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

DISEASES OF THE LIVER AND BILIARY SYSTEM

Diseases of the Liver and Biliary System

JAMES DOOLEY BSc, MD, FRCP Reader and Honorary Consultant in Medicine, Royal Free and University College Medical School, University College London, London

ELEVENTH EDITION

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First published 1955 Fourth edition 1968 Eighth edition 1989 Reprinted 1956 Reprinted 1969, 1971 Reprinted 1991 Second edition 1958 Fifth edition 1975 Ninth edition 1993 Reprinted 1959, 1961 Sixth edition 1981 Reprinted 1993 Third edition 1963 Reprinted 1982, 1983 Tenth edition 1997 Reprinted 1965, 1966 Seventh edition 1985 Eleventh edition 2002 Reprinted 1986, 1987

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Preface to the Eleventh Edition, xv Asialoglycoprotein receptor, 25 Excretory capacity (BSP), 25 Preface to the First Edition, xvi Lipid and lipoprotein metabolism, 26 Lipids, 26 Lipoproteins, 26 1 Anatomy and Function, 1 Changes in liver disease, 27 Bile acids, 28 Functional anatomy: sectors and segments, 2 Changes in disease, 29 Anatomy of the biliary tract, 3 Serum bile acids, 30 Development of the liver and bile ducts, 4 Amino acid metabolism, 31 Anatomical abnormalities of the liver, 4 Clinical significance, 31 Surface marking, 5 Plasma proteins, 32 Methods of examination, 5 Electrophoretic pattern of serum proteins, 33 Hepatic morphology, 6 Carbohydrate metabolism, 34 Electron microscopy and hepato-cellular function, 9 Effects of ageing on the liver, 34 Sinusoidal cells, 11 Hepatocyte death and regeneration, 13 Extra-cellular matrix, 14 3 Biopsy of the Liver, 37 Altered hepatic microcirculation and disease, 14 Selection and preparation of the patient, 37 Adhesion molecules, 14 Techniques, 37 Functional heterogeneity, 14 Difficulties, 40 Sinusoidal membrane traffic, 16 Liver biopsy in paediatrics, 40 Bile duct epithelial cells, 16 Risks and complications, 40 Pleurisy and peri-hepatitis, 40 2 Assessment of Liver Function, 19 Haemorrhage, 40 Intra-hepatic haematomas, 41 Selection of biochemical tests, 19 Haemobilia, 41 Bile pigments, 20 Arteriovenous fistula, 42 Bilirubin, 20 Biliary peritonitis, 42 Urobilinogen, 20 Puncture of other organs, 43 Bromsulphalein, 21 Infection, 43 Serum enzyme tests, 21 Carcinoid crisis, 43 Alkaline phosphatase, 21 Sampling variability, 43 Gamma glutamyl transpeptidase, 22 Naked eye appearances, 43 Aminotransferases, 22 Preparation of the specimen, 43 Other serum enzyme, 23 Interpretation, 43 Quantitative assessment of hepatic function, 23 Indications, 44 Galactose elimination capacity, 23 Special methods, 44 Breath tests, 23 Salivary caffeine clearance, 24 Lignocaine metabolite formation, 25 4 The Haematology of Liver Arterial blood ketone body ratio, 25 Disease, 47 Antipyrine, 25 General features, 47 Indocyanine green, 25 The liver and blood coagulation, 49 v vi Contents

Haemolytic jaundice, 53 Vascular spiders, 87 The liver in haemolytic anaemias, 54 Palmar erythema (liver palms), 88 Hereditary spherocytosis, 54 White nails, 89 Thalassaemia, 55 Mechanism of skin changes, 89 Paroxysmal nocturnal haemoglobinuria, 56 Endocrine changes, 89 Acquired haemolytic anaemia, 56 Hypogonadism, 90 Haemolytic disease of the newborn, 56 Hypothalamic–pituitary function, 91 Incompatible blood transfusion, 56 Metabolism of hormones, 91 The liver in myelo- and lymphoproliferative disease, 56 General treatment, 92 Leukaemia, 57 Precipitating factors, 92 Myeloid, 57 General measures, 92 Lymphoid, 57 Hairy cell leukaemia, 57 7 Hepatic Encephalopathy, 93 Bone marrow transplantation, 57 Lymphoma, 58 Clinical features, 93 Jaundice in lymphoma, 59 Investigations, 95 Primary hepatic lymphoma, 60 Neuropathological changes, 96 Lymphosarcoma, 60 Clinical variants in cirrhotics, 97 Multiple myeloma, 61 Differential diagnosis, 98 Angio-immunoblastic lymphadenopathy, 61 Prognosis, 99 Extra-medullary haemopoiesis, 61 Pathogenetic mechanisms, 99 Systemic mastocytosis, 61 Portal-systemic encephalopathy, 99 Langerhans’ cell histiocytosis (histiocytosis X), 61 Intestinal bacteria, 100 Lipid storage diseases, 62 Neurotransmission, 100 Primary and secondary xanthomatosis, 62 Conclusions, 103 Cholesteryl ester storage disease, 62 Treatment of hepatic encephalopathy, 104 Gaucher’s disease, 62 Diet, 104 Niemann–Pick disease, 63 Antibiotics, 105 Sea-blue histiocyte syndrome, 64 Lactulose and lactilol, 105 Sodium benzoate and l-ornithine-l-aspartate, 106 5 Ultrasound, Computed Levodopa and bromocriptine, 106 Tomography and Magnetic Flumazenil, 106 Resonance Imaging, 67 Branched-chain amino acids, 106 Other precipitating factors, 106 Radio-isotope scanning, 67 Shunt occlusion, 106 Positron emission tomography (PET), 67 Temporary hepatic support, 107 Ultrasound, 67 Hepatic transplantation, 107 Doppler ultrasound, 69 Endoscopic ultrasound, 70 8 Acute Liver Failure, 111 Computed tomography, 70 Magnetic resonance imaging, 74 Definition, 111 MR spectroscopy, 76 Causes, 111 Conclusions and choice, 77 Clinical features, 113 Investigations, 113 6 Hepato-cellular Failure, 81 Associations, 115 Prognosis, 118 General failure of health, 81 Treatment, 119 Jaundice, 81 Conclusion, 124 Vasodilatation and hyperdynamic circulation, 81 Hepato-pulmonary syndrome, 82 9 Ascites, 127 Pulmonary hypertension, 84 Fever and septicaemia, 86 Mechanism of ascites formation, 127 Fetor hepaticus, 87 Underfill and peripheral vasodilation hypotheses, 127 Changes in nitrogen metabolism, 87 Overfill hypothesis, 129 Skin changes, 87 Other renal factors, 129 Contents vii

Circulation of ascites, 130 Hepatic arterio-portal venous fistulae, 167 Summary, 130 Porto-hepatic venous shunts, 168 Clinical features, 130 Intra-hepatic pre-sinusoidal and sinusoidal portal Spontaneous bacterial peritonitis, 132 hypertension, 168 Treatment of cirrhotic ascites, 134 Portal tract lesions, 168 Refractory ascites, 138 Toxic causes, 168 Prognosis, 139 Hepato-portal sclerosis, 168 Hepato-renal syndrome, 140 Tropical splenomegaly syndrome, 169 Hyponatraemia, 143 Intra-hepatic portal hypertension, 169 Cirrhosis, 169 10 The Portal Venous System and Portal Non-cirrhotic nodules, 170 Hypertension, 147 Bleeding oesophageal varices, 170 Predicting rupture, 170 Collateral circulation, 147 Prevention of bleeding, 171 Intra-hepatic obstruction (cirrhosis), 147 Diagnosis of bleeding, 172 Extra-hepatic obstruction, 148 Prognosis, 172 Effects, 148 Management of acute variceal bleeding, 173 Pathology of portal hypertension, 148 Vaso-active drugs, 174 Varices, 149 Sengstaken-Blakemore tube, 174 Portal hypertensive intestinal vasculopathy, 151 Endoscopic sclerotherapy and banding, 175 Haemodynamics of portal hypertension, 151 Emergency surgery, 176 Clinical features of portal hypertension, 152 Prevention of re-bleeding, 176 History and general examination, 152 Portal-systemic shunt procedures, 177 Abdominal wall veins, 153 Porta-caval, 177 Spleen, 154 Meso-caval, 178 Liver, 154 Selective ‘distal’ spleno-renal, 178 Ascites, 154 General results of portal-systemic shunts, 178 Rectum, 154 TIPS (transjugular intrahepatic portosystemic X-ray of the abdomen and chest, 154 shunt), 178 Barium studies, 155 Shunt stenosis and occlusion, 179 Endoscopy, 155 Control of bleeding, 180 Imaging the portal venous system, 157 TIPS encephalopathy, 180 Ultrasound, 157 Circulatory changes, 180 Doppler ultrasound, 157 Other indications, 180 CT scan, 158 Conclusions, 180 Magnetic resonance angiography, 158 Hepatic transplantation, 180 Venography, 158 Pharmacological control of the portal circulation, 180 Venographic appearances, 158 Conclusions, 180 Visceral angiography, 159 Digital subtraction angiography, 159 11 The Hepatic Artery and Hepatic Splenic venography, 159 Veins: the Liver in Circulatory Carbon dioxide wedged venography, 160 Failure, 187 Portal pressure measurement, 160 Variceal pressure, 160 The hepatic artery, 187 Estimation of hepatic blood flow, 161 Hepatic artery occlusion, 188 Azygous blood flow, 162 Hepatic arterial lesions following liver Experimental portal venous occlusion and transplantation, 189 hypertension, 163 Aneurysms of the hepatic artery, 189 Classification of portal hypertension, 163 Hepatic arteriovenous shunts, 190 Extra-hepatic portal venous obstruction, 163 The hepatic veins, 190 Aetiology, 163 Experimental hepatic venous obstruction, 191 Clinical features, 165 Budd–Chiari (hepatic venous obstruction) syndrome, Prognosis, 166 192 Treatment, 167 Pathological changes, 193 Splenic vein obstruction, 167 Clinical features, 193 viii Contents

