimal, epidemiologically or treatment-response wise. Investigations The diagnosis of GORD is made on the basis of clinical history and confirmed by response to medications. Diagnostic testing is done to avert misdiagnosis, to identify complications of GORD and to evaluate the reason for failure of standard therapy. To avert misdiagnosis and identify reflux complications, the concept of alarm symptoms has been introduced; these include gastrointestinal blood loss, involuntary weight loss, dysphagia and anaemia. In these conditions an endoscopy is warranted. In case any lesion is seen, biopsies should be taken from it. Less than 50% of patients with GORD have endoscopic features of oesophagitis; visible breaks in mucosa is the most reliable marker of reflux oesophagitis.This does not correlate with the frequency or severity of reflux symptoms. Reflux stricture seen in less than 5% of GORD patients is defined by a persistent narrowing in the lumen of the oesophagus and manifests as troublesome mechanical dysphagia. If endoscopy is normal, the patient should be treated empirically as GORD, and further investigated if the symptoms do not resolve. Manometry is useful in detecting severe peristaltic dysfunction which is a contraindication for antireflux surgery. Investigations to demonstrate excessive oesophageal acid exposure are conventional catheter based pHmetry or wireless capsule pH-metry,and impedence-pH monitoring. Therapy Treatment is directed towards decreasing GOR and improving oesophageal clearance. The aim is to alleviate symptoms, heal oesophagitis and prevent complications.

Empirical initial management with acid reduction is the accepted approach currently in patients with uncomplicated heartburn. Evidence suggests that acid reduction helps healing of oesophagitis and relief from symptoms. Meta-analysis of randomised control trials show that proton pump inhibitors (PPIs) are more effective than H2 receptor antagonists (H2RAs) in treating oesophagitis and ameliorating symptoms. PPIs as a class (omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole) are all equally effective in standard doses. There does not appear to be any additional benefit of higher dosage/ twice daily dosing of PPIs or adding a H2RA, except in cases of severe oesophagitis. Patients whose heartburn has not responded to twice daily PPIs are considered treatment failures. Preference of a PPI over another is primarily to ameliorate the side-effects of the PPI need earlier. Patients with reflux chest pain can be given a trial of PPI once ischaemic heart disease has been ruled-out. Patients with extra-oesophageal symptoms require high doses. Maintenance therapy is usually necessary as GORD is a chronic disease, the lowest possible dose of PPI should be titrated for symptom control in patients with definite oesophagitis. PPIs have been shown to reduce the development of reflux strictures, but there is no evidence that they reduce the risk of Barrett’s oesophagus or adenocarcinoma. In patients with extraoesophageal symptoms, maintenance therapy is indicated only to control oesophageal symptoms. Long-term PPI therapy is potentially safe though there is a theoretical risk of hypergastrinaemia, pneumonia, Clostridium difficile colitis and hip fractures. Anti-reflux surgery and PPIs have equal efficacy for control of oesophageal reflux symptoms. Surgery should be offered when an individual is intolerant to PPIs, or when a patient with oesophageal reflux syndrome has troublesome regurgitation. The potential side-effects of anti-reflux surgery include excessive flatulence, inability to belch, dysphagia and recurrence of symptoms post-surgery (30% over 5 years). Patients well controlled on PPIs should not be offered surgery. The surgery recommended is laparoscopic fundoplication. INFECTIOUS OESOPHAGITIS Infectious oesophagitis can be due to viral, bacterial and fungal causes. With an increase in the number of patients with immunocompromised states, there has been an increased frequency of oesophageal infections. Infections of the oesophagus present with acute dysphagia, odynophagia and chest pain. In patients with severe ulceration of the mucosa, bleeding may occur; this is usually self-limiting and small in quantity, but life-threatening haemorrhage may occur. Viral Oesophagitis Herpes simplex virus (HSV) type 1 or 2 may cause oesophagitis in immunocompromised individuals. Systemic manifestations like

nausea, vomiting and fever may be present. On endoscopy, the oesophageal mucosa has 1 to 3 mm vesicles and small, discrete, punched-out lesions, which may proceed to confluent ulcers and diffuse erosive oesophagitis.These lesions may get superinfected by bacteria or fungi. Biopsy or cytology may show ballooning degeneration, ground-glass change in nuclei with eosinophilic inclusions (Cowdry type A) and giant cell formation. Culture may be positive.Treatment consists of acyclovir 250 mg/m2 intravenous 8 hourly. As the patient improves, oral therapy may be started with 200 to 400 mg acyclovir 5 times a day. Symptoms resolve within a week. Ulcers take a longer time to heal.

Oesophageal Disorders

Treatment usually begins with dietary and lifestyle modifications. The patient should be asked to avoid food items that increase reflux (fatty or fried food, caffeinated drinks, chocolate, mint) and decrease intake of acidic foods (citrus fruits, spicy food, carbonated drinks, tomatoes, onions). Lifestyle modifications include weight reduction in those who are obese, elevation of the head end of the bed and avoiding eating within 3 hours of bedtime in those with night time symptoms. Patients with postprandial symptoms are advised to take small frequent meals.

Varicella-zoster virus occasionally produces oesophagitis in children with chicken pox and adults with herpes zoster. The oesophageal lesions are similar to those of HSV, and necrotising oesophagitis may occur in a severely compromised patient. Biopsy from the edge of the ulcer shows findings similar to those of HSV, and differentiation requires culture studies. Acyclovir, in doses higher than for HSV, is required for treatment. Cytomegalovirus infection occurs only in the immunocompromised host. Endoscopy shows serpiginous ulcers which are large and deep with surrounding normal mucosa. In the distal oesophagus the ulcers may coalesce. Biopsy should be taken from the centre of the ulcer and reveals intranuclear and small cytoplasmic inclusions in fibroblasts and endothelial cells of blood vessels. Early diagnosis may be made by immunohistochemistry using monoclonal antibodies to CMV. Ganciclovir is the treatment of choice. Complete healing may take a few weeks to months and treatment should be continued until then. HIV causes oesophagitis during seroconversion and during inversion of T-cell helper: suppressor ratio. The oesophagitis is self-limiting. Steroids may help in this condition. Bacterial oesophagitis is very rare. However, patients with AIDS may develop oesophagitis due to Cryptosporidium or P. carinii. Tuberculosis of the oesophagus is rare and is almost always due to contiguous spread from the lung or mediastinal lymph nodes. Fungal Oesophagitis Candidiasis of the oesophagus occurs in immunodeficiency disorders like diabetes mellitus, chronic renal failure, and AIDS. Individuals receiving steroids or immunosuppressive chemotherapy for malignancy and those with underlying oesophageal diseases that cause stasis of food (achalasia or scleroderma) may also develop candidiasis. Candida is present in the non-pathogenic form in the oral flora in normal individuals. Patients who develop oesophagitis may be asymptomatic, or may have odynophagia and dysphagia. Rarely, bleeding may occur, and the deep ulcers may perforate or may form a stricture. Systemic invasion from oesophageal candidiasis is also reported. Oral candidiasis, if present, suggests the diagnosis by its white flake’s appearance. Endoscopy reveals raised white pseudomembranous plaques with mucosal erythema. In severe cases, confluent linear and nodular plaques with underlying ulcerations may be present. A smear taken from these plaques may reveal hyphae. Treatment in mild cases is with 10 to 20 mL of oral nystatin (100,000 units/mL) 6 hourly, or oral clotrimazole (10 mg 6 hourly), or fluconazole 100 mg per day for 7 days. If symptoms persist, endoscopic biopsy and culture are


recommended. If anti-fungal resistance is demonstrated, caspofungin may be effective. Narcotics are recommended for patients with severe odynophagia. Corrosive Injury Corrosive is any substance which causes tissue injury upon contact. Caustic injury of the oesophagus occurs following ingestion of strong alkali or acid, most often accidentally or with suicidal intent. Sodium hydroxide is the most frequent cause of alkaline injury. Hydrochloric and sulphuric acids are the common acids causing injury. Most corrosives are available as over-the-counter drain cleaners, dish washing detergents, bleaches, battery fluids, button batteries, nail polish removers, etc. Alkali ingestion provokes liquefaction or saponification necrosis of the oesophageal wall and thrombosis of blood vessels. Acids cause coagulative necrosis. Severity of tissue injury depends upon factors like substance pH, physical state (solids adhere to mucosa and cause more damage), quantity, intention (quantity is usually larger in suicidal cases), tissue contact time and concentration. There is an acute inflammatory response with mucosal necrosis, followed by sloughing of necrotic tissue and ulceration over 4 to 15 days. Risk of perforation is maximum up to 7 days. After 3 to 4 weeks, cicatrisation begins. Significant oesophageal strictures develop when there is circumferential damage. In the oesophagus, corrosives pool at the post-cricoid area, level of aortic arch, tracheal bifurcation, and lower oesophageal sphincter. These are common locations for strictures. In severe cases, there may be perforation into the mediastinum or pleural cavity or development of a tracheo-oesophageal fistula. The damage is mainly in the antrum in the fasting stomach, and in the gastric corpus if the patient has ingested a meal prior to corrosive ingestion. Symptoms include burning pain in the mouth and throat, odynophagia, excessive salivation, stridor, hoarseness, dysphagia and chest pain. Gastric involvement leads to abdominal pain and vomiting, and occasionally symptoms and signs of perforation. There may be oedema and ulceration of the lips, tongue and pharynx. Airway obstruction from severe epiglottic and laryngeal oedema may occur. As the acute inflammatory reaction subsides, odynophagia and dysphagia decrease; with the development of oesophageal stricture, dysphagia gradually returns, usually within 1 to 3 months after the accident. Mortality rate is of 1%, usually due to mediastinitis or peritonitis resulting in multi-organ failure.


The aim of therapy in the acute phase is resuscitation and supportive care. Assessment of the severity of damage is most important after resuscitation of the patient. Clinical features do not correlate with severity of damage. X-ray films of chest and abdomen are taken to check for perforation, pneumomediastinum or pneumoperitoneum, which if present can be confirmed by CT scan. If there is evidence of perforation, patient should be referred for surgery (oesophagectomy or gastrectomy). Flexible endoscopy should be done at the earliest or up to 96 hours of corrosive ingestion, after ruling out a perforation and is the best way to assess the severity of mucosal damage. Endoscopic grading is helpful in management and prognostication. Patients who have minimal injury can be started on oral liquids by 48 hours and can be discharged early; they also have a low risk of complications. In patients with advanced damage, a nasojejunal tube can be placed over a

guide wire during endoscopy; this serves as a route for maintaining nutrition and also provides a lumen for dilatation in future as these patients are prone to develop strictures. Measures which have shown to be of no use or are harmful are administration of activated charcoal, pH neutralisation or dilution, by inducing emesis, and intravenous steroids. Antibiotic therapy is required only if secondary infection sets in. Early dilatation of the oesophagus has been associated with a high-risk of perforation, and is therefore not recommended. Stricture of the oesophagus is the major long-term complication. Caustic strictures are often extensive and multiple, involving most of the lower oesophagus. They respond to repeated dilatation, and the frequency of dilatation may decrease over time. Recently, self-expandable plastic stents have been placed at the site of stricture for 6 to 8 weeks, with good results. Oesophageal resection with colon or gastric tube replacement may be necessary in cases where the lumen is too small for dilatation, or in cases of extensive damage. Oesophageal squamous cell carcinoma is a potential long-term complication of corrosive injury. Pill-Induced Oesophageal Injury Pill-induced oesophageal injury results from damage due to ingestion of certain medications which cause injury by either production of caustic solution, hyperosmolar solution or direct drug damage. Drugs commonly implicated are tetracycline, doxycycline, potassium chloride, nonsteroidal antiinflammatory drugs, alendronate, ferrous sulphate, theophylline, quinidine, etc. The injury is more common in individuals with anatomic or motility abnormalities of oesophagus. It could be predisposed by taking inadequate water or assuming recumbent posture immediately after taking the pill. Symptoms include severe chest pain, odynophagia and dysphagia. Endoscopy may reveal an ulcer, diffuse oesophagitis or pseudomembrane at the site of damage. Withdrawal of the offending medication, viscous lignocaine solution, adequate hydration, and use of PPIs to reduce acid exposure results in healing of the lesion. Rarely there can be perforation, oesophago-respiratory fistula or a chronic stricture at the site of the ulcer. The disorder is preventable in most cases. Eosinophilic Oesophagitis Eosinophilic oesophagitis (EO) is a disease characterised by eosinophilic infiltration of the oesophageal mucosa. Identified in 1978, the incidence of EO has been increasing in the Western world. Familial clustering and seasonal variation have been noted in patients with EO. Almost 80% of children and 40% to 60% of adults have history of allergies. It is postulated to be IgE or non-IgE mediated. Sensitisation could be via food or inhaled allergens. EO appears to be a Th2 mediated immune response; IL-5 and IL-13 appear to play a key role in pathogenesis. The pathognomonic feature of EO is eosinophilic infiltration of ≥15 eosinophils/HPF in the oesophageal mucosa; eosinophils should be counted in the most densely inflamed part of the biopsy (X 400). Other features are eosinophilic micro-abscesses, superficial infiltration of eosinophils in the upper half of mucosa, basal zone hyperplasia and papillary lengthening. Most of the patients are men with a male to female ratio of 3:1, in the third or fourth decade of life. Presentation varies from dysphagia (60% to 90%), food impaction (50% to 60%), heartburn

Endoscopic findings include oesophageal rings (felinisation or trachealisation), raised white specks, longitudinal furrows, whitish exudates and a friable mucosa which may tear by passage of endoscope. Normal mucosa can be seen in up to a third of the patients. Strictures could be seen in any part of the oesophagus. Multiple (>5) biopsies from different levels of the oesophagus should be taken. Oesophageal pH monitoring should be done in difficult cases to rule-out GORD, or biopsies should be repeated after 6 weeks of PPI treatment. Barium swallow may reveal strictures, Schatzki’s ring or a diffuse narrowing of the oesophagus. Allergic testing by skin prick, skin patch test or food specific radioallergosorbent testing can be done. Treatment Treatment is to control the inflammation using systemic steroids, prednisolone 1 to 2 mg/kg, tapered over 6 weeks in patients with severe dysphagia, weight loss and refractory oesophageal strictures. Steroids should not be used for maintenance therapy. Other steroids used are swallowed topical fluticasone propionate (440 to 500 μg/day) twice daily for 6 weeks, swallowed budesonide mixed with sucralose and beclomethasone have also been used. Symptoms recur in 50% of patients when treatment is stopped and can be managed with reintroduction of same therapy or, use of steroid-sparing drugs like azathioprine. Leukotriene receptor antagonist montelukast 10 to 40 mg/day has been used with some success. Endoscopic dilatation of strictures should be preferably limited to patients after a trial of medical therapy, because of the risk of perforation. Dietary therapy by eliminating foods like dairy, peanuts, soy, fish, eggs wheat and other foods identified by allergic testing has been found to be successful in 70% of paediatric cases. Because of poor tolerability, dietary therapy should be used in individuals not responding to medical and endoscopic treatment. Studies with targeted therapies to IL-5 are underway. Hiatus Hernia Herniation through the oesophageal hiatus occurs in two forms: axial or sliding type in which both the distal oesophagus and a varying portion of the stomach (i.e. the entire oesophagogastric junction) are situated above the diaphragm, and para-oesophageal or rolling type in which the lower most oesophagus and the oesophago-gastric junction retain their position below the diaphragm, while a portion of the proximal stomach protrudes into the thorax alongside the oesophagus. The size of the sliding hernia alone does not predict the presence or severity of symptoms; larger, long-standing hernias are more likely to be associated with symptomatic GOR. In the less common para-oesophageal or rolling hernia, the less-than-atmospheric intrathoracic pressure is transmitted directly through the pleura to the peritoneal sac. With positive intra-abdominal pressure exerting an upward push, this hernia tends to enlarge progressively. The typical para-oesophageal hernia is rarely associated with GOR; however, it can get incarcerated and strangulation or bleeding may occur. The management of symptomatic sliding hiatus hernia is similar to that of GORD. Para-oesophageal hernia needs surgical correction to avoid complications.

