Schiff's Diseases of the Liver E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 4264

Veröffentlichungsjahr: 2017

Beschreibung

The most important and reliable resource for treating diseases of the liver For more than 55 years, "Schiff" has been acclaimed as the most outstanding liver book in the world. This new 12th edition brings the field completely up to date and includes a companion website that features a wide-variety of accessory materials. The text is evidence-based to offer hepatologists and gastroenterologists treating patients with liver disease a comprehensive and essential resource. The text highlights clinical practice and covers anatomy, pathology, testing, imaging, and the effects of liver disease on other organs. The book is written in clear and accessible terms and key features include: * Treatment guidelines and management algorithms for every disease * Full-color attractive design throughout the text * Informative section overviews for each section * Concise key concepts box in every chapter * A full liver transplant section This 12th edition is thoroughly revised with the latest clinical information. The new edition offers: * Information on acute and chronic liver failure and infections in cirrhosis * Over 100 MCQs * Downloads for Powerpoint(TM) making the content ideal for presentations Schiff's Diseases of the Liver is designed to be a first-stop reference for dealing with today's demanding clinical situations.

Leseprobe

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.

Schiff’s Diseases of the Liver

TWELFTH EDITIONEDITED BY

Eugene R. Schiff

University of Miami, Schiff Center for Liver Diseases, Miami, FL, USA

Willis C. Maddrey

University of Texas Southwestern Medical Center, Dallas, TX, USA

K. Rajender Reddy

Hospital of University of Pennsylvania, Philadelphia, PA, USA

This edition first published 2018 © 2018 John Wiley & Sons Ltd.

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

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ISBN 9781119251224

Cover image: © ilbusca/Gettyimages Cover design by Wiley

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

Abnormal liver biochemical test levels or known liver disease

Known or suspected compensated or decompensated cirrhosis

References

CHAPTER 2: Laboratory Tests, Noninvasive Markers of Fibrosis, Liver Biopsy, and Laparoscopy

Introduction

Tests used for detection of injury to hepatocytes

Enzymes for detection of cholestasis

Test of liver synthetic function

Quantitative liver function tests

Use of liver function tests

Noninvasive markers of fibrosis

Liver biopsy

Further reading

References

CHAPTER 3: Noninvasive and Invasive Imaging of the Liver and Biliary Tract

Noninvasive imaging of liver and biliary tract

Invasive imaging of liver and biliary tract

References

PART II: General Considerations

CHAPTER 4: Physioanatomic Considerations

Surface anatomy

Segmental anatomy

Embryology

Large vessels of the liver

Lymphatics

Nerves

Biliary system

Microanatomy

Pathogenesis of chronic liver disease

Further reading

References

CHAPTER 5: Bilirubin Metabolism and Jaundice

Introduction

Sources, structure, and plasma transport of bilirubin

Hepatic disposition of bilirubin

Fate of bilirubin in the gastrointestinal tract

Bilirubin in the urine

Clinical physiology of bilirubin

Measurement of plasma bilirubin concentration

Hyperbilirubinemia and jaundice

I. Unconjugated hyperbilirubinemias

II. Conjugated hyperbilirubinemias

Familial hyperbilirubinemias

Familial cholestasis syndromes

Further reading

References

CHAPTER 6: Hepatic Histopathology

Systematic approach to the liver biopsy

Morphologic patterns of injury

Further reading

References

CHAPTER 7: Mechanisms of Liver Injury

Basic mechanisms

Disease mechanisms

Therapeutic implications

Acknowledgments

Further reading

References

CHAPTER 8: Hepatic Manifestations of Systemic Disorders

Infectious diseases

Hematology

Endocrinology

Gastroenterology

Rheumatology

Further reading

References

CHAPTER 9: The Liver in Pregnancy

The liver and hemodynamics in normal pregnancy

Liver tests

Liver diseases unique to pregnancy

Primary hepatic pregnancy

Hyperemesis gravidarum

Intrahepatic cholestasis of pregnancy

Preeclampsia liver disorders

HELLP syndrome

Acute fatty liver of pregnancy

Intercurrent liver disease in pregnancy

Pregnancy in women with chronic liver disease

Specific liver diseases

Further reading

References

PART III: Consequences of Liver Disease

CHAPTER 10: Hepatic Fibrosis

Biologic basis of hepatic fibrosis

Clinical aspects

Future prospects

Supporting research grants

References

CHAPTER 11: Preoperative Evaluation of the Patient with Liver Disease

Introduction

General principles of anesthesia care and preoperative evaluation

Effects of anesthesia on the liver

Effects of liver disease on anesthetic drug pharmacokinetics and pharmacodynamics

Preoperative evaluation

Preanesthetic assessment

Prediction of perioperative risk

Using MELD score to determine postoperative mortality risk

Operative risk related to specific liver diseases

Evaluation of cardiac risk in patients undergoing noncardiac surgery

Assessment of the respiratory system

Postoperative complications in patients with cirrhosis

Perioperative risks in patients with liver disease according to the nature of the surgery

Perioperative monitoring

Management of ascites and hepatic hydrothorax

Correction of coagulation abnormalities

Summary and conclusions

References

CHAPTER 12: Management of Portal Hypertension

Definition and classification of portal hypertension

Pathophysiology of portal hypertension

Stages of cirrhosis/portal hypertension

Evaluation of portal hypertension

Mechanism of action of therapies used in the management of portal hypertension

Management of portal hypertension: clinical settings

Management of gastric varices

Ectopic varices

Portal hypertensive gastropathy

References

CHAPTER 13: Renal Complications of Liver Disease and the Hepatorenal Syndrome

Introduction

Renal disease in compensated vliver disease

Renal disease in decompensated liver disease

Assessment of renal dysfunction

Management of functional renal failure including hepatorenal syndrome

Prognosis

Prevention

References

CHAPTER 14: Pulmonary Manifestations of Liver Disease

Hepatopulmonary syndrome

Portopulmonary hypertension

Summary and conclusions

Further reading

References

CHAPTER 15: Ascites and Spontaneous Bacterial Peritonitis

Diagnosis and differential diagnosis

Pathogenesis of ascites formation in liver disease

Evaluation of patients with ascites

Complications of ascites

Treatment of ascites

Management protocol of patients with cirrhosis and ascites

References

CHAPTER 16: Hepatic Encephalopathy

History

Epidemiology and burden

Nomenclature

Etiopathogenesis

Diagnosis

Management of covert hepatic encephalopathy

Management of overt hepatic encephalopathy

Management of hepatic encephalopathy following transhepatic internal jugular portosystemic shunts