Diagnosis, 195 Treatment, 248 Prognosis, 196 Immune cholangiopathy, 250 Treatment, 197 Autoimmune cholangitis, 253 Veno-occlusive disease, 198 Spread of disease by the hepatic veins, 198 15 Sclerosing Cholangitis, 255 Circulatory failure, 199 Hepatic changes in acute heart failure and shock, 199 Primary sclerosing cholangitis (PSC), 255 Ischaemic hepatitis, 200 Infective sclerosing cholangitis, 261 Post-operative jaundice, 200 Bacterial cholangitis, 261 Jaundice after cardiac surgery, 201 Immunodeficiency-related opportunistic The liver in congestive heart failure, 201 cholangitis, 261 The liver in constrictive pericarditis, 203 Graft-versus-host disease, 263 Vascular cholangitis, 263 12 Jaundice, 205 Drug-related cholangitis, 263 Histiocytosis X, 263 Bilirubin metabolism, 205 Hepatic transport and conjugation of bilirubin, 205 16 Viral Hepatitis: General Features, Distribution of jaundice in the tissues, 207 Hepatitis A, Hepatitis E and Other Factors determining the depth of jaundice, 207 Viruses, 267 Classification of jaundice, 208 Diagnosis of jaundice, 209 Pathology, 267 Clinical history, 209 Clinical types, 268 Examination, 211 Investigations, 271 Diagnostic routine, 212 Differential diagnosis, 271 Familial non-haemolytic hyperbilirubinaemias, 213 Prognosis, 272 Primary hyperbilirubinaemia, 213 Treatment, 272 Gilbert’s syndrome, 213 Follow-up, 272 Crigler–Najjar syndrome, 215 Hepatitis A virus, 273 Dubin–Johnson syndrome, 216 Epidemiology, 274 Rotor type, 217 Clinical course, 275 The group of familial non-haemolytic Prognosis, 275 hyperbilirubinaemias, 217 Prevention, 275 Hepatitis E virus, 276 13 Cholestasis, 219 Clinical features, 277 Diagnostic tests, 277 Anatomy of the biliary system, 219 Liver biopsy, 277 Secretion of bile, 220 Prevention, 277 Cellular mechanisms, 221 Hepatitis G virus, 278 Syndrome of cholestasis, 223 Hepatitis TT virus, 278 Definition, 223 Yellow fever, 279 Classification, 223 Pathology, 279 Pathogenesis, 224 Clinical features, 279 Pathology, 224 Treatment, 279 Clinical features, 226 Infectious mononucleosis (Epstein–Barr virus), 279 Diagnostic approach, 231 Hepatic histology, 279 Diagnostic possibilities, 232 Clinical features, 280 Diagnosis, 280 14 Primary Biliary Cirrhosis, 241 Distinction from viral hepatitis, 280 Other viruses, 281 Aetiology, 241 Cytomegalovirus, 281 Epidemiology and genetics, 243 Herpes simplex, 281 Clinical features, 243 Miscellaneous, 281 Diagnosis, 246 Hepatitis due to exotic viruses, 282 Prognosis, 247 Treatment, 283 Contents ix

17 Hepatitis B Virus and Hepatitis Delta Aetiology, 326 Virus, 285 Hepatic pathology, 328 Clinical features, 328 Hepatitis B virus (HBV), 285 Differential diagnosis, 330 Acute hepatitis B, 287 Treatment, 331 Epidemiology, 290 Course and prognosis, 332 Clinical course, 290 Syncytial giant-cell hepatitis, 332 Prevention, 292 Chronic hepatitis B, 294 Clinical relapse and reactivation, 294 20 Drugs and the Liver, 335 Laboratory tests, 295 Hepato-cellular zone 3 necrosis, 340 Needle liver biopsy, 295 Carbon tetrachloride, 342 Course and prognosis, 295 Amanita mushrooms, 343 Treatment, 296 Paracetamol (acetaminophen), 343 Outstanding problems, 298 Salicylates, 344 Screening for hepato-cellular carcinoma, 298 Hyperthermia, 344 Hepatitis delta virus (HDV), 300 Hypothermia, 344 Epidemiology, 300 Burns, 344 Diagnosis, 301 Hepato-cellular zone 1 necrosis, 344 Clinical features, 301 Ferrous sulphate, 345 Hepatic histology, 302 Phosphorus, 345 Prevention, 302 Mitochondrial cytopathies, 345 Treatment, 302 Sodium valproate, 345 Tetracyclines, 345 18 Hepatitis C Virus, 305 Tacrine, 345 Antiviral nucleoside analogues, 345 Molecular virology, 305 Bacillus cereus, 346 Serological tests, 306 Steato-hepatitis, 346 Immune response, 307 Perhexiline maleate, 346 Epidemiology, 307 Amiodarone, 346 Natural history, 308 Synthetic oestrogens, 346 Clinical course, 308 Calcium channel blockers, 347 Hepatic histology, 309 Fibrosis, 347 Hepatitis C and serum autoantibodies, 310 Methotrexate, 347 Associated diseases, 310 Other cytotoxic drugs, 347 Diagnosis, 311 Arsenic, 348 Prognosis, 311 Vinyl chloride, 348 Prevention: vaccines, 312 Vitamin A, 348 Treatment, 312 Retinoids, 348 Hepatic transplantation, 316 Vascular changes, 348 Sinusoidal dilatation, 348 19 Chronic Hepatitis: General Peliosis hepatis, 349 Features, and Autoimmune Chronic Veno-occlusive disease (VOD), 349 Disease, 321 Acute hepatitis, 349 Isoniazid, 350 Clinical presentation, 321 Methyl dopa, 351 Hepatic histology, 322 Halothane, 351 The role of liver biopsy, 322 Hydrofluorocarbons, 352 Classification, 324 Systemic antifungals, 352 Autoimmune chronic hepatitis, 325 Oncology drugs, 352 Type 1 (formerly called lupoid), 326 Nervous system modifiers, 353 Type 2, 326 Sustained-release nicotinic acid (niacin), 353 Primary biliary cirrhosis and immune cholangitis, 326 Sulphonamides and derivatives, 353 Chronic autoimmune hepatitis (type 1), 326 Non-steroidal anti-inflammatory drugs, 353 x Contents

Anti-thyroid drugs, 353 Associated features, 393 Quinidine and quinine, 353 Prognosis, 393 Troglitazone, 354 Treatment, 394 Anti-convulsants, 354 Acute alcoholic hepatitis, 394 Chronic hepatitis, 354 Cirrhosis, 395 Herbal remedies, 354 Hepatic transplantation, 395 Recreational drugs, 355 Canalicular cholestasis, 355 23 Iron Overload States, 399 Cyclosporin A, 355 Ciproﬂoxacin, 355 Normal iron metabolism, 399 Hepato-canalicular cholestasis, 355 Iron overload and liver damage, 401 Chlorpromazine, 356 Genetic haemochromatosis, 401 Penicillins, 357 Other iron storage diseases, 407 Sulphonomides, 357 Non-HFE-related inherited iron overload, 407 Erythromycin, 357 Dysmetabolic syndrome, 408 Haloperidol, 357 Erythropoietic siderosis, 408 Cimetidine and ranitidine, 357 Late stage cirrhosis, 408 Oral hypoglycaemics, 357 Chronic viral hepatitis, 408 Tamoxifen, 357 Non-alcoholic fatty liver disease, 408 Other causes, 357 Neonatal haemochromatosis, 409 Dextropropoxyphene, 357 African iron overload (Bantu siderosis), 409 Ductular cholestasis, 357 Porphyria cutanea tarda, 409 Biliary sludge, 357 Haemodialysis, 409 Sclerosing cholangitis, 357 Acaeruloplasminaemia, 409 Hepatic nodules and tumours, 358 Transferrin deﬁciency, 409 Hepato-cellular carcinoma, 358 Conclusions, 359 24 Wilson’s Disease, 413

