1. 1. Diseases of the Liver and Biliary System SHEILA SHERLOCK DBE, FRS MD (Edin.), Hon. DSc (Edin., New York, Yale), Hon. MD (Cambridge, Dublin, Leuven, Lisbon, Mainz, Oslo, Padua, Toronto), Hon. LLD (Aberd.), FRCP, FRCPE, FRACP, Hon. FRCCP, Hon. FRCPI, Hon. FACP Professor of Medicine, Royal Free and University College Medical School University College London, London JAMES DOOLEY BSc, MD, FRCP Reader and Honorary Consultant in Medicine, Royal Free and University College Medical School, University College London, London ELEVENTH EDITION Blackwell Science
2. 2. DISEASES OF THE LIVER AND BILIARY SYSTEM
3. 3. Diseases of the Liver and Biliary System SHEILA SHERLOCK DBE, FRS MD (Edin.), Hon. DSc (Edin., New York, Yale), Hon. MD (Cambridge, Dublin, Leuven, Lisbon, Mainz, Oslo, Padua, Toronto), Hon. LLD (Aberd.), FRCP, FRCPE, FRACP, Hon. FRCCP, Hon. FRCPI, Hon. FACP Professor of Medicine, Royal Free and University College Medical School University College London, London JAMES DOOLEY BSc, MD, FRCP Reader and Honorary Consultant in Medicine, Royal Free and University College Medical School, University College London, London ELEVENTH EDITION Blackwell Science
4. 4. 1963, 1968, 1975, 1981, 1985, 1989, 1993, 1997, 2002 by Blackwell Science Ltd a Blackwell Publishing Company Editorial Ofces: Osney Mead, Oxford OX2 0EL, UK Tel: +44 (0)1865 206206 108 Cowley Road, Oxford OX4 1JF, UK Tel: +44 (0)1865 791100 Blackwell Publishing USA, 350 Main Street, Malden, MA02148-5018, USA Tel: +1 781 388 8250 Iowa State Press, a Blackwell Publishing Company, 2121 State Avenue, Ames, Iowa 50014-8300, USA Tel: + 515 292 0140 Blackwell Munksgaard, Nrre Sgade 35, PO Box 2148, Copenhagen, DK-1016, Denmark Tel: +45 77 33 33 33 Blackwell Publishing Asia, 54 University Street, Carlton, Victoria 3053, Australia Tel: +61 (0)3 9347 0300 Blackwell Verlag, Kurfurstendamm 57, 10707 Berlin, Germany Tel: +49 (0)30 32 79 060 Blackwell Publishing, 10 rue Casimir Delavigne, 75006 Paris, France Tel: +33 1 53 10 33 10 The right of the Author to be identied as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. The Blackwell Publishing logo is a trade mark of Blackwell Publishing Ltd. First published 1955 Reprinted 1956 Second edition 1958 Reprinted 1959, 1961 Third edition 1963 Reprinted 1965, 1966 Fourth edition 1968 Reprinted 1969, 1971 Fifth edition 1975 Sixth edition 1981 Reprinted 1982, 1983 Seventh edition 1985 Reprinted 1986, 1987 Eighth edition 1989 Reprinted 1991 Ninth edition 1993 Reprinted 1993 Tenth edition 1997 Eleventh edition 2002 Catalogue records for this title are available from the Library of Congress and the British Library ISBN 0-632-05582-0 Set in 8/10 pt Palatino by Best-set Typesetter Ltd, Hong Kong Printed and bound in Italy, by Rotolito Lombarda, Milan For further information on Blackwell Science, visit our website: www.blackwell-science.com
5. 5. Preface to the Eleventh Edition, xv Preface to the First Edition, xvi 1 Anatomy and Function, 1 Functional anatomy: sectors and segments, 2 Anatomy of the biliary tract, 3 Development of the liver and bile ducts, 4 Anatomical abnormalities of the liver, 4 Surface marking, 5 Methods of examination, 5 Hepatic morphology, 6 Electron microscopy and hepato-cellular function, 9 Sinusoidal cells, 11 Hepatocyte death and regeneration, 13 Extra-cellular matrix, 14 Altered hepatic microcirculation and disease, 14 Adhesion molecules, 14 Functional heterogeneity, 14 Sinusoidal membrane trafc, 16 Bile duct epithelial cells, 16 2 Assessment of Liver Function, 19 Selection of biochemical tests, 19 Bile pigments, 20 Bilirubin, 20 Urobilinogen, 20 Bromsulphalein, 21 Serum enzyme tests, 21 Alkaline phosphatase, 21 Gamma glutamyl transpeptidase, 22 Aminotransferases, 22 Other serum enzyme, 23 Quantitative assessment of hepatic function, 23 Galactose elimination capacity, 23 Breath tests, 23 Salivary caffeine clearance, 24 Lignocaine metabolite formation, 25 Arterial blood ketone body ratio, 25 Antipyrine, 25 Indocyanine green, 25 Asialoglycoprotein receptor, 25 Excretory capacity (BSP), 25 Lipid and lipoprotein metabolism, 26 Lipids, 26 Lipoproteins, 26 Changes in liver disease, 27 Bile acids, 28 Changes in disease, 29 Serum bile acids, 30 Amino acid metabolism, 31 Clinical signicance, 31 Plasma proteins, 32 Electrophoretic pattern of serum proteins, 33 Carbohydrate metabolism, 34 Effects of ageing on the liver, 34 3 Biopsy of the Liver, 37 Selection and preparation of the patient, 37 Techniques, 37 Difculties, 40 Liver biopsy in paediatrics, 40 Risks and complications, 40 Pleurisy and peri-hepatitis, 40 Haemorrhage, 40 Intra-hepatic haematomas, 41 Haemobilia, 41 Arteriovenous stula, 42 Biliary peritonitis, 42 Puncture of other organs, 43 Infection, 43 Carcinoid crisis, 43 Sampling variability, 43 Naked eye appearances, 43 Preparation of the specimen, 43 Interpretation, 43 Indications, 44 Special methods, 44 4 The Haematology of Liver Disease, 47 General features, 47 The liver and blood coagulation, 49 Contents v
6. 6. Haemolytic jaundice, 53 The liver in haemolytic anaemias, 54 Hereditary spherocytosis, 54 Thalassaemia, 55 Paroxysmal nocturnal haemoglobinuria, 56 Acquired haemolytic anaemia, 56 Haemolytic disease of the newborn, 56 Incompatible blood transfusion, 56 The liver in myelo- and lymphoproliferative disease, 56 Leukaemia, 57 Myeloid, 57 Lymphoid, 57 Hairy cell leukaemia, 57 Bone marrow transplantation, 57 Lymphoma, 58 Jaundice in lymphoma, 59 Primary hepatic lymphoma, 60 Lymphosarcoma, 60 Multiple myeloma, 61 Angio-immunoblastic lymphadenopathy, 61 Extra-medullary haemopoiesis, 61 Systemic mastocytosis, 61 Langerhans cell histiocytosis (histiocytosis X), 61 Lipid storage diseases, 62 Primary and secondary xanthomatosis, 62 Cholesteryl ester storage disease, 62 Gauchers disease, 62 NiemannPick disease, 63 Sea-blue histiocyte syndrome, 64 5 Ultrasound, Computed Tomography and Magnetic Resonance Imaging, 67 Radio-isotope scanning, 67 Positron emission tomography (PET), 67 Ultrasound, 67 Doppler ultrasound, 69 Endoscopic ultrasound, 70 Computed tomography, 70 Magnetic resonance imaging, 74 MR spectroscopy, 76 Conclusions and choice, 77 6 Hepato-cellular Failure, 81 General failure of health, 81 Jaundice, 81 Vasodilatation and hyperdynamic circulation, 81 Hepato-pulmonary syndrome, 82 Pulmonary hypertension, 84 Fever and septicaemia, 86 Fetor hepaticus, 87 Changes in nitrogen metabolism, 87 Skin changes, 87 Vascular spiders, 87 Palmar erythema (liver palms), 88 White nails, 89 Mechanism of skin changes, 89 Endocrine changes, 89 Hypogonadism, 90 Hypothalamicpituitary function, 91 Metabolism of hormones, 91 General treatment, 92 Precipitating factors, 92 General measures, 92 7 Hepatic Encephalopathy, 93 Clinical features, 93 Investigations, 95 Neuropathological changes, 96 Clinical variants in cirrhotics, 97 Differential diagnosis, 98 Prognosis, 99 Pathogenetic mechanisms, 99 Portal-systemic encephalopathy, 99 Intestinal bacteria, 100 Neurotransmission, 100 Conclusions, 103 Treatment of hepatic encephalopathy, 104 Diet, 104 Antibiotics, 105 Lactulose and lactilol, 105 Sodium benzoate and l-ornithine-l-aspartate, 106 Levodopa and bromocriptine, 106 Flumazenil, 106 Branched-chain amino acids, 106 Other precipitating factors, 106 Shunt occlusion, 106 Temporary hepatic support, 107 Hepatic transplantation, 107 8 Acute Liver Failure, 111 Denition, 111 Causes, 111 Clinical features, 113 Investigations, 113 Associations, 115 Prognosis, 118 Treatment, 119 Conclusion, 124 9 Ascites, 127 Mechanism of ascites formation, 127 Underll and peripheral vasodilation hypotheses, 127 Overll hypothesis, 129 Other renal factors, 129 vi Contents
