Sherlock's Diseases of the Liver and Biliary System

James Dooley, Editor-in-Chief, worked with Professor Dame Sheila Sherlock on this book for three editions before her death in December 2001. He is a Consultant Hepatologist at the Royal Free Hospital, London. Andrew Burroughs is a Consultant Physician and Hepatologist at the Royal Free Hospital, Liver Transplantation and Hepato-biliary Medicine Unit. He qualified in Liverpool with a MB ChB Honours in 1976, gained his MRCP in 1978 and FRCP in 1991. He is a Fellow of the European Board of Gastroenterology. He has been Scientific Secretary of the European Association for the Study of the Liver 1997-1999. He continues his association with EASL as administrative secretary until 2001. He is a council member of the United European Gastroenterology Federation until 2002, and a council member of the International Association for the Study of the Liver. He is a member of the MRC advisory board in the UK, from 1997 onwards. He was a member of Council of the British Society of Gastroenterology from 1992 to 1995. Andrew Burroughs main research interests are portal hypertension, variceal bleeding and coagulopathy, primary biliary cirrhosis, prognosis in liver disease and liver transplantation. He has published over 200 peer-reviewed articles. Anna Lok is a Professor of Internal Medicine and the Director of Clinical Hepatology at the University of Michigan Medical Center. Her research focuses on the epidemiology and treatment of hepatitis B and C viruses. Millions of people worldwide are infected and are at risk for hepatitis-associated cirrhosis and hepatocellular carcinoma. Dr. Lok has made seminal contributions to our understanding of the natural history of hepatitis B and the role of hepatitis B virus genotypes and variants in the outcome of chronic hepatitis B infection. She has also made contributions to the treatment of hepatitis-induced diseases. She is currently testing new antiviral therapies for hepatitis B, developing cost-effective methods for preventing recurrent hepatitis B infection following liver transplantation, and studying the long-term effects of interferon treatment in patients with hepatitis C. During her distinguished career, she has received numerous awards for research and teaching. Jenny Heathcote, Toronto Western Hospital, Canada.

