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We dedicate the twelfth edition of Schiff's Diseases of the Liver to Dr. Thomas Starzl, the inspired and inspiring pioneer in the field of liver transplantation. Dr. Starzl influenced generations of hepatologists over his long and productive career, during which his work led to the development of successful liver replacement. Dr. Starzl taught, challenged, and inspired surgeons and hepatologists while opening and advancing the field of liver transplantation against many obstacles. His brilliance and tenacity brought liver transplantation from concept to reality. As a consequence of his efforts, hope and productive lives were restored to legions of patients. The editors are among the many who now view the world of hepatology with renewed hope based on an effective treatment for hitherto unapproachable problems.

We further dedicate this edition to our wives Dana, Ann, and Vanaja for their continuing support of our endeavors.

Edition History
John Wiley & Sons Ltd. (11e 2012). Previous editions: LippincottWilliams & Wilkins.

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ISBN 9781119251224

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CONTENTS

Contributors

Foreword

Preface

About the Companion Website

PART I: Overview: Clinical Fundamentals of Hepatology

CHAPTER 1: History Taking and Physical Examination for the Patient with Liver Disease
1. Abnormal liver biochemical test levels or known liver disease
2. Known or suspected compensated or decompensated cirrhosis
3. References
CHAPTER 2: Laboratory Tests, Noninvasive Markers of Fibrosis, Liver Biopsy, and Laparoscopy
1. Introduction
2. Tests used for detection of injury to hepatocytes
3. Enzymes for detection of cholestasis
4. Test of liver synthetic function
5. Quantitative liver function tests
6. Use of liver function tests
7. Noninvasive markers of fibrosis
8. Liver biopsy
9. Further reading
10. References
CHAPTER 3: Noninvasive and Invasive Imaging of the Liver and Biliary Tract
1. Noninvasive imaging of liver and biliary tract
2. Invasive imaging of liver and biliary tract
3. References

PART II: General Considerations

CHAPTER 4: Physioanatomic Considerations
1. Surface anatomy
2. Segmental anatomy
3. Embryology
4. Large vessels of the liver
5. Lymphatics
6. Nerves
7. Biliary system
8. Microanatomy
9. Pathogenesis of chronic liver disease
10. Further reading
11. References
CHAPTER 5: Bilirubin Metabolism and Jaundice
1. Introduction
2. Sources, structure, and plasma transport of bilirubin
3. Hepatic disposition of bilirubin
4. Fate of bilirubin in the gastrointestinal tract
5. Bilirubin in the urine
6. Clinical physiology of bilirubin
7. Measurement of plasma bilirubin concentration
8. Hyperbilirubinemia and jaundice
9. I. Unconjugated hyperbilirubinemias
10. II. Conjugated hyperbilirubinemias
11. Familial hyperbilirubinemias
12. Familial cholestasis syndromes
13. Further reading
14. References
CHAPTER 6: Hepatic Histopathology
1. Systematic approach to the liver biopsy
2. Morphologic patterns of injury
3. Further reading
4. References
CHAPTER 7: Mechanisms of Liver Injury
1. Basic mechanisms
2. Disease mechanisms
3. Therapeutic implications
4. Acknowledgments
5. Further reading
6. References
CHAPTER 8: Hepatic Manifestations of Systemic Disorders
1. Infectious diseases
2. Hematology
3. Endocrinology
4. Gastroenterology
5. Rheumatology
6. Further reading
7. References
CHAPTER 9: The Liver in Pregnancy
1. The liver and hemodynamics in normal pregnancy
2. Liver tests
3. Liver diseases unique to pregnancy
4. Primary hepatic pregnancy
5. Hyperemesis gravidarum
6. Intrahepatic cholestasis of pregnancy
7. Preeclampsia liver disorders
8. HELLP syndrome
9. Acute fatty liver of pregnancy
10. Intercurrent liver disease in pregnancy
11. Pregnancy in women with chronic liver disease
12. Specific liver diseases
13. Further reading
14. References