7. 7. Circulation of ascites, 130 Summary, 130 Clinical features, 130 Spontaneous bacterial peritonitis, 132 Treatment of cirrhotic ascites, 134 Refractory ascites, 138 Prognosis, 139 Hepato-renal syndrome, 140 Hyponatraemia, 143 10 The Portal Venous System and Portal Hypertension, 147 Collateral circulation, 147 Intra-hepatic obstruction (cirrhosis), 147 Extra-hepatic obstruction, 148 Effects, 148 Pathology of portal hypertension, 148 Varices, 149 Portal hypertensive intestinal vasculopathy, 151 Haemodynamics of portal hypertension, 151 Clinical features of portal hypertension, 152 History and general examination, 152 Abdominal wall veins, 153 Spleen, 154 Liver, 154 Ascites, 154 Rectum, 154 X-ray of the abdomen and chest, 154 Barium studies, 155 Endoscopy, 155 Imaging the portal venous system, 157 Ultrasound, 157 Doppler ultrasound, 157 CT scan, 158 Magnetic resonance angiography, 158 Venography, 158 Venographic appearances, 158 Visceral angiography, 159 Digital subtraction angiography, 159 Splenic venography, 159 Carbon dioxide wedged venography, 160 Portal pressure measurement, 160 Variceal pressure, 160 Estimation of hepatic blood ow, 161 Azygous blood ow, 162 Experimental portal venous occlusion and hypertension, 163 Classication of portal hypertension, 163 Extra-hepatic portal venous obstruction, 163 Aetiology, 163 Clinical features, 165 Prognosis, 166 Treatment, 167 Splenic vein obstruction, 167 Hepatic arterio-portal venous stulae, 167 Porto-hepatic venous shunts, 168 Intra-hepatic pre-sinusoidal and sinusoidal portal hypertension, 168 Portal tract lesions, 168 Toxic causes, 168 Hepato-portal sclerosis, 168 Tropical splenomegaly syndrome, 169 Intra-hepatic portal hypertension, 169 Cirrhosis, 169 Non-cirrhotic nodules, 170 Bleeding oesophageal varices, 170 Predicting rupture, 170 Prevention of bleeding, 171 Diagnosis of bleeding, 172 Prognosis, 172 Management of acute variceal bleeding, 173 Vaso-active drugs, 174 Sengstaken-Blakemore tube, 174 Endoscopic sclerotherapy and banding, 175 Emergency surgery, 176 Prevention of re-bleeding, 176 Portal-systemic shunt procedures, 177 Porta-caval, 177 Meso-caval, 178 Selective distal spleno-renal, 178 General results of portal-systemic shunts, 178 TIPS (transjugular intrahepatic portosystemic shunt), 178 Shunt stenosis and occlusion, 179 Control of bleeding, 180 TIPS encephalopathy, 180 Circulatory changes, 180 Other indications, 180 Conclusions, 180 Hepatic transplantation, 180 Pharmacological control of the portal circulation, 180 Conclusions, 180 11 The Hepatic Artery and Hepatic Veins: the Liver in Circulatory Failure, 187 The hepatic artery, 187 Hepatic artery occlusion, 188 Hepatic arterial lesions following liver transplantation, 189 Aneurysms of the hepatic artery, 189 Hepatic arteriovenous shunts, 190 The hepatic veins, 190 Experimental hepatic venous obstruction, 191 BuddChiari (hepatic venous obstruction) syndrome, 192 Pathological changes, 193 Clinical features, 193 Contents vii
8. 8. Diagnosis, 195 Prognosis, 196 Treatment, 197 Veno-occlusive disease, 198 Spread of disease by the hepatic veins, 198 Circulatory failure, 199 Hepatic changes in acute heart failure and shock, 199 Ischaemic hepatitis, 200 Post-operative jaundice, 200 Jaundice after cardiac surgery, 201 The liver in congestive heart failure, 201 The liver in constrictive pericarditis, 203 12 Jaundice, 205 Bilirubin metabolism, 205 Hepatic transport and conjugation of bilirubin, 205 Distribution of jaundice in the tissues, 207 Factors determining the depth of jaundice, 207 Classication of jaundice, 208 Diagnosis of jaundice, 209 Clinical history, 209 Examination, 211 Diagnostic routine, 212 Familial non-haemolytic hyperbilirubinaemias, 213 Primary hyperbilirubinaemia, 213 Gilberts syndrome, 213 CriglerNajjar syndrome, 215 DubinJohnson syndrome, 216 Rotor type, 217 The group of familial non-haemolytic hyperbilirubinaemias, 217 13 Cholestasis, 219 Anatomy of the biliary system, 219 Secretion of bile, 220 Cellular mechanisms, 221 Syndrome of cholestasis, 223 Denition, 223 Classication, 223 Pathogenesis, 224 Pathology, 224 Clinical features, 226 Diagnostic approach, 231 Diagnostic possibilities, 232 14 Primary Biliary Cirrhosis, 241 Aetiology, 241 Epidemiology and genetics, 243 Clinical features, 243 Diagnosis, 246 Prognosis, 247 Treatment, 248 Immune cholangiopathy, 250 Autoimmune cholangitis, 253 15 Sclerosing Cholangitis, 255 Primary sclerosing cholangitis (PSC), 255 Infective sclerosing cholangitis, 261 Bacterial cholangitis, 261 Immunodeciency-related opportunistic cholangitis, 261 Graft-versus-host disease, 263 Vascular cholangitis, 263 Drug-related cholangitis, 263 Histiocytosis X, 263 16 Viral Hepatitis: General Features, Hepatitis A, Hepatitis E and Other Viruses, 267 Pathology, 267 Clinical types, 268 Investigations, 271 Differential diagnosis, 271 Prognosis, 272 Treatment, 272 Follow-up, 272 Hepatitis Avirus, 273 Epidemiology, 274 Clinical course, 275 Prognosis, 275 Prevention, 275 Hepatitis E virus, 276 Clinical features, 277 Diagnostic tests, 277 Liver biopsy, 277 Prevention, 277 Hepatitis G virus, 278 Hepatitis TT virus, 278 Yellow fever, 279 Pathology, 279 Clinical features, 279 Treatment, 279 Infectious mononucleosis (EpsteinBarr virus), 279 Hepatic histology, 279 Clinical features, 280 Diagnosis, 280 Distinction from viral hepatitis, 280 Other viruses, 281 Cytomegalovirus, 281 Herpes simplex, 281 Miscellaneous, 281 Hepatitis due to exotic viruses, 282 Treatment, 283 viii Contents
9. 9. 17 Hepatitis B Virus and Hepatitis Delta Virus, 285 Hepatitis B virus (HBV), 285 Acute hepatitis B, 287 Epidemiology, 290 Clinical course, 290 Prevention, 292 Chronic hepatitis B, 294 Clinical relapse and reactivation, 294 Laboratory tests, 295 Needle liver biopsy, 295 Course and prognosis, 295 Treatment, 296 Outstanding problems, 298 Screening for hepato-cellular carcinoma, 298 Hepatitis delta virus (HDV), 300 Epidemiology, 300 Diagnosis, 301 Clinical features, 301 Hepatic histology, 302 Prevention, 302 Treatment, 302 18 Hepatitis C Virus, 305 Molecular virology, 305 Serological tests, 306 Immune response, 307 Epidemiology, 307 Natural history, 308 Clinical course, 308 Hepatic histology, 309 Hepatitis C and serum autoantibodies, 310 Associated diseases, 310 Diagnosis, 311 Prognosis, 311 Prevention: vaccines, 312 Treatment, 312 Hepatic transplantation, 316 19 Chronic Hepatitis: General Features, and Autoimmune Chronic Disease, 321 Clinical presentation, 321 Hepatic histology, 322 The role of liver biopsy, 322 Classication, 324 Autoimmune chronic hepatitis, 325 Type 1 (formerly called lupoid), 326 Type 2, 326 Primary biliary cirrhosis and immune cholangitis, 326 Chronic autoimmune hepatitis (type 1), 326 Aetiology, 326 Hepatic pathology, 328 Clinical features, 328 Differential diagnosis, 330 Treatment, 331 Course and prognosis, 332 Syncytial giant-cell hepatitis, 332 20 Drugs and the Liver, 335 Hepato-cellular zone 3 necrosis, 340 Carbon tetrachloride, 342 Amanita mushrooms, 343 Paracetamol (acetaminophen), 343 Salicylates, 344 Hyperthermia, 344 Hypothermia, 344 Burns, 344 Hepato-cellular zone 1 necrosis, 344 Ferrous sulphate, 345 Phosphorus, 345 Mitochondrial cytopathies, 345 Sodium valproate, 345 Tetracyclines, 345 Tacrine, 345 Antiviral nucleoside analogues, 345 Bacillus cereus, 346 Steato-hepatitis, 346 Perhexiline maleate, 346 Amiodarone, 346 Synthetic oestrogens, 346 Calcium channel blockers, 347 Fibrosis, 347 Methotrexate, 347 Other cytotoxic drugs, 347 Arsenic, 348 Vinyl chloride, 348 Vitamin A, 348 Retinoids, 348 Vascular changes, 348 Sinusoidal dilatation, 348 Peliosis hepatis, 349 Veno-occlusive disease (VOD), 349 Acute hepatitis, 349 Isoniazid, 350 Methyl dopa, 351 Halothane, 351 Hydrouorocarbons, 352 Systemic antifungals, 352 Oncology drugs, 352 Nervous system modiers, 353 Sustained-release nicotinic acid (niacin), 353 Sulphonamides and derivatives, 353 Non-steroidal anti-inammatory drugs, 353 Contents ix
10. 10. Anti-thyroid drugs, 353 Quinidine and quinine, 353 Troglitazone, 354 Anti-convulsants, 354 Chronic hepatitis, 354 Herbal remedies, 354 Recreational drugs, 355 Canalicular cholestasis, 355 Cyclosporin A, 355 Ciprooxacin, 355 Hepato-canalicular cholestasis, 355 Chlorpromazine, 356 Penicillins, 357 Sulphonomides, 357 Erythromycin, 357 Haloperidol, 357 Cimetidine and ranitidine, 357 Oral hypoglycaemics, 357 Tamoxifen, 357 Other causes, 357 Dextropropoxyphene, 357 Ductular cholestasis, 357 Biliary sludge, 357 Sclerosing cholangitis, 357 Hepatic nodules and tumours, 358 Hepato-cellular carcinoma, 358 Conclusions, 359 21 Hepatic Cirrhosis, 365 Classication of cirrhosis, 368 Clinical cirrhosis, 371 Compensated cirrhosis, 374 Decompenstated cirrhosis, 375 Prognosis, 376 Treatment, 377 22 Alcohol and the Liver, 381 Risk factors for alcoholic liver diseases, 381 Metabolism of alcohol, 382 Mechanisms of liver injury, 384 Morphological changes, 386 Fatty liver (steatosis), 386 Alcoholic hepatitis, 387 Cirrhosis, 387 Early recognition, 389 Investigation, 389 Clinical syndromes, 390 Fatty liver, 390 Acute alcoholic hepatitis, 390 Hepatic cirrhosis, 391 Cholestatic syndromes, 391 Relationship to hepatitis B and C, 391 Hepato-cellular cancer, 393 Associated features, 393 Prognosis, 393 Treatment, 394 Acute alcoholic hepatitis, 394 Cirrhosis, 395 Hepatic transplantation, 395 23 Iron Overload States, 399 Normal iron metabolism, 399 Iron overload and liver damage, 401 Genetic haemochromatosis, 401 Other iron storage diseases, 407 Non-HFE-related inherited iron overload, 407 Dysmetabolic syndrome, 408 Erythropoietic siderosis, 408 Late stage cirrhosis, 408 Chronic viral hepatitis, 408 Non-alcoholic fatty liver disease, 408 Neonatal haemochromatosis, 409 African iron overload (Bantu siderosis), 409 Porphyria cutanea tarda, 409 Haemodialysis, 409 Acaeruloplasminaemia, 409 Transferrin deciency, 409 24 Wilsons Disease, 413 Molecular genetics: pathogenesis, 413 Pathology, 414 Clinical picture, 415 Hepatic forms, 416 Neuropsychiatric forms, 417 Renal changes, 417 Other changes, 417 Laboratory tests, 417 Liver biopsy, 418 Scanning, 418 Diagnostic difculties, 418 Treatment, 419 Prognosis, 420 Indian childhood cirrhosis, 421 Hereditary acaeruloplasminaemia, 421 25 Nutritional and Metabolic Liver Diseases, 423 Malnutrition, 423 Fatty liver, 423 Diagnosis, 424 Classication, 424 Non-alcoholic fatty liver disease, 427 Non-alcoholic hepatic steatosis, 428 Non-alcoholic steatonecrosis, 428 Effects of jejuno-ileal bypass, 429 x Contents