Management of persistent hepatic encephalopathy

References

CHAPTER 17: Acute Liver Failure

Introduction

Definitions

Epidemiology

Pathogenesis

Etiology and disease-specific treatment

Approach to the patient with acute liver failure

Role of liver transplantation

Long-term outcomes

Investigational approaches

Conclusions

References

CHAPTER 18: Acute-on-Chronic Liver Failure

Introduction

The concept of acute-on-chronic liver failure

Definition of acute-on-chronic liver failure

Epidemiology

Pathophysiology

Predisposing factors for the development of ACLF

Precipitating factors for the development of ACLF

Organ failures

Diagnosis

Management

Prognosis

Conclusion

References

CHAPTER 19: Malnutrition and Liver Disease

Introduction

Assessment of malnutrition

Causes of malnutrition

Prevalence of malnutrition and impact on outcome

Nutrition: gut–microbiome–liver axis

Nutritional recommendations

Conclusions

References

PART IV: Cholestatic Disorders

CHAPTER 20: Primary Sclerosing Cholangitis

Introduction

Epidemiology and risk factors

Pathogenesis

Clinical aspects of primary sclerosing cholangitis

Medical management

Investigational therapies

Surgical therapies

Future treatment strategies

References

CHAPTER 21: Primary Biliary Cholangitis

Introduction

Epidemiology

Pathophysiology

Clinical presentation

Diagnosis

Treatment

Natural history of PBC

Liver transplantation for PBC

Variant syndromes

Conclusion

References

CHAPTER 22: Autoimmune Hepatitis

Introduction

Pathogenesis

Histopathology

Autoantibodies and autoantibody classification

Clinical features

Diagnosis

Treatment

Prognosis and the long term

Variant syndromes

Summary

Acknowledgments

References

PART V: Viral Hepatitis

CHAPTER 23: Hepatitis A and E

Historical perspective

Hepatitis A

Hepatitis E

References

CHAPTER 24: Hepatitis B and D

Hepatitis B virus

Hepatitis D virus

References

CHAPTER 25: Hepatitis C

A discovery that changed the practice of hepatology

Virion structure and genome organization

HCV replication

Innate immune responses to HCV

Small-molecule antivirals: mechanisms of action

Interactions of HCV with host immune cells

Adaptive immune responses against HCV

Epidemiology of hepatitis C infection

Risk factors for hepatitis C infection

Natural history

Histology

Therapy of hepatitis C

References

PART VI: Alcohol- and Drug-induced Liver Disease

CHAPTER 26: Alcoholic Liver Disease

Spectrum and clinical features of liver disease due to alcohol

Diagnosis and evaluation of alcoholic liver disease

Epidemiologic estimates of the risk of alcoholic liver disease

Mechanisms of liver injury from ethanol

Risk factors for alcoholic liver disease (Box 26.5)

Therapy for alcoholic liver disease

Future therapies for alcoholic liver disease and alcoholic hepatitis

Conclusions

References

CHAPTER 27: Drug-induced Hepatotoxicity

Introduction

Epidemiological aspects of hepatotoxicity

Mechanisms of hepatotoxicity

Recent definitions of liver injury

Causality assessment in drug-induced liver injury

Factors contributing to drug hepatotoxicity

Main drugs responsible for liver injury

Hepatotoxicity of herbal medicines and dietary complements

Illegal and recreational compounds

Hepatotoxicity of chemicals and industrial products

Perspectives and conclusion

References

CHAPTER 28: Mechanisms of Drug-induced Liver Injury

Mechanisms of drug-induced hepatocyte injury

Immune-mediated hepatotoxicity

Risk factors for drug-induced liver injury

Novel approaches to understanding and predicting drug-induced liver injury

New drug classes associated with drug-induced liver injury

Summary and future directions

References

PART VII: Genetic and Metabolic Disease

CHAPTER 29: Wilson Disease

History

Genetics

Pathophysiology

Pathology

Diagnosis

Clinical manifestations

Treatment

Further reading

References

CHAPTER 30: Hemochromatosis and Iron Storage Disorders

Background and history

Classification of hereditary hemochromatosis iron overload syndromes

Epidemiology of

HFE

-related hemochromatosis

Classification of hereditary hemochromatosis

Clinical features of hereditary hemochromatosis

Clinical and biochemical penetrance of hemochromatosis

Diagnosis

Screening

Long-term management

(Fig. 3.4)

Prognosis

Secondary iron overload (Table 30.4)

Conclusions

Acknowledgments

Further reading

References

CHAPTER 31: Alpha-1 Antitrypsin Deficiency

Incidence

Clinical manifestations

Alpha-1 antitrypsin structure, function, and physiology

Mechanism for deficiency of α

1

-antitrypsin in PIZZ individuals

Pathogenesis of liver injury in PIZZ individuals

Mechanism of liver injury

Diagnosis

Treatment

Genetic counseling

Population screening

Further reading

References

CHAPTER 32: Nonalcoholic Fatty Liver Disease

Introduction

Terminology and diagnostic criteria

Historical perspective

Epidemiology and prevalence

Genetic and familial factors in nonalcoholic fatty liver disease

Clinical and laboratory findings

Liver imaging

The role of liver biopsy in nonalcoholic fatty liver disease

Natural history and prognosis

Experimental and animal models of nonalcoholic fatty liver disease

Pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Other conditions associated with NAFLD/NASH (“secondary” NASH)

The obese, diabetic patient with newly discovered cirrhosis

Treatment of nonalcoholic fatty liver disease

Further reading

References

PART VIII: Vascular Diseases of the Liver

CHAPTER 33: Vascular Liver Disease

Hepatic venous outflow tract obstruction – Budd–Chiari syndrome

Extrahepatic portal vein obstruction – portal vein thrombosis and portal cavernoma in the absence of cirrhosis