21 Hepatic Cirrhosis, 365 Molecular genetics: pathogenesis, 413 Pathology, 414 Classification of cirrhosis, 368 Clinical picture, 415 Clinical cirrhosis, 371 Hepatic forms, 416 Compensated cirrhosis, 374 Neuropsychiatric forms, 417 Decompenstated cirrhosis, 375 Renal changes, 417 Prognosis, 376 Other changes, 417 Treatment, 377 Laboratory tests, 417 Liver biopsy, 418 22 Alcohol and the Liver, 381 Scanning, 418 Diagnostic difficulties, 418 Risk factors for alcoholic liver diseases, 381 Treatment, 419 Metabolism of alcohol, 382 Prognosis, 420 Mechanisms of liver injury, 384 Indian childhood cirrhosis, 421 Morphological changes, 386 Hereditary acaeruloplasminaemia, 421 Fatty liver (steatosis), 386 Alcoholic hepatitis, 387 25 Nutritional and Metabolic Liver Cirrhosis, 387 Diseases, 423 Early recognition, 389 Investigation, 389 Malnutrition, 423 Clinical syndromes, 390 Fatty liver, 423 Fatty liver, 390 Diagnosis, 424 Acute alcoholic hepatitis, 390 Classification, 424 Hepatic cirrhosis, 391 Non-alcoholic fatty liver disease, 427 Cholestatic syndromes, 391 Non-alcoholic hepatic steatosis, 428 Relationship to hepatitis B and C, 391 Non-alcoholic steatonecrosis, 428 Hepato-cellular cancer, 393 Effects of jejuno-ileal bypass, 429 Contents xi

Parenteral nutrition, 429 Viral hepatitis, 457 Vitamins, 429 Non-viral causes of hepatitis, 459 Carbohydrate metabolism in liver disease, 431 Urinary tract infections, 459 Hypoglycaemia, 431 Neonatal hepatitis syndrome, 459 Hyperglycaemia, 431 Infantile cholangiopathies, 460 The liver in diabetes mellitus, 431 Biliary atresia, 460 Insulin and the liver, 431 Extra-hepatic biliary atresia, 460 Hepatic histology, 431 Alagille’s syndrome (arterio-hepatic dysplasia), 462 Clinical features, 432 Prolonged parenteral nutrition, 462 Liver function tests, 432 Abnormal bile acid synthesis, 463 Hepato-biliary disease and diabetes, 432 Genetic cholestatic syndromes, 463 Glucose intolerance of cirrhosis, 432 Symptomatic treatment of cholestatic Treatment of diabetes in cirrhotic patients, 433 syndromes, 464 Glycogen storage diseases, 434 Other causes of cholestatic jaundice, 464 Type I (von Gierke’s disease), 435 Reye’s syndrome, 465 Type II (Pompe’s disease), 436 Reye-like syndromes, 465 Type III (Cori’s disease), 436 Cirrhosis in infancy and childhood, 465 Type IV (Andersen’s disease), 437 Indian childhood cirrhosis, 466 Type VI (Hers’ disease), 437 Non-Indian childhood cirrhosis (copper-associated Hepatic glycogen synthetase deﬁciency (type 0), 437 liver disease), 466 Hereditary fructose intolerance, 438 Hepatic steatosis, 467 Glutaric aciduria type II, 438 Fetal alcohol syndrome, 467 Galactosaemia, 438 Idiopathic steato-hepatitis, 467 Mucopolysaccharidoses, 439 Tumour of the liver, 467 Familial hypercholesterolaemia, 439 Hamartomas, 467 Amyloidosis, 440 Mesenchymal hamartoma, 467

a1-Antitrypsin deﬁciency, 443 Malignant mesenchymoma (undifferentiated Hereditary tyrosinaemia, 445 sarcoma), 467 Cystic ﬁbrosis, 446 Adenomas, 467 Liver and thyroid, 447 Hepato-cellular carcinoma, 467 Thyrotoxicosis, 447 Hepatoblastoma, 467 Myxoedema, 447 Infantile haemangio-endothelioma, 467 Changes with hepato-cellular disease, 447 Nodular regenerative hyperplasia, 468 Liver and adrenal, 448 Hepatic transplantation, 468 Liver and growth homone, 448 Hepatic porphyrias, 448 27 The Liver in Pregnancy, 471 Acute intermittent porphyria, 449 Hereditary coproporphyria, 450 Normal pregnancy, 471 Variegate porphyria, 450 Liver disease in pregnancy, 471 Porphyria cutanea tarda, 450 Hyperemesis gravidarum, 471 Erythropoietic protoporphyria, 450 Liver diseases of late pregnancy, 471 Congenital erythropoietic porphyria, 451 Acute fatty liver of pregnancy, 471 Hepato-erythropoietic porphyria, 451 Pregnancy toxaemias, 474 Secondary coproporphyrias, 451 The HELLP syndrome, 474 Hereditary haemorrhagic telangiectasia, 452 Toxaemia and the HELLP syndrome, 475 Dystrophia myotonica, 452 Hepatic haemorrhage, 475 Cholestasis of pregnancy, 475 26 The Liver in Infancy and Budd–Chiari syndrome, 476 Childhood, 453 Intercurrent jaundice, 476 Viral hepatitis, 476 Neonatal hyperbilirubinaemia, 453 Biliary tract disease, 477 Unconjugated hyperbilirubinaemia, 453 Hepato-toxic drugs and the pregnant woman, 478 Haemolytic disease of the newborn, 454 Effect of pregnancy on pre-existing chronic liver Hepatitis and cholestatic syndromes (conjugated disease, 478 hyperbilirubinaemia), 455 Pregnancy in liver transplant recipients, 478 xii Contents

28 The Liver in Systemic Disease, Fasciola hepatica, 519 Granulomas and Hepatic Recurrent pyogenic cholangitis, 519 Trauma, 481 Peri-hepatitis, 520 Hepato-biliary disease in HIV infection, 520 The liver in collagen diseases, 481 Infections, 521 Arthropathy associated with liver disease, 481 Hepatitis B, C and D co-infection, 522 Genetic haemochromatosis, 481 Neoplasms, 522 Hepatitis B virus (HBV) associations, 481 Hepato-biliary disease, 523 Hepatitis C virus (HCV) associations, 482 Acaculous cholecystitis, 524 Hepatic granulomas, 482 Jaundice of infections, 525 Clinical syndrome of hepatic granulomas, 483 Bacterial pneumonia, 525 ‘Granulomatous hepatitis’, 484 Septicaemia and septic shock, 525 Sarcoidosis, 484 Granulomatous drug reactions, 486 Granulomas associated with infections, 487 30 Nodules and Benign Liver Hepatic granulomas in the patient with AIDS, 488 Lesions, 527 Industrial causes, 489 Small hepato-cellular cancer, 527 Other conditions with hepatic granulomas, 489 Nodules in the absence of underlying liver disease, 528 Hepato-biliary associations of inﬂammatory bowel Simple cysts, 528 disease, 490 Haemangioma, 528 Hepatic trauma, 490 Focal nodular hyperplasia, 530 Rupture of the gallbladder, 492 Hepatic adenoma, 531 Focal nodular hyperplasia and adenoma contrasted, 532 29 The Liver in Infections, 495 Liver metastases, 532 Other benign tumours, 534 Pyogenic liver abscess, 495 Cholangioma (bile duct adenoma), 534 Other infections, 498 Biliary cystadenoma, 534 Hepatic amoebiasis, 498 Nodular regenerative hyperplasia, 534 Tuberculosis of the liver, 501 Partial nodular transformation, 535 Hepatic actinomycosis, 502 Other fungal infections, 502 Syphilis of the liver, 503 31 Malignant Liver Tumours, 537 Congenital, 503 Hepato-cellular cancer, 537 Secondary, 503 Aetiological factors, 537 Tertiary, 503 Pathology, 540 Jaundice complicating penicillin treatment, 504 Clinical features, 541 Leptospirosis, 504 Tumour localization, 543 Weil’s disease, 504 Needle liver biopsy, 546 Other types of leptospirosis, 506 Screening, 546 Relapsing fever, 507 Prognosis and risk factors, 547 Lyme disease, 507 Surgical treatment, 547 Q fever, 507 Non-surgical treatment, 548 Rocky mountain spotted fever, 508 Fibro-lamellar carcinoma of the liver, 551 Schistosomiasis (bilharziasis), 508 Hepatoblastoma, 551 Malaria, 510 Intra-hepatic cholangiocarcinoma, 552 Kala-azar (leishmaniasis), 511 Combined hepato-cellular–cholangiocarcinoma, 553 Hydatid disease, 511 Other primary liver tumours, 553 Echinococcus multilocularis (alveolar Cystadenocarcinoma, 553 echinococcosis), 516 Angiosarcoma (haemangio-endothelioma), 553 Ascariasis, 517 Epitheloid haemangio-endothelioma, 554 Strongyloides stercoralis, 518 Undifferentiated sarcoma of the liver, 554 Trichiniasis, 518 Benign tumours of the liver, 554 Toxocara canis (visceral larva migrans), 518 Mesenchymal hamartoma, 554 Liver ﬂukes, 518 Paraneoplastic hepatopathy, 554 Clonorchis sinensis, 518 Hepatic metastases, 554 Contents xiii