PART III: Consequences of Liver Disease

CHAPTER 10: Hepatic Fibrosis
1. Biologic basis of hepatic fibrosis
2. Clinical aspects
3. Future prospects
4. Supporting research grants
5. References
CHAPTER 11: Preoperative Evaluation of the Patient with Liver Disease
1. Introduction
2. General principles of anesthesia care and preoperative evaluation
3. Effects of anesthesia on the liver
4. Effects of liver disease on anesthetic drug pharmacokinetics and pharmacodynamics
5. Preoperative evaluation
6. Preanesthetic assessment
7. Prediction of perioperative risk
8. Using MELD score to determine postoperative mortality risk
9. Operative risk related to specific liver diseases
10. Evaluation of cardiac risk in patients undergoing noncardiac surgery
11. Assessment of the respiratory system
12. Postoperative complications in patients with cirrhosis
13. Perioperative risks in patients with liver disease according to the nature of the surgery
14. Perioperative monitoring
15. Management of ascites and hepatic hydrothorax
16. Correction of coagulation abnormalities
17. Summary and conclusions
18. References
CHAPTER 12: Management of Portal Hypertension
1. Definition and classification of portal hypertension
2. Pathophysiology of portal hypertension
3. Stages of cirrhosis/portal hypertension
4. Evaluation of portal hypertension
5. Mechanism of action of therapies used in the management of portal hypertension
6. Management of portal hypertension: clinical settings
7. Management of gastric varices
8. Ectopic varices
9. Portal hypertensive gastropathy
10. References
CHAPTER 13: Renal Complications of Liver Disease and the Hepatorenal Syndrome
1. Introduction
2. Renal disease in compensated vliver disease
3. Renal disease in decompensated liver disease
4. Assessment of renal dysfunction
5. Management of functional renal failure including hepatorenal syndrome
6. Prognosis
7. Prevention
8. References
CHAPTER 14: Pulmonary Manifestations of Liver Disease
1. Hepatopulmonary syndrome
2. Portopulmonary hypertension
3. Summary and conclusions
4. Further reading
5. References
CHAPTER 15: Ascites and Spontaneous Bacterial Peritonitis
1. Diagnosis and differential diagnosis
2. Pathogenesis of ascites formation in liver disease
3. Evaluation of patients with ascites
4. Complications of ascites
5. Treatment of ascites
6. Management protocol of patients with cirrhosis and ascites
7. References
CHAPTER 16: Hepatic Encephalopathy
1. History
2. Epidemiology and burden
3. Nomenclature
4. Etiopathogenesis
5. Diagnosis
6. Management of covert hepatic encephalopathy
7. Management of overt hepatic encephalopathy
8. Management of hepatic encephalopathy following transhepatic internal jugular portosystemic shunts
9. Management of persistent hepatic encephalopathy
10. References
CHAPTER 17: Acute Liver Failure
1. Introduction
2. Definitions
3. Epidemiology
4. Pathogenesis
5. Etiology and disease-specific treatment
6. Approach to the patient with acute liver failure
7. Role of liver transplantation
8. Long-term outcomes
9. Investigational approaches
10. Conclusions
11. References
CHAPTER 18: Acute-on-Chronic Liver Failure
1. Introduction
2. The concept of acute-on-chronic liver failure
3. Definition of acute-on-chronic liver failure
4. Epidemiology
5. Pathophysiology
6. Predisposing factors for the development of ACLF
7. Precipitating factors for the development of ACLF
8. Organ failures
9. Diagnosis
10. Management
11. Prognosis
12. Conclusion
13. References
CHAPTER 19: Malnutrition and Liver Disease
1. Introduction
2. Assessment of malnutrition
3. Causes of malnutrition
4. Prevalence of malnutrition and impact on outcome
5. Nutrition: gut–microbiome–liver axis
6. Nutritional recommendations
7. Conclusions
8. References

PART IV: Cholestatic Disorders

CHAPTER 20: Primary Sclerosing Cholangitis
1. Introduction
2. Epidemiology and risk factors
3. Pathogenesis
4. Clinical aspects of primary sclerosing cholangitis
5. Medical management
6. Investigational therapies
7. Surgical therapies
8. Future treatment strategies
9. References
CHAPTER 21: Primary Biliary Cholangitis
1. Introduction
2. Epidemiology
3. Pathophysiology
4. Clinical presentation
5. Diagnosis
6. Treatment
7. Natural history of PBC
8. Liver transplantation for PBC
9. Variant syndromes
10. Conclusion
11. References
CHAPTER 22: Autoimmune Hepatitis
1. Introduction
2. Pathogenesis
3. Histopathology
4. Autoantibodies and autoantibody classification
5. Clinical features
6. Diagnosis
7. Treatment
8. Prognosis and the long term
9. Variant syndromes
10. Summary
11. Acknowledgments
12. References