Portal vein thrombosis in patients with cirrhosis

Idiopathic noncirrhotic intrahepatic portal hypertension

Sinusoidal obstruction syndrome/veno-occlusive disease

Hepatic vascular malformations in hereditary hemorrhagic telangiectasia

Congenital portosystemic shunt – Abernethy malformation

Nonobstructive sinusoidal dilatation and peliosis

References

CHAPTER 34: The Liver in Circulatory Failure

Anatomy and physiology of hepatic blood flow

Ischemic hepatic injury

Hepatic infarction

Congestive hepatopathy

Hepatic outflow obstruction

Ischemic cholangiopathy

Heat stroke and the liver

The liver in atherosclerotic cardiovascular disease

References

PART IX: Benign and Malignant Tumors; Cystic Disorders

CHAPTER 35: Benign Tumors, Nodules, and Cystic Diseases of the Liver

Tumors or pseudotumors derived from hepatocytes

Tumors or pseudotumors derived from cholangiocytes

Tumors or pseudotumors derived from mesenchymal/endothelial cells

Cystic diseases

References

CHAPTER 36: Hepatocellular Carcinoma

Epidemiology

Risk factors for hepatocellular carcinoma

Pathogenesis

Pathology

Clinical manifestations

Surveillance

Diagnosis

Staging and prognosis

Treatment

References

CHAPTER 37: Surgical Options in Liver Cancers

Epidemiology of hepatocellular carcinoma

Pathogenesis and pathophysiology of hepatocellular carcinoma

Screening and imaging for hepatocellular carcinoma

Assessment of liver function and reserve

Overview of hepatocellular carcinoma treatment options

Liver resection for hepatocellular carcinoma

Portal vein embolization

Liver transplantation for hepatocellular carcinoma

Treatments for patients who cannot undergo resection or transplant

The epidemiology and pathogenesis of cholangiocarcinoma

Preoperative portal vein embolization in patients with cholangiocarcinoma

Preoperative biliary drainage in patients with cholangiocarcinoma

Hilar cholangiocarcinoma

Surgical resection of mid and distal cholangiocarcinoma

Liver transplantation vs. resection for cholangiocarcinoma

Mixed hepatocellular carcinoma and cholangiocarcinoma

Acknowledgments

Further reading

References

PART X: Infectious and Granulomatous Disease

CHAPTER 38: Amoebic and Pyogenic Liver Abscesses

Amoebic liver abscess

Pyogenic liver abscess

Further reading

References

CHAPTER 39: Parasitic Diseases

Protozoal diseases

Helminthic liver diseases

Further reading

References

CHAPTER 40: Granulomas of the Liver

Introduction

Histopathology

Pathophysiology

Etiology

Neoplasms

Clinical consequences

Clinical evaluation

Specific causes

Treatment of hepatic granulomas and granulomatous hepatitis

Conclusions

Further reading

References

PART XI: Elements of Liver Transplantation

CHAPTER 41: Selection of Candidates and Timing of Liver Transplantation

Background

Indications for liver transplantation

Evaluation for liver transplantation

Contraindications to liver transplantation

Timing of liver transplantation

Conclusion

References

CHAPTER 42: Immunosuppression: The Global Picture

Historical perspective

Immunologic mechanisms of rejection: the three-signal pathway of lymphocyte activation

Classification of immunosuppressive drugs

Nonbiologic immunosuppressive agents

P450 inducers

P450 inhibitors

Biologic immunosuppressive agents

Costimulation blockade

Liver allograft rejection

Goals of immunosuppression

References

CHAPTER 43: The First Six Months Following Liver Transplantation

Introduction

Intensive care unit management

Floor care

Clinic visits

Long-term follow-up

References

CHAPTER 44: Long-term Management of the Liver Transplant Patient

Preventive care

Metabolic complications

Inflammatory bowel disease

Renal dysfunction

Transplant-related diseases

Causes of mortality

References

CHAPTER 45: The Liver Transplant Procedure

Introduction

Terminology

Historical background

Donor considerations

Recipient operation

Complications

Survey of liver transplantation practices

Conclusions

References

CHAPTER 46: Recurrent Disease Following Liver Transplantation

Introduction

Hepatitis C

Hepatitis B

Prevention of hepatitis B recurrence

Primary biliary cholangitis

Primary sclerosing cholangitis

Autoimmune hepatitis

Nonalcoholic steatohepatitis

Alcohol-related liver disease

Vascular diseases

Metabolic disease

Acute liver failure

Summary

References

CHAPTER 47: The Role of Retransplantation

Rate of retransplantation and indications

Indications for early retransplantation

Indications for late retransplantation

Results of retransplantation

Living donor liver transplantation and retransplantation

Liver retransplantation in patients with HIV-1

Conclusions

Further reading

References

CHAPTER 48: Controversies in Liver Transplantation

Liver allocation and distribution

MELD exception scores

Simultaneous liver–kidney transplantation allocation

Further reading

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

List of Illustrations

Chapter 1

Figure 1.1

Cutaneous findings in cirrhosis. (A) Palmar erythema. (B) Terry's nails. (C) Clubbing. (D) Xanthelasma. (E) Spider telangiectasia. (C–E: Reproduced from [24] with permission from John Wiley & Sons.)

Figure 1.2

Percussion of the liver in cirrhosis. (A) Image of the abdomen and chest showing location of the liver and spleen. In healthy persons, the liver descends 1–3 cm with deep inspiration. (B) In cirrhosis, there may be shrinking of the right lobe of the liver with enlargement of the left and caudate lobes. This results in the finding of an enlarged liver span in the midsternal line and palpation of the liver edge in the epigastrium. (Reproduced from [34] with permission from Taylor and Francis, www.tandfonline.com.)

Figure 1.3

The fluid wave test for the detection of ascites. While an assistant (either a second clinician or the patient) places one hand firmly in the patient's abdominal midline, the examiner holds one hand still on the patient's right flank, while the other hand taps or presses firmly but gently on the left flank. Detection of an impulse in the right flank indicates the presence of fluid.

Chapter 2

Figure 2.1

Age and gender effect on upper limits of normal for ALT (circles, males; squares, females). (Reproduced from [1] with permission from the American Association for Clinical Chemistry.)

Figure 2.2

Age and gender effect on upper limits of normal for ALP (circles, males; squares, females). (Reproduced from [1] with permission from the American Association for Clinical Chemistry.)

Figure 2.3

Endoscopic ultrasound-guided needle biopsy of the left lobe of the liver.

Figure 2.4

Multiple liver biopsy fragments of the left lobe of the liver obtained by endoscopic ultrasound-guided transgastric approach.

Chapter 3

Figure 3.1

Two images from a normal ultrasound of the liver. (A) Grayscale image showing liver parenchyma with normal homogeneous echogenicity. The main portal vein extending into the liver has a normal appearance. (B) On the Doppler ultrasound image the portal vein blood flow is hepatopedal and normal velocity.

Figure 3.2

Postcontrast coronal CT images of the liver from three different patients. (A) Irregular peripheral enhancement in the right hepatic lobe, extending up to the dome, compatible with infection in this patient with a history of IV drug use. The infection has not become a collection. (B) An infection has walled off into an abscess and liquefied centrally. The irregular black areas at the edge of the collection are bubbles of gas forming in the abscess. (C) A hypoenhancing mass, predominantly in segment IV. At biopsy, this was found to be hepatocellular carcinoma.

Figure 3.3

In this HIDA scan, the radiotracer is taken up by the liver and is being excreted through the CBD into the duodenum. The gallbladder is not seen; the lack of tracer in the gallbladder implies an obstruction in the cystic duct and cholecystitis in this patient with an equivocal ultrasound study.

Figure 3.4

In this coronal fused PET and CT image, there are multiple areas of fluorodeoxyglucose-avidity in the right hepatic lobe. On biopsy, these were found to be metastases in this patient with a history of colon cancer.

Figure 3.5

In this MRCP sequence, the extrahepatic biliary system, pancreatic duct, and gallbladder are all well visualized. The numerous bright areas in the region of the liver represent biliary hamartomas.

Figure 3.6

Contrast-enhanced MRI in the evaluation of focal nodular hyperplasia. In the initial ultrasound image, the radiologist noted an irregular region of altered echogenicity in this patient's right hepatic lobe (A), but was unable to characterize it further and recommended MRI. On the T2-weighted image and precontrast image (B and C), the mass in the right hepatic lobe blends in with the background parenchyma, but does cause mass effect in the area, distorting right hepatic lobe vessels. After the administration of contrast, the mass pops into view on the arterial phase (D), blends into liver again on the equilibrium phase (E), and then brightly enhances on the delayed phase (F). Because gadoxetic acid (Eovist®) was used, this lesion is compatible with focal nodular hyperplasia. A second lesion in the left hepatic lobe that had not been seen on ultrasound also revealed itself.