32 Imaging of the Biliary Tract: Floating gallbladder and torsion of the Interventional Radiology and gallbladder, 594 Endoscopy, 563 Anomalies of the cystic duct and cystic artery, 595

Plain film of the abdomen, 563 Ultrasound (US), 563 34 Gallstones and Inflammatory Bile ducts, 563 Gallbladder Diseases, 597 Gallbladder, 563 Composition of gallstones, 597 Computed tomography (CT), 564 Composition of bile, 597 Magnetic resonance cholangiopancreatography Factors in cholesterol gallstone formation, 598 (MRCP), 565 Pigment gallstones, 603 Endoscopic ultrasound (EUS), 566 Radiology of gallstones, 603 Biliary scintigraphy, 567 Natural history of gallstones, 604 Oral cholecystography, 567 Silent gallstones, 605 Intravenous cholangiography, 568 Treatment of gallstones in the gallbladder, 605 Endoscopic retrograde cholangiopancreatography, 568 Cholecystectomy, 605 Endoscopic sphincterotomy, 570 Laparoscopic cholecystectomy, 605 Endoscopic biliary endoprostheses, 573 Non-surgical treatment of gallstones in the Percutaneous trans-hepatic cholangiography, 576 gallbladder, 607 Percutaneous bile drainage, 576 Dissolution therapy, 607 Percutaneous biliary endoprosthesis, 577 Direct solvent dissolution, 608 Resectability of tumours, 578 Shock-wave therapy, 608 Choice between surgical and non-surgical palliation of Percutaneous cholecystolithotomy, 609 malignant obstruction, 578 Conclusions, 609 Choice between endoscopic and percutaneous Acute cholecystitis, 610 approach, 578 Empyema of the gallbladder, 612 Percutaneous cholecystostomy, 578 Perforation of the gallbladder, 612 Operative and post-operative cholangiography, 579 Emphysematous cholecystitis, 612 Chronic calculous cholecystitis, 613 33 Cysts and Congenital Biliary Acalculous cholecystitis, 614 Abnormalities, 583 Acute, 614 Chronic, 614 Fibropolycystic disease, 583 Typhoid cholecystitis, 614 Childhood fibropolycystic diseases, 584 Acute cholecystitis in AIDS, 614 Adult polycystic disease, 584 Other associations, 615 Congenital hepatic fibrosis, 586 Other gallbladder pathology, 615 Congenital intra-hepatic biliary dilatation (Caroli’s Cholesterolosis of the gallbladder, 615 disease), 588 Xanthogranulomatous cholecystitis, 615 Congenital hepatic fibrosis and Caroli’s disease, 589 Adenomyomatosis, 615 Choledochal cyst, 589 Porcelain gallbladder, 615 Microhamartoma (von Meyenberg complexes), 591 Post-cholecystectomy problems, 615 Carcinoma secondary to fibropolycystic Sphincter of Oddi dysfunction, 616 disease, 591 Gallstones in the common bile duct Solitary non-parasitic liver cyst, 591 (choledocholithiasis), 616 Other cysts, 591 Managment of common duct stones, 618 Congenital anomalies of the biliary tract, 592 Acute obstructive suppurative cholangitis, 618 Absence of the gallbladder, 592 Acute cholangitis, 618 Double gallbladder, 592 Common duct stones without cholangitis, 619 Accessory bile ducts, 593 Patients with gallbladder in situ, 619 Left-sided gallbladder, 594 Acute gallstone pancreatitis, 619 Rokitansky–Aschoff sinuses, 594 Large common duct stones, 619 Folded gallbladder, 594 Trans T-tube tract removal of stones, 620 Diverticula of the gallbladder and ducts, 594 Intra-hepatic gallstones, 620 Intra-hepatic gallbladder, 594 Mirizzi’s syndrome, 620 Congenital adhesions to the gallbladder, 594 Biliary fistulae, 621 xiv Contents

External, 621 38 Hepatic Transplantation, 657 Internal, 621 Gallstone ileus, 621 Selection of patients, 657 Haemobilia, 622 Candidates: outcome, 657 Bile peritonitis, 622 Cirrhosis, 659 Association of gallstones with other diseases, 623 Autoimmune chronic hepatitis, 659 Colorectal and other cancers, 623 Chronic viral hepatitis, 659 Diabetes mellitus, 623 Neonatal hepatitis, 660 Alcoholic liver disease, 660 Cholestatic liver disease, 660 35 Benign Stricture of the Bile Primary metabolic disease, 661 Ducts, 629 Acute liver failure, 662 Post-cholecystectomy, 629 Malignant disease, 662 Bile duct/bowel anastomotic stricture, 634 Miscellaneous, 663 Post liver transplantation, 635 Absolute and relative contraindications, 663 Primary sclerosing cholangitis, 636 Absolute, 663 Other causes, 636 Relative (higher risk), 664 Summary, 636 General preparation of the patient, 664 Donor selection and operation, 664 The recipient operation, 665 36 Diseases of the Ampulla of Vater and Segmental (split liver) transplantation, 665 Pancreas, 639 Auxiliary liver transplantation, 666 Peri-ampullary carcinoma, 639 Xeno-transplantation, 666 Benign villous adenoma of the ampulla of Vater, 644 Domino liver transplantation, 666 Cystic tumours of the pancreas, 644 Hepatocyte transplantation, 667 Endocrine tumours of the pancreas, 644 Liver transplantation in paediatrics, 667 Chronic pancreatitis, 644 Immunosuppression, 667 Obstruction of the common bile duct by enlarged lymph Tolerance, 668 glands, 645 Post-operative course, 668 Other causes of extrinsic pressure on the common bile Post-transplantation complications, 668 duct, 645 Rejection, 671 Infections, 673 Malignancies, 675 37 Tumours of the Gallbladder and Bile Drug-related toxicity, 675 Ducts, 647 Disease recurrence, 675 Benign lesions of the gallbladder, 647 Central nervous system toxicity, 675 Carcinoma of the gallbladder, 647 Bone disease, 675 Other tumours, 648 Ectopic soft-tissue calciﬁcation, 675 Benign tumours of the extra-hepatic bile duct, 648 Conclusion, 675 Carcinoma of the bile duct (cholangiocarcinoma), 648 Cholangiocellular carcinoma, 654 Index, 681 Metastases at the hilum, 655 Preface to the Eleventh Edition

The eleventh edition welcomes the new Millenium. Susan Davies for histological material, and Dr Robert Progress in basic and clinical hepatology remains ex- Dick, Dr Tony Watkinson and Dr Jon Tibballs for radio- ponential. Since 1997, the advances have been wide- logical images. We would also like to express our great ranging, with those in molecular and cellular biology, thanks to Dr Leslie Berger, Dr Andrew Burroughs, Dr and in diagnosis and treatment, leading the way. In a John Buscombe, Dr Martyn Caplin, Professor Geoffrey world in which information technology gives all too Dusheiko, Dr David Harry, Dr Andrew Hilson, Professor ready access to individual publications, the eleventh Humphrey Hodgson, Professor Neil McIntyre, Dr Kevin edition sets the new within established knowledge and Moore, Dr Marsha Morgan, Dr Chris Kibbler and Dr practice. David Patch for their help in the preparation of this Viral hepatitis remains the worldwide hepatological edition. challenge. This is reflected in a change in format with Miss Aileen Duggan and Miss Karma Raines have separate chapters on hepatitis B and C. Molecular virol- assisted tirelessly with their meticulous secretarial ogy continues to expose the inner workings of all the support. The clarity and style of figures preserved from viruses. New therapeutic approaches are proving more previous editions owes much to the artistry of Miss effective against hepatitis C. Molecular and cellular biol- Janice Cox over many years. ogists are showing us the importance of apoptosis and We are grateful to Blackwell Publishing and, in par- the intricate regulation of fibrosis. Mutation analysis for ticular, Rebecca Huxley for her tireless help with both diagnosis of genetic haemochromatosis is routine, while manuscript and proofs, and for responding without a the identification of the haemochromatosis gene has led murmur to demands within a tight schedule. We also to a surge of exploration in iron metabolism. Canalicular thank Jane Fallows who has reformatted and coloured transporters have been cloned and linked to cholestatic all the previous line drawings as well as creating the syndromes, giving a new perspective to the bile plug many new and visually inviting figures for the eleventh seen under the microscope. Advances in imaging, par- edition. ticularly magnetic resonance, continue to reduce the The preface to the first edition which was published need for invasive techniques. Patients needing trans- in 1955 refers to daughters Amanda and Auriole. plantation benefit from improvements in immuno- Amanda is now an ordained Minister in the Baptist suppression and surgical techniques, while there is Church, and Auriole is working with Kent Police. steady progress in the management of complications of Grandchildren have arrived, including Alice aged 9 and cirrhosis. Emily aged 6. This edition contains more than 1000 new references On the 13th July 2001, the senior author was elected a and 100 new figures. Developments in publishing allow Fellow of the Royal Society in its 341st year, a Society a more colourful format, but care has been taken to founded to improve natural knowledge. This honour preserve clarity. Experience has shown that students, was achieved because of the support of all the clinicians interns, postgraduate trainees as well as generalists and and scientists who have contributed to the Liver Unit specialist clinicians have found previous editions useful. and its associated departments at The Royal Free. The The goal of the book remains unchanged: a textbook of new Millenium is indeed an exciting time for all those manageable size, critical and current. working to solve the puzzles within hepato-biliary We are indebted to many colleagues for their generous disease. contributions to this edition including in particular sheila sherlock Professor Peter Scheuer, Professor Amar Dhillon and Dr james dooley November 2001