List of Contributors, xi


Preface to the Twelfth Edition, xv


Preface to the First Edition, xvi


1 Anatomy and Function, 1
Jay H. Lefkowitch


Development of the liver and bile ducts, 1


Anatomy of the liver, 1


Functional liver anatomy: sectors and segments, 3


Anatomical abnormalities of the liver, 4


Anatomy of the biliary tract, 5


Surface marking, 6


Methods of examination, 6


Microanatomy of the liver, 7


Hepatic ultrastructure (electron microscopy) and organelle functions, 11


Functional heterogeneity of the liver, 15


Dynamics of the hepatic microenvironment in physiology and disease, 16


Hepatocyte death and regeneration, 17


2 Assessment of Liver Function, 20
Sandeep Mukherjee & John L. Gollan


Selection of biochemical tests, 20


Bile pigments, 21


Serum enzyme tests, 22


Quantitative assessment of hepatic function, 25


Lipid and lipoprotein metabolism, 25


Bile acids, 27


Amino acid metabolism, 30


Plasma proteins, 30


Carbohydrate metabolism, 33


Effects of ageing on the liver, 33


3 Biopsy of the Liver, 36
David Patch & Amar Paul Dhillon


Selection and preparation of the patient, 36


Techniques, 37


Risks and complications, 40


Sampling variability, 41


Naked-eye appearances, 43


Preparation of the specimen, 43


Interpretation, 43


Indications, 43


Special methods, 45


4 Haematological Disorders of the Liver, 48
Pramod K. Mistry & Dhanpat Jain


The liver and blood coagulation, 50


Haemolytic jaundice, 53


The liver in haemolytic anaemias, 54


The liver in myelo- and lymphoproliferative disease, 57


Leukaemia, 57


Bone marrow transplantation, 57


Lymphoma, 58


Lipid storage diseases, 62


5 Acute Liver Failure, 70
Shannan R. Tujios & William M. Lee


Definition, 70


Epidemiology and aetiologies, 71


Clinical features, 74


Initial investigations, 75


Complications and management of acute liver failure, 77


Specific therapies, 84


Prognosis, 86


Liver transplantation, 86


Liver support systems, 88


Conclusion, 88


6 Hepatic Fibrogenesis, 94
Meena B. Bansal & Scott L. Friedman


Introduction, 94


Natural history of hepatic fibrosis, 94


Cellular and molecular features of hepatic fibrosis, 95


Clinical aspects of hepatic fibrosis, 100


Emerging antifi brotic targets and strategies, 101


7 Hepatic Cirrhosis, 103
P. Aiden McCormick


Definition, 103


Causes of cirrhosis, 103


Anatomical diagnosis, 104


Reversible cirrhosis, 106


Clinical cirrhosis: compensated versus decompensated, 106


Vasodilatation and hyperdynamic circulation, 108


Prognosis (Child Pugh score, MELD, UKELD), 110


Clinical and pathological associations, 111


Management, 117


8 Hepatic Encephalopathy in Patients with Cirrhosis, 121
Marsha Y. Morgan


Classification, 121


Diagnosis, 124


Differential diagnosis, 130


Hepatic encephalopathy and liver transplantation, 131


Prognosis, 131


Pathogenesis, 131


Management of hepatic encephalopathy, 139


Prevention, 146


9 The Hepatic Artery, Portal Venous System and Portal Hypertension: the Hepatic Veins and Liver in Circulatory Failure, 152
Andrew K. Burroughs