OESOPHAGEAL WEBS, RINGS AND DIVERTICULA Oesophageal webs usually occur in the upper oesophagus, but may occur in the mid or lower oesophagus as well. They are thin horizontal membranes of stratified squamous epithelium, usually protrude from the anterior wall, rarely complete and are best demonstrated on the lateral view in the barium swallow. They are usually acquired, but webs in the upper third may be congenital in origin (Figure 6). A syndrome of cervical oesophageal web, anaemia and platonychia, which occurs mainly in middle-aged women, is called the Patterson-Kelly or Plummer-Vinson syndrome.

Oesophageal Disorders

and regurgitation (24% to 50%), refractory GORD, chest pain, abdominal pain, diarrhoea and weight loss. Children present with poor feeding, vomiting, regurgitation and failure to thrive.

Figure 6: Barium swallow shows a web in upper oesophagus.

Oesophageal rings are found near the lower oesophageal sphincter (LOS). They are of 2 types. Type A is a muscular ring, 4 to 5 mm thick and is the hypertrophied upper portion of LOS. Type B ring, or Schatzki ring, is a mucosal ring at the squamocolumnar junction; its upper surface is squamous epithelium and undersurface is columnar. It is usually associated with GORD or rarely EO. Rings and webs present with intermittent dysphagia to solid food. Rarely, dysphagia progresses to a severe state. Treatment consists of breaking the web or ring by dilatation; webs may rupture even during a diagnostic endoscopy. The underlying disorder like anaemia or GOR needs appropriate treatment. Diverticula are outpouchings of the oesophageal wall from an area of muscular weakness. Zenker’s diverticulum occurs due to weakness in the posterior hypopharynx; patients present with dysphagia and regurgitation. Treatment consists of cricopharyngeal myotomy. Epiphrenic diverticula occur in the distal oesophagus and are associated with oesophageal motility disorders. RECOMMENDED READINGS 1.

Clouse RE, Diamant NE. Esophageal motor and sensory function and motor disorders of the esophagus. In: Feldman M, Freidman LS, Brandt LJ, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease; 8th Ed. Saunders Elsevier; 2006: pp 855-904.


Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133: 1342.


Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological Association Institute Technical Review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:13921413.



Diseases of the Stomach and Duodenum

The stomach is a J-shaped organ continuous with the oesophagus proximally and the duodenum distally. It is divided from the proximal to distal end into the cardia, fundus, body or corpus, antrum and pylorus (pyloric channel). The duodenum is the first part of the small intestine and is in continuity with the pylorus of the stomach proximally and the jejunum distally. It forms a C-shaped loop around the head of the pancreas. The arterial blood supply of the stomach is derived from the coeliac artery and its major branches, the common hepatic, splenic and left gastric arteries while the duodenum receives additionally from the superior mesenteric artery. The venous drainage is into the portal vein or its tributaries, the superior mesenteric and splenic veins. The lymphatic drainage of the stomach is to the coeliac lymph nodes. The autonomic innervation stems from both the sympathetic (coeliac plexus) and the parasympathetic (right and left vagus nerves) nervous systems. The latter synapses with ganglion cells in the submucosa (Meissner’s plexus) and myenteric plexuses (Auerbach’s plexus). From these plexuses fibres are distributed to secretory components including cells and glands as well as to the gastric smooth muscle. MOTOR PHYSIOLOGY The motor function of the gastrointestinal (GI) tract is controlled at 3 levels. The first is the extrinsic neural control from the parasympathetic pathways via the vagus nerve and the sympathetic supply through the coeliac ganglion. The second level is provided by the enteric nervous system, which constitutes the complex network of ganglion cells in the layers of the gut wall. The third level of control of GI motility is in the excitable smooth muscle cells. Specific receptors in the cell membrane of the smooth muscle bind to amines, peptides, and other transmitters that reach the smooth muscle membrane via neurocrine, endocrine and paracrine routes. The main transmitters involved in excitation of the gastric muscle are acetylcholine and tachykinins, such as substance P and substance K. The main inhibitory transmitters are nitric oxide and vasoactive intestinal peptide (VIP). GASTRIC SECRETION The human stomach secretes water and electrolytes (H+, Na+, K+, Cl– and HCO3–), enzymes (pepsins and gastric lipase) and glycoproteins (intrinsic factor and mucins). The gastric exocrine secretions have a variety of functions.


Acid Secretion The most important secretion of the stomach is gastric acid, secreted from parietal cells in the fundus and body of the stomach. Parietal cells have on their basolateral membrane receptors for 3 stimulants: histamine (H2) receptor for histamine released from ECL cells and possible mast cells, a muscarinic

Pankaj Dhawan (M3) type of cholinergic receptor for acetylcholine released from post-ganglionic neurons and a cholecystokinin (CCK) receptor for gastrin released from pyloric and duodenal G cells. Hydrogen ions are generated in the parietal cell from water. The corresponding hydroxyl ions combine with cellular carbon dioxide (CO 2) to form HCO 3. This reaction is catalysed by carbonic anhydrase. HCO 3 ions are exchanged at the basolateral membrane for Cl – ions, which are ultimately secreted by the parietal cells. Hydrogen ions are exchanged for K+ catalysed by the magnesium dependant H+-K+ ATPase pump. The H+-K+ ATPase is inhibited by covalent antagonists such as the substituted benzimidazoles (e.g. omeprazole). The apical membrane of the parietal cell is impermeable to H+ and Cl– and hence, it does not diffuse back from the lumen into the cell. Other Secretions The other important gastric secretion is pepsinogen (PG). This is a proenzyme S which gets activated to pepsin in the gastric lumen by the gastric acid. Two types of pepsinogen are PG I and PG II. The gastric mucosa also secretes bicarbonates through the surface cells that are rich in carbonic anhydrase. Under most conditions, luminal HCO3 is overwhelmed by luminal H+ and is converted to CO2. Therefore, HCO3 is not ordinarily present in gastric juice. The other secretory products are gastric mucin and intrinsic factor. The role of intrinsic factor in vitamin B12 absorption is discussed elsewhere. GASTRITIS Gastritis is acute or chronic inflammation of the stomach and is most often diffuse. It is usually diagnosed on upper GI endoscopy and can be confirmed and classified histologically by performing a gastric biopsy. A detailed system for classification (Sydney system) has been adopted recently. Acute Gastritis This is also called erosive or haemorrhagic gastritis. Of these, the most common cause is use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). These agents cause gastric mucosal damage by inhibiting prostaglandins, gastric bicarbonate and mucous, disrupting epithelial tight junctions and altering gastric mucosal micro-circulation. The mucosal damage can result in either slow upper GI bleeding which can be detected as positive faecal occult blood test or can manifest as massive upper GI bleeding. In some patients, epigastric discomfort, anorexia and nausea may be present. Treatment includes omission of the offending agent, acid-suppressive agents such as H2 receptor antagonists and proton-pump inhibitors, prostaglandin analogues such as misoprostol (more useful for prevention) and cytoprotective agents, such as sucralfate.

Diseases of the Stomach and Duodenum

Chronic Gastritis Chronic gastritis progresses over years in three stages. In chronic superficial gastritis, there is infiltration of lymphocytes and plasma cells in the lamina propria; however, the mucosal thickness is normal. In atrophic gastritis, there is reduction in the gastric glands (parietal and chief cells) along with infiltration of plasma cells and lymphocytes. When there is associated polymorphonuclear cells infiltration, gastritis is termed active. In gastric atrophy, glands are lost, mucosal thickness is reduced, infiltration of lymphocytes and plasma cells is minimal and there may be foci of intestinal metaplasia. The two main types of chronic gastritis are autoimmune (formerly type A) and H. pylori-associated (formerly type B). Autoimmune gastritis involves the gastric body and spares the antrum. Parietal cell and intrinsic factor antibodies are serum markers of autoimmune chronic gastritis. Patients present with pernicious anaemia (megaloblastic anaemia with absolute achlorhydria) and features of vitamin B 12 deficiency. Also, autoimmune chronic gastritis is a pre-malignant condition and can progress to gastric cancer. H. pylori-associated chronic gastritis usually involves the antrum but over a period of time may involve the body as well (see Infection Section).

Figure 2: Duodenal ulcer in first part of duodenum.

An uncommon cause of chronic gastritis is Menetrier’s disease (hypertrophic gastritis). The most common presentation is in middle age with features of protein-losing enteropathy. On upper GI endoscopy, enlarged rugal folds in the fundus and body are evident. Histologically, gastric pits and glands are elongated and tortuous and the parietal and chief cells are replaced by mucous-secreting glands. Treatment with protonpump inhibitors may decrease protein loss. However, in patients who do not respond, gastric resection may become necessary. PEPTIC ULCER DISEASE Peptic ulcers are defects in the GI mucosa that result when injury occurs due to the effects of acid and pepsin in the GI lumen. Although the term ‘peptic ulcer’ is commonly used to describe ulcers in the stomach (Figure 1) and duodenum (Figure 2), peptic ulcers can develop in any portion of the GI tract exposed to acid and pepsin such as the oesophagus, Meckel’s diverticulum or site of gastrojejunostomy (Figure 3). In the early Figure 3: Barium meal showing an anastomotic ulcer at the gastro-jejunostomy site.

part of the 20th Century, stress and diet were thought to be important pathogenetic factors. During the 1980s, it was established that most peptic ulcers were related to either H. pylori infection or due to consumption of NSAIDs. This revolutionised the management of peptic ulcer disease. Pathophysiology Peptic ulcer occurs when the deleterious effects of acid and pepsin overwhelm the ability of the mucosa to resist these effects.

Figure 1: Benign gastric ulcer at incisura.

Defence Mechanisms The mechanisms that normally enable the mucosa to resist acidpeptic attack can be divided into three components: preepithelial, epithelial and post-epithelial defence mechanisms.


Pre-epithelial defence mechanisms A prominent coat of mucous and a layer of unstirred water rich in bicarbonate constitutes this component. Within the mucous layer glycoprotein form a physical barrier to the diffusion of pepsin. Mucous also contains phospholipids which protect the mucosa by forming a hydrophobic layer.

are asymptomatic, but may cause symptoms as well as complications such as, bleeding, perforation and obstruction. Asymptomatic ulcers can be endoscopically documented in 15% to 45% of patients receiving chronic NSAID therapy. However, 1% to 4% of patients receiving NSAIDs for 1 year will experience serious GI complications.

Epithelial defence mechanisms The apical cell membranes and the tight junctional complexes between the surface cells limit the diffusion of hydrogen. Excess hydrogen ions can be removed actively by ion pumps in the basolateral membrane, such as Na+/H+ exchanger and Cl–/HCO3– exchanger. Mucosal cell restitution regulated by growth factors (epidermal and fibroblast growth factors) also plays a part.

The major mechanism of NSAIDs-induced injury appears to be due to its topical effects leading to ulcers, erosions and sometimes acute haemorrhages. Most NSAIDs are weak organic acids that in acidic gastric juice become unionised, and thus, are freely lipid soluble. These diffuse across the gastric epithelium into the cytoplasm. Uncoupling of oxidative phosphorylation resulting in decreased mitochondrial energy production, reduction in cellular integrity and increase in cellular permeability. Attenuation of the gastric mucous gel layer also occurs. Enteric coated NSAIDs produce considerably less acute topical erosive injury than non-enteric coated formulations over short term (1 to 2 weeks) usage.

Post-epithelial defence mechanisms Mucosal blood flow comprises the post-epithelial defence mechanism. Abnormalities in Gastric Acid Secretion, Acid Homeostasis and Gastroduodenal Motility In 1910, Schwarz proposed his famous dictum ‘no acid, no ulcer’. This followed numerous studies on abnormalities in acid homeostasis in peptic ulcer. After the discovery of H. pylori it has been shown that many of these abnormalities may not be the primary defects but reversible consequences of infection with H. pylori. Abnormalities associated with duodenal ulcer Studies have shown these patients to be hypersecretors of gastric acid with an increase in the number of parietal cells. This may be related to H. pylori induced increases in cytokines such as tumour necrosis factor which stimulates gastrin release from G cells and H. pylori mediated decrease in somatostatin, a peptide which suppresses gastric release. Also an increased rate of liquid gastric emptying with increased acid burden in duodenum has also been described. Abnormalities associated with gastric ulcer Whereas the mucosa of the fundus and body is acid secreting (oxyntic) mucosa with abundant parietal cells, the gastric antrum is normally lined by a columnar epithelium that does not secrete gastric acid. The majority of gastric ulcers occur in the non-acid secreting epithelium at or near its junction with oxyntic mucosa. Long standing gastritis as occurs in H. pylori infection can cause atrophy of oxyntic mucosa with development of intestinal metaplasia and extension of the non-acid secreting epithelium into the proximal stomach. Patients who have gastric ulcers in the proximal stomach have chronic gastritis, substantial gastric atrophy and low gastric acid outputs. Helicobacter pylori H. pylori is associated with more than 80% of duodenal ulcers and more than 60% of gastric ulcers patients. Host factors as well as bacterial virulence factors (such as cagA positive H. pylori) may determine disease predisposition in those who are H. pylori positive.