11. 11. Parenteral nutrition, 429 Vitamins, 429 Carbohydrate metabolism in liver disease, 431 Hypoglycaemia, 431 Hyperglycaemia, 431 The liver in diabetes mellitus, 431 Insulin and the liver, 431 Hepatic histology, 431 Clinical features, 432 Liver function tests, 432 Hepato-biliary disease and diabetes, 432 Glucose intolerance of cirrhosis, 432 Treatment of diabetes in cirrhotic patients, 433 Glycogen storage diseases, 434 Type I (von Gierkes disease), 435 Type II (Pompes disease), 436 Type III (Coris disease), 436 Type IV (Andersens disease), 437 Type VI (Hers disease), 437 Hepatic glycogen synthetase deciency (type 0), 437 Hereditary fructose intolerance, 438 Glutaric aciduria type II, 438 Galactosaemia, 438 Mucopolysaccharidoses, 439 Familial hypercholesterolaemia, 439 Amyloidosis, 440 a1-Antitrypsin deciency, 443 Hereditary tyrosinaemia, 445 Cystic brosis, 446 Liver and thyroid, 447 Thyrotoxicosis, 447 Myxoedema, 447 Changes with hepato-cellular disease, 447 Liver and adrenal, 448 Liver and growth homone, 448 Hepatic porphyrias, 448 Acute intermittent porphyria, 449 Hereditary coproporphyria, 450 Variegate porphyria, 450 Porphyria cutanea tarda, 450 Erythropoietic protoporphyria, 450 Congenital erythropoietic porphyria, 451 Hepato-erythropoietic porphyria, 451 Secondary coproporphyrias, 451 Hereditary haemorrhagic telangiectasia, 452 Dystrophia myotonica, 452 26 The Liver in Infancy and Childhood, 453 Neonatal hyperbilirubinaemia, 453 Unconjugated hyperbilirubinaemia, 453 Haemolytic disease of the newborn, 454 Hepatitis and cholestatic syndromes (conjugated hyperbilirubinaemia), 455 Viral hepatitis, 457 Non-viral causes of hepatitis, 459 Urinary tract infections, 459 Neonatal hepatitis syndrome, 459 Infantile cholangiopathies, 460 Biliary atresia, 460 Extra-hepatic biliary atresia, 460 Alagilles syndrome (arterio-hepatic dysplasia), 462 Prolonged parenteral nutrition, 462 Abnormal bile acid synthesis, 463 Genetic cholestatic syndromes, 463 Symptomatic treatment of cholestatic syndromes, 464 Other causes of cholestatic jaundice, 464 Reyes syndrome, 465 Reye-like syndromes, 465 Cirrhosis in infancy and childhood, 465 Indian childhood cirrhosis, 466 Non-Indian childhood cirrhosis (copper-associated liver disease), 466 Hepatic steatosis, 467 Fetal alcohol syndrome, 467 Idiopathic steato-hepatitis, 467 Tumour of the liver, 467 Hamartomas, 467 Mesenchymal hamartoma, 467 Malignant mesenchymoma (undifferentiated sarcoma), 467 Adenomas, 467 Hepato-cellular carcinoma, 467 Hepatoblastoma, 467 Infantile haemangio-endothelioma, 467 Nodular regenerative hyperplasia, 468 Hepatic transplantation, 468 27 The Liver in Pregnancy, 471 Normal pregnancy, 471 Liver disease in pregnancy, 471 Hyperemesis gravidarum, 471 Liver diseases of late pregnancy, 471 Acute fatty liver of pregnancy, 471 Pregnancy toxaemias, 474 The HELLP syndrome, 474 Toxaemia and the HELLP syndrome, 475 Hepatic haemorrhage, 475 Cholestasis of pregnancy, 475 BuddChiari syndrome, 476 Intercurrent jaundice, 476 Viral hepatitis, 476 Biliary tract disease, 477 Hepato-toxic drugs and the pregnant woman, 478 Effect of pregnancy on pre-existing chronic liver disease, 478 Pregnancy in liver transplant recipients, 478 Contents xi
12. 12. 28 The Liver in Systemic Disease, Granulomas and Hepatic Trauma, 481 The liver in collagen diseases, 481 Arthropathy associated with liver disease, 481 Genetic haemochromatosis, 481 Hepatitis B virus (HBV) associations, 481 Hepatitis C virus (HCV) associations, 482 Hepatic granulomas, 482 Clinical syndrome of hepatic granulomas, 483 Granulomatous hepatitis, 484 Sarcoidosis, 484 Granulomatous drug reactions, 486 Granulomas associated with infections, 487 Hepatic granulomas in the patient with AIDS, 488 Industrial causes, 489 Other conditions with hepatic granulomas, 489 Hepato-biliary associations of inammatory bowel disease, 490 Hepatic trauma, 490 Rupture of the gallbladder, 492 29 The Liver in Infections, 495 Pyogenic liver abscess, 495 Other infections, 498 Hepatic amoebiasis, 498 Tuberculosis of the liver, 501 Hepatic actinomycosis, 502 Other fungal infections, 502 Syphilis of the liver, 503 Congenital, 503 Secondary, 503 Tertiary, 503 Jaundice complicating penicillin treatment, 504 Leptospirosis, 504 Weils disease, 504 Other types of leptospirosis, 506 Relapsing fever, 507 Lyme disease, 507 Q fever, 507 Rocky mountain spotted fever, 508 Schistosomiasis (bilharziasis), 508 Malaria, 510 Kala-azar (leishmaniasis), 511 Hydatid disease, 511 Echinococcus multilocularis (alveolar echinococcosis), 516 Ascariasis, 517 Strongyloides stercoralis, 518 Trichiniasis, 518 Toxocara canis (visceral larva migrans), 518 Liver ukes, 518 Clonorchis sinensis, 518 Fasciola hepatica, 519 Recurrent pyogenic cholangitis, 519 Peri-hepatitis, 520 Hepato-biliary disease in HIV infection, 520 Infections, 521 Hepatitis B, C and D co-infection, 522 Neoplasms, 522 Hepato-biliary disease, 523 Acaculous cholecystitis, 524 Jaundice of infections, 525 Bacterial pneumonia, 525 Septicaemia and septic shock, 525 30 Nodules and Benign Liver Lesions, 527 Small hepato-cellular cancer, 527 Nodules in the absence of underlying liver disease, 528 Simple cysts, 528 Haemangioma, 528 Focal nodular hyperplasia, 530 Hepatic adenoma, 531 Focal nodular hyperplasia and adenoma contrasted, 532 Liver metastases, 532 Other benign tumours, 534 Cholangioma (bile duct adenoma), 534 Biliary cystadenoma, 534 Nodular regenerative hyperplasia, 534 Partial nodular transformation, 535 31 Malignant Liver Tumours, 537 Hepato-cellular cancer, 537 Aetiological factors, 537 Pathology, 540 Clinical features, 541 Tumour localization, 543 Needle liver biopsy, 546 Screening, 546 Prognosis and risk factors, 547 Surgical treatment, 547 Non-surgical treatment, 548 Fibro-lamellar carcinoma of the liver, 551 Hepatoblastoma, 551 Intra-hepatic cholangiocarcinoma, 552 Combined hepato-cellularcholangiocarcinoma, 553 Other primary liver tumours, 553 Cystadenocarcinoma, 553 Angiosarcoma (haemangio-endothelioma), 553 Epitheloid haemangio-endothelioma, 554 Undifferentiated sarcoma of the liver, 554 Benign tumours of the liver, 554 Mesenchymal hamartoma, 554 Paraneoplastic hepatopathy, 554 Hepatic metastases, 554 xii Contents
13. 13. 32 Imaging of the Biliary Tract: Interventional Radiology and Endoscopy, 563 Plain lm of the abdomen, 563 Ultrasound (US), 563 Bile ducts, 563 Gallbladder, 563 Computed tomography (CT), 564 Magnetic resonance cholangiopancreatography (MRCP), 565 Endoscopic ultrasound (EUS), 566 Biliary scintigraphy, 567 Oral cholecystography, 567 Intravenous cholangiography, 568 Endoscopic retrograde cholangiopancreatography, 568 Endoscopic sphincterotomy, 570 Endoscopic biliary endoprostheses, 573 Percutaneous trans-hepatic cholangiography, 576 Percutaneous bile drainage, 576 Percutaneous biliary endoprosthesis, 577 Resectability of tumours, 578 Choice between surgical and non-surgical palliation of malignant obstruction, 578 Choice between endoscopic and percutaneous approach, 578 Percutaneous cholecystostomy, 578 Operative and post-operative cholangiography, 579 33 Cysts and Congenital Biliary Abnormalities, 583 Fibropolycystic disease, 583 Childhood bropolycystic diseases, 584 Adult polycystic disease, 584 Congenital hepatic brosis, 586 Congenital intra-hepatic biliary dilatation (Carolis disease), 588 Congenital hepatic brosis and Carolis disease, 589 Choledochal cyst, 589 Microhamartoma (von Meyenberg complexes), 591 Carcinoma secondary to bropolycystic disease, 591 Solitary non-parasitic liver cyst, 591 Other cysts, 591 Congenital anomalies of the biliary tract, 592 Absence of the gallbladder, 592 Double gallbladder, 592 Accessory bile ducts, 593 Left-sided gallbladder, 594 RokitanskyAschoff sinuses, 594 Folded gallbladder, 594 Diverticula of the gallbladder and ducts, 594 Intra-hepatic gallbladder, 594 Congenital adhesions to the gallbladder, 594 Floating gallbladder and torsion of the gallbladder, 594 Anomalies of the cystic duct and cystic artery, 595 34 Gallstones and Inammatory Gallbladder Diseases, 597 Composition of gallstones, 597 Composition of bile, 597 Factors in cholesterol gallstone formation, 598 Pigment gallstones, 603 Radiology of gallstones, 603 Natural history of gallstones, 604 Silent gallstones, 605 Treatment of gallstones in the gallbladder, 605 Cholecystectomy, 605 Laparoscopic cholecystectomy, 605 Non-surgical treatment of gallstones in the gallbladder, 607 Dissolution therapy, 607 Direct solvent dissolution, 608 Shock-wave therapy, 608 Percutaneous cholecystolithotomy, 609 Conclusions, 609 Acute cholecystitis, 610 Empyema of the gallbladder, 612 Perforation of the gallbladder, 612 Emphysematous cholecystitis, 612 Chronic calculous cholecystitis, 613 Acalculous cholecystitis, 614 Acute, 614 Chronic, 614 Typhoid cholecystitis, 614 Acute cholecystitis in AIDS, 614 Other associations, 615 Other gallbladder pathology, 615 Cholesterolosis of the gallbladder, 615 Xanthogranulomatous cholecystitis, 615 Adenomyomatosis, 615 Porcelain gallbladder, 615 Post-cholecystectomy problems, 615 Sphincter of Oddi dysfunction, 616 Gallstones in the common bile duct (choledocholithiasis), 616 Managment of common duct stones, 618 Acute obstructive suppurative cholangitis, 618 Acute cholangitis, 618 Common duct stones without cholangitis, 619 Patients with gallbladder in situ, 619 Acute gallstone pancreatitis, 619 Large common duct stones, 619 Trans T-tube tract removal of stones, 620 Intra-hepatic gallstones, 620 Mirizzis syndrome, 620 Biliary stulae, 621 Contents xiii