PART V: Viral Hepatitis

CHAPTER 23: Hepatitis A and E
1. Historical perspective
2. Hepatitis A
3. Hepatitis E
4. References
CHAPTER 24: Hepatitis B and D
1. Hepatitis B virus
2. Hepatitis D virus
3. References
CHAPTER 25: Hepatitis C
1. A discovery that changed the practice of hepatology
2. Virion structure and genome organization
3. HCV replication
4. Innate immune responses to HCV
5. Small-molecule antivirals: mechanisms of action
6. Interactions of HCV with host immune cells
7. Adaptive immune responses against HCV
8. Epidemiology of hepatitis C infection
9. Risk factors for hepatitis C infection
10. Natural history
11. Histology
12. Therapy of hepatitis C
13. References

PART VI: Alcohol- and Drug-induced Liver Disease

CHAPTER 26: Alcoholic Liver Disease
1. Spectrum and clinical features of liver disease due to alcohol
2. Diagnosis and evaluation of alcoholic liver disease
3. Epidemiologic estimates of the risk of alcoholic liver disease
4. Mechanisms of liver injury from ethanol
5. Risk factors for alcoholic liver disease (Box 26.5)
6. Therapy for alcoholic liver disease
7. Future therapies for alcoholic liver disease and alcoholic hepatitis
8. Conclusions
9. References
CHAPTER 27: Drug-induced Hepatotoxicity
1. Introduction
2. Epidemiological aspects of hepatotoxicity
3. Mechanisms of hepatotoxicity
4. Recent definitions of liver injury
5. Causality assessment in drug-induced liver injury
6. Factors contributing to drug hepatotoxicity
7. Main drugs responsible for liver injury
8. Hepatotoxicity of herbal medicines and dietary complements
9. Illegal and recreational compounds
10. Hepatotoxicity of chemicals and industrial products
11. Perspectives and conclusion
12. References
CHAPTER 28: Mechanisms of Drug-induced Liver Injury
1. Mechanisms of drug-induced hepatocyte injury
2. Immune-mediated hepatotoxicity
3. Risk factors for drug-induced liver injury
4. Novel approaches to understanding and predicting drug-induced liver injury
5. New drug classes associated with drug-induced liver injury
6. Summary and future directions
7. References

PART VII: Genetic and Metabolic Disease

CHAPTER 29: Wilson Disease
1. History
2. Genetics
3. Pathophysiology
4. Pathology
5. Diagnosis
6. Clinical manifestations
7. Treatment
8. Further reading
9. References
CHAPTER 30: Hemochromatosis and Iron Storage Disorders
1. Background and history
2. Classification of hereditary hemochromatosis iron overload syndromes
3. Epidemiology of HFE-related hemochromatosis
4. Classification of hereditary hemochromatosis
5. Clinical features of hereditary hemochromatosis
6. Clinical and biochemical penetrance of hemochromatosis
7. Diagnosis
8. Screening
9. Long-term management (Fig. 3.4)
10. Prognosis
11. Secondary iron overload (Table 30.4)
12. Conclusions
13. Acknowledgments
14. Further reading
15. References
CHAPTER 31: Alpha-1 Antitrypsin Deficiency
1. Incidence
2. Clinical manifestations
3. Alpha-1 antitrypsin structure, function, and physiology
4. Mechanism for deficiency of α₁-antitrypsin in PIZZ individuals
5. Pathogenesis of liver injury in PIZZ individuals
6. Mechanism of liver injury
7. Diagnosis
8. Treatment
9. Genetic counseling
10. Population screening
11. Further reading
12. References
CHAPTER 32: Nonalcoholic Fatty Liver Disease
1. Introduction
2. Terminology and diagnostic criteria
3. Historical perspective
4. Epidemiology and prevalence
5. Genetic and familial factors in nonalcoholic fatty liver disease
6. Clinical and laboratory findings
7. Liver imaging
8. The role of liver biopsy in nonalcoholic fatty liver disease
9. Natural history and prognosis
10. Experimental and animal models of nonalcoholic fatty liver disease
11. Pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
12. Other conditions associated with NAFLD/NASH (“secondary” NASH)
13. The obese, diabetic patient with newly discovered cirrhosis
14. Treatment of nonalcoholic fatty liver disease
15. Further reading
16. References