Nonsteroidal Anti-Inflammatory Drugs A large number of peptic ulcers not related to H. pylori are related to NSAIDs use. Typically NSAIDs-induced ulcers

Injury also occurs through its systemic effects. Peptic ulcers will develop after intravenous or rectal suppository further supporting a systemic effect. Cyclo-oxygenase (COX) is the rate limiting enzyme for prostaglandin synthesis. Most NSAIDs (excepting the specific COX-2 inhibitors) reduce mucosal prostaglandin. A small dose of 10 mg of oral aspirin can decrease gastric prostaglandin levels by 60% and can cause gastric ulcers. Levels do not recover till 5 to 8 days. Animal experiments indicate that for gastric ulcers to occur both COX-1 and COX-2 must be inhibited. Hence, theoretically, COX-2 specific inhibitors are associated with improved GI toxicity profile. Besides COX inhibition NSAIDs increase gastric acid secretion, decrease gastric mucosal blood flow, decrease mucous production and duodenal bicarbonate. Nitric oxide (NO) protects the GI mucosa from NSAIDs-induced injury. Nitric oxide donating NSAIDs or COX inhibiting nitric oxide donating drugs (CINODs) exhibit reduced GI toxicity in animal and human trials. Other Ulcerogenic Drugs Besides NSAIDs the other ulcerogenic drugs are 5-fluorouracil, potassium chloride, mycophenolate mofetil, and bisphosphonates (alendronate and risedronate). Hypersecretory Conditions These should be considered in any patient who has peptic ulcer not associated with H. pylori or NSAIDs. Other clues include severe complicated disease, ulcers in the post-bulbar duodenum and diarrhoea. Hypersecretory conditions include gastrinoma, systemic mastocytosis and myeloproliferative disorders with basophilia, and antral G cell hyperfunction. Epidemiology It has been observed that there is a declining prevalence of peptic ulcer disease, in part related to falling prevalence of H.pylori. In contrast ulcer related complications as well as hospitalisation is on the rise, particularly in elderly due to increased use of NSAIDs. Cigarette smoking is a risk factor for peptic ulcer disease and its complications. It slows healing and predisposes to relapses. However, if H. pylori is eradicated, smoking does not influence relapses.

Clinical Features of Uncomplicated Peptic Ulcer Disease The main symptom of peptic ulcer disease is abdominal pain. Patients with duodenal ulcer describe burning or gnawing epigastric pain. Pain occurs 2 to 3 hours after a meal and is relieved after food or with antacids. Pain may occur in the night. Anorexia and weight loss are uncommon. Patients with gastric ulcers may have pain indistinguishable from duodenal ulcer. Peptic ulcers may be asymptomatic. Symptoms are neither specific nor sensitive for diagnosing peptic ulcers. If peptic ulcer is suspected, investigations must be carried out. Increase in severity of pain, radiation of pain to the back, pallor, vomiting or bleeding should point to the development of complications. It should be remembered that the symptoms of gastric cancer may be very similar to those of peptic ulcer. Presence of alarm signs like increased severity of pain, pallor, weight loss, vomiting, high ESR and presence of occult blood in stool should prompt investigations. In uncomplicated peptic ulcer the clinical examination will be unremarkable or the only sign will be tenderness in the epigastrium or slightly to the right of the midline in the upper abdomen. Diagnostic Tests Upper GI endoscopy has become the gold standard for diagnosis of peptic ulcer. Barium-meal is a far less sensitive investigation. Also endoscopy allows an opportunity for mucosal biopsy. Studies of acid secretion have little role in the diagnosis of peptic ulcer. However, these are useful in the work up of hypergastrinaemia, and to assess the completeness of vagotomy in recurrent ulcer. In patients with refractory peptic ulcer, serum calcium and fasting serum gastrin are indicated. Treatment The treatment of peptic ulcer has dramatically changed over the years. From bed rest and prescription of ‘bland diets’ came the era of antacids. The discovery of H2 receptor antagonists and later of proton pump inhibitors (PPIs) achieved greater ulcer healing rates. The real revolution occurred, however, with discovery of the link between H. pylori and peptic ulcer.

containing) or constipation (aluminium containing). Antacids must be used cautiously in patients with renal insufficiency. Histamine (H2) receptor antagonits These include cimetidine, ranitidine, famotidine, roxatidine and nizatidine. These agents competitively inhibit histamine stimulated acid secretion. All of them decrease basal as well as meal stimulated acid output. These agents are well absorbed after oral dosing and are not affected by food. All of them are eliminated by a combination of renal excretion and hepatic metabolism. H 2 receptor antagonists are remarkably safe and well tolerated. Overall incidence of sideeffects is less than 4% and serious side effects are very uncommon. A variety of central nervous system symptoms have been rarely reported; these include headache, dizziness, depression. Drug interactions (inhibiting elimination of theophylline, phenytoin, lidocaine, quinidine and warfarin) have been reported due to binding of hepatic cytochrome P450 (CYP) system. Tolerance appears to develop quickly and frequently.

Diseases of the Stomach and Duodenum

As far as alcohol is concerned, wine and beer are potent acid secretagogues but its importance in pathogenesis of peptic ulcer is dubious. There is no study which has clearly demonstrated a link between diet and peptic ulcer disease. Coffee (both caffeinated and decaffeinated), tea and colas are potent acid secretagogues. Amongst the diseases associated with peptic ulcer are alcoholic cirrhosis, chronic pulmonary disease and chronic renal failure. Despite popular belief, there is no role of emotional stress and peptic ulcers. Some studies have suggested that genetics may predispose to peptic ulcer disease.

Proton pump inhibitors These agents decrease gastric acid by inhibiting the H+/K+ ATPase pump of the parietal cell. Currently five PPIs are available; omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole. They are all substituted benzimidazoles and are weak bases. They are prodrugs and are acid labile. PPIs are most effective when administered immediately before meals. If the dose is once daily, it is preferable to administer immediately before breakfast. Single dose may inhibit gastric acid secretion for more than 24 hours. Newer PPIs inhibit H+/ K+ ATPase more rapidly than omeprazole. PPIs are remarkably safe. Common side-effects are headache and diarrhoea. No dose adjustment is required in patients with renal or hepatic impairment. Elevation of gastric pH can interfere with absorption of drugs such as ketoconazole (decrease) and digoxin (increase). Drug interactions are uncommon. Potential interactions may occur since PPIs are metabolised by CYP system. One such example is reduction in the effect of clopidogrel. Although PPIs cause hypergastrinaemia, there is no human report of development of gastric carcinoid tumours. Tolerance to the anti-secretory effects of PPIs is not seen. There is no need for routine H. pylori eradication prior to initiating treatment with PPIs. Mucosa protective agents

Acid lowering drugs These are not routinely required for patients with uncomplicated H. pylori ulcers in whom the bacterium has been successfully eradicated. However, anti-ulcer drugs are important for healing of large ulcers, management of complicated ulcer disease such as bleeding, reducing the risk of ulcer relapse in patients on NSAIDs and treating idiopathic ulcers.

Sucralfate: This is a complex metal salt of sulphated sucrose and aluminium hydroxide. When exposed to gastric acid, the aluminium hydroxide dissociates, leaving sulphate anions that can bind electrostatically to positively charged proteins in damaged tissue. It forms a protective layer over the ulcer craters. Other beneficial effects include increase in mucosal prostaglandins, stimulation of mucous and bicarbonate secretions, binding of bile salts and promotion of angiogenesis. It is effective in promoting healing when given in a dose of 1 g four times a day. Since it is not absorbed, there is no systemic toxicity.

Antacids: Besides increasing the gastric pH, antacids have a variety of cytoprotective effects. At present, they are used mainly for relieving symptoms. Side-effects include diarrhoea (magnesium

Bismuth: The two commonly used preparations are colloidal bismuth subcitrate and bismuth subsalicylate. The bismuth component forms complexes with mucous and coats the ulcer 809

craters. Also bismuth has anti-microbial action against H. pylori. Bismuth is unabsorbed if given over a short duration and systemic toxicity is rare.

compliance, failed H. pylori eradication, ongoing NSAIDs, smoking, hyper-secretory condition and other aetiologies (neoplastic, infective).

Prostaglandin E analogues: Prostaglandin E2 regulates mucosal blood flow, epithelial cell proliferation, epithelial restitution, mucosal immunocyte function, mucous and bicarbonate secretion, and basal acid secretion. Misoprostol, a prostaglandin analogue is used for prevention of NSAIDs-induced ulcer disease. It is well absorbed after oral administration. Dose related diarrhoea is observed in nearly one-third of the patients. It is contraindicated in pregnant women.

Complications The complications of peptic ulcer are penetration, perforation, haemorrhage and obstruction.

Ulcers associated with H. pylori Peptic ulcer management was revolutionised after discovery of H. pylori. It is well established that H. pylori eradication not only heals ulcers but also prevents relapses. H. pylori is associated with 70% to 90% of duodenal ulcers and 40% to 70% of gastric ulcers. For uncomplicated duodenal ulcers, additional antisecretory treatment is not required. For large gastric ulcers additional anti-secretory treatment may promote ulcer healing. For large gastric ulcers, biopsy must be taken to exclude malignancy. After successful eradication, maintenance therapy with anti-secretory agents is not required. Ulcers associated with NSAIDs In this situation NSAIDs should be discontinued, if possible. PPIs are more effective than H2 receptor antagonists or misoprostol for healing of NSAIDs-induced ulcers. There is little role of substituting a selective COX 2 inhibitor in place of conventional NSAIDs once an ulcer develops. H. pylori needs to be eradicated if present in these patients. Prophylaxis of NSAIDs ulcers H2 receptor antagonists reduce the risk of duodenal ulcers but not gastric ulcers. Misoprostol reduces the risk of NSAIDsinduced gastric and duodenal ulcers. Higher dose (800 μg/day) of misoprostol reduced ulcer complications. PPIs are very effective in reducing the risk of NSAID-induced gastric and duodenal ulcers. COX 2 inhibitors induced fewer ulcers than conventional NSAIDs. New data suggest that a combination of non-selective NSAIDs with PPI is as effective or better than using selective COX 2 inhibitors in prevention of NSAIDs-ulcers. Also studies have shown increased serious cardiovascular events with the use of COX 2 inhibitors. If H. pylori is present, it needs to be eradicated. This is also recommended for patients on long-term, low-dose aspirin. In patients with risk factors for ulcer complications (Table 1), co-therapy with a PPI is recommended.

Penetration refers to the extension of the ulcer through the bowel wall into the adjacent structures without producing free perforation into the peritoneal cavity. The ulcer can penetrate into the pancreas, biliary tract, omentum or colon. Perforation into the colon leads to gastro-colic fistula. Symptoms of penetration vary depending on the organ involved. It manifests as increase in severity and duration of pain and failure of pain relief with antacids or food. Bleeding from peptic ulcer is a life-threatening complication.The patient may present with melaena, haematemesis or both. When the bleeding is massive haematochezia will be present. Old age, shock at the time of admission and massive bleeding necessitating transfusion of more than five units of blood indicate poor prognosis, and surgery should be considered in these situations. The first step in the management is resuscitation of the patient by replacing the blood volume and managing haemodynamic instability. Upper GI endoscopy should be done as soon as the patient is stable. This will show the site of bleed. Active bleeding or the presence of high-risk lesions—visible vessel or adherent clot (Figure 4)—call for endoscopic management. Injection of saline or dilute adrenaline (Figure 5), application of heater probe, endoscopic application of clips (Figure 6) can all arrest the bleeding. Anti-secretory treatment (intravenous, continuous infusion of PPI) should be started.

Table 1: Risk Factors for NSAIDs-Induced Ulcer Complications History of peptic ulcer complication Increasing age Use of steroids Use of anti-coagulants Use of combination NSAIDs Co-morbid diseases Smoking


Refractory Peptic Ulcers Most peptic ulcers heal with 8 to 12 weeks of anti-secretory therapy. If this does not occur, consider the following: lack of

Figure 4: Duodenal ulcer with stigmata of recent bleed (black base).

Perforation of peptic ulcer is an emergency. The patient presents with sudden onset of abdominal pain; peritonitis and free gas in the peritoneum are present. Patients who present late and those who develop perforation while in the hospital have a poor prognosis. Surgical treatment, which involves closure of the perforation with an omental patch is the procedure often employed. Effective treatment of H. pylori infection and strong acid suppressants are available now, and

Diseases of the Stomach and Duodenum

Figure 5: Injection sclerotherapy being done for bleeding duodenal ulcer with stigmata of recent bleed (visible vessel).

Figure 7: Endoscopic balloon dilatation for pyloroduodenal stenosis.

Ulcers in the lower end of the oesophagus may in the long run lead to peptic strictures and dysphagia. Endoscopic balloon dilatation gives symptomatic relief to these patients. Fibrosis during healing of gastric ulcers may result in rare deformities of the stomach like ‘tea-pot stomach’ or the ‘hourglass stomach’. Recurrent ulcer is the term used for recurrence of ulcers after surgical treatment of duodenal ulcer. Incomplete vagotomy and retained antrum are the most common causes. Duodenal ulcer does not turn malignant. H. pylori is implicated as an aetiological agent in carcinoma stomach. In spite of the high prevalence of H. pylori in persons with peptic ulcer, duodenal ulcer is not a risk factor for the cancer of the stomach or of the duodenum. However, persons who had undergone surgery (partial gastrectomy) for duodenal ulcer are at increased risk of developing cancer in the post-operative stomach. Figure 6: Haemoclips applied to base of bleeding ulcer.

hence, a definitive surgical treatment may not be necessary in selected patients; small leaks into peritoneum can be managed conservatively. Obstruction in peptic ulcer may be due to fibrosis, inflammation or spasm. It is the pyloric channel ulcers or ulcers in the first part of duodenum that develop gastric outlet obstruction. Gastric outlet obstruction (pyloric stenosis) (Figure 7) presents with postprandial bloating, fullness and vomiting. Vomiting brings out food consumed several (>6) hours ago. Foul smelling eructations may be present. Examination reveals a visibly dilated stomach, visible peristalsis or succussion splash. Barium meal shows a dilated stomach with delayed emptying. Endoscopy should be performed after thorough cleaning of the stomach. Carcinoma of the stomach should be excluded in every patient with gastric outlet obstruction as malignancy is seen in about half of such cases. Management includes gastric lavage to remove food debris, correction of fluid and electrolyte disturbances and metabolic consequences of prolonged vomiting and loss of gastric acid. Anti-secretory drugs should be administered parenterally since absorption is poor. H. pylori infection and NSAID intake should be looked for and managed. If the symptoms fail to respond, surgery is indicated. Endoscopic balloon dilatation of the narrowed segment has also been used successfully (Figure 7).