xv Preface to the First Edition

My aim in writing this book has been to present a com- reading. Miss D. F. Atkins gave much assistance with prehensive and up-to-date account of diseases of the proof reading and with the bibliography. Mr Per liver and biliary system, which I hope will be of value to Saugman and Mrs J. M. Green of Blackwell Scientific physicians, surgeons and pathologists and also a refer- Publications have co-operated enthusiastically in the ence book for the clinical student. The modern literature production of this book. has been reviewed with special reference to articles of The photomicrographs were taken by Mr E. V. Will- general interest. Many older more specialized classical mott, frps, and Mr C. A. P. Graham from section pre- contributions have therefore inevitably been excluded. pared by Mr J. G. Griffin and the histology staff of the Disorders of the liver and biliary system may be classi- Postgraduate Medical School. Clinical photographs are fied under the traditional concept of individual diseases. the work of Mr C. R. Brecknell and his assistants. The Alternatively, as I have endeavoured in this book, they black and white drawings were made by Mrs H. M. G. may be described by the functional and morphological Wilson and Mr D. Simmonds. I am indebted to them all changes which they produce. In the clinical management for their patience and skill. of a patient with liver disease, it is important to assess the The text includes part of unpublished material degree of disturbance of four functional and morpho- included in a thesis submitted in 1944 to the University logical components of the liver—hepatic cells, vascular of Edinburgh for the degree of MD, and part of an essay system (portal vein, hepatic artery and hepatic veins), awarded the Buckston–Browne prize of the Harveian bile ducts and reticulo-endothelial system. The typical Society of London in 1953. Colleagues have allowed me reaction pattern is thus sought and recognized before to include published work of which they are jointly attempting to diagnose the causative insult. Clinical and responsible. Dr Patricia P. Franklyn and Dr R. E. Steiner laboratory methods of assessing each of these com- have kindly loaned me radiographs. Many authors have ponents are therefore considered early in the book. given me permission to reproduce illustrations and Descriptions of individual diseases follow as illustrative detailed acknowledgments are given in the text. I wish examples. It will be seen that the features of hepatocellu- also to thank the editors of the following journals for lar failure and portal hypertension are described in permission to include illustrations: American Journal of general terms as a foundation for subsequent discussion Medicine, Archives of Pathology, British Heart Journal, of virus hepatitis, nutrition liver disease and the cir- Circulation, Clinical Science, Edinburgh Medical Journal, rhoses. Similarly blood diseases and infections of the Journal of Clinical Investigation, Journal of Laboratory and liver are included with the reticulo-endothelial system, Clinical Investigation, Journal of Pathology and Bacteriology, and disorders of the biliary tract follow descriptions of Lancet, Postgraduate Medical Journal, Proceedings of the acute and chronic bile duct obstruction. Staff Meetings of the Mayo Clinic, Quarterly Journal of Medi- I would like to acknowledge my indebtedness to my cine, Thorax and also the following publishers: Butter- teachers, the late Professor J. Henry Dible, the late Pro- worth’s Medical Publications, J. & A. Churchill Ltd, The fessor Sir James Learmonth and Professor Sir John Josiah Macy Junior Foundation and G. D. Searle & Co. McMichael, who stimulated my interest in hepatic Finally I must thank my husband, Dr D. Geraint disease, and to my colleagues at the Postgraduate James, who, at considerable personal inconvenience, Medical School and elsewhere who have generously encouraged me to undertake the writing of this book and invited me to see patients under their care. I am grateful also criticized and rewrote most of it. He will not allow to Dr A. G. Bearn for criticizing part of the typescript me to dedicate it to him. and to Dr A. Paton for his criticisms and careful proof sheila sherlock

xvi Chapter 1 Anatomy and Function

The liver, the largest organ in the body, weighs posteriorly by the fissure for the ligamentum veno- 1200–1500g and comprises one-fiftieth of the total adult sum and inferiorly by the fissure for the ligamentum body weight. It is relatively larger in infancy, comprising teres. one-eighteenth of the birth weight. This is mainly due to The liver has a double blood supply. The portal vein a large left lobe. brings venous blood from the intestines and spleen and Sheltered by the ribs in the right upper quadrant, the the hepatic artery, coming from the coeliac axis, supplies upper border lies approximately at the level of the the liver with arterial blood. These vessels enter the liver nipples. There are two anatomical lobes, the right being through a fissure, the porta hepatis, which lies far back on about six times the size of the left (figs 1.1–1.3). Lesser the inferior surface of the right lobe. Inside the porta, the segments of the right lobe are the caudate lobe on the portal vein and hepatic artery divide into branches to the posterior surface and the quadrate lobe on the inferior right and left lobes, and the right and left hepatic bile surface. The right and left lobes are separated anteriorly ducts join to form the common hepatic duct. The hepatic by a fold of peritoneum called the falciform ligament, nerve plexus contains fibres from the sympathetic ganglia

Right lobe Diaphragm Left Caudate Barearea lobe lobe

Fissure for Left lobe ligamentum venosum Falciform ligament Right Inferior lobe Ligamentum teres venacava

Gallbladder Gallbladder

Fig. 1.1. Anterior view of the liver. Fig. 1.2. Posterior view of the liver.

Fissure for ligamentum venosum

Gastric impression Portal vein Renal impression Porta hepatis Hepatic artery Duodenal Bile duct impression

Ligamentum teres Colonic impression Gallbladder Quadrate lobe Fig. 1.3. Inferior view of the liver. 1 2 Chapter 1

T7–T10, which synapse in the coeliac plexus, the right branches and each of these supplies two further subunits and left vagi and the right phrenic nerve. It accompanies (variously called sectors). The sectors on the right side the hepatic artery and bile ducts into their finest ramifi- are anterior and posterior and, in the left lobe, medial cations, even to the portal tracts and hepatic parenchyma and lateral — giving a total of four sectors (fig. 1.4). Using [4]. this definition, the right and left side of the liver are The ligamentum venosum, a slender remnant of the divided not along the line of the falciform ligament, but ductus venosus of the fetus, arises from the left branch of along a slightly oblique line to the right of this, drawn the portal vein and fuses with the inferior vena cava at from the inferior vena cava above to the gallbladder the entrance of the left hepatic vein. The ligamentum teres, bed below. The right and left side are independent a remnant of the umbilical vein of the fetus, runs in the with regard to portal and arterial blood supply, and bile free edge of the falciform ligament from the umbilicus to drainage. Three plains separate the four sectors and the inferior border of the liver and joins the left branch of contain the three major hepatic vein branches. the portal vein. Small veins accompanying it connect the Closer analysis of these four hepatic sectors produces portal vein with veins around the umbilicus. These a further subdivision into segments (fig. 1.5). The right become prominent when the portal venous system is anterior sector contains segments V and VIII; right poste- obstructed inside the liver. rior sector, VI and VII; left medial sector, IV; left lateral The venous drainage from the liver is into the right and sector, segments II and III. There is no vascular anasto- left hepatic veins which emerge from the back of the liver mosis between the macroscopic vessels of the segments and at once enter the inferior vena cava very near its but communications exist at sinusoidal level. Segment I, point of entry into the right atrium. the equivalent of the caudate lobe, is separate from the Lymphatic vessels terminate in small groups of glands other segments and does not derive blood directly from around the porta hepatis. Efferent vessels drain into the major portal branches or drain by any of the three glands around the coeliac axis. Some superficial hepatic major hepatic veins. lymphatics pass through the diaphragm in the falciform This functional anatomical classification allows inter- ligament and finally reach the mediastinal glands. pretation of radiological data and is of importance to the 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. Right side The gallbladder lies in a fossa extending from the inferior border of the liver to the right end of the porta posterior hepatis. anterior 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 Right Left 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, Leftside however, does not correlate with blood supply or biliary medial drainage. A functional anatomy is now recognized based upon studies of vascular and biliary casts made by inject- lateral ing vinyl into the vessels and bile ducts. This classiﬁca- tion correlates with that seen by imaging techniques. The main portal vein divides into right and left Fig. 1.4. The sectors of the human liver. Anatomy and Function 3