14. 14. External, 621 Internal, 621 Gallstone ileus, 621 Haemobilia, 622 Bile peritonitis, 622 Association of gallstones with other diseases, 623 Colorectal and other cancers, 623 Diabetes mellitus, 623 35 Benign Stricture of the Bile Ducts, 629 Post-cholecystectomy, 629 Bile duct/bowel anastomotic stricture, 634 Post liver transplantation, 635 Primary sclerosing cholangitis, 636 Other causes, 636 Summary, 636 36 Diseases of the Ampulla of Vater and Pancreas, 639 Peri-ampullary carcinoma, 639 Benign villous adenoma of the ampulla of Vater, 644 Cystic tumours of the pancreas, 644 Endocrine tumours of the pancreas, 644 Chronic pancreatitis, 644 Obstruction of the common bile duct by enlarged lymph glands, 645 Other causes of extrinsic pressure on the common bile duct, 645 37 Tumours of the Gallbladder and Bile Ducts, 647 Benign lesions of the gallbladder, 647 Carcinoma of the gallbladder, 647 Other tumours, 648 Benign tumours of the extra-hepatic bile duct, 648 Carcinoma of the bile duct (cholangiocarcinoma), 648 Cholangiocellular carcinoma, 654 Metastases at the hilum, 655 38 Hepatic Transplantation, 657 Selection of patients, 657 Candidates: outcome, 657 Cirrhosis, 659 Autoimmune chronic hepatitis, 659 Chronic viral hepatitis, 659 Neonatal hepatitis, 660 Alcoholic liver disease, 660 Cholestatic liver disease, 660 Primary metabolic disease, 661 Acute liver failure, 662 Malignant disease, 662 Miscellaneous, 663 Absolute and relative contraindications, 663 Absolute, 663 Relative (higher risk), 664 General preparation of the patient, 664 Donor selection and operation, 664 The recipient operation, 665 Segmental (split liver) transplantation, 665 Auxiliary liver transplantation, 666 Xeno-transplantation, 666 Domino liver transplantation, 666 Hepatocyte transplantation, 667 Liver transplantation in paediatrics, 667 Immunosuppression, 667 Tolerance, 668 Post-operative course, 668 Post-transplantation complications, 668 Rejection, 671 Infections, 673 Malignancies, 675 Drug-related toxicity, 675 Disease recurrence, 675 Central nervous system toxicity, 675 Bone disease, 675 Ectopic soft-tissue calcication, 675 Conclusion, 675 Index, 681 xiv Contents
15. 15. The eleventh edition welcomes the new Millenium. Progress in basic and clinical hepatology remains ex- ponential. Since 1997, the advances have been wide- ranging, with those in molecular and cellular biology, and in diagnosis and treatment, leading the way. In a world in which information technology gives all too ready access to individual publications, the eleventh edition sets the new within established knowledge and practice. Viral hepatitis remains the worldwide hepatological challenge. This is reected in a change in format with separate chapters on hepatitis B and C. Molecular virol- ogy continues to expose the inner workings of all the viruses. New therapeutic approaches are proving more effective against hepatitis C. Molecular and cellular biol- ogists are showing us the importance of apoptosis and the intricate regulation of brosis. Mutation analysis for diagnosis of genetic haemochromatosis is routine, while the identication of the haemochromatosis gene has led to a surge of exploration in iron metabolism. Canalicular transporters have been cloned and linked to cholestatic syndromes, giving a new perspective to the bile plug seen under the microscope. Advances in imaging, par- ticularly magnetic resonance, continue to reduce the need for invasive techniques. Patients needing trans- plantation benet from improvements in immuno- suppression and surgical techniques, while there is steady progress in the management of complications of cirrhosis. This edition contains more than 1000 new references and 100 new gures. Developments in publishing allow a more colourful format, but care has been taken to preserve clarity. Experience has shown that students, interns, postgraduate trainees as well as generalists and specialist clinicians have found previous editions useful. The goal of the book remains unchanged: a textbook of manageable size, critical and current. We are indebted to many colleagues for their generous contributions to this edition including in particular Professor Peter Scheuer, Professor Amar Dhillon and Dr Susan Davies for histological material, and Dr Robert Dick, Dr Tony Watkinson and Dr Jon Tibballs for radio- logical images. We would also like to express our great thanks to Dr Leslie Berger, Dr Andrew Burroughs, Dr John Buscombe, Dr Martyn Caplin, Professor Geoffrey Dusheiko, Dr David Harry, DrAndrew Hilson, Professor Humphrey Hodgson, Professor Neil McIntyre, Dr Kevin Moore, Dr Marsha Morgan, Dr Chris Kibbler and Dr David Patch for their help in the preparation of this edition. Miss Aileen Duggan and Miss Karma Raines have assisted tirelessly with their meticulous secretarial support. The clarity and style of gures preserved from previous editions owes much to the artistry of Miss Janice Cox over many years. We are grateful to Blackwell Publishing and, in par- ticular, Rebecca Huxley for her tireless help with both manuscript and proofs, and for responding without a murmur to demands within a tight schedule. We also thank Jane Fallows who has reformatted and coloured all the previous line drawings as well as creating the many new and visually inviting gures for the eleventh edition. The preface to the rst edition which was published in 1955 refers to daughters Amanda and Auriole. Amanda is now an ordained Minister in the Baptist Church, and Auriole is working with Kent Police. Grandchildren have arrived, including Alice aged 9 and Emily aged 6. On the 13th July 2001, the senior author was elected a Fellow of the Royal Society in its 341st year, a Society founded to improve natural knowledge. This honour was achieved because of the support of all the clinicians and scientists who have contributed to the Liver Unit and its associated departments at The Royal Free. The new Millenium is indeed an exciting time for all those working to solve the puzzles within hepato-biliary disease. sheila sherlock james dooley November 2001 Preface to the Eleventh Edition xv
16. 16. My aim in writing this book has been to present a com- prehensive and up-to-date account of diseases of the liver and biliary system, which I hope will be of value to physicians, surgeons and pathologists and also a refer- ence book for the clinical student. The modern literature has been reviewed with special reference to articles of general interest. Many older more specialized classical contributions have therefore inevitably been excluded. Disorders of the liver and biliary system may be classi- ed under the traditional concept of individual diseases. Alternatively, as I have endeavoured in this book, they may be described by the functional and morphological changes which they produce. In the clinical management of a patient with liver disease, it is important to assess the degree of disturbance of four functional and morpho- logical components of the liverhepatic cells, vascular system (portal vein, hepatic artery and hepatic veins), bile ducts and reticulo-endothelial system. The typical reaction pattern is thus sought and recognized before attempting to diagnose the causative insult. Clinical and laboratory methods of assessing each of these com- ponents are therefore considered early in the book. Descriptions of individual diseases follow as illustrative examples. It will be seen that the features of hepatocellu- lar failure and portal hypertension are described in general terms as a foundation for subsequent discussion of virus hepatitis, nutrition liver disease and the cir- rhoses. Similarly