GASTRIC VOLVULUS Twisting of the stomach upon itself leads to gastric volvulus which can present clinically either acutely or as chronic volvulus. Three types have been described—organoaxial volvulus is the most common; in this type the stomach twists along its long axis (cardiopyloric line); mesenteroaxial volvulus is one in which the stomach falls on itself along an imaginary line drawn from the mid-point of the lesser curvature to the mid-point of the greater curvature and is the least common of the three; mixed gastric volvulus is a combination of organoaxial and mesenteroaxial types. Anatomical anomalies such as ligamentous laxity, paraoesophageal hiatus hernia, eventration of the diaphragm, extrinsic compression from adjacent organs or submucosal tumours of the stomach can cause gastric volvulus. Patients with acute gastric volvulus present as an acute abdomen with the classical triad of violent retching and little vomiting, severe epigastric pain and inability to advance a nasogastric tube into the stomach. In patients with chronic volvulus the major symptoms are epigastric pain, bloating and eructations. Barium-meal examination usually demonstrates the twisted stomach. Acute volvulus is an emergency and usually requires an emergent laparotomy although endoscopic derotation of the


volvulus is sometimes successful. Recurrent symptoms in patients with chronic volvulus need surgical treatment wherein the stomach is fixed to the anterior abdominal wall by performing a gastropexy. Recently, percutaneous endoscopic gastrostomy has been found to be an alternative to surgical gastropexy. BEZOARS These have been classified into two main groups: hair or trichobezoar and plant or phytobezoars. Other materials such as chemical concretions, food boluses and foreign bodies may also cause bezoars. For phytobezoars, hypochlorhydria, gastroparesis and incomplete mastication are important predisposing factors. In patients with trichobezoar, underlying neuropsychiatric disturbances may be present. Bezoars present with pain in the upper abdomen, periodic attacks of nausea and vomiting and a lump in the abdomen. Complications such as gastric ulcer, perforation and peritonitis may occur. Plain X-ray abdomen in the standing position occasionally demonstrates a mass invading the gastric air bubble. Barium-meal examination demonstrates a barium shell coating an irregular large filling defect. In most cases upper GI endoscopy is diagnostic. For treating phytobezoars, endoscopic internal fragmentation using forceps and polypectomy snares may be tried. Chemical dissolution using papain, cellulase and acetylcysteine is sometimes successful. If these methods fail, surgical removal needs to be done. In most cases of trichobezoars, surgery is required. DUODENAL DIVERTICULUM It is usually single and present along the medial wall of the duodenum. It is acquired as an outpouching of the duodenal mucosa at the point of maximum weakness. Most often this diverticulum is asymptomatic and incidentally detected during a barium-meal examination or Upper GI endoscopy (Figure 8). Rarely, duodenal diverticulum may perforate retroperitoneally, cause upper GI bleeding or obstruct the bile duct or pancreatic


Figure 8: Barium-meal examination showing duodenal diverticulum along medial wall.

duct. The treatment of a complicated duodenal diverticulum is surgical. RECOMMENDED READINGS 1.

Chiba N, Hunt RH. Ulcer disease and Helicobacter pylori infection: aetiology and treatment. In: McDonald JWD, Burroughs AK, Feagan BG, editors. Evidence Based Gastroenterology and Hepatology. Bangalore: Panther Publishers; 1999: pp 91-117.


Desai HG. Gastritis: Indian Perspective. Vakils, Feffer and Simons Pvt Ltd 2008.


Spechler JS, Cryer B. Peptic ulcer disease. In: Mark Feldman, Lawrence S. Friedman, Lawrence J. Brandt editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases Pathophysiology/Diagnosis/Management. WB Saunders & Co.; 2006: pp 1089-110.

13.9 ACUTE PANCREATITIS Acute pancreatitis (AP) is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems. Mild acute pancreatitis consists of minimal or no organ dysfunction and an uneventful recovery. Severe pancreatitis manifests as organ failure and/or local complications such as necrosis, abscess, or pseudocyst (Table 1). Overall, about 20% of patients with acute pancreatitis have a severe course, and 10% to 30% of those with severe acute pancreatitis die. Table 1: Criteria of Severe Acute Pancreatitis Organ failure Shock: Systolic blood pressure of 500 mL in 24 hours And/Or local complications Necrosis Abscess Pseudocyst Unfavourable prognostic signs >3 Ranson’s signs >8 APACHE II points

Aetiopathogenesis The gallstone disease and alcohol are the two most common causes for AP (Table 2). The initial step in the pathogenesis of acute pancreatitis is conversion of trypsinogen to trypsin within acinar cells.Trypsin, in turn, catalyses conversion of pro-enzymes, including trypsinogen and inactive precursors of elastase, phospholipase A2, and carboxypeptidase, to active enzymes. Active enzymes autodigest the pancreas and initiate a cycle of releasing more active enzymes. Factors that may initiate gallstone pancreatitis include reflux of bile into the pancreatic duct or obstruction of the pancreatic duct at the ampulla by a stone(s) or oedema resulting from the passage of a stone. The pathophysiology of acute pancreatitis includes microcirculatory injury, leucocyte chemoattraction and release of cytokines, oxidative stress, and bacterial translocation. Clinical Features Abdominal pain is present at the onset, but the timing of abdominal pain is variable. Biliary colic may herald or progress to acute pancreatitis. Alcohol-related acute pancreatitis frequently occurs 1 to 3 days following drinking. The pain radiates to back and is associated with nausea and vomiting. Its onset is rapid and reaches maximal intensity in 10 to 20 minutes. Occasionally, pain takes several hours to reach maximum intensity. It is steady and moderate to very severe in intensity. Physical findings depend on the severity of an attack. Patients with mild pancreatitis may not appear acutely ill and have mild

Diseases of the Pancreas V Balakrishnan, G Rajesh abdominal tenderness. In severe pancreatitis, patients look severely ill and often have abdominal distention, especially epigastric, which is due to gastric ileus or dilatation of the transverse colon. Bowel sounds are reduced and may be absent. Table 2: Aetiology of Acute Pancreatitis Gallstones Biliary sludge and microlithiasis Alcohol Mechanical obstruction of ampulla Metabolic: Hypertriglyceridaemia and hypercalcaemia Infections: Mumps, HIV, CMV, EBV, Clonorchiasis, and Ascariasis Toxins: Scorpion venom, organophosphorous insecticides Trauma Post ERCP Pregnancy Post-operative Hereditary Ischaemia Drugs: Pentamidine, didanosine, salicylates, sulindac, frusemide, thiazides Sulphasalazine, mesalamine, L-asparaginase, azathioprine, valproic acid, ACE-inhibitors

Diagnosis Acute pancreatitis can be diagnosed by the presence of typical clinical features along with corroborative laboratory findings of elevated serum enzymes (amylase/lipase) and/or imaging features. It needs to be differentiated from other abdominal causes which may present as an acute abdomen. Investigations Blood investigations The white blood cell count is usually elevated, markedly so in severe pancreatitis. A raised haematocrit, indicative of haemoconcentration, may indicate severe disease. Serum amylase is the most frequently ordered test. However, hyperamylasemia can also occur in other conditions. In acute pancreatitis, the serum amylase concentration is usually more than three times the upper limit of normal. Measurement of serum lipase is performed less frequently. Amylase levels tend to return to normal faster than lipase levels, so that measurement of the latter is particularly useful in patients who present several days after the onset of pain. An increase in serum alanine aminotransferase (ALT) 3 to 4 times the base-line level suggests gallstone-induced pancreatitis. Imaging There can be localised ileus of a segment of small intestine (‘sentinel loop’) or the colon cut-off sign on a plain radiograph of the abdomen. Thirty per cent of patients with acute pancreatitis have abnormalities in chest radiograph in the form of elevation of a hemi-diaphragm, pleural effusion(s), basal or


plate-like atelectasis secondary to limited respiratory excursion, and pulmonary infiltrates. Transabdominal ultrasonography is the best initial imaging modality. It is used during the first 24 hours of hospitalisation to search for gallstones, dilatation of the common bile duct due to choledocholithiasis and ascites. Pancreas is usually diffusely enlarged and hypoechoic. A contrast enhanced computed tomography (CECT) scan of the abdomen is the most important imaging test for the diagnosis of acute pancreatitis and its intra-abdominal complications and is also used to assess the severity of the disease. Magnetic resonance imaging (MRI) shows the pancreas as well CT scan. In addition, it has certain advantages over the latter. It does not carry the potential nephrotoxicity of the contrast required to perform CECT, better than it avoids the radiation exposure of CT scan and finally, it shows a greater ability than CT scan to distinguish necrosis from fluid. Endoscopic ultrasound (EUS) helps in timely diagnosis of common bile duct (CBD) or ampullary stones in the setting of acute gallstone pancreatitis; hence it can be used instead of diagnostic endoscopic retrograde cholangio-pancreatography (ERCP) to identify patients who would likely benefit from therapeutic ERCP. Treatment The algorithm for treatment of acute pancreatitis is outlined in Figure 1.

Mild acute pancreatitis The prognosis of mild pancreatitis is good and can be managed in a regular hospital ward with fluid administration, bowel rest and analgesics. Fluid resuscitation is important to replace low intravascular volume due to vomiting, diaphoresis, and third-space losses. Abdominal pain is treated with parenteral analgesics. Most patients require no further therapy and recover within a week. Severe acute pancreatitis Patients with signs of severe acute pancreatitis should be identified early and admitted promptly to an intensive care unit. The goal is to provide supportive care and treatment of complications when they develop. Maintaining adequate intravascular volume may require 5 to 10 litres of fluid daily for the initial few days. Hypoxaemia (oxygen saturation 55 16000 >200 >350 >250

>70 18000 >220 >400 >250

>10 >5 6L

>10 >2 5 >4L

CHRONIC PANCREATITIS Chronic pancreatitis (CP) is characterised by pancreatic inflammation and fibrosis, the end point of which is destruction of pancreatic parenchyma with eventual loss of exocrine and endocrine function. Aetiology The aetiologic risk factors associated with chronic pancreatitis is given in Table 5. Alcohol The most common cause of chronic pancreatitis in the Western world and in Japan is excessive alcohol consumption. In most patients, at least five years of alcohol intake exceeding 80 g/ day is required prior to the development of chronic pancreatitis. Tropical pancreatitis Tropical pancreatitis ( TCP) remains an important form of chronic pancreatitis in certain areas of India. The exact aetiopathogenesis of TCP remains unknown. Nutritional

deficiencies, especially of micronutrients and antioxidants or/ and dietary toxins such as cyanogenic glycosides (cassava or tapioca), have been considered as likely aetiological factors. Hereditary pancreatitis Hereditary pancreatitis is a rare autosomal dominant disorder with approximately 80% penetrance. It presents typically in childhood or early adulthood with abdominal pain and recurrent acute attacks of pancreatitis.

Diseases of the Pancreas

scoring systems like Ranson’s score, Glasgow score, acute physiology and chronic health evaluation (APACHE) II, among others (Tables 3 and 4). A new prognostic scoring system, the bedside index for severity in acute pancreatitis—BISAP (blood urea nitrogen >25 mg/dL, impaired mental status, systemic inflammatory response syndrome (SIRS), age >60 years, and pleural effusions) was comparable to existing scoring systems.

Table 5: Aetiologic Risk Factors Associated with Chronic Pancreatitis: TIGAR-O Classification System Toxic-metabolic Alcohol, tobacco smoking, hypercalcaemia (hyperparathyroidism), chronic renal failure, medications (phenacetin), toxins (organotin compounds, e.g. DBTC) Idiopathic Early onset, late onset Tropical (tropical calcific pancreatitis,fibrocalculous pancreatic diabetes) Genetic Autosomal dominant (Cationic trypsinogen codon 29 and 122 mutations) Autosomal recessive/modifier genes (CFTR mutations,SPINK1 mutations Cationic trypsinogen codon 16, 22, 23 mutations, α1-antitrypsin deficiency) Autoimmune Isolated autoimmune chronic pancreatitis Syndromic autoimmune chronic pancreatitis (Sjögren syndromeassociated chronic pancreatitis, inflammatory bowel disease-associated chronic pancreatitis Primary biliary cirrhosis—associated chronic pancreatitis) Recurrent and severe acute pancreatitis Post-necrotic (severe acute pancreatitis), recurrent acute pancreatitis, vascular diseases/ischaemic, post-irradiation Obstructive Pancreatic divisum, sphincter of Oddi disorders, duct obstruction (e.g. tumour) Pre-ampullary duodenal wall cysts,post-traumatic pancreatic duct scars

Obstructive chronic pancreatitis Obstruction of the main pancreatic duct by tumours, scars, cysts, or stenosis of the papilla of Vater or minor papilla can produce chronic pancreatitis in the parenchyma upstream of the obstruction. Blunt and penetrating trauma to the pancreas can also lead to pancreatic duct strictures. Autoimmune pancreatitis This is characterised by presence of autoantibodies, elevated levels of immunoglobulins especially IgG4, enlargement of the pancreas (diffuse or focal), pancreatic duct strictures, and pathologic features of a dense lymphocytic infiltrate. A common presentation is that of a pancreatic mass mimicking cancer. It is often steroid responsive. Low dose steroids or immunomodulators may be needed to maintain remission. Idiopathic chronic pancreatitis Idiopathic chronic pancreatitis accounts for 10% to 30% of all cases of CP in the West and 40% to 60% in India, and appears to occur in two forms, early onset and late onset type. Pathophysiology The pathophysiology of CP remains incompletely understood. Four major theories include toxic-metabolic, oxidative stress, stone and duct obstruction, and necrosis-fibrosis.


Pathology In early CP, areas of interlobular fibrosis are seen, with the fibrosis often extending to the ductal structures. Infiltration of the fibrotic area and lobules with lymphocytes, plasma cells, and macrophages is seen. In affected lobules, acinar cells are replaced by fibrosis. As the disease progresses, fibrosis within the lobules and between lobules becomes more widespread. The pancreatic ducts become more abnormal, with progressive fibrosis, stricture formation, and dilation. Protein plugs may calcify and obstruct major pancreatic ducts. Clinical Features The cardinal symptom of CP is abdominal pain. Fat malabsorption leading to steatorrhoea and weight loss is common in CP. Steatorrhoea does not occur until pancreatic lipase secretion is reduced to less than 10% of normal. Diabetes in CP is considered as a secondary form of diabetes mellitus. Weight loss is most commonly due to decreased intake in episodes of acute exacerbation. Weight loss may also occur owing to the development of small bowel bacterial overgrowth, malabsorption, uncontrolled diabetes or pancreatic or extrapancreatic malignancy. Physical examination might show evidence of nutritional deficiencies. Complications of common bile duct obstruction or a pseudocyst may produce physical findings of jaundice, or a palpable swelling in the epigastrium. Ascites may rarely follow a leak from a ruptured pancreatic duct. A palpable spleen may be seen following thrombosis of the splenic vein (Table 6). Diagnosis Serum amylase or lipase may be found to be elevated only during acute exacerbations. A full diabetic work-up should be done for all patients with suspected pancreatitis. A prediabetic stage has been well described.

Imaging The demonstration of pancreatic calcification on imaging is pathognomonic of CP. Diagnosis is difficult in early cases of pancreatitis where the patient may have typical symptoms but lack diagnostic imaging features on ultrasonography (USG)/CT. In such cases, an endoscopic retrograde pancreatography (ERP) or a EUS may be helpful. Pancreatic calcifications are most common in alcoholic, lateonset idiopathic, hereditary and especially in tropical pancreatitis and may be detected on abdominal radiograph. Ultrasonography findings indicative of CP include dilation of the pancreatic duct, pancreatic ductal stones, gland atrophy or enlargement, irregular gland margins, pseudocysts and changes in the parenchymal echotexture. CECT scan of the abdomen is superior to USG. The sensitivity of CT for CP is 75% to 90% and specificity 85% or more. ERCP is considered the most specific and sensitive test of pancreatic structure. The sensitivity of ERCP is between 70% and 90%, with a specificity of 80% to 100%. Magnetic resonance cholangiopancreatography (MRCP) agrees with ERCP in 70% to 80% of findings. MRCP is noninvasive, avoids ionising radiation and contrast administration, and does not routinely require sedation, making it a diagnostic procedure of choice in some groups of patients, particularly children. EUS is the best among currently available tests for the detection of early changes of CP. Typical findings in CP include parenchyma features like hyperechoic strands, hyperechoic foci, lobularity, cysts; and ductal features like stones, main duct irregularity, hyperechoic main duct, visible side branches, main duct dilatation.