Figure 3.7

In point shear-wave elastography the sonographer or radiologist can vary the rectangular region of interest to pick a representative area of liver.

Figure 3.8

Part of a postprocessed elastogram from MR elastography. In the second panel, regions of interest are measured to estimate the degree of fibrosis.

Figure 3.9

On this patient's MRI, the liver markedly loses signal on the out-of-phase component of a dual-echo sequence. This amount of signal loss is compatible with severe hepatic steatosis.

Figure 3.10

In this axial T2

*

gradient echo sequence, the liver is losing signal and darker than expected. The tail of the pancreas is also losing signal, but the spleen is normal signal, compatible with primary hemachromatosis

Figure 3.11

In this patient with a history of ulcerative colitis, an MRCP was originally obtained to evaluate the bile ducts (A). There is diffuse irregular stricturing of the ducts and the ducts are more dilated in the left hepatic lobe than in the right. ERCP was then performed, which again shows the irregular beading and structuring in the right hepatic lobe ducts (B). On the ERCP, the left hepatic lobe ducts could not be well opacified due to the tight downstream stricture; these ducts were better evaluated on MRCP.

Figure 3.12

In this patient with right upper quadrant pain, an ultrasound detected a mildly dilated common bile duct, but no obstructing stone. The patient then went to MRCP and a 4 mm oval defect was seen in the distal common bile duct (A). The stone was confirmed and removed by ERCP (B).

Figure 3.13

Catheter-directed per-oral digital cholangioscopy/choledoscopy and diagnosis of intraductal hepatocellular cancer. A 56-year-old man presented with a left liver mass seen on coronal CT (A) and T2-weighted MRI (B). Multiple attempts at percutaneous biopsy were unsuccessful. ERCP with direct cholangioscopy were performed and demonstrated an apparent soft tissue mass in the right intrahepatic duct (C) that was successfully biopsied with cholangioscopic forceps (D). Successful histologic diagnosis was achieved with this technique.

Figure 3.14

ERCP cannulation, sphincterotomy, and stone extraction. (A) Normal endoscopic view of the major papilla. (B) Successful papillary cannulation and endoscopic sphincterotomy. (C) Normal cholangiogram with nondilated common bile duct, filling of the tortuous cystic duct, and right/left intrahepatic ducts. (D) Demonstration of a rounded filling defect consistent with a stone in the distal common bile duct. (E) Successful completion of a sphincterotomy and balloon stone extraction. The stone is seen fluoroscopically in the duodenum with drainage of contrast. (F) Endoscopic image of (E) with stone successfully removed into the duodenal lumen.

Figure 3.15

Removal of a large stone with sphincterotomy and adjunctive balloon sphincteroplasty. An 80-year-old woman presented with jaundice, altered mental status, acidosis, and septic shock not improving despite the placement of a percutaneous cholecystostomy drain. (A) Cholangiogram demonstrated a large amount of stone debris and sludge in a dilated common bile duct and ready filling of the cystic duct. (B) A successful biliary sphincterotomy was performed with adjunctive sphincteroplasty. (C) Fluoroscopically, the waist associated with the biliary sphincter was obliterated with balloon dilation. (D) Successful clearance of the bile duct was achieved with sequential balloon sweeps.

Figure 3.16

Mirizzi syndrome and choledocolithiasis in a patient following liver transplant. (A,B) A 39-year-old woman with metastatic serous ovarian cancer presented with jaundice, fever, and altered mental status. (A) Cholangiogram confirmed type I Mirizzi syndrome with compression of the common hepatic duct due to a large gallstone in the gallbladder neck. (B) The obstruction was successfully traversed and remediated with the placement of a 10 Fr plastic stent into the common hepatic duct. (C,D) A 71-year-old woman who underwent deceased donor orthotopic liver transplant 4 years ago for cryptogeneic cirrhosis presented with abdominal pain and jaundice. (C) Cholangiogram confirmed irregular filling defects in the mid and distal CBD with a patent but narrowed choledoco-choldochostomy. (D) Successful extraction of obstructing stones and remediation of stricture.

Figure 3.17

Removal of a large stone in a patient post Roux-en-Y gastric bypass. A 62-year-old woman with a remote history of Roux-en-Y gastric bypass surgery for morbid obesity now presents with jaundice and abdominal pain. (A) MRCP demonstrated common bile duct filling defects and dilation of the intrahepatic bile ducts. (B) Successful identification and cannulation of the major papilla with a Fujinon double balloon enteroscope with the performance of a sphincterotomy. (C) Cholangiogram demonstrating stone in the distal common bile duct. (D) Adjunctive balloon sphincteroplasty. (E) Successful stone extraction visualized endoscopically.

Figure 3.18

Remediation of malignant biliary strictures with plastic and metal stenting. A 63-year-old man presented with jaundice and a distal common bile duct stricture on CT concerning for cholangiocarcinoma. (A,B) Initial injection of contrast demonstrated severe, irregular stenosis in the distal common bile duct concerning for malignancy. (C) A 10 Fr plastic stent was placed across the stricture into the common bile duct with resolution of the patient's jaundice. A 52-year-old patient with metastatic colorectal cancer presents with painless jaundice without fever or leukocytosis. (D) MRI/MRCP demonstrates severe extrinsic compression of the mid-common bile duct with upstream dilation. (E) Cholangiogram confirms a severe stricture of the mid-common bile duct with (F) successful placement of an uncovered SEMS.

Figure 3.19

Remediation of a high-grade malignant hilar stricture with bilateral metal stenting. A 46-year-old woman with breast cancer metastatic to the lymph nodes, bones, and liver presents with jaundice, abdominal pain, nausea, and vomiting. (A) MRI/MRCP demonstrates a high-grade hilar obstruction involving the bifurcation, right and left intrahepatic ducts and proximal common bile duct which is confirmed on cholangiography (B). (C) Subsequently successful selective, bilateral biliary cannulation, dilation, and placement of a side-by-side uncovered self-expanding metal stents was performed.

Figure 3.20

Remediation of benign biliary strictures due to iaterogenic injury and chronic calcific pancreaititis. (A–C) A 46-year-old man with acute cholecystitis who underwent laparoscopic cholecystectomy complicated by the postoperative development of jaundice and elevated alkaline phosphatase. (A) MRI/MRCP demonstrates severe stricture and absence of the common bile duct at the level of the cystic duct takeoff. (B) Cholangiogram demonstrates numerous surgical clips in the region of the common bile duct with an associated severe stricture. (C) The stricture is traversed and a 10 Fr plastic stent is successfully deployed. (D–G) A 60-year-old man with a history of alcoholic, chronic calcific pancreatitis presented with abdominal pain and jaundice. (D) Scout film confirms chronic calcificiations in the head and body of the pancreas. (E) Cholangiogram demonstrates a smooth tapered stricture of the intrapancreatic portion of the common bile duct. (F) Sequential dilation and placement of 10 Fr plastic stents for approximately 12 months yielded ultimate remediation of the stricture (G).