VIII VII II

I IV

III V VI 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 ﬁngers of two hands [5].

surgeon planning a liver resection. There are wide varia- tions in portal and hepatic vessel anatomy which can be Heister's spiral valve demonstrated by spiral computed tomography (CT) and Hepatic ducts magnetic resonance imaging (MRI) reconstruction [41]. Cystic duct Neck Common Anatomy of the biliary tract (fig. 1.6) Hartmann's hepatic pouch duct 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. Common The common bile duct runs between the layers of the bile lesser omentum, lying anterior to the portal vein and to duct the right of the hepatic artery. Passing behind the first part of the duodenum in a groove on the back of the head of the pancreas, it enters the second part of the duodenum. The Pancreatic duct duct runs obliquely through the postero-medial wall, usually joining the main pancreatic duct to form the Duodenal Ampulla of Vater ampulla of Vater (1720). The ampulla makes the mucous papilla Sphincter of Oddi membrane bulge inwards to form an eminence: the Duodenum duodenal papilla. In about 10–15% of subjects the bile and pancreatic ducts open separately into the duodenum. The dimensions of the common bile duct depend on Fig. 1.6. Gallbladder and biliary tract. the technique used. At operation it is about 0.5–1.5cm in diameter. Using ultrasound the values are less, the common bile duct being 2–7mm, with values greater than 7mm being regarded as abnormal. Using endo- The gallbladder is a pear-shaped bag 9cm long with a scopic cholangiography, the duct diameter is usually less capacity of about 50ml. It always lies above the trans- than 11mm, although after cholecystectomy it may be verse colon, and is usually next to the duodenal cap more in the absence of obstruction. overlying, but well anterior to, the right renal shadow. The duodenal portion of the common bile duct is sur- Any decrease in concentrating power is accompanied rounded by a thickening of both longitudinal and circu- by reduced distensibility. The fundus is the wider end lar muscle fibres derived from the intestine. This is called and is directed anteriorly; this is the part palpated when the sphincter of Oddi (1887). the abdomen is examined. The body extends into a 4 Chapter 1 narrow neck which continues into the cystic duct. The foregut, the biliary part of the endodermal bud, will form valves of Heister are spiral folds of mucous membrane in the gallbladder and extra-hepatic bile ducts. Bile begins the wall of the cystic duct and neck of the gallbladder. to flow at about the 12th week. Haemopoietic cells, Hartmann’s pouch is a sacculation at the neck of the gall- Kupffer cells and connective tissue cells are derived from bladder; this is a common site for a gallstone to lodge. the mesoderm of the septum transversum. The fetal The wall consists of a musculo-elastic network liver has a major haemopoietic function which subsides without definite layers, the muscle being particularly during the last 2 months of intra-uterine life so that only well developed in the neck and fundus. The mucous a few haemopoietic cells remain at birth. membrane is in delicate closely woven folds; instead of glands there are deep indentations of mucosa, the crypts Anatomical abnormalities of the liver of Luschka, which penetrate into the muscular layer. There is no submucosa or muscularis mucosae. These are being increasingly diagnosed with more wide- The Rokitansky–Aschoff sinuses are branching evagina- spread use of CT and ultrasound scanning. tions from the gallbladder lumen lined by mucosa reach- Accessory lobes. The livers of the pig, dog and camel are ing into the muscularis of the gallbladder. They play an divided into distinct and separate lobes by strands of important part in acute cholecystitis and gangrene of the connective tissue. Occasionally, the human liver may gallbladder wall. show this reversion and up to 16 lobes have been Blood supply. The gallbladder receives blood from the reported. This abnormality is rare and without clinical cystic artery. This branch of the hepatic artery is large, significance. The lobes are small and usually on the tortuous and variable in its anatomical relationships. under surface of the liver so that they are not detected Smaller blood vessels enter from the liver through the clinically but are noted incidentally at scanning, opera- gallbladder fossa. The venous drainage is into the cystic tion or necropsy. Rarely they are intrathoracic. An acces- vein and thence into the portal venous system. sory lobe may have its own mesentery containing The arterial blood supply to the supra-duodenal bile hepatic artery, portal vein, bile duct and hepatic vein. duct is generally by two main (axial) vessels which This may twist and demand surgical intervention. run beside the bile duct. These are supplied predomi- Riedel’s lobe is fairly common and is a downward nantly by the retro-duodenal artery from below, and the tongue-like projection of the right lobe of the liver. It is a right hepatic artery from above, although many other simple anatomical variation; it is not a true accessory vessels contribute. This pattern of arterial supply would lobe. The condition is more frequent in women. It is explain why vascular damage results in bile duct detected as a mobile tumour on the right side of the stricturing [24]. abdomen which descends with the diaphragm on inspi- Lymphatics. There are many lymphatic vessels in the ration. It may come down as low as the right iliac region. submucous and subperitoneal layers. These drain It is easily mistaken for other tumours in this area, es- through the cystic gland at the neck of the gallbladder pecially a visceroptotic right kidney. It does not cause to glands along the common bile duct, where they anas- symptoms and treatment is not required. Scanning may tomose with lymphatics from the head of the pancreas. be used to identify Riedel’s lobe and other anatomical Nerve supply. The gallbladder and bile ducts are liber- abnormalities. ally supplied with nerves, from both the parasympa- Cough furrows on the liver are parallel grooves on the thetic and the sympathetic system. convexity of the right lobe. They are one to six in number and run antero-posteriorly, being deeper posteriorly. Development of the liver and bile ducts They are said to be associated with a chronic cough. Corset liver. This is a fibrotic furrow or pedicle on the The liver begins as a hollow endodermal bud from the anterior surface of both lobes of the liver just below the foregut (duodenum) during the third week of gestation. costal margin. The mechanism is unknown, but it affects The bud separates into two parts — hepatic and biliary. elderly women who have worn corsets for many years. It The hepatic part contains bipotential progenitor cells that presents as an abdominal mass in front of and below the differentiate into hepatocytes or ductal cells, which form liver and is isodense with the liver. It may be confused the early primitive bile duct structures (ductal plates). with a hepatic tumour. Differentiation is accompanied by changes in cytoker- Lobar atrophy. Interference with the portal supply or atin type within the cell [40]. Normally, this collection biliary drainage of a lobe may cause atrophy. There is of rapidly proliferating cells penetrates adjacent meso- usually hypertrophy of the opposite lobe. Left lobe dermal tissue (the septum transversum) and is met by atrophy found at post-mortem or during scanning is not ingrowing capillary plexuses from the vitelline and uncommon and is probably related to reduced blood umbilical veins which will form the sinusoids. The con- supply via the left branch of the portal vein. The lobe is nection between this proliferating mass of cells and the decreased in size with thickening of the capsule, fibrosis Anatomy and Function 5 and prominent biliary and vascular markings. The vas- Gallbladder. Usually the fundus lies at the outer border cular problem may date from the time of birth. of the right rectus abdominis muscle at its junction with Obstruction to the right or left hepatic bile duct by the right costal margin (9th costal cartilage) (fig. 1.8). In benign stricture or cholangiocarcinoma is now the most an obese subject it may be difficult to identify the outer common cause of lobar atrophy [16]. The alkaline phos- border of the rectus sheath and the gallbladder may then phatase is usually elevated. The bile duct may not be be located by the Grey–Turner method. A line is drawn dilated within the atrophied lobe. Relief of obstruction from the left anterior superior iliac spine through the may reverse the changes if cirrhosis has not developed. umbilicus; its intersection with the right costal margin Distinction between a biliary and portal venous aetiol- indicates the position of the gallbladder. These guide- ogy may be made using technetium-labelled iminodi- lines depend upon the individual’s build. The fundus acetic acid (IDA) and colloid scintiscans. A small lobe may occasionally be found below the iliac crest. with normal uptake of IDA and colloid is compatible with a portal aetiology. Reduced or absent uptake of Methods of examination both isotopes favours biliary disease. Agenesis of the right lobe [27]. This rare lesion may be an Liver. The lower edge should be determined by palpa- incidental finding associated, probably coincidentally, tion just lateral to the right rectus muscle. This avoids with biliary tract disease and also with other congenital mistaking the upper intersection of the rectus sheath for abnormalities. It can cause pre-sinusoidal portal hyper- the liver edge. 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 (ﬁgs 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-clavicular 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. Fig. 1.7. The surface marking of the liver.