Table 6: Complications of Chronic Pancreatitis No.


Signs and Symptoms





Biliary obstruction

Increased abdominal pain, nausea, vomiting, jaundice, palpable mass, bleeding, increase in amylase and lipase Jaundice, biliary pain, cholangitis, pruritus


Gastric outlet obstruction Pancreatic adenocarcinoma External pancreatic fistula

Abdominal pain, early satiety, nausea and vomiting Increased pain, weight loss, jaundice, elevated Ca 19-9 Consequence of surgical or percutaneous therapy for chronic pancreatitis or pseudocyst


Pancreatic ascites


Pleural effusion


Splenic vein thrombosis

Increased abdominal girth, high ascitic fluid amylase typically greater than 4000 units/L Shortness of breath, high amylase in pleural fluid typically greater than 4000 units/L Bleeding from gastric varices

Endoscopic drainage (transmural or transpapillary) Surgical drainage (cyst-gastrostomy or cyst-jejunostomy) Percutaneous drainage Drainage of obstructing pseudocyst Endoscopic decompression Surgical decompression Surgical biliary bypass, either with a cholecystojejunostomy or choledochojejunostomy Drainage of pseudocyst Surgical gastrojejunostomy Whipple’s or modified Whipple’s surgery Palliation if advanced disease NPO, parenteral nutrition, octreotide and endoscopic stent placement Surgical treatment includes pancreatic resection (if the fistula is in the tail) or a fistulojejunostomy, in which the fistula tract is ‘capped’ with a defunctionalised limb of jejunum Endoscopic stent placement, total parenteral nutrition

4. 5.


Therapeutic thoracentesis, endoscopic stent placement, total parenteral nutrition Splenectomy

Relief of pain Analgesics like acetaminophen for mild pain or non-narcotic agents for moderate to severe pain are usually used. If nonnarcotic agents fail, it is useful to begin with the less potent opioid agents like propoxyphene napsylate or tramadol before starting morphine. Pancreatic enzyme preparations, particularly those with high protease content and antioxidants may also help to relieve pain. Failure of medical management necessitates use of interventions like coeliac plexus block, extra-corporeal shock wave lithotripsy (ESWL), endoscopic therapy or surgery. Correction of maldigestion Pancreatic enzymes (~ 30,000 units of lipase) have to be given along with each meal. The enzyme activity tends to be degraded by the gastric acid, especially in case of non-enteric coated preparations; hence it is better to also administer proton pump inhibitors or H2 receptor antagonists. Management of diabetes A few newly detected diabetics in CP can be controlled with diet and regular exercise. The majority can be managed with oral hypoglycaemic agents for varying periods. A large group will require insulin for glycaemic control. Endotherapy The general goal of endoscopic therapy is to improve drainage of the pancreatic duct by relieving obstruction. Patients with a solitary stone or a few small stones in the head region with a dilated proximal duct are the ideal candidates. Sphincterotomy, with pancreatic duct stenting, sometimes undertaken after ESWL to crush the stones, is the usual procedure. Surgery Surgery is indicated for intractable abdominal pain that has failed medical therapy. Other indications for surgery include complications involving adjacent organs (duodenal, splenic vein, or biliary obstruction), pseudocysts failing endoscopic or radiologic management, internal pancreatic fistulas, and suspected or proven malignancy. Surgical options for pain can include pancreatic ductal drainage, resection of all or part of the pancreas, or both. If there is suspicion of a malignancy in the head, a pancreaticoduodenectomy should be undertaken. PANCREATIC CANCER Pancreatic cancer remains a leading cause of death with 5-year survival rates of less than 5%. Despite advances in diagnosis and staging, most cancers are diagnosed in an advanced stage and are suitable only for palliative treatment. Pathophysiology Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15% to 20% occur in the body of the pancreas, and 5% to 10% occur in the tail. It is a very

aggressive neoplasm. At the time of diagnosis, 80% will already have metastasised. Clinical Features The presenting symptoms of pancreatic carcinoma are generally non-specific. Cancer that originates from the head of the pancreas can produce obstructive jaundice, epigastric pain and weight loss. The presence of pain is a late symptom and back pain typically signifies advanced disease. Jaundice is usually progressive and associated with pruritus, which can often be severe. Dyspepsia and early satiety may be present due to delayed gastric emptying (gastroparesis). Vomiting may be present if the tumour has invaded or compressed the second portion of the duodenum, creating a partial or complete intestinal obstruction.

Diseases of the Pancreas

Treatment Continued alcohol abuse hastens the development of pancreatic dysfunction and continued alcohol abuse, along with smoking, increases mortality. Moreover, smoking is one of the risk factors for the progression to pancreatic cancer. There are good reasons, therefore, to encourage patients to stop drinking and smoking.

The patient is usually jaundiced and may be anaemic or cachectic. There may be an epigastric mass or an irregular, enlarged liver because of metastases. There may be a palpable gallbladder secondary to common bile duct obstruction. Other findings include left supraclavicular lymphadenopathy (Virchow’s node) and superficial thrombophlebitis (Trousseau’s sign). Investigations The lesion may have a variable appearance on ultrasonography; it may be hypoechoic, isoechoic, or hyperechoic as compared to normal pancreas. Pancreatic ductal dilatation and biliary ductal dilatation are easily demonstrated in patients with a tumour in the head of pancreas. Lymphadenopathy, relation of the tumour to peripancreatic vessels, and the tumour margins are demonstrated less reliably with sonography. CECT scan of abdomen using a pancreas protocol is the most useful and widely used imaging modality especially when some intervention is planned. Features on CT scan include: alterations in morphology of the gland with abnormalities of CT attenuation values, obliteration of peripancreatic fat, loss of sharp margins with surrounding structures, involvement of adjacent vessels and regional lymph nodes, pancreatic ductal dilatation, pancreatic atrophy, and obstruction of the common bile duct. Tumours less than 1 cm are readily visualised with EUS. ERCP has a sensitivity of 95% and a specificity of 85% for pancreatic malignancy. MRCP is a non-invasive alternative to ERCP. Serum carbohydrate antigen (CA) 19-9 has an overall sensitivity of approximately 80% and specificity of 90%. Treatment Surgery is the mainstay of treatment, but it is of value only if the primary tumour is less than 3 cm, free of major blood vessels and if there is no metastatic spread (Tables 7 and 8). Suitable patients undergo Whipple’s procedure, which involves excision of the head of the pancreas, the distal common bile duct, the gall bladder, the duodenum and distal stomach, followed by anastomosis of the pancreatic duct, the common hepatic duct, and the distal stomach to a loop of jejunum. Perioperative mortality is less than 5% in experienced hands. Modified Whipple’s procedure involves preservation of the distal stomach and pylorus, which may have long-term nutritional benefits. Distal pancreatectomy may be suitable for carcinoma of the body or tail.


Table 7: American Joint Committee for Cancer (AJCC) Staging of Carcinoma of the Pancreas (2002) T stage TX – Primary tumour cannot be assessed T0 – No evidence of tumour Tis – Carcinoma in situ T1 – Tumour limited to the pancreas,2 cm or less in greatest dimension T2 – Tumour limited to the pancreas, more than 2 cm in greatest dimension T3 – Tumour extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4 – Tumour involves the coeliac axis or the superior mesenteric artery (unresectable primary tumour) N Stage NX – Regional lymph nodes not assessed N0 – No regional lymph node metastasis N1 – Regional lymph nodes involved M stage MX – Distant metastases cannot be assessed M0 – No distant metastases M1 – Distant metastases present

Palliative Treatment Jaundice is palliated by stenting the biliary stricture. Both plastic and self-expandable metal stents (SEMS) have been used for palliation of jaundice. When endoscopic biliary drainage is unsuccessful or contraindicated, percutaneous transhepatic biliary drainage is done. Pain requires graded use of analgesic agents. Coeliac plexus block (percutaneous or EUS guided) and splanchnectomy are useful interventions for palliation of pain. Gemcitabine is the standard chemotherapeutic agent used for pancreatic cancer. Other drugs are capecitabine, 5-fluorouracil, cisplatin and oxaliplatin. RECOMMENDED READINGS 1.

Balakrishnan V, Unnikrishnan AG, Thomas V, et al. Chronic pancreatitis. A prospective nationwide study of 1,086 subjects from India. J Pancreas (Online) 2008; 9 (5): 593-600.


Banks PA, Freeman ML. Practice Parameters Committee of the American College of Gastroenterology. Practice Guidelines in Acute Pancreatitis. Am J Gastroenterol 2006; 101(10): 2379-2400.


Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008; 371(9607): 143-52.


Whitcomb DC, Beger HG. Definitions of pancreatic diseases and their complications. In: Beger H, et al editors. The Pancreas: An integrated Textbook of Basic Science, Medicine, and Surgery. Blackwell; 2008: pp 1-6.


Working Party of the British Society of Gastroenterology; Association of Surgeons of Great Britain and Ireland; Pancreatic Society of Great Britain and Ireland; Association of Upper GI Surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut 2005;54 (suppl 3): iii1-9.

Table 8: TNM Staging of Pancreatic Cancer Stage Classification 0 1A 1B IIA IIB III IV


Clinical classification

5-year survival rate

Tis, N0, M0 Resectable (7.5%) 15.2% T1, N0, M0 T2, N0, M0 T3, N0, M0 T1-3, N1, M0 Locally advanced (29.3%) 6.3% T4, any N, M0 Any T, any N, M1 Metastatic (47.2%) 1.6%


Functional Gastrointestinal Disorders

The term ‘functional gastrointestinal disorders’ is used for a group of conditions with clinical manifestations in the absence of obvious organic disease in gastrointestinal (GI) tract. These disorders constitute the most common gastrointestinal cause for consultation. The characterisation and classification of these disorders is based on predominant symptoms (which may suggest region of origin in the GI tract), because no single aetiological factor or investigative pattern has been identified in any subgroup. CLASSIFICATION For the sake of convenience, the disorders have been broadly classified as due to upper or lower GI disturbance. Although each subgroup has distinct features, many subjects have overlapping symptoms, suggesting that the disorder may be more diffuse than implied by the predominant symptom. Thus, patients with the irritable bowel syndrome (IBS), a predominantly lower GI disturbance, often have dyspeptic symptoms in addition. Also, in IBS, what is considered abnormal bowel frequency by the patient may overlap what is considered normal by a segment of the general population, suggesting visceral hypersensitivity in the patient. The Rome III criteria for functional bowel disorders (Table 1) are an attempt to improve on several previous classifications. FUNCTIONAL DYSPEPSIA (Synonyms: Idiopathic, essential or non-ulcer dyspepsia) Functional dyspepsia is a chronic or recurrent heterogeneous symptom complex that has its origin in the upper gastrointestinal tract, is localised to the upper abdomen, and is generally mealrelated. The Rome III criteria identifies two primary symptom groups, namely, epigastric pain or burning (the epigastric pain syndrome) and meal-related early satiety or postprandial fullness (the postprandial distress syndrome). The diagnosis of functional dyspepsia ideally requires that organic conditions with similar symptoms (peptic ulcer disease, gastro-oesophageal reflux disease, giardiasis, pancreatic and biliary diseases) be excluded first. In clinical practice, however, a normal upper gastrointestinal endoscopy is generally taken as adequate evidence, unless the suspicion of pancreatic or biliary disorder is strong enough to merit investigation. The likelihood of endoscopy detecting an organic lesion is low if it is undertaken as a regular practice. Aetiopathogenesis Recent data implicates phenotypic changes in acid secretion; alterations of fundic accommodation, antro-duodenal motility and gastric emptying; gastric hypersensitivity triggered by chemo- or mechanoreceptors; and hormonal disturbances; as the possible causes of dyspepsia, but each of these is present in only a proportion of the patients. A possible role of alphaadrenoceptor gene polymorphism has also been suggested.

Philip Abraham

Table 1: Rome III Diagnostic Criteria for Functional Bowel Disorders Functional Dyspepsia At least 3 months, with onset at least 6 months previously, of one or more of the following: Bothersome postprandial fullness Early satiation Epigastric pain Epigastric burning No evidence of structural disease (including an upper GI endoscopy) that is likely to explain the symptoms This is subclassified into: Epigastric pain syndrome At least 3 months, with onset at least 6 months previously, with all of the following: Pain and burning that is: Intermittent Localised to the epigastrium of at least moderate severity, at least once per week, And not: Generalised or localised to other abdominal or chest regions relieved by defaecation or flatulence Fulfilling criteria for gall bladder or sphincter of Oddi disorders Postprandial distress syndrome At least 3 months, with onset at least 6 months previously, of one or more of the following: Bothersome postprandial fullness occurring after ordinary-sized meals at least several times a week or Early satiation, which prevents finishing a regular meal and occurs at least several times a week Cyclic vomiting syndrome At least 3 months, with onset at least 6 months previously, of: Stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week) Three or more discrete episodes in the prior year Absence of nausea and vomiting between episodes Supportive criteria: History of migraine headaches or a family history of migraine headaches Chronic idiopathic nausea At least 3 months, with onset at least 6 months previously, of: Bothersome nausea, occurring at least several times per week in the last 3 months Not usually associated with vomiting Absence of abnormalities at upper endoscopy or metabolic disease that explains the nausea Irritable Bowel Syndrome At least 3 months, with onset at least 6 months previously, of recurrent abdominal pain or discomfort* associated with two or more of the following: Improvement with defaecation; and/or Onset associated with a change in frequency of stool; and/or Onset associated with a change in form (appearance) of stool * Discomfort means an uncomfortable sensation not described as pain.


It is generally agreed that Helicobacter pylori has a poor or irrelevant role in the pathophysiology. Gastric acid secretion is normal in most patients although acid-related symptoms may be present. Non-painful dyspeptic symptoms are suggestive of motor disorder. Post-prandial fullness and vomiting have been associated with delayed gastric emptying of solids, and early satiety to postcibal impaired accommodation of the gastric fundus. Many patients with this condition implicate particular articles of diet as cause of symptoms. Higher anxiety and neuroticism scores have also been described.

Idiopathic gastroparesis

Investigations Investigations are mandatory in the following situations (‘alarm’ or ‘red flag’ features): recent onset, late age at onset of symptoms (>40 years), weight loss, no response to adequate standard therapy, and any abnormality on physical examination.

The diagnosis rests on documenting delayed gastric emptying by radionuclide scan or other appropriate techniques. More frequent small meals, liquids or soft solids, and prokinetic drugs are the mainstay of therapy.