Figure 3.21

Remediation of a benign anastomotic stricture after living donor orthotopic liver transplantation. A 64-year-old man with alcoholic cirrhosis underwent living donor liver transplantation from his son and developed jaundice 1 year after his transplant. (A) Initial cholangiogram demonstrated a completed strictured anastomosis without opacification of the donor bile duct or ability to traverse the stricture. Cholangioscopic guidance was attempted and unsuccessful. (B) Successful recanalization of the anastomosis via percutaneous transhepatic cholangiography. (C–F) Subsequent sequential ERCP every 3 months for a year with dilation and placement of multiple 10 Fr biliary stents (D) ultimately improved the stricture (F).

Figure 3.22

Benign biliary stricture due to hepatic artery thrombosis in a patient after liver transplantation. A 58-year-old woman with alcoholic cirrhosis and hepatocellular cancer underwent deceased donor orthotopic liver transplantation complicated by the development of hepatic artery thrombosis. (A) MR angiogram demonstrating hepatic artery thrombosis. (B,C) Cholangiogram demonstrating severe, irregular structuring, most notably at the hilum. (D) Successful placement of two 10 Fr plastic stents for remediation of the stricture.

Figure 3.23

Cholangiography and treatment of primary sclerosing cholangitis. A 37-year-old man with a history of primary sclerosing cholangitis and ulcerative colitis presented with worsening jaundice and malaise. (A) Cholangiogram demonstrated a dominant stricture of the mid-common bile duct that was balloon dilated (B). (C) Subsequently, a cholangiogram demonstrated severe stricturing and beading of the intra- and extrahepatic bile duct consistent with the patient's diagnosis of primary sclerosing cholangitis. Incidentally the patient was noted with aberrant cystic duct emerging from the right hepatic. Stents were not place given the risk of developing cholangitis and improvement seen with dilation alone.

Figure 3.24

Bile leak after cholecystectomy. A 50-year-old man with idiopathic pulmonary fibrosis who underwent a bilateral lung transplant and whose postoperative course was complicated by gangrenous cholecystitis developed a bile leak after an open cholecystectomy. (A) Initial cholangiogram demonstrated extravasation of contrast at the cystic duct remnant adjacent to the surgical drain and two small stones in the distal common bile duct. (B) A biliary sphincterotomy was completed and the stones were removed. (C) A 10 Fr plastic stent was placed across the cystic duct takeoff. However, despite this, the patient continued with bilious output from his drains. (D) Repeat ERCP was performed and demonstrated contrast extavasation in the area of the cystic duct stump. (E) A fully covered SEMS was placed across the cystic duct stump and a 10 Fr, 10 cm long plastic double pig tail stent was deployed through the SEMS subsequently to limit migration (F). Subsequently, bilious output resolved and 6 weeks afterwards the stents were removed and leak had resolved.

Figure 3.25

Complex bile leaks. (A,B) A 46-year-old woman with breast cancer metastatic to her liver with fiducial placement and stereotactic radiation therapy developed cholecystitis and underwent laparoscopic cholecystectomy complicated by a bile leak. (A) Cholangiogram demonstrated expected surgical clips in the right upper quadrant, multiple radiopaque fiducials, and extravasation of contrast into the gallbladder fossa likely from the ducts of Lushka. (B) Subsequently sphincterotomy and placement of a 10 Fr plastic stent across the cystic duct stump were performed. (C,D) A 60-year-old woman with a history of a Roux-en-Y gastric bypass for morbid obesity developed cholecystitis and underwent laparoscopic cholecystectomy complicated by a bile leak. (C) A Fujinon double balloon-assisted enteroscope was used to visualize the major papilla. A cholangiogram demonstrated extravasation from the cystic duct stump. (D) Successful placement of a 7 Fr stent in the distal common bile duct. (E–G) A 58-year-old man with a history of hepatitis C-induced cirrhosis underwent living donor transplant with postoperative bile leak treated with ERCP, sphincterotomy, and stent placement. (E) Cholangiogram obtained adjacent to indwelling plastic stents demonstrated extravasation of contrast from the donor right anterior hepatic duct anastomosis to the recipient right hepatic duct. (F) After removal of the plastic stents a disruption and leak at the right anterior anastomosis is noted. (G) Successful placement of a 10 Fr plastic stent across the anastomosis.

Figure 3.26

Anomalous pancreatobiliary junction. In the congenital malformation seen here, the common bile duct terminus is to the main pancreatic duct at the level of the genu.

Figure 3.27

Endoscopic ultrasound findings of choledocolithiasis and biliary stricture due to chronic calcific pancreatitis. (A–C) A 69-year-old man with an episode of unexplained pancreatitis. (A) Radial EUS of the distal common bile duct demonstrates a nonobstructing, hyperechoic stone with posterior shadowing confirmed on Doppler (second panel). Subsequent ERCP, confirmed the stone on cholangiography (B) and endoscopy (C). (D,E) A 60-year-old man with a history of alcoholic, chronic calcific pancreatitis presented with abdominal pain and jaundice. (D) Radial EUS examination of a patient with chronic calcific pancreatitis. Note the hyperechoic parenchymal calcifications that limit imaging. (E) Radial EUS showing chronic calcific pancreatitis with a distal common bile duct stricture and upstream dilation of the common bile duct (BD). Cholangiogram and remediation of this patient's stricture is seen in Fig 3.20D–G.

Figure 3.28

Endoscopic ultrasound sampling of solid hepatic/perihepatic lesions. (A) A 73-year-old man presented with painless jaundice with MRI concerning for intrahepatic cholangiocarcinoma at the hilum with intrahepatic metastasis to the left liver lobe. A discrete, round, hyperechoic, solid mass lesion is noted on linear EUS in the left lobe of the liver. FNA was performed of the lesion and confirmed the diagnosis of cholangiocarcinoma. (B,C) A 60-year-old woman with a history of pancreatic head adenocarcinoma who underwent a Whipple's resection now presents with jaundice. (B) Linear EUS of the bile duct (

*

) from a transgastric position demonstrates an ill-defined hyperechoic soft tissue mass encroaching (red arrow). (C) FNA is performed of the lesion and confirms recurrence of pancreatic adenocarcinoma.

Chapter 4

Figure 4.1

Posterior view of the liver. The marks impressed on the liver surface by neighboring organs mirror its topographic relations. (Reproduced from [197] with permission from Elsevier.)

Figure 4.2

Liver with Reidel lobe, a prominent caudal extension of the right lobe.