PART VIII: Vascular Diseases of the Liver

CHAPTER 33: Vascular Liver Disease
1. Hepatic venous outflow tract obstruction – Budd–Chiari syndrome
2. Extrahepatic portal vein obstruction – portal vein thrombosis and portal cavernoma in the absence of cirrhosis
3. Portal vein thrombosis in patients with cirrhosis
4. Idiopathic noncirrhotic intrahepatic portal hypertension
5. Sinusoidal obstruction syndrome/veno-occlusive disease
6. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia
7. Congenital portosystemic shunt – Abernethy malformation
8. Nonobstructive sinusoidal dilatation and peliosis
9. References
CHAPTER 34: The Liver in Circulatory Failure
1. Anatomy and physiology of hepatic blood flow
2. Ischemic hepatic injury
3. Hepatic infarction
4. Congestive hepatopathy
5. Hepatic outflow obstruction
6. Ischemic cholangiopathy
7. Heat stroke and the liver
8. The liver in atherosclerotic cardiovascular disease
9. References

PART IX: Benign and Malignant Tumors; Cystic Disorders

CHAPTER 35: Benign Tumors, Nodules, and Cystic Diseases of the Liver
1. Tumors or pseudotumors derived from hepatocytes
2. Tumors or pseudotumors derived from cholangiocytes
3. Tumors or pseudotumors derived from mesenchymal/endothelial cells
4. Cystic diseases
5. References
CHAPTER 36: Hepatocellular Carcinoma
1. Epidemiology
2. Risk factors for hepatocellular carcinoma
3. Pathogenesis
4. Pathology
5. Clinical manifestations
6. Surveillance
7. Diagnosis
8. Staging and prognosis
9. Treatment
10. References
CHAPTER 37: Surgical Options in Liver Cancers
1. Epidemiology of hepatocellular carcinoma
2. Pathogenesis and pathophysiology of hepatocellular carcinoma
3. Screening and imaging for hepatocellular carcinoma
4. Assessment of liver function and reserve
5. Overview of hepatocellular carcinoma treatment options
6. Liver resection for hepatocellular carcinoma
7. Portal vein embolization
8. Liver transplantation for hepatocellular carcinoma
9. Treatments for patients who cannot undergo resection or transplant
10. The epidemiology and pathogenesis of cholangiocarcinoma
11. Preoperative portal vein embolization in patients with cholangiocarcinoma
12. Preoperative biliary drainage in patients with cholangiocarcinoma
13. Hilar cholangiocarcinoma
14. Surgical resection of mid and distal cholangiocarcinoma
15. Liver transplantation vs. resection for cholangiocarcinoma
16. Mixed hepatocellular carcinoma and cholangiocarcinoma
17. Acknowledgments
18. Further reading
19. References

PART X: Infectious and Granulomatous Disease

CHAPTER 38: Amoebic and Pyogenic Liver Abscesses
1. Amoebic liver abscess
2. Pyogenic liver abscess
3. Further reading
4. References
CHAPTER 39: Parasitic Diseases
1. Protozoal diseases
2. Helminthic liver diseases
3. Further reading
4. References
CHAPTER 40: Granulomas of the Liver
1. Introduction
2. Histopathology
3. Pathophysiology
4. Etiology
5. Neoplasms
6. Clinical consequences
7. Clinical evaluation
8. Specific causes
9. Treatment of hepatic granulomas and granulomatous hepatitis
10. Conclusions
11. Further reading
12. References

PART XI: Elements of Liver Transplantation

CHAPTER 41: Selection of Candidates and Timing of Liver Transplantation
1. Background
2. Indications for liver transplantation
3. Evaluation for liver transplantation
4. Contraindications to liver transplantation
5. Timing of liver transplantation
6. Conclusion
7. References
CHAPTER 42: Immunosuppression: The Global Picture
1. Historical perspective
2. Immunologic mechanisms of rejection: the three-signal pathway of lymphocyte activation
3. Classification of immunosuppressive drugs
4. Nonbiologic immunosuppressive agents
5. P450 inducers
6. P450 inhibitors
7. Biologic immunosuppressive agents
8. Costimulation blockade
9. Liver allograft rejection
10. Goals of immunosuppression
11. References
CHAPTER 43: The First Six Months Following Liver Transplantation
1. Introduction
2. Intensive care unit management
3. Floor care
4. Clinic visits
5. Long-term follow-up
6. References
CHAPTER 44: Long-term Management of the Liver Transplant Patient
1. Preventive care
2. Metabolic complications
3. Inflammatory bowel disease
4. Renal dysfunction
5. Transplant-related diseases
6. Causes of mortality
7. References
CHAPTER 45: The Liver Transplant Procedure
1. Introduction
2. Terminology
3. Historical background
4. Donor considerations
5. Recipient operation
6. Complications
7. Survey of liver transplantation practices
8. Conclusions
9. References
CHAPTER 46: Recurrent Disease Following Liver Transplantation
1. Introduction
2. Hepatitis C
3. Hepatitis B
4. Prevention of hepatitis B recurrence
5. Primary biliary cholangitis
6. Primary sclerosing cholangitis
7. Autoimmune hepatitis
8. Nonalcoholic steatohepatitis
9. Alcohol-related liver disease
10. Vascular diseases
11. Metabolic disease
12. Acute liver failure
13. Summary
14. References
CHAPTER 47: The Role of Retransplantation
1. Rate of retransplantation and indications
2. Indications for early retransplantation
3. Indications for late retransplantation
4. Results of retransplantation
5. Living donor liver transplantation and retransplantation
6. Liver retransplantation in patients with HIV-1
7. Conclusions
8. Further reading
9. References
CHAPTER 48: Controversies in Liver Transplantation
1. Liver allocation and distribution
2. MELD exception scores
3. Simultaneous liver–kidney transplantation allocation
4. Further reading
5. References