The utility of routine laboratory testing is debated. Haematocrit, stool examination (including test for occult blood in the elderly), and liver and renal profiles are used as screening tests. Diagnostic oesophago-gastroduodenoscopy with or without biopsy-based testing for H. pylori should be considered with the slightest suspicion of organic disease. The most common finding is antral gastritis; its relevance in the absence of H. pylori infection is not clear. Ultrasound screening for biliary and pancreatic diseases is done when suspicion exists. Specialised tests (antro-duodenal manometry, electrogastrography, radionuclide evaluation of gastric emptying) are confined to the research setting. Management Simple dietary precautions may go a long way in alleviating symptoms. Regular meal timings; having unhurried meals; not habitually sipping fluids during meals; avoidance of excessively spicy and fatty food; restricting intake of caffeinated and aerated beverages may all be helpful to the patients.‘Avoid what you cannot tolerate’ is a better advice than a blanket ban on food items; this also leaves the patient feeling in charge of himself. Tobacco in any form, and immoderate alcohol consumption, should be avoided. The most common medication used is antacid; since most of the commercial preparations are antacid-antiflatulent combinations, they may alleviate a wide range of symptoms. When this is not effective (its long-term use is also not desirable), a histamine H2-receptor antagonist (ranitidine, famotidine) can be substituted in patients with acid-peptic symptoms. More powerful acid suppressants (proton pump inhibitors) are seldom required. In patients with symptoms of gastroduodenal dysmotility (bloating, early satiety) a prokinetic agent (metoclopramide, domperidone, mosapride, itopride, levosulpiride) may be beneficial; cisapride may be preferred when the patient has additional lower gastrointestinal symptoms (constipation, incomplete evacuation); its use is, however, restricted by fears of cardiotoxicity. There is no evidence to show that treatment for H. pylori is indicated.


Other distinct functional upper gastrointestinal conditions with features suggesting dysmotility have been described, but these are uncommon in clinical practice. These include:

As the term implies, these patients have defective gastric contraction and emptying. While this may be a consequence of systemic diseases, e.g. diabetes mellitus, acute viral infections, or of drug therapy (beta-adrenergic agonists, dopamine D2 agonists such as bromocriptine, levodopa and opioids), in some cases no cause is identified. These patients may present with dyspepsia-like symptoms (early satiety, bloat, nausea and occasional vomiting) acutely over months or years.

Aerophagia and belching syndrome Aerophagia is the semivoluntary swallowing of abnormal amounts of air while eating or drinking. When this results in increased intragastric air volume, belching occurs. Patients with the syndrome voluntarily aspirate air into the oesophagus, and then expel it loudly. Frequent swallowing is an accompanying feature. Some of them push the air further into the stomach and present with bloat and discomfort. Anxiety may aggravate the condition, which takes on the nature of a compulsive tic. Gastric hypomotility has been documented in such subjects, but whether this is a cause or effect is not known. Management is empirical, and should include a search for psychological factors. Cyclic vomiting syndrome This condition is characterised by stereotypic episodes of vomiting, with absence of nausea and vomiting in between episodes. Sometimes it is confused with other functional gastrointestinal syndromes because abdominal pain is not uncommon when episodes occur. The causes remain unclear, but some investigators have considered it to represent a migraine variant. Antral hypomotility and delayed emptying have been recorded in some patients. Nutritional compromise may occur in the long term. Available evidence suggests poor response to prokinetics. Anti-depressants work in some individuals, suggesting a central origin for the symptoms. Rumination syndrome Rumination is a process by which food from the stomach is brought back into the mouth; some of the food is chewed and re-swallowed, and the process is repeated. Contraction of abdominal muscles and simultaneous relaxation of the lower oesophageal sphincter seem to occur as an effortless, semivoluntary action. A psychological element seems to be underlying. Apart from erosion of tooth enamel and bad breath (halitosis), this condition may also lead to nutritional deficiencies because patients tend to be withdrawn. Psychological support and physical training to overcome the muscle activity may be helpful. IRRITABLE BOWEL SYNDROME (IBS) The terms spastic colon, mucous colitis, irritable colon, among others were used to describe this condition earlier. While each of them reflected the predominant symptom or the

Patients with IBS report with abdominal pain and altered bowel habits. The earlier criteria laid down by Manning et al for its diagnosis have been supplemented by the recent Rome III symptom criteria (Table 1). These identified pain or discomfort as an overwhelming symptom and introduced a time factor for diagnosis. It is accepted now that a positive clinical diagnosis of IBS can be made and the condition need not be a diagnosis established by absence of evidence for structural disease. The presence of certain ‘alarm’ features (Table 2), however, requires that the patient be investigated. Table 2: Features Against Diagnosis of IBS History Late age (>40 years) at onset of symptoms Large-volume diarrhoea or steatorrhoea Frequent nocturnal symptoms Blood in stools (except from anal lesions, e.g. haemorrhoids, fissure) Fever, dehydration Significant weight loss Progression of symptoms or development of new symptoms Physical examination Abdominal mass Signs of malabsorption, bowel obstruction, thyroid dysfunction Extraintestinal manifestations (arthritis, skin lesions) Laboratory findings Occult blood in stools

Epidemiology About 15% of the general population have symptoms that justify a diagnosis of IBS; however, only about 20% of these will seek medical opinion, prompting a suggestion of hypersensitivity in them. IBS is the most common single reason for referral to gastroenterologists. In Western series, female patients predominate; in South Asia and in India, most reporting patients are young men. The reason for this difference is not known. Clinical Features Pain (or discomfort) is an important feature of IBS, and is localised to the periumbilical region or lower abdomen, especially the left side. Altered bowel habit is the other symptom. While Indian patients generally do not have the alternating diarrhoea and constipation pattern described from the West, whether diarrhoea or constipation predominates varies regionally within the country. Abdominal pain and other accompanying features like gas bloat are usually relieved temporarily by defaecation. In patients with constipation, sense of incomplete evacuation is a particularly distressing symptom; since these patients actually have increased attempts at defaecation, they may wrongly be labelled as having diarrhoea and are treated accordingly, with worsening of symptoms. Some of them attempt digital evacuation of the anal canal; these patients often have a profusion of mucous, and may develop ulcers in the anal canal or lower rectum (solitary rectal ulcer syndrome). Many patients with straining at stools as their only complaint may actually have an evacuation disorder.

Stool consistency may vary from small-quantity semisolid or liquid with mucous in those with diarrhoea, to hard, pellet-like with mucous in constipated subjects. Blood in stools may take the form of streaks or fresh drops after defaecation; the former are due usually to anal fissures and the latter to haemorrhoids, two conditions these patients are predisposed to. Though the predominant symptoms arise from the colon, up to one-third of patients have accompanying upper gastrointestinal symptoms like dyspepsia, heartburn and bloat. Extraintestinal symptoms like dysmenorrhoea, dyspareunia, urinary frequency and headache are also common in female patients. Abnormal psychological features have been reported in over 70% of patients; stressful life events are also reported with increased frequency. However, a cause and effect relationship is not certain.

Functional Gastrointestinal Disorders

understanding of the condition at that time, they all reflect the recognition that the symptoms arise primarily in the colon.

Pathophysiology The pathophysiology of IBS is considered to be multifactorial, generated by interplay between genetic, psychosocial and environmental factors. These produce abnormalities in central nervous system processing as well as in the periphery, where they generate abnormal motility and possibly abnormal secretory activity. No consistent anatomic, physiological or microbiological abnormality has, however, been demonstrated; it is unlikely there is a single unifying explanation. Alterations in bowel motility and transit, as a consequence of abnormal myoelectric rhythm, are the most common features identified. In a subgroup of patients the onset of symptoms follows an episode of infective diarrhoea (post-infective IBS). These and other patients with documented bacterial overgrowth may benefit from short courses of antibacterial treatment. This response to drugs, including a nitroimidazole, has often led to a wrong label of ‘chronic amoebiasis’, especially when this is associated with incidental stool detection of amoebae. As stated earlier, a proportion of individuals from the general population have symptoms overlapping those of IBS, but do not consult a physician. Whether this represents a noncomplainant group, or suggests that visceral hypersensitivity plays a role in distinguishing ‘patient’ from ‘normal’, is an open question. Investigations The diagnosis is generally based on history with normal physical examination (at most, tenderness in the lower abdomen, especially on the left side). Finding anal fissures or haemorrhoids on proctoscopic examination confirms the source of local pain and bleeding. Twenty four hours stool weight is recorded to rule out causes of large-volume (small intestinal or pancreatic) diarrhoea; stool weight in normal Indian subjects and those with IBS is less than 350 g/24 hours. Routine stool examination is done for amoebae and giardia. Sigmoidoscopy or colonoscopy is done when features against the diagnosis of IBS exist (Table 2). Recent Western studies suggest that routine investigation of all patients with diarrhoea predominance may identify a small number with unsuspected coeliac disease, bacterial overgrowth syndrome, or inflammatory bowel disease.



Table 3: Drugs with Potential for Use in Treatment of IBS

The most important component of management is reassurance and psychological support. Cancer phobia is often the reason for medical consultation, and some investigations may become necessary if only to allay this fear. Despite the lasting discomfort and morbidity, patients should be assured that no complications arise out of IBS. Tranquilisers or anxiolytics may be required in the highly apprehensive patients (Table 3). Non-pharmacological relaxation modalities like yoga and biofeedback may also help.

Predominantly centrally acting drugs Selective serotonin-reuptake inhibitors (SSRIs) Centrally and peripherally acting drugs Neurokinin-receptor antagonists Serotonin-receptor (mainly 5-HT3 and 5-HT4) modulators: alosetron, tegaserod, prucalopride Drugs with opioid (mu, kappa, delta) action: diphenoxylate, loperamide Neurotrophins Corticotrophin-releasing factor (CRF) antagonists Somatostatin analogues Predominantly peripherally acting drugs Antibiotics (rifaximin) and probiotics Selective chloride-channel activators: lubiprostone Cholecystokinin (CCK) antagonists Peripheral receptor modulators: guanylate cyclase

Dietary advice should include restriction on items known to aggravate symptoms. Thus, milk and spicy food may need to be restricted in those with diarrhoea; milk, legumes and cabbage in those with gas bloat. Patients often report relief by eliminating meat from the diet. Obviously, advice will have to be individualised. High-fibre diets are most effective in patients with constipation; when adequate fibre is already being consumed in the diet with no relief (as often happens in Indian patients), fibre supplementation may be tried. Commercially available isaphgol husk preparations can be taken with meals; usually 1 to 2 teaspoons of the refined preparations are given with breakfast and dinner, to ensure an additional 15 to 20 g fibre/day. These hydrophilic agents bind water and so prevent stool dehydration and add bulk. They may also help in patients with diarrhoea. One side-effect of fibre supplementation that is particularly distressing to patients with IBS is bloat. Relief can be obtained by combining this with preparations of simethicone or methylpolysiloxane. An alternative is the fibre substitute calcium polycarbophil. Drugs that have the potential for use in the treatment of IBS are listed in Table 3. Tegaserod, a specific serotonin (5-HT4) agonist, can improve symptoms in patients with IBS and constipation. Lactulose, lactitol and oral solutions containing polyethylene glycol (PEG) have been associated with improvement in stool frequency and consistency. Bowel retraining may improve bowel regularity. Patients with diarrhoea may benefit from a morning dose, or if necessary thrice-daily doses, of the anti-diarrhoeal agent loperamide; milder symptoms may be controlled with racecadotril. Abdominal pain may require anti-spasmodics (e.g. mebeverine, dicyclomine).


FUNCTIONAL ABDOMINAL PAIN SYNDROME Many of these patients are young women with other features to suggest psychological problems, including somatisation. Where suspicion is strong, investigation for the rare metabolic cause, e.g. porphyria, or poisoning (lead) should be done. The more common metabolic causes of abdominal pain (diabetes mellitus, uraemia) usually have other characteristic features present. The diagnosis of functional abdominal pain should be entertained only after organic causes are eliminated with reasonable certainty. Management includes reassurance, psychologic support measures, anxiolytics if necessary, and spasmolytics, antacids, analgesics or other similar drugs depending on the type of pain described by the patient. RECOMMENDED READINGS 1.

Gaman A, Bucur MC, Kuo B. Therapeutic advances in functional gastrointestinal disease: irritable bowel syndrome. Therap Adv Gastroenterol 2009; 2: 169-81.


Ghoshal UC, Abraham P, Bhatt C, Choudhuri G, Bhatia SJ, Shenoy KT, et al. Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol 2008; 27: 22-8.


Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006; 130: 1480-91.


Talley NJ, Vakil N. Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005; 100: 2324-37.

13.11 INTRODUCTION About 20% of patients with tuberculosis (TB) have extrapulmonary TB and 7% to 10% of them have abdominal TB. While abdominal TB continues to be a common problem in the developing countries including India; increasing population migration, epidemic of acquired immunodeficiency syndrome (AIDS) and use of more potent chemotherapeutic agents led to resurgence of this disease in regions where TB had previously been largely controlled. Reliable epidemiologic data on abdominal TB from India is lacking. Of all hospital admissions, nearly 0.8% is reported to be due to intestinal TB. Three per cent to twenty per cent of all intestinal obstruction and 5% to 7% of intestinal perforation are due to intestinal TB in India. In the abdomen, TB infection can involve many organs including gastrointestinal (GI) tract, peritoneum and many others (Table 1). In an analysis of 6 reports including 596 patients, Marshall et al reported that 42%, 50% and 8% had peritoneal, GI and lymph node TB, respectively and only a minority had combined peritoneal and GI TB. Table 1: Classification of Abdominal Tuberculosis Gastrointestinal tuberculosis Intestinal (both small and large) Gastroduodenal tuberculosis Oesophageal tuberculosis Peritoneal tuberculosis Acute tuberculosis peritonitis Chronic peritoneal tuberculosis Ascitic form Encysted (loculated) form Dry type Tuberculosis of the solid viscera Hepatobiliary Spleen Pancreas Tuberculosis of the abdominal lymph nodes Tubercular mesenteric lymphadenitis Tubercular retroperitoneal lymphadenitis Genitourinary tuberculosis

INTESTINAL TUBERCULOSIS Site of Involvement While any part of GI tract may be involved by the TB infection, the most common site of involvement is ileocaecum (ileum, ileocaecal valve and caecum). Other common sites of involvement are the colon (where the frequency decreases segmentally from the ascending colon to the rectum), appendix, jejunum, stomach, duodenum and oesophagus.The preferential location of ileo-caecum is because of a number of reasons including: the abundance of lymphoid tissue, relative physiologic stasis, higher electrolyte and water absorption, and