Figure 4.3

Schematic diagram of planes of division in the liver. The liver can be visualized as being divided into two hemilivers by the midplane of the liver. The hemilivers are each subdivided into two sections by right and left intersectional planes. Three of the sections are further subdivided into two segments each by intersegmental planes, based on the divisions of the ducts and arteries. The left medial section does not have a regular duct and artery division and is therefore called one segment (IV). However, for surgical convenience, it is subdivided into the posterior and anterior portions (segments IVa and IVb, respectively, not shown). The caudate lobe is a separate segment (I) that is not part of the four main sections. (Reproduced from [18] with permission from Elsevier.)

Figure 4.4

Schematic demonstration of the vascular relations of the segments. The segments are numbered using the nomenclature of Couinaud. The remaining elements of nomenclature are those of Strasberg. The midplane extends along the Cantlie line from the vena cava to the gallbladder. The middle hepatic vein runs in this plane. The right and left intersectional planes contain the right and left hepatic veins, respectively. Each section is supplied by one of the four major arteries and bile ducts. The portal pedicles and hepatic veins interdigitate, so they do not lie in the same planes except for the umbilical portion of the left portal vein and the umbilical vein (a medial branch of the left hepatic vein), both of which are found in the umbilical fissure (also known as the left intersectional plane). The

sections

of Strasberg coincide exactly to the

segments

of Healey and Schroy. The two

sections

of the right hemiliver correspond to the two right

sectors

of Couinaud. The tertiary structures of Strasberg and of Couinaud are called

segments

; these coincide to the

areas

of Healey and Schroy, except that segment IV is divided into two

areas

by these authors. (Adapted from [197] with permission from Elsevier.)

Figure 4.5

Drawing to show three stages in the development of the hepatic vasculature. (A) In the embryo, there are three paired venous beds that drain the placenta (umbilical veins), yolk sac, and intestinal tract (omphalomesenteric or vitelline veins), and the remainder of the body (cardinal veins). These beds converge on the sinal horns before entering the heart. The left and right vitelline veins are joined by three anastomoses to form a ladder-like structure with the intestinal tract intertwined. The extrahepatic portal vein develops from these vessels after selective obliteration of portions of the ladder (B, C). (B) The left vitelline vein receives a tap from the left umbilical vein. The intrahepatic segment of this tap becomes the umbilical portion of the left portal vein. Flow in this segment reverses after birth and supplies segments of the left hemiliver. As the liver develops, the venous drainage of the parenchyma becomes focused into two vessels, the future right and left hepatic veins, and later the middle vein (not shown), which usually drains into the left hepatic vein. The ductus venosus develops as a through-channel from the left portal vein to the common hepatic vein. The remainder of the portal vein blood perfuses sinusoids before reaching the hepatic veins. (C) The vasculature has been simplified with the removal of several segments including the most caudal anastomosis between the vitelline veins, the rostral portions of the left vitelline and left umbilical veins, and the right umbilical vein. The right lobe has grown faster than the left as the left lobe has lost the supply from the left vitelline vein and left umbilical vein blood is shunted through the ductus venosus. The left umbilical vein actually lies in the midline and later shifts to the right of midline.

Figure 4.6

Measurements of the portal vein and its main branches, in centimeters. (Reproduced from Gilfillan [31] with permission from American Medical Association.)

Figure 4.7

Hepatic veins shown on a postmortem angiogram. The major rami branch dichotomously and receive smaller branches nearly at right angles (see magnified portion on right).

Figure 4.8

Diagram of the portal circulation. The most important sites for the potential development of portosystemic collaterals are shown. (A) Esophageal submucosal veins, supplied by the left gastric vein and draining into the superior vena cava via the azygous vein. (B) Paraumbilical veins, supplied by the umbilical portion of the left portal vein and draining into abdominal wall veins near the umbilicus. These veins may form a

caput medusa

at the umbilicus. (C) Rectal submucosal veins, supplied by the inferior mesenteric vein via the superior rectal vein and draining into the internal iliac veins via the middle rectal veins. (D) Splenorenal shunts, created spontaneously or surgically. (E) Short gastric veins communicate with the esophageal plexus. (Reproduced from [197] with permission from Elsevier.)

Figure 4.9

Normal portal tract from a human liver, showing several small ducts, two arteries, a portal vein, and occasional lymphocytes. Hematoxylin and eosin (H&E).

Figure 4.10

Ultrastructure of sinusoids. (A) Sinusoid showing endothelium (E) covering the subendothelial space of Disse (stars). This space contains stellate cell processes (asterisks) and hepatocellular microvilli. Note that the microvilli extend into recesses between hepatocytes. The endothelial cells are fenestrated (arrows). Transmission electron micrograph (TEM), original ×4840. (B) Closer view showing endothelial fenestrations and microvilli of a hepatocyte. TEM, original ×10 000. (C) Endothelial fenestrations are clustered into sieve plates. Scanning electron micrograph (SEM), original ×29 400. (D) Hepatocellular plates are one cell in width with bile canaliculi (short black arrow) visible on the fractured edges of the plates. Hepatocytes (H), sinusoids (S), and Kupffer cells (K) are seen. Collagen fibers have been pulled from the spaces of Disse. SEM, original ×2000. (E) The space of Disse (eight-pointed star) contains several stellate cell processes (asterisks) and collagen bundles (C). Endothelial fenestrations are labeled (arrows). H

,

hepatocyte nucleus. TEM, original ×6000. (F) Sinusoid with a Kupffer cell in the lumen and a stellate cell containing lipid (asterisk) in the space of Disse. TEM, original ×2000. (A,B, Courtesy of Dr. P. Bioulac-Sage. C, Reproduced from [94] with permission from Springer-Verlag.)

Figure 4.11

Mall's original drawing of portal and periportal tissue showing the space of Disse (perivascular lymph space, PVL), the space of Mall (perilobular lymph space, PLL), and a lymph vessel (l) after injection with gelatin. The space of Disse is continuous with the space of Mall. In life, the space of Mall may be a virtual space where lymph percolates among interstitial matrix fibers. Also shown are lobule (L), sinusoids (C), connective tissue fibers (W), bile duct (B), and artery (A). (Reproduced from [130] with permission from Johns Hopkins University Press.)

Figure 4.12

Bile canaliculi. (A) Scanning electron micrograph of a methacrylate injection cast of a rat biliary tree (×860). B, terminal twig of the bile duct; b, canal of Hering; c, bile canaliculi emptying into canals of Hering. (B) Photomicrograph of human liver stained for polyclonal carcinoembryonic antigen (CEA). CEA is present in the distribution of the bile canaliculi that could not be seen on H&E. A similar pattern may be seen with CD10 staining. (A, Reproduced from [199] with permission from Japanese Society of Histological Documentation.)

Figure 4.13

Scanning electron micrograph of cast blood vessels in the liver of a rhesus monkey. Peribiliary arterial plexus (B) receives blood from arterial branches (A) by means of afferent arterioles (a). The plexus supplies sinusoids (S) through efferent arterioles (e). Note the grooves indicating arteriolar sphincters (Sph). Arterioles (a

1

) bypass the plexus and empty directly into sinusoids. P, portal vein. Methyl methacrylate cast, original ×135. (Reproduced from [198] with permission from Japanese Society of Histological Documentation.)