blood diseases and infections of the liver are included with the reticulo-endothelial system, and disorders of the biliary tract follow descriptions of acute and chronic bile duct obstruction. I would like to acknowledge my indebtedness to my teachers, the late Professor J. Henry Dible, the late Pro- fessor Sir James Learmonth and Professor Sir John McMichael, who stimulated my interest in hepatic disease, and to my colleagues at the Postgraduate Medical School and elsewhere who have generously invited me to see patients under their care. I am grateful to Dr A. G. Bearn for criticizing part of the typescript and to Dr A. Paton for his criticisms and careful proof reading. Miss D. F. Atkins gave much assistance with proof reading and with the bibliography. Mr Per Saugman and Mrs J. M. Green of Blackwell Scientic Publications have co-operated enthusiastically in the production of this book. The photomicrographs were taken by Mr E. V. Will- mott, frps, and Mr C. A. P. Graham from section pre- pared by Mr J. G. Grifn and the histology staff of the Postgraduate Medical School. Clinical photographs are the work of Mr C. R. Brecknell and his assistants. The black and white drawings were made by Mrs H. M. G. Wilson and Mr D. Simmonds. I am indebted to them all for their patience and skill. The text includes part of unpublished material included in a thesis submitted in 1944 to the University of Edinburgh for the degree of MD, and part of an essay awarded the BuckstonBrowne prize of the Harveian Society of London in 1953. Colleagues have allowed me to include published work of which they are jointly responsible. Dr Patricia P. Franklyn and Dr R. E. Steiner have kindly loaned me radiographs. Many authors have given me permission to reproduce illustrations and detailed acknowledgments are given in the text. I wish also to thank the editors of the following journals for permission to include illustrations: American Journal of Medicine, Archives of Pathology, British Heart Journal, Circulation, Clinical Science, Edinburgh Medical Journal, Journal of Clinical Investigation, Journal of Laboratory and Clinical Investigation, Journal of Pathology and Bacteriology, Lancet, Postgraduate Medical Journal, Proceedings of the Staff Meetings of the Mayo Clinic, Quarterly Journal of Medi- cine, Thorax and also the following publishers: Butter- worths Medical Publications, J. & A. Churchill Ltd, The Josiah Macy Junior Foundation and G. D. Searle & Co. Finally I must thank my husband, Dr D. Geraint James, who, at considerable personal inconvenience, encouraged me to undertake the writing of this book and also criticized and rewrote most of it. He will not allow me to dedicate it to him. sheila sherlock Preface to the First Edition xvi
17. 17. The liver, the largest organ in the body, weighs 12001500g and comprises one-ftieth of the total adult body weight. It is relatively larger in infancy, comprising one-eighteenth of the birth weight. This is mainly due to a large left lobe. Sheltered by the ribs in the right upper quadrant, the upper border lies approximately at the level of the nipples. There are two anatomical lobes, the right being about six times the size of the left (gs 1.11.3). Lesser segments of the right lobe are the caudate lobe on the posterior surface and the quadrate lobe on the inferior surface. The right and left lobes are separated anteriorly by a fold of peritoneum called the falciform ligament, posteriorly by the ssure for the ligamentum veno- sum and inferiorly by the ssure for the ligamentum teres. The liver has a double blood supply. The portal vein brings venous blood from the intestines and spleen and the hepatic artery, coming from the coeliac axis, supplies the liver with arterial blood. These vessels enter the liver through a ssure, the porta hepatis, which lies far back on the inferior surface of the right lobe. Inside the porta, the portal vein and hepatic artery divide into branches to the right and left lobes, and the right and left hepatic bile ducts join to form the common hepatic duct. The hepatic nerve plexus contains bres from the sympathetic ganglia 1 Chapter 1 Anatomy and Function Right lobe Diaphragm Left lobe Falciform ligament Ligamentum teres Gallbladder Fig. 1.1. Anterior view of the liver. Caudate lobe Left lobe Fissure for ligamentum venosum Inferior vena cava Gallbladder Right lobe Bare area Fig. 1.2. Posterior view of the liver. Gastric impression Portal vein Porta hepatis Hepatic artery Bile duct Ligamentum teres Quadrate lobe Renal impression Duodenal impression Colonic impression Gallbladder Fissure for ligamentum venosum Fig. 1.3. Inferior view of the liver.
18. 18. branches and each of these supplies two further subunits (variously called sectors). The sectors on the right side are anterior and posterior and, in the left lobe, medial and lateralgiving a total of four sectors (g. 1.4). Using this denition, the right and left side of the liver are divided not along the line of the falciform ligament, but along a slightly oblique line to the right of this, drawn from the inferior vena cava above to the gallbladder bed below. The right and left side are independent with regard to portal and arterial blood supply, and bile drainage. Three plains separate the four sectors and contain the three major hepatic vein branches. Closer analysis of these four hepatic sectors produces a further subdivision into segments (g. 1.5). The right anterior sector contains segments V and VIII; right poste- rior sector, VI and VII; left medial sector, IV; left lateral sector, segments II and III. There is no vascular anasto- mosis between the macroscopic vessels of the segments but communications exist at sinusoidal level. Segment I, the equivalent of the caudate lobe, is separate from the other segments and does not derive blood directly from the major portal branches or drain by any of the three major hepatic veins. This functional anatomical classication allows inter- pretation of radiological data and is of importance to the 2 Chapter 1 T7T10, which synapse in the coeliac plexus, the right and left vagi and the right phrenic nerve. It accompanies the hepatic artery and bile ducts into their nest rami- cations, even to the portal tracts and hepatic parenchyma [4]. The ligamentum venosum, a slender remnant of the ductus venosus of the fetus, arises from the left branch of the portal vein and fuses with the inferior vena cava at the entrance of the left hepatic vein. The ligamentum teres, a remnant of the umbilical vein of the fetus, runs in the free edge of the falciform ligament from the umbilicus to the inferior border of the liver and joins the left branch of the portal vein. Small veins accompanying it connect the portal vein with veins around the umbilicus. These become prominent when the portal venous system is obstructed inside the liver. The venous drainage from the liver is into the right and left hepatic veins which emerge from the back of the liver and at once enter the inferior vena cava very near its point of entry into the right atrium. Lymphatic vessels terminate in small groups of glands around the porta hepatis. Efferent vessels drain into glands around the coeliac axis. Some supercial hepatic lymphatics pass through the diaphragm in the falciform ligament and nally reach the mediastinal glands. Another group accompanies the inferior vena cava into the thorax and ends in a few small glands around the intrathoracic portion of the inferior vena cava. The inferior vena cava makes a deep groove to the right of the caudate lobe about 2cm from the mid-line. The gallbladder lies in a fossa extending from the in- ferior border of the liver to the right end of the porta hepatis. The liver is completely covered with peritoneum, except in three places. It comes into direct contact with the diaphragm through the bare area which lies to the right of the fossa for the inferior vena cava. The other areas without peritoneal covering are the fossae for the inferior vena cava and gallbladder. The liver is kept in position by peritoneal ligaments and by the intra-abdominal pressure transmitted by the tone of the muscles of the abdominal wall. Functional anatomy: sectors and segments Based on the external appearances described above, the liver has a right and left lobe separated along the line of insertion of the falciform ligament. This separation, however, does not correlate with blood supply or biliary drainage. A functional anatomy is now recognized based upon studies of vascular and biliary casts made by inject- ing vinyl into the vessels and bile ducts. This classica- tion correlates with that seen by imaging techniques. The main portal vein divides into right and left posterior anterior medial Left side Right side Right Left lateral Fig. 1.4. The sectors of the human liver.