Abdominal Tuberculosis Govind K Makharia minimal digestive activity, permitting greater contact time of the acid-fast bacilli (AFB) with the mucosal surface. Pathogenesis The mycobacterial infection can develop primarily within the intestinal tract or secondary to a focus elsewhere in the body. There are 4 possible ways by which an infection can reach GI tract: direct invasion by the ingested mycobacteria, transport by the way of infected bile, extension from adjacent diseased organs or tissues and spread through mycobacterial bacteraemia. Animal studies have shown that intestinal TB can result from ingestion of food containing tubercle bacilli, especially milk. With widespread pasteurisation of milk, milk is not a significant cause of TB. Secondary infection of the GI tract may arise from contamination of enteric chyme by bacteria from another site, usually the lungs, through swallowing of infected sputum. Intestinal involvement is probably related to the number and virulence of the ingested organisms and the nutritional status of the patient. Invasion of the intestine does not seem to occur when there is TB involvement of the peritoneum. Generalised tuberculous peritonitis is usually not associated with intestinal TB other than as a consequence of the extension of the infectious process transmurally or from an infected, ulcerating lymph node to the serosal surface. Pathology Traditionally, intestinal TB is described as of three types— ulcerative, hypertrophic and ulcero-hypertrophic.The ulcerative form of the disease is mainly due to deprivation of blood supply, because of endarteritis. In GI TB, ulcerogenesis is relatively slow, and an inflammatory wall develops ahead of the advancing ulcer. Thus, most perforations are confined. There is an accumulation of collagenous tissue during the process of ulcer healing that subsequently contracts and cause circumferential stricture of the intestinal lumen. The diseased segment is moderately indurated and the serosa is studded with nodules. The mesenteric lymph nodes are usually enlarged. The mucosal surface may show single or multiple ulcers, and skip areas may be present with normal appearing mucosa between involved segments. The ulcers are characteristically transverse and circumferential, but may be round, stellate, or longitudinal. The ulcers are deep, these however, generally do not penetrate the muscularis propria. In the acute phase, there may be a functional stenosis of the involved segment because of the spasm. In the more chronic phase, circumferential strictures may develop. The hypertrophic form of the disease, there is a marked inflammatory fibroblastic reaction in the submucosa and subserosa of the involved segment mostly ileocaecum. Caseating granulomas (Figure 1) are the histologic hallmark of TB. The granulomas in intestinal TB are usually larger (>200 μm), multiple in number (>5/section) and confluent (Figure 1). Careful scrutiny should be made of acid-fast stained tissue for


tubercle bacilli. The ulcers usually do not penetrate beyond the muscularis and are lined by non-specific inflammatory granulation tissue. It must be emphasised that the histologic features of intestinal TB may be altered and may remain undiagnostic in patients who have received anti-tuberculosis drugs earlier or where tissue specimen is small.

obstruction, (c) fistula formation between the small and large intestine, (d) deconjugation of bile salts secondary to bacterial overgrowth, and (e) decreased bile salt pool because of impaired active absorption in the distal ileum. Bleeding per rectum is seen in 10% to 15% of patients with intestinal TB and occasionally massive bleeding. Almost half of patients have constipation. Constitutional symptoms in the form of fever, malaise, night sweats, anorexia, and weight loss are reported by 40% to 70% of patients with intestinal TB. A few patients may have active TB elsewhere especially lungs. On examination, there are no characteristic signs. Most patients appear sick, poorly nourished and febrile. Doughy consistency of abdomen (due to extensive fibro-adhesive inflammation) is infrequent and non-specific. Abdominal tenderness is frequently present in the right lower quadrant. Palpable mass, which is a conglomerate of adhered bowel loops, lymph nodes and sometimes mesentery, may be observed in 10% to 20% patients.

Figure 1: Photomicrograph showing caseating granuloma, multiple submucosal large (> 200 μm diameter) epitheloid cell granuloma with lymphocytic cuffing. Focally, the granuloma show central necrosis and presence of Langhan’s giant cells (Haematoxylin and Eosin x 40).

Clinical Features The most common age of patients with intestinal TB is between 20 to 40 years it, however, can occur in any age. Intestinal TB may have symptoms arising from the (a) intestinal ulceroconstrictive disease (intestinal colic, abdominal distension, nausea, vomiting, constipation, bleeding manifestations); (b) symptoms due to chronic inflammatory process (fever, weakness, weight loss, night sweats); (c) symptoms due to associated adjacent tissue involvement (ascites, lymph node enlargement or tubo-ovarian symptoms); and (d) coincident pulmonary TB (chronic cough, expectoration, haemoptysis).


The symptoms of GI TB will depend upon the site(s) of involvement of the GI tract and also the type of lesions it produces. As discussed earlier in the pathogenesis, ileocaecal area is the most common site of involvement in patients with intestinal TB, and most of the lesions are ulcerative or ulceroconstrictive. Abdominal pain is the most common manifestation and occurs because of stricture of the lumen, stretch on the surrounding tissue, mesenteric inflammation and peritoneal involvement. While the pain arising from the intestine is mostly colicy in nature, the pain arising from mesentery or peritoneum is diffuse and dull ache. As disease advances with time, the severity and frequency of pain increases. Therefore, the patient may initially present with occasional episodes of intestinal colic only, which may be disregarded by a physician as an episode of GI infection. As the stricture advances, the patient may develop partial intestinal obstruction (abdominal distension, gurgling in the abdomen, partial or complete cessation of flus, vomiting or movement of ball of wind in the abdomen). Diarrhoea is seen in 20% to 30% of patients and can be because of both small and large intestinal involvement. Malabsorption results from: (a) decreased small intestinal mucosal surface, (b) lymphatic

Complications The complications of intestinal TB are partial or complete intestinal obstruction, lower GI bleeding, intra-abdominal abscess, malnutrition and at occasions intestinal perforation. Intestinal obstruction occurs due to contraction of intestine following healing of circumferential tuberculous ulcers, bowel wall thickening, kinking of the intestine by intra-peritoneal adhesions, retraction of the mesentery and obstruction at the ileocaecal junction (due to changing the angle of entrance of the ileum into the colon of 90° to nearly 180°). Malnutrition occurs because of anorexia, inadequate food intake (because of sitophobia and poverty), and malabsorption. Investigations The haemogram in patients with intestinal TB shows a mild-tomoderately severe normochromic, normocytic anaemia, thrombocytosis and a normal white cell count with relative lymphocytosis. The erythrocyte sedimentation rate is almost always raised. Mantoux test is positive in over 70% of patients but high prevalence of Mantoux positivity in developing countries (≈ 60%) limits its usefulness. False-negative result is often seen in the elderly, malnourished, immunosuppressed, or in patients with disseminated disease. Pulmonary lesions on chest radiograph may be noted in a quarter of subjects; recognition of active pulmonary disease reduces the cost and expedites the diagnosis. Plain radiograph abdomen should be done in those who present with intestinal obstruction and may reveal air-fluid level and dilated bowel loops. One should review the radiograph properly to see other suggestive evidences, such as calcified lymph nodes, calcified granuloma in the spleen, liver and pancreas and enteroliths. The aims of the investigations in patients suspected to have intestinal TB are detection of lesion, site and extent of the lesion, type of lesion, detection of any associated complication, histological diagnosis, microbiological confirmation and detection of TB either active or healed elsewhere, most commonly lungs. Intestinal imaging includes: luminal imaging (endoscopic, barium studies), and imaging of the wall and extra-intestinal extent which is detected by cross sectional imaging, such as CT scan and MRI. Both these techniques may be combined in one, such as CT-enteroclysis or MRenteroclysis.

ulcers become confluent. In patients with TB, barium findings in the advanced stage of fibrosis are more definitive. There is a thickening of the ileocaecal valve with narrowing of the terminal ileum (Fleischner or inverted umbrella sign). In further advanced disease, the characteristic deformity include symmetric, annular stenosis with obstruction, and shortening of the intestine and the colon. The caecum classically becomes conical, shrunken, and pulled up from the iliac fossa due to contraction of the mesocolon. There may be a loss of the normal ileocaecal angle (Figure 3). A localised narrowing opposite the ileocaecal valve with a rounded smooth caecum and a dilated terminal ileum is termed as ‘purse string stenosis’. Spasm of the distal ileum and the ascending colon with contraction of the caecum (Stierlin sign) may be seen in association with shrunken ascending colon. The ileocaecal valve classically becomes incompetent, rigid and fixed with an irregular outline.Tubercular strictures are typically short and multiple separated by unaffected segments. Enteroliths may form proximal to the

Abdominal Tuberculosis

Endoscopic Investigation Since ileocaecal area is involved in the majority of the patients with intestinal TB, colonoscopy with retrograde ileoscopy is the investigation of choice. Colonoscopic examination provides an opportunity to visualise the lesion directly and one can obtain biopsies from the lesions at the same time. The morphological appearance of intestinal TB depends upon the stage of the disease. The lesions may vary from mild lesions, such as loss of vascular pattern, erythema, small ulcerations and superficial ulcerations, to more advanced lesions including deep ulcerations, nodularity and strictures. One should realise that the evolution of intestinal TB takes from months to years. The classical morphological features described in the textbooks are seen in advanced cases. Some of the patients may present in early stages of evolution of the disease, thereby one may not find classical lesions and instead finds minute lesions. The wisdom lies in identifying these minute lesions so that the progression of the disease can be prevented. Common colonoscopic features of intestinal TB include deep ulcers (50% to 80%), nodules (30% to 60%) and strictures (Figure 2). One should take multiple biopsies from the lesion for not only histological examination but also for M. tuberculosis culture, PCR and AFB staining. For small intestinal lesions, newer endoscopic techniques such as single and double balloon enteroscopic examination can be done. Capsule endoscopic examination is generally not done for those patients where obstructive lesion such as intestinal TB is suspected.

Figure 2: Colonoscopic picture showing ulceration of the ileocaecal valve in a patient with intestinal tuberculosis.

Radiological Investigations Although there are many suggestive features on radiological investigations, none however is diagnostic of intestinal TB. The radiological features depend upon the stage of the disease, site of involvement and severity of the disease. In the early stage of mucosal invasion and ulceration, barium findings of ileocaecal TB are non-specific and include spasm and hyper-motility of the intestinal segment, oedema of the ileocaecal valve and mucosal thickening. Tubercular ulcers are circumferential or transverse in orientation. With progression of the disease, the

Figure 3: Barium-meal follow through study showing contracted and pulled up caecum with narrowing of the ileocaecal junction and loss of the normal ileocaecal angle. The terminal ileum appears suspended and hanging from the caecum.


strictures and may vary from a single large lamellated calculus to multiple small stones visible on the radiograph. CECT or CT-enteroclysis/MR-enteroclysis is essential for the evaluation of extra-luminal, peritoneal, nodal and visceral involvement. CT is more accurate than ultrasonography in detecting most of these manifestations including peritoneal and intestinal involvement. CECT/CT enteroclysis may show intestinal wall thickening (unifocal or multifocal), stricture with proximal dilation of the intestine, and regional lymphadenopathy. The pattern of lymphadenopathy in TB may vary widely, including increased number of normal sized nodes, mildly enlarged nodes to large confluent nodal masses. The involved lymph nodes typically show hypodense centre and peripheral enhancement in 40% to 70% cases; which reflects central necrosis (Figure 4).

2. Histological demonstration of typical ATB. 3. Histological evidence of necrotising granuloma. 4. Definite response to ATT in a patient with probable TB based on clinical, endoscopic, histological features (Logan’s modification). Differential Diagnosis Crohn’s disease (CD) and intestinal TB are granulomatous diseases of the intestine. The clinical, morphological and histological features of intestinal TB and Crohn’s disease are so similar that it becomes difficult to differentiate between these two entities. In geographical regions like Asia where both Crohn’s disease and intestinal TB are prevalent, differential diagnosis between the two may be challenging. In Asia, intestinal TB is common, but CD is also being increasingly reported from all over Asia. Natural history of CD is quite different from that of intestinal TB. While intestinal TB gets cured by appropriate ATT, CD has a remitting/relapsing or persistent course and usually stays lifelong. Because of similarity in the clinical presentation and morphology of these two entities, at times such patients are treated empirically with anti-tuberculous drugs. The clinical, endoscopic and histological features which can differentiate these two diseases are summarised in Table 2. Table 2: Clinical, Endoscopic and Histological Differentiation between Intestinal Tuberculosis and Crohn’s Disease Variables

Figure 4: A contrast enhanced computerised tomography showing enlarged mesenteric lymph nodes with central hypodensity and thickening of the caecum (arrow) in a patient with abdominal tuberculosis.

Microbiological Tests Isolation of M.tuberculosis using culture is the most specific method for diagnosis of active TB. It can detect 10-100 bacilli per mL of the sample. The most commonly used solid media is the LowensteinJensen medium, on which it usually takes 4 to 6 weeks to grow. Radiometric (BACTEC) method and MGIT culture system can grow M. tuberculosis in shorter period of time, however, these are expensive. PCR using M. tuberculosis specific primer shows a positivity varying from 20% to 65%. Identification of acid-fast bacilli (AFB) on microscopy is presumptive for TB infection as saprophytic mycobacteria may give false-positive result. Serological Tests Although enzyme-linked immunosorbent assay (ELISA) using semi-purified antigens has sensitivity of 80% in abdominal TB; however, it fails to distinguish active from the past infection and it has high false positive rate. At present, there is no role of commercially available ELISA in making diagnosis of TB. One should not base one’s decision of starting anti-tuberculous treatment (ATT) on ELISA report unless there are enough clinical, endoscopic and histological evidences.


Diagnostic Criteria for Tuberculosis At least one of the following criteria must be met: 1. Culture of tissue (colonic biopsy, lymph nodes) resulting in growth of M. tuberculosis.

Intestinal Tuberculosis

Crohn’s Disease

Symptoms Chronic diarrhoea Blood in the stools Abdominal pain Constipation Partial intestinal obstruction Peri-anal disease Fever Loss of appetite Weight loss Extra-intestinal manifestations

20 to 40% 10 to 20% 90% 50% 50 to 60% 5% 40 to 70% 40 to 80% 60 to 90% 10%

60 to 80% 50 to 70% 60 to 80% 10 to 30% 20 to 30% 30 to 80% 30% 40 to 60% 50 to 60% 20 to 50%

Involvement of the Intestine Anal canal Rectum Sigmoid colon Descending colon Ascending colon Ileocaecal area Ileum

90/min Present




90% Ileal involvement 1.5, patients with platelet counts less than 80,000/mm3 and inability to tackle complication as a result of the procedure. Liver biopsy carries a small but definite risk of mortality and complications, with rates of approximately 0.01% and 0.1 to 0.3%, respectively. The common complications include pain arising from pleura, peritoneum or diaphragm, intra-peritoneal haemorrhage, intra-hepatic haematoma, haemobilia, bile peritonitis, infection, etc. These complications can be managed using intravenous analgesics, blood transfusions, and radiological or endoscopic interventions. Surgical intervention is rarely required. Transjugular liver biopsy is used in patients with abnormal coagulation, massive ascites or small liver, or those who need measurement of hepatic venous pressures. It does not carry the risk of bleeding complications, but is costly and needs a trained operator. IMAGING STUDIES These are discussed in chapter on “Hepatobiliary Disorders— Imaging”. HAEMODYNAMIC STUDIES A balloon catheter is introduced into the hepatic vein via the femoral or internal jugular veins. Pressure measurements are taken in the hepatic veins by inflating [wedged hepatic venous pressure (WHVP)] and deflating [free hepatic venous pressure (FHVP)] the balloon catheter. The hepatic venous pressure gradient (HVPG) represents the difference between the WHVP and the FHVP, and is a measure of portal hypertension. 853

The normal value for HVPG is less than 5 mm Hg. The HVPG value more than 5 mm Hg signifies “portal hypertension” and more than 10 mm Hg signifies “clinically significant portal hypertension”. Increase in value above 10 mm Hg is required for the development of oesophageal varices and above 12 mm Hg for the appearance of other complications, such as variceal bleeding. Decline of HVPG below 12 mm Hg or through more than 20% of the baseline level is associated with prevention of variceal bleeding, and at times with


a reduction in size and possibly disappearance of varices. The achievement of these haemodynamic targets also lowers the risk of developing ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome and death. RECOMMENDED READING 1.