Figure 4.14

Liver acinus in a human. The acinus occupies sectors of only two adjacent hexagonal fields and reaches their central veins (CV). The terminal portal branch (TPV) is injected with India ink and runs perpendicular to the two terminal hepatic venules (THV) with which it interdigitates. Thick cleared section, original ×300.

Figure 4.15

Complex acinus in a human. The sinusoids injected with India ink are supplied by three terminal portal branches and their parent preterminal vessel (pret). These portal venules help form the axial channels of a complex acinus cut longitudinally. The sleeve of parenchyma around the preterminal vessel is formed by acinuli (a

1

, a

2

). axpv

,

axial portal venule supplying the sinusoids of a

1

. The poorly injected white areas (in the upper corners) are parts of zone 3 around the terminal hepatic venules, which are not shown. 150 μm thick cleared section, original ×88.

Figure 4.16

Group of acinar agglomerates in a human liver injected with India ink. Three large portal branches grow out in different directions from a portal space (PS). One of these runs diagonally through the field and represents the axis of an acinar agglomerate. From this portal branch, preterminal (1) and terminal (2) branches grow out and form the axes of complex and simple acini, respectively. 100 μm thick cleared section, original ×18.

Figure 4.17

Interdigitation of portal and hepatic vein branches in a human liver injected with India ink. Two horizontal terminal portal branches (2, 3), forming the axes of acini, interdigitate with three vertical terminal hepatic venules (4, 5, 6), around which they arch. Thick cleared section, original ×110.

Figure 4.18

Vascular and biliary architecture of an acinar agglomerate and the relation of the acini to the adjacent hexagonal lobule. Note the arcuate courses of the terminal portal branches, the irregularly arranged simple acini, and the short portal vessels that form the axes of tiny acinuli constituting the mantle of parenchyma around the longitudinally cut portal space. Intercommunicating paths of acini and acinuli are shown by white arrows. D, channels of Deysach; LA, LA

1

, simple liver acinus; LA

2

, simple acinus penetrating a hexagonal field situated well above the level of origin of the acinus; PS I, PS II, PS III

,

portal spaces; THV, terminal hepatic venule; 1, 2, 3

,

circulatory zones of the simple liver acinus.

Figure 4.19

Blood supply of the simple liver acinus and the zonal arrangement of cells. The acinus occupies adjacent sectors of neighboring hexagonal fields. Zones 1, 2, and 3, respectively, represent areas supplied with blood of first, second, and third quality with regard to substrate, oxygen, and nutrients. These zones center around the terminal afferent vascular branches, terminal bile ductules, lymph vessels, and nerves and extend into the triangular portal field from which these branches crop out. Zones 1′, 2′, and 3′ designate corresponding areas in a portion of an adjacent acinar unit. In zones 1 and 1′, portal inlet venules empty into sinusoids. Note that zone 3 approaches the preterminal portal tract, nearly reaching the inner circle (A). PS, portal space; THV, terminal hepatic venules (central veins).

Figure 4.20

The acinar structure of the hepatic microcirculation, as conceived by Rappaport [160] and modified by Matsumoto and Kawakami [157]. In both models, the margins of the shaded zones represent planes of equal blood pressure (isobars), oxygen content, or other characteristics. The models differ in the shape of the isobars surrounding the terminal portal venules. The acinus is bulb-shaped, and the classic hexagonal lobule is comprised of several wedge-shaped portions (called primary lobules, indicated by dotted lines, upper left), which have cylindrical (sickle-shaped) isobars. The nodal region is the nodal point of Mall [23]. (Reproduced from [197] with permission from Elsevier.)

Figure 4.21

Schematic diagram of various metabolic processes that show zonal differences across the acinus. BD, bile duct; hep art, hepatic arteriole; PV, portal vein; THV, terminal hepatic venule; Z1, periportal area; Z3, periacinar and perivenular area (the latter is derived from portions of zone 3 of several adjacent acini). For description, see text; for sources of data see [161, 164]. ATP, adenosine triphospate; CoA, coenzyme A; ER, endoplasmic reticulum; NAD, NADH, nicotinamide-adenine dinucleotide (and reduced form); NADP, NADPH, nicotinamide-adenine dinucleotide phosphate (and reduced form). (Adapted from Rappaport and Wanless [161] with permission from Lippincott.)

Figure 4.22

These cartoons demonstrate how parenchymal extinction evolves into cirrhosis and how vascular disease may determine the regenerative potential of parenchyma (modified from [190, 196]). (A) Liver tissue is represented as a grid of portal tracts interspersed with hepatic veins. Obstructed vessels are black circles. Several small regions with obstructed veins have collapsed to form parenchymal extinction lesions (PELs, gray). (B–D) Evolution from Laennec stages 2–4C. Obstruction of larger hepatic veins is accompanied by more extensive destruction of tissue, causing PELs to aggregate into larger regions of collapse that remodel to form septa (gray). As tissue collapses the remains of original structures are approximated within the septa. Note that tissue in panels C–E are smaller than panels A and B. In panel D, five regions are labeled and enlarged in panels D1–D5 to explain the regenerative potential of acinar tissue having various physiological states. (D1) This region within residual parenchyma has patent portal and hepatic veins. Blood flow is expected to be normal. Regenerating buds have not appeared, as there is no stimulus for repair. (D2) Obstruction of the hepatic vein (OHV, black) impedes flow which may drain retrogradely into the portal vein if collateral drainage to other hepatic veins is not sufficient. Tissue is congested (pink). (D3) In response to tissue injury and extinction, progenitor cells located in terminal bile ducts (green) form buds (olive green) of new hepatocytes that are largely supplied by arterial blood. Successful growth of buds depends on adequate blood flow to available low-pressure channels whether portal veins or hepatic veins. (D4) When adequate drainage channels are not available, distal ducts may attempt regeneration, seen as ductular reaction (DR) but without successful bud growth. (D5) If there is ischemic duct loss (DL), ductular reaction and budding are absent. (E) Regressed cirrhosis develops when regenerated hepatocytes reexpand the original architecture. Infill of septa causes them to become thin and often disappear. Regenerated hepatocytes may be derived from residual parenchyma (tan or pink) or from buds (olive green). Note that the pink nodule labeled 2 has poor hepatic vein drainage, causing congestion and retrograde portal vein flow. The nodule in region 3 has ductular reaction and is composed of bud-derived hepatocytes. Regions 4 and 5 have failed to regenerate, leaving a region of parenchymal extinction that has not repopulated. Successfully regenerated regions usually have visible patent hepatic veins and/or portal veins. (Adapted from [190, 196].)

Chapter 5

Figure 5.1

Pathway for the degradation of heme to bilirubin. Stereo-specific opening of the heme macrocycle at the α-bridge carbon by the microsomal enzyme heme oxygenase results in the formation of equimolar amount of biliverdin and carbon monoxide. Biliverdin is subsequently reduced to bilirubin by the enzyme biliverdin reductase. MET, microsomal electron transport system. (Reproduced from [5] with permission from Elsevier.)