Costal Gallbladder Gallbladder Fig. 1.8. Surface markings of the margin Umbilicus gallbladder. Method I: the gallbladder is Outer border found where the outer border of the right Anterior right rectus superior rectus abdominis muscle intersects the sheath spine 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 Method I Method II the gallbladder. 6 Chapter 1

The liver edge moves 1–3cm downwards with deep the inability to take a deep breath when the examining inspiration. It is usually palpable in normal subjects fingers are hooked up below the liver edge. The inflamed inspiring deeply. The edge may be tender, regular or gallbladder is then driven against the fingers and the irregular, firm or soft, thickened or sharp. The lower pain causes the patient to catch their breath. edge may be displaced downwards by a low diaphragm, The enlarged gallbladder must be distinguished from for instance in emphysema. Movements may be particu- a visceroptotic right kidney. This, however, is more mobile, larly great in athletes or singers. Some patients with can be displaced towards the pelvis and has the resonant practice become very efficient at ‘pushing down’ the colon anteriorly. A regenerative or malignant nodule feels liver. The normal spleen can become palpable in similar much firmer. fashion. Common causes of a liver palpable below Imaging. A plain film of the abdomen, including the the umbilicus are malignant deposits, polycystic or diaphragms, may be used to assess liver size and in par- Hodgkin’s disease, amyloidosis, congestive cardiac ticular to decide whether a palpable liver is due to actual failure and gross fatty change. Rapid change in liver size enlargement or to downward displacement. On moder- may occur when congestive cardiac failure is corrected, ate inspiration the normal level of the diaphragm, on the cholestatic jaundice relieved, or when severe diabetes is right side, is opposite the 11th rib posteriorly and the 6th controlled. The surface can be palpated in the epigas- rib anteriorly. trium and any irregularity or tenderness noted. An Ultrasound, CT or MRI can also be used to study liver enlarged caudate lobe, as in the Budd–Chiari syndrome size, shape and content. or with some cases of cirrhosis, may be palpated as an epigastric mass. Hepatic morphology Pulsation of the liver, usually associated with tricus- pid valvular incompetence, is felt by manual palpation Kiernan (1833) introduced the concept of hepatic lobules with one hand behind the right lower ribs posteriorly as the basic architecture. He described circumscribed and the other anteriorly on the abdominal wall. pyramidal lobules consisting of a central tributary of the The upper edge is determined by fairly heavy percus- hepatic vein and at the periphery a portal tract contain- sion passing downwards from the nipple line. The lower ing the bile duct, portal vein radicle and hepatic artery edge is recognized by very light percussion passing branch. Columns of liver cells and blood-containing upwards from the umbilicus towards the costal margin. sinusoids extend between these two systems. Percussion is a valuable method of determining liver Stereoscopic reconstructions and scanning electron size and is the only clinical method of determining a microscopy have shown the human liver as columns of small liver. liver cells radiating from a central vein, and interlaced in The anterior liver span is obtained by measuring the orderly fashion by sinusoids (fig. 1.9). vertical distance between the uppermost and lowermost The liver tissue is pervaded by two systems of tunnels, points of hepatic dullness by percussion in the right mid- the portal tracts and the hepatic central canals which clavicular line. This is usually 12–15cm. Direct percus- dovetail in such a way that they never touch each other; sion is as accurate as ultrasound in estimating liver span the terminal tunnels of the two systems are separated [33]. by about 0.5mm (fig. 1.10). As far as possible the two Friction may be palpable and audible, usually due to systems of tunnels run in planes perpendicular to each recent biopsy, tumour or peri-hepatitis. The venous hum other. The sinusoids are irregularly disposed, normally of portal hypertension is audible between the umbilicus in a direction perpendicular to the lines connecting the and the xiphisternum. An arterial murmur over the liver central veins. The terminal branches of the portal vein may indicate a primary liver cancer or acute alcoholic discharge their blood into the sinusoids and the direction hepatitis. of flow is determined by the higher pressure in the portal The gallbladder is palpable only when it is distended. It vein than in the central vein. is felt as a pear-shaped cystic mass usually about 7cm The central hepatic canals contain radicles of the hepatic long. In a thin person, the swelling can sometimes be vein and their adventitia. They are surrounded by a lim- seen through the anterior abdominal wall. It moves iting plate of liver cells. downwards on inspiration and is mobile laterally but The portal triads (syn. portal tracts, Glisson’s capsule) not downwards. The swelling is dull to percussion and contain the portal vein radicle, the hepatic arteriole and directly impinges on the parietal peritoneum, so that the bile duct with a few round cells and a little connective colon is rarely in front of it. Gallbladder dullness is con- tissue (fig. 1.11). They are surrounded by a limiting plate tinuous with that of the liver. of liver cells. Portal dyads are as frequent as triads, with Abdominal tenderness should be noted. Inflammation the portal vein being the most frequently absent element. of the gallbladder causes a positive Murphy’s sign. This is Within each linear centimetre of liver tissue obtained at Anatomy and Function 7

Arterial capillary emptying into Arterial capillary emptying into para-portal sinusoid para-portal sinusoid Peri-portal Central Perisinusoidal Portal Limiting connective (hepatic) Lymph vessel space of Disse vein plate tissue veins Sinusoids

Central (hepatic) veins

Perisinusoidal space of Disse

Sub- lobular Central vein (hepatic) veins Central (hepatic) veins

Intra-lobular cholangiole

Bilecanaliculi on thesurface Arterial capillary Inlet of liver plates (not frequent) emptying into venules Cholangioles in intra-lobular sinusoid Portal Bile Hepatic vein duct artery Limiting portal canals plate Portal tract

Fig. 1.9. The structure of the normal human liver.

H P

H P P

P Fig. 1.10. Normal hepatic histology. P H, terminal hepatic vein; P, portal tract. (H & E, ¥60.) 8 Chapter 1

B A

Fig. 1.11. Normal portal tract. A, hepatic artery; B, bile duct; P, portal vein. (H & E.)

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 regeneration will proceed. The contribution of each acinar zone to liver cell regeneration depends on the acinar location of 1 2 3 damage [28]. Efferent vein The liver cells (hepatocytes) comprise about 60% of the liver. They are polygonal and approximately 30mm in Simple acinus 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 (fig. 1.14). There is no Preterminal Terminal basement membrane. vessel vessel The sinusoids are lined by endothelial cells. Associ- ated with the sinusoids are the phagocytic cells of the Fig. 1.12. The complex acinus according to Rappaport. Zone 1 reticulo-endothelial system (Kupffer cells), and the is adjacent to the entry (portal venous) system. Zone 3 is hepatic stellate cells, which have also been called fat- adjacent to the exit (hepatic venous) system. storing cells, Ito cells and lipocytes. There are approximately 202¥103 cells in each mil- ligram of normal human liver, of which 171¥103 are biopsy there are usually two interlobular bile ducts, two parenchymal and 31¥103 littoral (sinusoidal, including hepatic arteries and one portal vein per portal tract, with Kupffer cells). six full portal triads [8]. The space of Disse is a tissue space between hepatocytes The liver has to be divided functionally. Traditionally, and sinusoidal endothelial cells. The hepatic lymphatics the unit is based on a central hepatic vein and its sur- are found in the peri-portal connective tissue and are rounding liver cells. However, Rappaport [28] envisages lined throughout by endothelium. Tissue fluid seeps a series of functional acini, each centred on the portal through the endothelium into the lymph vessels. triad with its terminal branch of portal vein, hepatic The branch of the hepatic arteriole forms a plexus artery and bile duct (zone 1) (figs 1.12, 1.13). These inter- around the bile ducts and supplies the structures digitate, mainly perpendicularly, with terminal hepatic in the portal tracts. It empties into the sinusoidal veins of adjacent acini. The circulatory peripheries of network at different levels. There are no direct hepatic acini (adjacent to terminal hepatic veins) (zone 3) suffer arteriolar–portal venous anastomoses. most from injury whether viral, toxic or anoxic. Bridging The excretory system of the liver begins with the bile Anatomy and Function 9

LIVER THV

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 fields. Zones 1, 2 and 3, respectively, represent areas supplied with blood of first, 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 field 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 starfish (darker tint around a terminal hepatic venule, THV, in the centre). 1–3, microcirculatory zones; 1¢–3¢, zones of neighbouring acinus [28].