Boyer TD, Wright TL, Manns MP, editors: Zakim and Boyer’s Hepatology: A Textbook of Liver Disease; 5th Ed. Philadelphia: Saunders; 2006.


Hepatobiliary Disorders—Imaging Shrinivas B Desai

Imaging plays a crucial role in the management of hepatobiliary diseases. This topic can be divided into imaging in liver diseases and imaging of the biliary system.

well-defined, non-enhancing and thin walled cystic lesions. On MRI, they are hypointense on T1 WI images and hyperintense on T2 WI images.

IMAGING IN LIVER DISEASES Techniques for studying the liver include plain radiograph, ultrasonography (USG), computed tomography (CT), magnetic resonance imaging (MRI), angiography and radionuclide scanning.

Haemangioma It is the most common benign tumour of the liver. On sonography, these appear as well-defined homogenously hyperechoic lesions (Figure 1). On non-enhanced CT (NECT) (Figure 2), they are seen as hypodense well defined mass lesions. Following contrast administration, there is filling in of the contrast from the periphery. On MRI, haemangiomas show a characteristic very long T2 relaxation time and therefore appear hyperintense on T2 WI images. On labelled RC SPECT scans, they appear as filling defects on early scans with prolonged and persistent radiotracer uptake on delayed scans.

Abdominal Radiograph The liver casts an appreciable soft tissue density shadow, with its borders outlined against fat and gas in adjacent organs. Hepatomegaly can be made out on plain radiographs of the abdomen by noting the displacement of gas in the adjacent gasfilled organs. Riedel’s lobe, a normal variant seen commonly in women, is an inferior tongue-like projection of the right lobe. Focal hepatic lesions may distort one or more hepatic margins or may be seen as diffuse hepatomegaly on the plain radiograph. Calcification within the liver may be localised or diffuse. Hydatid disease is the commonest cause. Other causes include old abscess or granuloma (single or multiple foci), hepatocellular carcinoma (stippled or sunburst type) and metastasis from mucous secreting adenocarcinoma and medullary carcinoma of the thyroid gland (faint fluffy calcification).

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is a developmental hyperplastic lesion comprising of hepatocytes, Kupffer cells, biliary ducts and components of portal triads. It appears as a well-defined mass

Gas is normally not seen in the liver. It may be seen confined to the parenchyma (e.g. abscess), within the biliary tree (e.g. after bilioenteric anastomosis or endoscopic papillotomy) or within the portal vein radicals (e.g. necrotising enterocolitis). Distribution of air helps in differentiation between air in the biliary tree (centrally located) and that in the portal veins (more peripherally distributed). FOCAL HEPATIC LESIONS Simple Liver Cyst A liver cyst is a fluid-filled space with an epithelial lining. On sonography, liver cysts appear as anechoic, thin-walled lesions with posterior acoustic enhancement. On CT, they appear as

Figure 1: Ultrasound showing a hyperechoic lesion in segment 3 of left lobe of liver. Diagnosis: Haemangioma. Courtesy: Dr Raju Sharma, AIIMS.

Figures 2A to C: Triple phase CT of the abdomen. Arterial phase (A) shows peripheral nodular discontinous enhancement with progressive centripetal extension on venous (B) and delayed (C) phase. Retention of contrast in the lesion is seen on the delayed image (C). Diagnosis: Liver haemangioma. Courtesy: Dr Raju Sharma, AIIMS.


lesion with a central stellate scar that is isoechoic with the liver parenchyma on USG. The central scar appears hyperechoic with significant vascularity on Doppler imaging. On NECT, these lesions are iso- to hypodense to the liver parenchyma with a hypoattenuating central scar. Being highly vascular, these lesions show marked enhancement on arterial phase of contrast-enhanced CT (CECT) with rapid washout of the contrast, whereas the scar shows persistent enhancement. On T1 WI images, FNH appears iso- to slightly hypointense and turns iso- to slightly hyperintense on T2 WI images. The central scar is typically hypointense on T1 and hyperintense on T2 WI images. On administration of gadolinium contrast agents, the enhancement pattern is similar to that seen on CECT. On sulphur colloid scan, 50% of these lesions take up sulphur similar to adjacent normal liver and 10% appear as hot spots. Hepatocellular Adenoma It is a benign neoplasm that contains hepatocytes with dilated sinusoids but lacks bile duct components. The lesions are very heterogeneous on imaging due to the presence of fat, old or fresh blood and necrosis. Majority of adenomas are hyperintense to surrounding liver parenchyma on T1 WI images, and iso- to hyperintense on T2 WI images. They show marked contrast enhancement and are seen as cold spots on sulphur colloid scans.


Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is a common malignant tumour. It can be solitary, multifocal or a diffusely infiltrating tumour. The sonographic features of HCC are very variable. It can be hypoechoic, echogenic or complex. In smaller tumours, there is seen a hypoechoic halo corresponding to fibrous capsule. Portal vein thrombosis is a frequent feature. The CT appearance is also variable. Most HCC are hypodense to the liver parenchyma on NECT, show enhancement on arterial phase and become isoto hypodense on portal venous phase. As they are vascular tumours supplied by the hepatic artery, hypertrophy of the hepatic artery may be noted. Calcification is seen in 5% to 10% of HCC. Portal and hepatic vein thrombosis and arterioportal shunting may also be seen. On MRI, they are seen to be iso-, hypo- or hyperintense to the liver parenchyma on T1 WI images, and usually hyperintense on T2 WI images. They are heterogeneous with intratumoural septations. Fibrolamellar HCC is a histological subtype that shows no gender predilection and occurs in a younger age group. It arises commonly in noncirrhotic livers. It is a vascular mass with a central scar, which is often calcified. On MRI, it is hypointense on T1 and hyperintense on T2 WI images, whereas the central scar remains hypointense on both sequences and shows no contrast enhancement. Metastatic Tumours They are usually multiple and hypoechoic on USG. Hyperechoic lesions are seen with GIT and urogenital tumours. Occasionally, metastatic disease may be seen as target lesions.They are typically hypodense to the liver parenchyma on NECT and show peripheral rim enhancement on arterial phase in CECT (Figure 3). Hypervascular metastases may become isodense to liver on portal venous phase and may be visualised on arterial phase as hyperdense lesions. Therefore, it is necessary to do dual phase imaging of the liver when looking for metastatic disease. On MRI, they are usually hypointense on T1 and hyperintense on T2 WI images and show an enhancement pattern similar to CT.

Figures 3A to D: Triple phase CT of the abdomen. Non-contrast CT (A) shows no lesion. Arterial phase (B) shows multiple hypodense lesions with thick rim enhancement. Portal venous phase (C) and delayed phase (D) shows washout from these lesions. Diagnosis: Liver metastases. Courtesy: Dr Raju Sharma, AIIMS.

Liver Abscess Liver abscesses may be pyogenic, amoebic (Figure 4) or fungal in nature. They are seen as hypoechoic lesions. As liquefaction sets in, the abscesses become more echo poor. Fungal abscesses show a hyperechoic central punctum, which represents an artery plugged by the fungus. On CT and MRI, they are seen as necrotic lesions with thick enhancing capsule.

Figure 4: CT scan shows a hypodense lesion in segment IV of liver with thick peripheral enhancement and oedema in adjacent liver. Diagnosis: Amoebic liver abscess. Courtesy: Dr Raju Sharma, AIIMS.

Hydatid Disease Liver presents as a hypodense mass with multiple daughter cysts (water lily sign) (Figures 5 to 7). Hydatid cysts can rupture into the peritoneal cavity, biliary tree or pleural cavity with resultant pleural effusion. Calcification can be noted in longstanding hydatid cysts.

Hepatobiliary Disorders—Imaging

deposition show signal drop-out. In focal fatty deposition, focal deposits of fat stand out against the background of normal liver parenchyma; the reverse occurs in focal fatty sparing. None of above the imaging methods can differentiate simple fatty liver from those with steatohepatitis and fibrosis. Ultrasound elastography (Fibroscan) is a new non-invasive method for assessment for hepatic fibrosis. It uses a modified

Figure 5: Ultrasound shows a multiloculated mass with daughter cysts in the periphery. Diagnosis: Hydatid cyst. Courtesy: Dr Raju Sharma, AIIMS.

Figure 8: CECT scan shows liver is markedly hypodense as compared to the spleen suggestive of diffuse fatty change. Courtesy: Dr Raju Sharma, AIIMS.

Figure 6: Hydatid cyst: CT scan shows a multilocular lesion in the left lobe of the liver. Density of daughter cysts is less than the centre of the lesion. Courtesy: Dr Raju Sharma, AIIMS.

ultrasound probe to measure the velocity of a shear wave created by a vibratory source. Estimates of stiffness (fibrosis) of the liver by ultrasound correlate with fibrosis stage, and values above 12.5 kPa are indicative of cirrhosis. This technique is used in fatty liver/chronic hepatitis for separating patients with minimal or no fibrosis from those with significant fibrosis or cirrhosis. A linear correlation with increasing fibrosis has not been demonstrated, and 15% discordance between elastography scores and histologic fibrosis has been observed. Cirrhosis Sonographic features of cirrhosis include coarse echogenic echotexture, nodular surface and regenerating nodules surrounded by fibrous septae. The nodules are seen as iso- to hypoechoic lesions with echogenic borders corresponding to fibrous septae. There may be features of complication of cirrhosis in the form of portal hypertension or HCC. The caudate lobe to right lobe liver ratio of >0.65 is highly specific for cirrhosis.

Figure 7: Hydatid cyst: Ultrasound reveals a right lobe cyst with multiple daughter cysts, pre and post aspiration.

DIFFUSE DISEASE OF THE LIVER Fatty Liver On USG, this is seen as diffuse increase in the echogenicity of the liver with poor visualisation of intrahepatic vessels and diaphragm. On CT (Figure 8), it is seen as a generalised low attenuation of the liver. MRI can confirm the diagnosis by utilising chemical shift imaging. On opposed phase images, areas of fat

CT and MRI show similar features (Figure 9). Regenerating nodules appear iso- to hyperdense to liver on NECT. Better appreciated on MRI, they are seen as hyperintense lesions on T1 and hypointense lesions on T2 WI sequences, and show an enhancement pattern similar to the rest of the liver. These features help in differentiating metastases and hepatomas from regenerating nodules. Of the various imaging techniques, MRI is the most sensitive and specific for this differentiation. Viral Hepatitis Imaging has little role in the diagnosis of viral hepatitis, and may reveal hepatomegaly, diffuse fatty change, periportal oedema and gall bladder (GB) wall thickening in the acute phase.


Figures 9A to C: Triple phase CT abdomen. Arterial phase (A) shows multiple lesions showing homogeneous arterial enhancement with washout in venous phase; (B) with suggestion of a peripheral capsule around some lesions.; (C) Background changes of cirrhosis in the form of nodular liver and ascites are noted. Diagnosis: Multifocal HCC in cirrhotic liver. Courtesy: Dr Raju Sharma, AIIMS.

VASCULAR DISORDERS Portal Hypertension Ultrasonography may show features of underlying liver disease, collaterals, splenomegaly and ascites. Colour Doppler imaging is a non-invasive modality for studying portal haemodynamics (Figure 10). A portal vein diameter of >13 mm is characteristic of portal hypertension. Portal venous velocity is reduced in portal hypertension. Colour Doppler imaging can demonstrate the direction of flow in the portal vein. When paraumbilical vein is the major decompressive collateral, the flow in portal vein is hepatopetal. When other collateral channels open up, if the resistance to portal venous flow exceeds that in the collateral bed, the flow in portal vein becomes hepatofugal.

portovenography can show the collateral circulation, and the presence of underlying cirrhosis, splenomegaly and ascites. It can also effectively monitor for development of hepatoma in the cirrhotic liver. The currently available 3D CT techniques can provide excellent three-dimensional images of the portal venous system with the entire collateral circulation, and have replaced splenoportograms (Figure 11).

Figure 11: Contrast-enhanced computed tomography in a patient with portal hypertension: Multiple tortuous serpiginous splenic hilar, lienorenal gastric bed and paraoesophageal collateral channels.

Figure 10: Colour Doppler in portal hypertension: Multiple tortuous serpiginous periportal collateral channels.

Portal vein thrombosis can be well evaluated by sonography. A portal cavernoma comprises multiple tubular structures in the porta hepatis. A pulsed Doppler spectral waveform of portal flow from multiple tubular channels at the porta is highly diagnostic of a portal cavernoma. In portal hypertension, variability of calibre of the splenic and superior mesenteric veins with respiration is lost. 858

Colour Doppler imaging can also be used to assess surgical porto-system shunts for patency. CT with angiography and

Budd-Chiari Syndrome Obstruction to the hepatic venous outflow either due to hepatic veno-occlusive disease or due to IVC obstruction can be well evaluated by colour Doppler, CT, MRI and inferior venacavogram. The flow on Doppler imaging in IVC and hepatic veins changes from the normal phasic flow to absent, reversed, turbulent or continuous flow. In long standing disease, changes of cirrhosis and porta hypertension may set in. In the acute stage, NECT shows a large liver with generalised hypoattenuation, due to congestion and ascites. CECT shows patchy parenchymal enhancement and thrombosis of the IVC or the hepatic veins. In chronic stages, caudate lobe hypertrophy and dilated azygous and hemiazygous veins can be seen. MRI is very sensitive in Budd-Chiari syndrome and shows hepatomegaly, reduction in calibre or non-visualisation of hepatic veins, IVC thrombosis and generalised increase in signal intensity on T2 WI images due to congestion in the acute stage. Once the disease becomes chronic, the hepatic signal is low on both T1 and T2 WI images. Caudate lobe hypertrophy, dilated azygous and hemiazygous venous systems, and comma-shaped foci of signal void representing intrahepatic collaterals are seen.

Ultrasonography (USG) The free availability, low cost, lack of ionising radiation and high sensitivity and specificity in detecting biliary diseases make USG a favoured imaging modality. The biliary system can be visualised by subcostal scanning. The normal GB is well distended after a fast of 8 to 12 hours and its wall should not be >3 mm in thickness. The GB should be scanned in two planes and in two patient positions so as not to miss any dise