19. 19. surgeon planning a liver resection. There are wide varia- tions in portal and hepatic vessel anatomy which can be demonstrated by spiral computed tomography (CT) and magnetic resonance imaging (MRI) reconstruction [41]. Anatomy of the biliary tract (g. 1.6) The right and left hepatic ducts emerge from the liver and unite in the porta hepatis to form the common hepatic duct. This is soon joined by the cystic duct from the gallbladder to form the common bile duct. The common bile duct runs between the layers of the lesser omentum, lying anterior to the portal vein and to therightofthehepaticartery.Passingbehindtherstpart oftheduodenuminagrooveonthebackoftheheadofthe pancreas, it enters the second part of the duodenum. The duct runs obliquely through the postero-medial wall, usually joining the main pancreatic duct to form the ampulla of Vater (1720). The ampulla makes the mucous membrane bulge inwards to form an eminence: the duodenal papilla. In about 1015% of subjects the bile and pancreatic ducts open separately into the duodenum. The dimensions of the common bile duct depend on the technique used. At operation it is about 0.51.5cm in diameter. Using ultrasound the values are less, the common bile duct being 27mm, with values greater than 7mm being regarded as abnormal. Using endo- scopic cholangiography, the duct diameter is usually less than 11mm, although after cholecystectomy it may be more in the absence of obstruction. The duodenal portion of the common bile duct is sur- rounded by a thickening of both longitudinal and circu- lar muscle bres derived from the intestine. This is called the sphincter of Oddi (1887). The gallbladder is a pear-shaped bag 9cm long with a capacity of about 50ml. It always lies above the trans- verse colon, and is usually next to the duodenal cap overlying, but well anterior to, the right renal shadow. Any decrease in concentrating power is accompanied by reduced distensibility. The fundus is the wider end and is directed anteriorly; this is the part palpated when the abdomen is examined. The body extends into a Anatomy and Function 3 VII VIII V VI IV I II III Fig. 1.5. Schematic representation of the functional anatomy of the liver. Three main hepatic veins (dark blue) divide the liver into four sectors, each of them receiving a portal pedicle; hepatic veins and portal veins are intertwined as the ngers of two hands [5]. Sphincter of Oddi Common hepatic duct Common bile duct Hepatic ducts Pancreatic duct Ampulla of VaterDuodenal papilla Hartmann's pouch Neck Cystic duct Heister's spiral valve Duodenum Fig. 1.6. Gallbladder and biliary tract.
20. 20. narrow neck which continues into the cystic duct. The valves of Heister are spiral folds of mucous membrane in the wall of the cystic duct and neck of the gallbladder. Hartmanns pouch is a sacculation at the neck of the gall- bladder; this is a common site for a gallstone to lodge. The wall consists of a musculo-elastic network without denite layers, the muscle being particularly well developed in the neck and fundus. The mucous membrane is in delicate closely woven folds; instead of glands there are deep indentations of mucosa, the crypts of Luschka, which penetrate into the muscular layer. There is no submucosa or muscularis mucosae. The RokitanskyAschoff sinuses are branching evagina- tions from the gallbladder lumen lined by mucosa reach- ing into the muscularis of the gallbladder. They play an important part in acute cholecystitis and gangrene of the gallbladder wall. Blood supply. The gallbladder receives blood from the cystic artery. This branch of the hepatic artery is large, tortuous and variable in its anatomical relationships. Smaller blood vessels enter from the liver through the gallbladder fossa. The venous drainage is into the cystic vein and thence into the portal venous system. The arterial blood supply to the supra-duodenal bile duct is generally by two main (axial) vessels which run beside the bile duct. These are supplied predomi- nantly by the retro-duodenal artery from below, and the right hepatic artery from above, although many other vessels contribute. This pattern of arterial supply would explain why vascular damage results in bile duct stricturing [24]. Lymphatics. There are many lymphatic vessels in the submucous and subperitoneal layers. These drain through the cystic gland at the neck of the gallbladder to glands along the common bile duct, where they anas- tomose with lymphatics from the head of the pancreas. Nerve supply. The gallbladder and bile ducts are liber- ally supplied with nerves, from both the parasympa- thetic and the sympathetic system. Development of the liver and bile ducts The liver begins as a hollow endodermal bud from the foregut (duodenum) during the third week of gestation. The bud separates into two partshepatic and biliary. The hepatic part contains bipotential progenitor cells that differentiate into hepatocytes or ductal cells, which form the early primitive bile duct structures (ductal plates). Differentiation is accompanied by changes in cytoker- atin type within the cell [40]. Normally, this collection of rapidly proliferating cells penetrates adjacent meso- dermal tissue (the septum transversum) and is met by ingrowing capillary plexuses from the vitelline and umbilical veins which will form the sinusoids. The con- nection between this proliferating mass of cells and the foregut, the biliary part of the endodermal bud, will form the gallbladder and extra-hepatic bile ducts. Bile begins to ow at about the 12th week. Haemopoietic cells, Kupffer cells and connective tissue cells are derived from the mesoderm of the septum transversum. The fetal liver has a major haemopoietic function which subsides during the last 2 months of intra-uterine life so that only a few haemopoietic cells remain at birth. Anatomical abnormalities of the liver These are being increasingly diagnosed with more wide- spread use of CT and ultrasound scanning. Accessory lobes. The livers of the pig, dog and camel are divided into distinct and separate lobes by strands of connective tissue. Occasionally, the human liver may show this reversion and up to 16 lobes have been reported. This abnormality is rare and without clinical signicance. The lobes are small and usually on the under surface of the liver so that they are not detected clinically but are noted incidentally at scanning, opera- tion or necropsy. Rarely they are intrathoracic. An acces- sory lobe may have its own mesentery containing hepatic artery, portal vein, bile duct and hepatic vein. This may twist and demand surgical intervention. Riedels lobe is fairly common and is a downward tongue-like projection of the right lobe of the liver. It is a simple anatomical variation; it is not a true accessory lobe. The condition is more frequent in women. It is detected as a mobile tumour on the right side of the abdomen which descends with the diaphragm on inspi- ration. It may come down as low as the right iliac region. It is easily mistaken for other tumours in this area, es- pecially a visceroptotic right kidney. It does not cause symptoms and treatment is not required. Scanning may be used to identify Riedels lobe and other anatomical abnormalities. Cough furrows on the liver are parallel grooves on the convexity of the right lobe. They are one to six in number and run antero-posteriorly, being deeper posteriorly. They are said to be associated with a chronic cough. Corset liver. This is a brotic furrow or pedicle on the anterior surface of both lobes of the liver just below the costal margin. The mechanism is unknown, but it affects elderly women who have worn corsets for many years. It presents as an abdominal mass in front of and below the liver and is isodense with the liver. It may be confused with a hepatic tumour. Lobar atrophy. Interference with the portal supply or biliary drainage of a lobe may cause atrophy. There is usually hypertrophy of the opposite lobe. Left lobe atrophy found at post-mortem or during scanning is not uncommon and is probably related to reduced blood supply via the left branch of the portal vein. The lobe is decreased in size with thickening of the capsule, brosis 4 Chapter 1
21. 21. and prominent biliary and vascular markings. The vas- cular problem may date from the time of birth. Obstruction to the right or left hepatic bile duct by benign stricture or cholangiocarcinoma is now the most common cause of lobar atrophy [16]. The alkaline phos- phatase is usually elevated. The bile duct may not be dilated within the atrophied lobe. Relief of obstruction may reverse the changes if cirrhosis has not developed. Distinction between a biliary and portal venous aetiol- ogy may be made using technetium-labelled iminodi- acetic acid (IDA) and colloid scintiscans. A small lobe with normal uptake of IDA and colloid is compatible with a portal aetiology. Reduced or absent uptake of both isotopes favours biliary disease. Agenesis of the right lobe [27]. This rare lesion may be an incidental nding associated, probably coincidentally, with biliary tract disease and also with other congenital abnormalities. It can cause pre-sinusoidal portal hyper- tension. The other liver segments undergo compen- satory hypertrophy. It must be distinguished from lobar atrophy due to cirrhosis or hilar cholangiocarcinoma. Anatomical abnormalities of the gallbladder and biliary tract are discussed in Chapter 33. Surface marking (gs 1.7, 1.8) Liver. The upper border of the right lobe is on a level with the 5th rib at a point 2cm medial to the right mid-clavicu- lar line (1cm below the right nipple). The upper border of the left lobe corresponds to the upper border of the 6th rib at a point in the left mid-clavicular line (2cm below the left nipple). Here only the diaphragm separates the liver from the apex of the heart. The lower border passes obliquely upwards from the 9th right to the 8th left costal cartilage. In the right nipple line it lies between a point just under to 2cm below the costal margin. It crosses the mid-line about mid-way between the base of the xiphoid and the umbilicus and the left lobe extends only 5cm to the left of the sternum. Gallbladder. Usually the fundus lies at the outer border of the right rectus abdominis muscle at its junction with the right costal margin (9th costal cartilage) (g. 1.8). In an obese subject it may be difcult to identify the outer border of the rectus sheath and the gallbladder may then be located by the GreyTurner method. A line is drawn from the left anterior superior iliac spine through the umbilicus; its intersection with the right costal margin indicates the position of the gallbladder. These guide- lines depend upon the individuals build. The fundus may occasionally be found below the iliac crest. Methods of examination Liver. The lower edge should be determined by palpa- tion just lateral to the right rectus muscle. This avoids mistaking the upper intersection of the rectus sheath for the liver edge. Anatomy and Function 5 Fig. 1.7. The surface marking of the liver. Method I Gallbladder Outer border right rectus sheath Method II Costal margin Gallbladder Umbilicus Anterior superior spine Fig. 1.8. Surface markings of the gallbladder. Method I: the gallbladder is found where the outer border of the right rectus abdominis muscle intersects the 9th costal cartilage. Method II: a line drawn from the left anterior superior iliac spine through the umbilicus intersects the costal margin at the site of the gallbladder.