The hepatic artery, 152


The portal venous system, 156


Haemodynamics of portal hypertension, 160


Clinical features of portal hypertension, 162


Diagnosis of varices, 163


Imaging the portal venous system, 166


Classification of portal hypertension, 171


Extrahepatic portal venous obstruction, 171


Presinusoidal intrahepatic and sinusoidal portal hypertension, 176


Bleeding oesophageal varices, 179


Management of acute variceal bleeding, 181


The hepatic veins, 189


Budd Chiari (hepatic venous obstruction) syndrome, 191


Circulatory failure, 197


10 Ascites, 210
Guadalupe Garcia-Tsao


Mechanisms of ascites formation, 210


Clinical features, 213


Differential diagnosis, 215


Spontaneous bacterial peritonitis, 216


Treatment of cirrhotic ascites, 218


Hyponatraemia, 222


Refractory ascites, 223


Hepatorenal syndrome, 224


Prognosis, 228


11 Jaundice and Cholestasis, 234
Elwyn Elias


Introduction, 234


Classification of jaundice, 234


Physiology and pathophysiology, 235


Syndrome of cholestasis, 240


Investigation of the jaundiced patient, 245


Differential diagnosis, 247


Treatment, 249


Familial non-haemolytic hyperbilirubinaemias, 250


12 Gallstones and Benign Biliary Diseases, 257
James S. Dooley


Imaging, 258


Composition of gallstones, 261


Formation of cholesterol stones, 261


Factors in cholesterol stone formation, 264


Pigment gallstones, 266


Natural history of gallbladder stones, 266


Acute calculous cholecystitis, 267


Empyema of the gallbladder, 269


Emphysematous cholecystitis, 269


Chronic calculous cholecystitis, 269


Acalculous cholecystitis, 270


Cholecystectomy, 271


Postcholecystectomy bile duct damage, 273


Postcholecystectomy syndromes, 275


Non-surgical treatment of gallstones in the gallbladder, 276


Other gallbladder pathology, 277


Biliary fi stulae, 279


Gallstone ileus, 280


Bile peritonitis, 280


Association between cholecystectomy and colorectal cancer, 281


Common duct stones, 281


Management of duct stones, 282


Haemobilia, 285


Bile duct bowel anastomotic stricture, 285


Chronic pancreatitis, 286


Primary sclerosing cholangitis and autoimmune pancreatitis, 287


Bile duct pathology following liver transplantation, 287


13 Malignant Biliary Diseases, 294
Rahul S. Koti & Brian R. Davidson


Carcinoma of the gallbladder, 294


Carcinoma of the bile duct (cholangiocarcinoma), 296


Intrahepatic cholangiocarcinoma, 302


Other biliary malignancies, 302


Metastases at the hilum, 302


Periampullary carcinoma, 302


Conclusions, 308


14 Cysts and Congenital Biliary Abnormalities, 312
Giorgina Mieli-Vergani & Nedim Hadzic


Fibropolycystic diseases, 312


Adult polycystic disease, 314


Congenital hepatic fibrosis, 316


Caroli's disease, 318


Microhamartoma (von Meyenberg complexes), 319


Choledochal cysts, 320


Congenital anomalies of the biliary tract, 322


15 Primary Biliary Cirrhosis, 329
Margaret F. Bassendine


Clinical features, 329


Diagnosis, 332


Aetiology, 335


Epidemiology and genetics, 336


Treatment, 337


Prognosis, 338


16 Sclerosing Cholangitis, 342
Simon Rushbrook & Roger W. Chapman


Introduction, 342


Primary sclerosing cholangitis, 342


Secondary sclerosing cholangitis, 348


References, 350


17 Enterically Transmitted Viral Hepatitis: Hepatitis A and Hepatitis E, 353
Peter Karayiannis & Howard C. Thomas


General features of enterically transmitted viral


hepatitis, 353


Hepatitis A virus, 358


Hepatitis E virus, 362


18 Hepatitis B, 367
Anna S. F. Lok


Introduction, 367


Hepatitis B virus, 367


Immune response and mechanisms of hepatic injury, 369


Epidemiology, 370


Prevention, 371


Diagnosis, 374


Clinical manifestations, 376


Natural history, 377


Treatment, 380


19 Hepatitis D, 393
Patrizia Farci


History, 393


Hepatitis D virus, 393


Epidemiology, 395


Pathogenesis, 396


Modes of infection and clinical course, 396


Diagnosis, 399


Treatment, 400


Prevention, 403


20 Hepatitis C, 406
Geoffrey Dusheiko


Introduction, 406


Epidemiology, 406


Virology, 408


Pathology and pathogenesis, 409


Diagnostic tests for hepatitis C, 410


Acute hepatitis C, 411


Chronic hepatitis C, 412


21 Hepatitis due to Non-A E Viruses, 427
Antonio Craxi & Rosa Di Stefano


General features of non-A E hepatitides, 427


Hepatotropic viruses, 429


Systemic viral infections that often cause transient liver involvement, 431


22 HIV and the Liver, 438
Marion G. Peters & Vincent Soriano


Viral hepatitis and human immunodefi ciency virus (HIV) infection, 438


Cirrhosis and liver transplantation, 444


HIV-associated opportunistic infections and the liver, 444


HIV-associated neoplasms of the liver, 446


Antiretroviral-related liver injury in HIV, 446


23 Autoimmune Hepatitis and Overlap Syndromes, 452
Gideon M. Hirschfield & E. Jenny Heathcote


Introduction, 452


Disease overview, 452


Biological determinants of disease, 454


Disease presentation, 455


Laboratory features, 457


Imaging, 459


Liver biopsy and histological features, 459


Differential diagnosis, 461


Diagnostic dilemmas, 463


Making a diagnosis in practice, 463


Management strategies, 464


Pregnancy and autoimmune hepatitis, 468


Contraception choices for patients with autoimmune hepatitis, 469


The elderly and autoimmune hepatitis, 469


Childhood-onset autoimmune hepatitis, 469


Autoimmune hepatitis and liver transplantation, 471


Overlap syndromes, 471


Conclusion, 475


24 Drug-Induced Liver Injury, 478
Leonard B. Seeff & Robert J. Fontana


Introduction, 478


Worldwide epidemiology, 479


Expressions of hepatotoxicity, 481


Classification of hepatotoxicity, 482


Predictors of susceptibility and outcome in druginduced liver injury, 483


Mechanisms of injury, drug metabolism and pharmacokinetics, 484


Diagnostic approaches and causality assessment of drug-induced liver injury, 487


Clinical and biochemical presentations of drug-induced liver disease, 488


Assessment of suspected drug-induced liver disease, 489


Assessing causality for drug-induced liver disease, 489


Medical management, 491


Liver injury from specifi c drugs, 491


25 Alcohol and the Liver, 507
Stephen Stewart & Chris Day


Introduction, 507


Alcohol metabolism, 507


Pathogenesis, 508


Susceptibility, 510


Histological features, 511


Clinical features, 513


Clinical syndromes, 516


Prognosis, 517


Treatment, 517


26 Iron Overload States, 521
Paul Adams


Normal iron metabolism, 521


Iron overload and liver damage, 523


Genetic haemochromatosis, 523


Other iron storage diseases, 530


27 Wilson's Disease, 534
Eve A. Roberts


Molecular genetics: pathogenesis, 534


Pathology, 536


Clinical picture, 537


Genetic strategies, 539


Diagnostic diffi culties, 540


Treatment, 540


Prognosis, 542


Indian childhood cirrhosis, 543


28 Non-alcoholic Fatty Liver Disease and Nutrition, 546
Stephen H. Caldwell & Curtis K. Argo


Introduction, 546


Clinical features, 548


Laboratory testing, 549


Mitochondriopathies and lipodystrophy, 549


Epidemiology of non-alcoholic fatty liver disease, 549


Pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, 550


The natural history of non-alcoholic fatty liver disease (non-alcoholic steatohepatitis and non-NASH fatty liver), 556