Index

EULA

List of Tables

Chapter 1

Table 1.1
Table 1.2
Table 1.3
Table 1.4
Table 1.5
Table 1.6
Table 1.7

Chapter 2

Table 2.1
Table 2.2
Table 2.3
Table 2.4

Chapter 4

Table 4.1
Table 4.2

Chapter 5

Table 5.1
Table 5.2
Table 5.3

Chapter 6

Table 6.1
Table 6.2

Chapter 8

Table 8.1
Table 8.2

Chapter 11

Table 11.1
Table 11.2
Table 11.3

Chapter 12

Table 12.1
Table 12.2

Chapter 13

Table 13.1
Table 13.2
Table 13.3
Table 13.4
Table 13.5

Chapter 15

Table 15.1
Table 15.2
Table 15.3
Table 15.4

Chapter 16

Table 16.1
Table 16.2
Table 16.3
Table 16.4
Table 16.5
Table 16.6

Chapter 17

Table 17.1
Table 17.2
Table 17.3
Table 17.4
Table 17.5
Table 17.6
Table 17.7

Chapter 18

Table 18.1A
Table 18.1B
Table 18.2
Table 18.4

Chapter 19

Table 19.1
Table 19.2

Chapter 20

Table 20.1
Table 20.2
Table 20.3
Table 20.4
Table 20.5
Table 20.6
Table 20.7

Chapter 21

Table 21.1
Table 21.2
Table 21.3
Table 21.4

Chapter 22

Table 22.1
Table 22.2
Table 22.3
Table 22.4
Table 22.5
Table 22.6

Chapter 23

Table 23.1
Table 23.2

Chapter 24

Table 24.1
Table 24.2
Table 24.3
Table 24.4
Table 24.5
Table 24.6
Table 24.7
Table 24.8
Table 24.9
Table 24.10
Table 24.11
Table 24.12

Chapter 25

Table 25.1
Table 25.2
Table 25.3
Table 25.4

Chapter 26

Table 26.1
Table 26.2
Table 26.3
Table 26.4
Table 26.5
Table 26.6

Chapter 27

Table 27.1
Table 27.2
Table 27.3
Table 27.4
Table 27.5
Table 27.6
Table 27.7
Table 27.8
Table 27.9
Table 27.10
Table 27.11

Chapter 28

Table 28.1
Table 28.2
Table 28.3
Table 28.4

Chapter 29

Table 29.1
Table 29.2
Table 29.3

Chapter 30

Table 30.1
Table 30.2
Table 30.3
Table 30.4

Chapter 31

Table 31.1
Table 31.2

Chapter 32

Table 32.1
Table 32.2
Table 32.3
Table 32.4

Chapter 33

Table 33.1

Chapter 36

Table 36.1

Chapter 38

Table 38.1

Chapter 39

Table 39.1
Table 39.2
Table 39.3

Chapter 40

Table 40.1
Table 40.2
Table 40.3
Table 40.4
Table 40.5
Table 40.6

Chapter 41

Table 41.1

Chapter 42

Table 42.1
Table 42.2
Table 42.3
Table 42.4

Chapter 43

Table 43.1
Table 43.2
Table 43.3
Table 43.4
Table 43.5

Chapter 44

Table 44.1

Chapter 45

Table 45.1
Table 45.2

Chapter 46

Table 46.1
Table 46.2
Table 46.3

Chapter 47

Table 47.1
Table 47.2
Table 47.3

Chapter 48

Table 48.1
Table 48.2