22. 22. The liver edge moves 13cm downwards with deep inspiration. It is usually palpable in normal subjects inspiring deeply. The edge may be tender, regular or irregular, rm or soft, thickened or sharp. The lower edge may be displaced downwards by a low diaphragm, for instance in emphysema. Movements may be particu- larly great in athletes or singers. Some patients with practice become very efcient at pushing down the liver. The normal spleen can become palpable in similar fashion. Common causes of a liver palpable below the umbilicus are malignant deposits, polycystic or Hodgkins disease, amyloidosis, congestive cardiac failure and gross fatty change. Rapid change in liver size may occur when congestive cardiac failure is corrected, cholestatic jaundice relieved, or when severe diabetes is controlled. The surface can be palpated in the epigas- trium and any irregularity or tenderness noted. An enlarged caudate lobe, as in the BuddChiari syndrome or with some cases of cirrhosis, may be palpated as an epigastric mass. Pulsation of the liver, usually associated with tricus- pid valvular incompetence, is felt by manual palpation with one hand behind the right lower ribs posteriorly and the other anteriorly on the abdominal wall. The upper edge is determined by fairly heavy percus- sion passing downwards from the nipple line. The lower edge is recognized by very light percussion passing upwards from the umbilicus towards the costal margin. Percussion is a valuable method of determining liver size and is the only clinical method of determining a small liver. The anterior liver span is obtained by measuring the vertical distance between the uppermost and lowermost points of hepatic dullness by percussion in the right mid- clavicular line. This is usually 1215cm. Direct percus- sion is as accurate as ultrasound in estimating liver span [33]. Friction may be palpable and audible, usually due to recent biopsy, tumour or peri-hepatitis. The venous hum of portal hypertension is audible between the umbilicus and the xiphisternum. An arterial murmur over the liver may indicate a primary liver cancer or acute alcoholic hepatitis. The gallbladder is palpable only when it is distended. It is felt as a pear-shaped cystic mass usually about 7cm long. In a thin person, the swelling can sometimes be seen through the anterior abdominal wall. It moves downwards on inspiration and is mobile laterally but not downwards. The swelling is dull to percussion and directly impinges on the parietal peritoneum, so that the colon is rarely in front of it. Gallbladder dullness is con- tinuous with that of the liver. Abdominal tenderness should be noted. Inammation of the gallbladder causes a positive Murphys sign. This is the inability to take a deep breath when the examining ngers are hooked up below the liver edge. The inamed gallbladder is then driven against the ngers and the pain causes the patient to catch their breath. The enlarged gallbladder must be distinguished from a visceroptotic right kidney. This, however, is more mobile, can be displaced towards the pelvis and has the resonant colon anteriorly. A regenerative or malignant nodule feels much rmer. Imaging. A plain lm of the abdomen, including the diaphragms, may be used to assess liver size and in par- ticular to decide whether a palpable liver is due to actual enlargement or to downward displacement. On moder- ate inspiration the normal level of the diaphragm, on the right side, is opposite the 11th rib posteriorly and the 6th rib anteriorly. Ultrasound, CT or MRI can also be used to study liver size, shape and content. Hepatic morphology Kiernan (1833) introduced the concept of hepatic lobules as the basic architecture. He described circumscribed pyramidal lobules consisting of a central tributary of the hepatic vein and at the periphery a portal tract contain- ing the bile duct, portal vein radicle and hepatic artery branch. Columns of liver cells and blood-containing sinusoids extend between these two systems. Stereoscopic reconstructions and scanning electron microscopy have shown the human liver as columns of liver cells radiating from a central vein, and interlaced in orderly fashion by sinusoids (g. 1.9). The liver tissue is pervaded by two systems of tunnels, the portal tracts and the hepatic central canals which dovetail in such a way that they never touch each other; the terminal tunnels of the two systems are separated by about 0.5mm (g. 1.10). As far as possible the two systems of tunnels run in planes perpendicular to each other. The sinusoids are irregularly disposed, normally in a direction perpendicular to the lines connecting the central veins. The terminal branches of the portal vein discharge their blood into the sinusoids and the direction of ow is determined by the higher pressure in the portal vein than in the central vein. The central hepatic canals contain radicles of the hepatic vein and their adventitia. They are surrounded by a lim- iting plate of liver cells. The portal triads (syn. portal tracts, Glissons capsule) contain the portal vein radicle, the hepatic arteriole and bile duct with a few round cells and a little connective tissue (g. 1.11). They are surrounded by a limiting plate of liver cells. Portal dyads are as frequent as triads, with the portal vein being the most frequently absent element. Within each linear centimetre of liver tissue obtained at 6 Chapter 1
23. 23. Anatomy and Function 7 Perisinusoidal space of Disse Sinusoids Arterial capillary emptying into para-portal sinusoid Arterial capillary emptying into para-portal sinusoid Portal vein Limiting plate Peri-portal connective tissue Central (hepatic) veins Lymph vessel Sub- lobular vein Central (hepatic) veins Intra-lobular cholangiole Bile canaliculi on the surface of liver plates (not frequent) Cholangioles in portal canals Hepatic artery Bile duct Portal vein Limiting plate Portal tract Inlet venules Arterial capillary emptying into intra-lobular sinusoid Central (hepatic) veins Perisinusoidal space of Disse Central (hepatic) veins Fig. 1.9. The structure of the normal human liver. P P P P H H P Fig. 1.10. Normal hepatic histology. H, terminal hepatic vein; P, portal tract. (H & E, 60.)
24. 24. biopsy there are usually two interlobular bile ducts, two hepatic arteries and one portal vein per portal tract, with six full portal triads [8]. The liver has to be divided functionally. Traditionally, the unit is based on a central hepatic vein and its sur- rounding liver cells. However, Rappaport [28] envisages a series of functional acini, each centred on the portal triad with its terminal branch of portal vein, hepatic artery and bile duct (zone 1) (gs 1.12, 1.13). These inter- digitate, mainly perpendicularly, with terminal hepatic veins of adjacent acini. The circulatory peripheries of acini (adjacent to terminal hepatic veins) (zone 3) suffer most from injury whether viral, toxic or anoxic. Bridging necrosis is located in this area. The regions closer to the axis formed by afferent vessels and bile ducts survive longer and may later form the core from which regenera- tion will proceed. The contribution of each acinar zone to liver cell regeneration depends on the acinar location of damage [28]. The liver cells (hepatocytes) comprise about 60% of the liver. They are polygonal and approximately 30mm in diameter. The nucleus is single or, less often, multiple and divides by mitosis. The lifespan of liver cells is about 150 days in experimental animals. The hepatocyte has three surfaces: one facing the sinusoid and space of Disse, the second facing the canaliculus and the third facing neighbouring hepatocytes (g. 1.14). There is no basement membrane. The sinusoids are lined by endothelial cells. Associ- ated with the sinusoids are the phagocytic cells of the reticulo-endothelial system (Kupffer cells), and the hepatic stellate cells, which have also been called fat- storing cells, Ito cells and lipocytes. There are approximately 202103 cells in each mil- ligram of normal human liver, of which 171103 are parenchymal and 31103 littoral (sinusoidal, including Kupffer cells). The space of Disse is a tissue space between hepatocytes and sinusoidal endothelial cells. The hepatic lymphatics are found in the peri-portal connective tissue and are lined throughout by endothelium. Tissue uid seeps through the endothelium into the lymph vessels. The branch of the hepatic arteriole forms a plexus around the bile ducts and supplies the structures in the portal tracts. It empties into the sinusoidal network at different levels. There are no direct hepatic arteriolarportal venous anastomoses. The excretory system of the liver begins with the bile 8 Chapter 1 P A B Fig. 1.11. Normal portal tract. A, hepatic artery; B, bile duct; P, portal vein. (H & E.) 1 2 3 Efferent vein Simple acinus Preterminal vessel Terminal vessel Fig. 1.12. The complex acinus according to Rappaport. Zone 1 is adjacent to the entry (portal venous) system. Zone 3 is adjacent to the exit (hepatic venous) system.