Therapy of non-alcoholic fatty liver disease, 558


Other forms of non-alcoholic fatty liver, 560


29 The Liver in the Neonate, in Infancy and Childhood, 568
Deirdre A. Kelly


Investigation of liver disease in children, 568


Neonatal jaundice, 569


Neonatal liver disease (conjugated hyperbilirubinaemia), 571


Neonatal hepatitis syndrome, 574


Inherited disease in the neonate, 576


Genetic cholestatic syndromes, 578


Structural abnormalities: biliary atresia and choledochal cyst, 580


Acute liver failure in infancy, 583


Liver disease in older children, 585


Metabolic disease in older children, 587


Cirrhosis and portal hypertension, 594


Liver transplantation, 594


Tumours of the liver, 595


30 The Liver in Pregnancy, 602
Andrew K. Burroughs & E. Jenny Heathcote


Normal pregnancy, 602


Liver disease in pregnancy, 602


Diseases specifi c to pregnancy, 602


Diseases of late pregnancy, 603


Pregnancy in those with acute or chronic liver disease, 608


Hepatotoxic drugs and the pregnant woman, 609


Pre-existing liver disease, 610


Pregnancy in liver transplant recipients, 611


31 The Liver in Systemic Disease, 615
Humphrey J. F. Hodgson


Collagen-vascular and autoimmune disorders, 615


Hepatic granulomas, 616


The liver in diabetes mellitus, 622


Liver and thyroid, 622


Liver and adrenal, 623


Liver and growth hormone, 623


Amyloidosis, 623


Porphyrias, 626


Non-metastatic complications of malignancy, 628


Bone-marrow/stem cell transplantation; graft-versushost disease, 629


32 The Liver in Infections, 632
Christopher C. Kibbler


Introduction, 632


Jaundice of infections, 632


Pyogenic liver abscess, 632


Hepatic amoebiasis, 635


Tuberculosis of the liver, 637


Hepatic actinomycosis, 638


Syphilis of the liver, 639


Perihepatitis, 640


Leptospirosis, 640


Relapsing fever, 643


Lyme disease, 643


Rickettsial infections, 643


Fungal infections, 644


Schistosomiasis (bilharzia), 645


Malaria, 647


Kala-azar (visceral leishmaniasis), 648


Hydatid disease, 648


Ascariasis, 652


Strongyloides stercoralis, 654


Trichinosis, 654


Toxocara canis (visceral larva migrans), 654


Liver fl ukes, 654


33 Space-Occupying Lesions: the Diagnostic Approach, 660
Neil H. Davies & Dominic Yu


Ultrasound, 660


Computed tomography, 661


Magnetic resonance imaging, 663


Radioisotope scanning, 666


Positron emission tomography, 667


MR spectroscopy, 668


Conclusions and choice of imaging technique, 669


34 Benign Liver Tumours, 671
Ian R. Wanless


Diagnosis of focal liver lesions, 671


Hepatocellular tumours, 671


Biliary and cystic lesions, 676


Mesenchymal tumours, 677


35 Primary Malignant Neoplasms of the Liver, 681
Morris Sherman


Hepatocellular carcinoma, 681


Cholangiocarcinoma, 696


Other malignant neoplasms of the liver, 698


36 Hepatic Transplantation, 704
Andrew K. Burroughs & James O'Beirne


Selection of patients, 704


Candidates: outcome, 706


Absolute and relative contraindications, 712


General preparation of the patient, 713


Donor selection and operation, 713


The recipient operation, 714


Immunosuppression, 716


Postoperative course, 717


Post-transplantation complications, 718


Conclusion, 726


37 Liver Transplantation in Patients with Hepatitis B, C or HIV Infection, 731
Norah Terrault


Introduction, 731


Hepatitis B and liver transplantation, 731


Hepatitis C and liver transplantation, 735


HIV and liver transplantation, 740


References, 741


Index, 747