canaliculi (see figs 13.2, 13.3). These have no walls but are ing pegs (desmosomes). From it, equally sized and simply grooves on the contact surfaces of liver cells spaced microvilli project into the lumen of the bile (see fig. 13.1). Their surfaces are covered by microvilli. canaliculi. Along the sinusoidal border, irregularly sized The plasma membrane is reinforced by micro-filaments and spaced microvilli project into the peri-sinusoidal forming a supportive cytoskeleton (see fig. 13.2). The tissue space. The microvillous structure indicates active canalicular surface is sealed from the rest of the inter- secretion or absorption, mainly of fluid. cellular surface by junctional complexes including tight The nucleus has a double contour with pores allowing junctions, gap junctions and desmosomes. The intra- interchange with the surrounding cytoplasm. Human lobular canalicular network drains into thin-walled liver after puberty contains tetraploid nuclei and, at terminal bile ducts or ductules (cholangioles, canals of about age 20, in addition, octoploid nuclei are found. Hering) lined with cuboidal epithelium. These terminate Increased polyploidy has been regarded as precancer- in larger (interlobular) bile ducts in the portal canals. ous. In the chromatin network one or more nucleoli are They are classified into small (less than 100mm in diame- embedded. ter), medium (about 100mm) and large (more than The mitochondria also have a double membrane, the 100mm). inner being invaginated to form grooves or cristae. An enormous number of energy-providing processes take Electron microscopy and hepato-cellular place within them, particularly those involving oxida- tive phosphorylation. They contain many enzymes, par- function (figs 1.14, 1.15) ticularly those of the citric acid cycle and those involved The liver cell margin is straight except for a few anchor- in b-oxidation of fatty acids. They can transform energy 10 Chapter 1

Hepatic stellate cell Endothelial cell

Kupffer cell Sinusoid

Reticulin fibre Space of Disse

Cell membrane Lysosome Peroxisome Desmosome Gap junction Vacuole Tight junction Nucleolus Biliary canaliculus

Golgi apparatus Chromatin

Lipid

Rough Mitochondrion endoplasmic reticulum Smooth endoplasmic Glycogen reticulum

Fig. 1.14. The organelles of the liver cell. so released into adenosine diphosphate (ADP). Haem glyoxalate cycle, ether lipid synthesis, and cholesterol synthesis occurs here. and dolichol biosynthesis. Several disorders of per- The rough endoplasmic reticulum (RER) is seen as lamel- oxisomal function are recognized of which Zellweger lar structures lined by ribosomes. These are responsible syndrome is one [14]. Endotoxin severely damages for basophilia under light microscopy. They synthesize peroxisomes [7]. specific proteins, particularly albumin, those used in The lysosomes are dense bodies adjacent to the bile blood coagulation and enzymes. They may adopt a canaliculi. They contain many hydrolytic enzymes helix arrangement, as polysomes, for co-ordination of which, if released, could destroy the cell. They are proba- this function. Glucose-6-phosphatase is synthesized. bly intra-cellular scavengers which destroy organelles Triglycerides are synthesized from free fatty acids with shortened lifespans. They are the site of deposition and complexed with protein to be secreted by of ferritin, lipofuscin, bile pigment and copper. Pinocytic exocytosis as lipoprotein. The RER may participate in vacuoles may be observed in them. Some peri- glycogenesis. canalicular dense bodies are termed microbodies. The smooth endoplasmic reticulum (SER) forms tubules The Golgi apparatus consists of a system of particles and vesicles. It contains the microsomes. It is the site of and vesicles again lying near the canaliculus. It may be bilirubin conjugation and the detoxification of many regarded as a ‘packaging’ site before excretion into the drugs and other foreign compounds (P450 systems). bile. This entire group of lysosomes, microbodies and Steroids are synthesized, including cholesterol and the Golgi apparatus is a means of sequestering any material primary bile acids, which are conjugated with the amino which is ingested and has to be excreted, secreted or acids glycine and taurine. The SER is increased by stored for metabolic processes in the cytoplasm. The enzyme inducers such as phenobarbital. Golgi apparatus, lysosomes and canaliculi are concerned Peroxisomes are versatile organelles, which have com- in cholestasis (Chapter 13). plex catabolic and biosynthetic roles, and are distri- The intervening cytoplasm contains granules of buted near the SER and glycogen granules. Peroxisomal glycogen, lipid and fine fibrils. enzymes include simple oxidases, b-oxidation cycles, the The cytoskeleton supporting the hepatocyte consists Anatomy and Function 11

of microtubules, micro-filaments and intermediate filaments [12]. Microtubules contain tubulin and control subcellular mobility, vesicle movement and plasma protein secretion. Micro-filaments are made up of actin, are contractile and are important for the integrity and motility of the canaliculus and for bile flow. Intermediate filaments are elongated branched filaments comprising cytokeratins [40]. They extend from the plasma membrane 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 (fig. 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 (fig. 1.17). Disse’s space contains tissue fluid which flows out- wards into lymphatics in the portal zones. When sinu- Fig. 1.15. Electron microscopic appearances of part of a soidal pressure rises, lymph production in Disse’s space normal human liver cell. G, glycogen granules; IC, inter- increases and this plays a part in ascites formation where cellular space; L, lysosomes; M, mitochondria; Mv, microvilli in there is hepatic venous outflow obstruction. the intra-cellular space; N, nucleus; Nu, nucleolus; R, rough Endothelial cells. These cells form a continuous lining to endoplasmic reticulum. (Courtesy of Ms J. Lewin.) the sinusoids. They differ from endothelial cells else-

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.) 12 Chapter 1

Fig. 1.17. Transmission electron micrograph of a hepatic stellate cell. Note the characteristic fat droplets (F). C, bile canaliculus; D, space of Disse; M, mitochondria; N, nucleus; P, parenchymal cell; S, lumen of sinusoid. (¥12000.) (Courtesy of Professor E. Wisse.)

where in not having a regular basal lamina. The endothe- nective tissue) is taken up and this provides a method for lial cells act as a sieve between the sinusoid and space of assessing hepatic endothelial cell capacity. Endothelial Disse, have specific and non-specific endocytotic activity cells can also clear small particles (<0.1mm) from the cir- and have a variety of receptors. Their capacity to act as a culation, as well as denatured collagen. Scanning elec- sieve is due to fenestrae, around 0.15mm in diameter (fig. tron microscopy has shown a striking reduction in the 1.16). These make up 6–8% of the total endothelial cell number of fenestrae, particularly in zone 3 in alcoholic surface, and there are more in the centrilobular zone of patients, with formation of a basal lamina, which is also the sinusoid than the peri-portal area. Extra-cellular termed capillarization of the sinusoid [17]. matrix affects their function. Kupffer cells. These are highly mobile macrophages Fenestrae are clustered into sieve plates, and act attached to the endothelial lining of the sinusoid, par- as a biofilter between sinusoidal blood and the plasma ticularly in the peri-portal area. They stain with peroxi- within the space of Disse. They have a dynamic dase. They have microvilli and intra-cytoplasmic-coated cytoskeleton [6]. This maintains and regulates their size, vesicles and dense bodies which make up the lysosomal which can be changed by many influences including apparatus. They proliferate locally but under certain alcohol, nicotine, serotonin, endotoxin and partial hepa- circumstances macrophages can immigrate from an tectomy. The fenestrae filter macro-molecules of differ- extra-hepatic site. They are responsible for removing old ing size. Particles >0.2mm diameter, which includes and damaged blood cells or cellular debris, also bac- large triglyceride-rich parent chylomicrons, will not teria, viruses, parasites and tumour cells. They do this pass. Smaller triglyceride-depleted, cholesterol-rich and by endocytosis (phagocytosis, pinocytosis), including retinol-rich remnants can enter the space of Disse [15]. In absorptive (receptor-mediated) and fluid phase (non- this way the fenestrae have an important role in chylomi- receptor-mediated) mechanisms [39]. Several processes cron and lipoprotein metabolism. aid this, including cell surface Fc and complement recep- Endothelial cells have a high capacity for endocytosis tors. Coating of the particle with plasma fibronectin or (accounting for 45% of all pinocytotic vesicles in the opsonin also facilitates phagocytosis, since Kupffer cells liver) and are active in clearing macro-molecules and have specific binding sites for fibronectin on the cell small particles from the circulation [35]. There is surface. These cells also take up and process oxidized receptor-mediated endocytosis for several molecules LDL (thought to be atherogenic), and remove fibrin including transferrin, caeruloplasmin, modified high in disseminated intravascular coagulation. Alcohol density lipoprotein (HDL) and low density lipoprotein reduces the phagocytic capacity. (LDL), hepatic lipase and very low density lipoprotein Kupffer cells are activated by a wide range of agents, (VLDL). Hyaluronan (a major polysaccharide from con- including endotoxin, sepsis, shock, interferon-g, arachi-