25. 25. canaliculi (see gs 13.2, 13.3). These have no walls but are simply grooves on the contact surfaces of liver cells (see g. 13.1). Their surfaces are covered by microvilli. The plasma membrane is reinforced by micro-laments forming a supportive cytoskeleton (see g. 13.2). The canalicular surface is sealed from the rest of the inter- cellular surface by junctional complexes including tight junctions, gap junctions and desmosomes. The intra- lobular canalicular network drains into thin-walled terminal bile ducts or ductules (cholangioles, canals of Hering) lined with cuboidal epithelium. These terminate in larger (interlobular) bile ducts in the portal canals. They are classied into small (less than 100mm in diame- ter), medium (about 100mm) and large (more than 100mm). Electron microscopy and hepato-cellular function (gs 1.14, 1.15) The liver cell margin is straight except for a few anchor- ing pegs (desmosomes). From it, equally sized and spaced microvilli project into the lumen of the bile canaliculi. Along the sinusoidal border, irregularly sized and spaced microvilli project into the peri-sinusoidal tissue space. The microvillous structure indicates active secretion or absorption, mainly of uid. The nucleus has a double contour with pores allowing interchange with the surrounding cytoplasm. Human liver after puberty contains tetraploid nuclei and, at about age 20, in addition, octoploid nuclei are found. Increased polyploidy has been regarded as precancer- ous. In the chromatin network one or more nucleoli are embedded. The mitochondria also have a double membrane, the inner being invaginated to form grooves or cristae. An enormous number of energy-providing processes take place within them, particularly those involving oxida- tive phosphorylation. They contain many enzymes, par- ticularly those of the citric acid cycle and those involved in b-oxidation of fatty acids. They can transform energy Anatomy and Function 9 THV PS PS PS LIVER 1 Fig. 1.13. Blood supply of the simple liver acinus, zonal arrangements of cells and the microcirculatory periphery. The acinus occupies adjacent sectors of the neighbouring hexagonal elds. Zones 1, 2 and 3, respectively, represent areas supplied with blood of rst, second and third quality with regard to oxygen and nutrient content. These zones centre on the terminal afferent vascular branches, bile ductules, lymph vessels and nerves (PS) and extend into the triangular portal eld from which these branches crop out. Zone 3 is the microcirculatory periphery of the acinus since its cells are as remote from their own afferent vessels as from those of adjacent acini. The peri-venular area is formed by the most peripheral portions of zone 3 of several adjacent acini. In injury progressing along this zone, the damaged area assumes the shape of a starsh (darker tint around a terminal hepatic venule, THV, in the centre). 13, microcirculatory zones; 13, zones of neighbouring acinus [28].
26. 26. so released into adenosine diphosphate (ADP). Haem synthesis occurs here. The rough endoplasmic reticulum (RER) is seen as lamel- lar structures lined by ribosomes. These are responsible for basophilia under light microscopy. They synthesize specic proteins, particularly albumin, those used in blood coagulation and enzymes. They may adopt a helix arrangement, as polysomes, for co-ordination of this function. Glucose-6-phosphatase is synthesized. Triglycerides are synthesized from free fatty acids and complexed with protein to be secreted by exocytosis as lipoprotein. The RER may participate in glycogenesis. The smooth endoplasmic reticulum (SER) forms tubules and vesicles. It contains the microsomes. It is the site of bilirubin conjugation and the detoxication of many drugs and other foreign compounds (P450 systems). Steroids are synthesized, including cholesterol and the primary bile acids, which are conjugated with the amino acids glycine and taurine. The SER is increased by enzyme inducers such as phenobarbital. Peroxisomes are versatile organelles, which have com- plex catabolic and biosynthetic roles, and are distri- buted near the SER and glycogen granules. Peroxisomal enzymes include simple oxidases, b-oxidation cycles, the glyoxalate cycle, ether lipid synthesis, and cholesterol and dolichol biosynthesis. Several disorders of per- oxisomal function are recognized of which Zellweger syndrome is one [14]. Endotoxin severely damages peroxisomes [7]. The lysosomes are dense bodies adjacent to the bile canaliculi. They contain many hydrolytic enzymes which, if released, could destroy the cell. They are proba- bly intra-cellular scavengers which destroy organelles with shortened lifespans. They are the site of deposition of ferritin, lipofuscin, bile pigment and copper. Pinocytic vacuoles may be observed in them. Some peri- canalicular dense bodies are termed microbodies. The Golgi apparatus consists of a system of particles and vesicles again lying near the canaliculus. It may be regarded as a packaging site before excretion into the bile. This entire group of lysosomes, microbodies and Golgi apparatus is a means of sequestering any material which is ingested and has to be excreted, secreted or stored for metabolic processes in the cytoplasm. The Golgi apparatus, lysosomes and canaliculi are concerned in cholestasis (Chapter 13). The intervening cytoplasm contains granules of glycogen, lipid and ne brils. The cytoskeleton supporting the hepatocyte consists 10 Chapter 1 Hepatic stellate cell Endothelial cell Sinusoid Space of Disse Lysosome Peroxisome Vacuole Nucleolus Chromatin Lipid Rough endoplasmic reticulum Smooth endoplasmic reticulum Kupffer cell Reticulin fibre Cell membrane Desmosome Gap junction Tight junction Biliary canaliculus Golgi apparatus Mitochondrion Glycogen Fig. 1.14. The organelles of the liver cell.
27. 27. of microtubules, micro-laments and intermediate laments [12]. Microtubules contain tubulin and con- trol subcellular mobility, vesicle movement and plasma protein secretion. Micro-laments are made up of actin, are contractile and are important for the integrity and motility of the canaliculus and for bile ow. Intermediate laments are elongated branched laments comprising cytokeratins [40]. They extend from the plasma mem- brane to the peri-nuclear area and are fundamental for the stability and spatial organization of the hepatocyte. Sinusoidal cells The sinusoidal cells (endothelial cells, Kupffer cells, hepatic stellate cells and pit cells) form a functional and histological unit together with the sinusoidal aspect of the hepatocyte [34]. Endothelial cells line the sinusoids and have fenestrae which provide a graded barrier between the sinusoid and space of Disse (g. 1.16). The Kupffer cells are attached to the endothelium. The hepatic stellate cells lie in the space of Disse between the hepatocytes and the endothelial cells (g. 1.17). Disses space contains tissue uid which ows out- wards into lymphatics in the portal zones. When sinu- soidal pressure rises, lymph production in Disses space increases and this plays a part in ascites formation where there is hepatic venous outow obstruction. Endothelial cells. These cells form a continuous lining to the sinusoids. They differ from endothelial cells else- Anatomy and Function 11 Fig. 1.15. Electron microscopic appearances of part of a normal human liver cell. G, glycogen granules; IC, inter- cellular space; L, lysosomes; M, mitochondria; Mv, microvilli in the intra-cellular space; N, nucleus; Nu, nucleolus; R, rough endoplasmic reticulum. (Courtesy of Ms J. Lewin.) Fig. 1.16. Scanning electron micrograph of sinusoid showing fenestrae (F) grouped into sieve plates (S). D, space of Disse; E, endothelial cell; M, microvilli; P, parenchymal cell. (Courtesy of Professor E. Wisse.)
28. 28. where in not having a regular basal lamina. The endothe- lial cells act as a sieve between the sinusoid and space of Disse, have specic and non-specic endocytotic activity and have a variety of receptors. Their capacity to act as a sieve is due to fenestrae, around 0.15mm in diameter (g. 1.16). These make up 68% of the total endothelial cell surface, and there are more in the centrilobular zone of the sinusoid than the peri-portal area. Extra-cellular matrix affects their function. Fenestrae are clustered into sieve plates, and act as a biolter between sinusoidal blood and the plasma within the space of Disse. They have a dynamic cytoskeleton [6]. This maintains and regulates their size, which can be changed by many inuences including alcohol, nicotine, serotonin, endotoxin and partial hepa- tectomy. The fenestrae lter macro-molecules of differ- ing size. Particles >0.2mm diameter, which includes large triglyceride-rich parent chylomicrons, will not pass. Smaller triglyceride-depleted, cholesterol-rich and retinol-rich remnants can enter the space of Disse [15]. In this way the fenestrae have an important role in chylomi- cron and lipoprotein metabolism. Endothelial cells have a high capacity for endocytosis (accounting for 45% of all pinocytotic vesicles in the liver) and are active in clearing macro-molecules and small particles from the circulation [35]. There is receptor-mediated endocytosis for several molecules including transferrin, caeruloplasmin, modied high density lipoprotein (HDL) and low density lipoprotein (LDL), hepatic lipase and very low density lipoprotein (VLDL). Hyaluronan (a major polysaccharide from con- nective tissue) is taken up and this provides a method for assessing hepatic endothelial cell capacity. Endothelial cells can also clear small particles (