Figure 5.2

Relative specific activities of hemoglobin protoporphyrin, fecal urobilin (stercobilin), and hippuric acid after administration of labeled glycine. The early labeled peak of stercobilin is derived from ineffective erythropoiesis and the turnover of heme enzymes; the late peak reflects the death of senescent erythrocytes. The observed specific activity of hemoglobin protoporphyrin is less than that predicted from the continued availability of labeled glycine for hemoglobin synthesis as determined from the hippuric acid curve. This suggests some random loss of labeled erythrocytes, which may be the source of fraction II of labeled stercobilin. (Reproduced from [5] with permission from Elsevier.)

Figure 5.3

Structure and conformation of bilirubin. (A) Conventional “linear tetrapyrrole” structure of the naturally occurring isomer of bilirubin, designated bilirubin IXα. The oxygen functions on the A and D rings are depicted as the lactam tautomers, and the bridge carbons at positions 5 and 15 are shown in the

Z

configuration. In this configuration they and their attached hydrogens project toward the substituted β positions on the adjacent pyrrole rings, just as in the protoporphyrin ring from which bilirubin is derived. (B) Planar representation of the 3D conformation of the bilirubin molecule, showing hydrogen bonding (…) between each of the -COOH side-chains and the -C=O and =NH groups of the end rings (rings A and D) of the opposite half of the molecule. These hydrogen bonds hold the molecule in a rigid 3D conformation. (C) Three-dimensional representation of bilirubin-IXα. The molecule takes the form of a ridge tile (i.e., a tile that fits along the top of a roof), with the ridge line defined by the carbons at positions 8, 10, and 12. Rings A and B lie in one plane, and C and D lie in another, with the interplanar angle being approximately 98°. (Reproduced from [5] with permission from Elsevier.)

Figure 5.4

Bilirubin isomers. (A) Formation of α, β, γ, and δ isomers of biliverdin by nonenzymatic cleavage of the protoporphyrin ring of heme at the α, β, γ, and δ bridge carbons, respectively. (B) Dipyrrolic scrambling. This process involves the nonenzymatic dissociation of the bilirubin tetapyrrole into dipyrrolic units, which may then reassemble at random into symmetrical (bilirubin-IIIα and -XIIIα) and nonsymmetrical (bilirubin-IXα) tetrapyrroles. When this process occurs in a mixture of the C8 and C12 isomers of bilirubin-IXα monoglucuronide, final products will include -IIIα, -IXα, and -XIIIα isomers of both unconjugated bilirubin and its mono- and diglucuronides. (C) Nomenclature of the

Z

and

E

configurational isomers of bilirubin. If a plane is erected perpendicular to the page along the 4,5 double bond (illustrated by the dashed lines), the B ring may be together (German:

Zuzammen

[

Z

]) on the same side of the plane or on opposite sides (

Entegegen

[

E

]) of the plane from the NH group in the A ring. In the

Z

configuration, the meso hydrogen at position 5 is

trans

to the A-ring lactam hydrogen, while in the

E

configuration it is

cis

. (D)

E

,

Z

isomerization at the 4,5 double bond. In the 4

Z

,15

Z

configuration, the molecule is rigidly hydrogen bonded. In the 4

E

,15

Z

configuration, the A-ring nitrogen and oxygen groups are not spatially available to form hydrogen bonds with the C12 propionic acid side-chain. Because of free rotation about the C5–6 bond, the two 4

E

,15

Z

structures are equivalent. Analogous geometric isomerization may occur at the 15,16 double bond. (Reproduced from [49] with permission from Elsevier.)

Figure 5.5

Hepatocellular transport of bilirubin. Efficient transfer of bilirubin from blood to bile is dependent on normal sinusoidal architecture, plasma membrane transport processes and intracellular binding and conjugation. Albumin-bound unconjugated bilirubin (UCB) in sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell primarily by a facilitated process mediated by an as yet unknown bilirubin transporter (BT). Within the cell it is bound to glutathione-

S

-transferases (GST), and glucuronidated by bilirubin UDP-glucuronosyltransferase (UGT1A1) to conjugated bilirubins (CB; monoglucuronides and diglucuronides), which are actively transported across the canalicular membrane into the bile by MRP2.

Figure 5.6

Structural organization of the human

UGT1

gene complex. This large complex on chromosome 2 contains at least 13 substrate-specific first exons (A1, A2, etc.), each with its own promoter, that encode the N-terminal substrate-specific 286 amino acids of the various

UGT1

-encoded isoforms, and common exons 2–5, that encode the 245 C-terminal amino acids common to all of the isoforms. mRNAs for specific isoforms are assembled by splicing a particular first exon, such as the bilirubin-specific exon A1, to exons 2–5. The resulting message encodes a complete enzyme, in this particular case bilirubin UDP-glucuronosyltransferase (UGT1A1). Mutations in a first exon affect only a single isoform. Those in exons 2–5 affect all enzymes encoded by the UGT1 complex. (Reprinted from [87] with permission from McGraw-Hill Education.)

Figure 5.7

Relationship between plasma bilirubin turnover (BRT), hepatic bilirubin clearance (

C

BR

), and the plasma concentration of unconjugated bilirubin (

). Shaded area represents the normal range for bilirubin turnover; bar on horizontal axis is the normal range (mean ± 2 standard deviations) for hepatic bilirubin clearance. (Reproduced from [120] with permission from the American College of Physicians. ©American College of Physicians.)

Figure 5.8

Relationship between plasma bilirubin turnover and the plasma concentration of unconjugated bilirubin. Normal plasma bilirubin turnover is up to 5 mg/kg body weight per day. Higher values indicate increased bilirubin production, usually from hemolysis. When hepatic bilirubin clearance is within the normal range, the plasma unconjugated bilirubin concentration increases linearly with increases in bilirubin turnover, as indicated by the regression line (the stippled area represents ± 2 standard errors of the estimate about the regression line). Extrapolation of the regression line to the maximal rate of steady-state bilirubin production indicates the highest level of unconjugated hyperbilirubinemia that can result from sustained hemolysis in an individual with normal hepatic bilirubin clearance. Since the bone marrow can only increase erythrocyte production by about eight-fold in response to hemolysis, the maximum sustainable rate of bilirubin turnover is ∼40 mg/kg/day, and the corresponding value of plasma unconjugated bilirubin is 4 mg/dL. (Reproduced from [120] with permission from the American College of Physicians. ©American College of Physicians.)

Figure 5.9

Relationship between the mean values for hepatic bilirubin clearance (

C

BR

) and bilirubin UDP-glucuronosyltransferase (UDPGT) activity in patients with Crigler–Najjar syndrome type I, Gilbert syndrome, and normal controls. For the control group, data are presented for both untreated and phenobarbital-treated subjects. The line represents a least-squares fit to the mean values for the four groups represented. Subsequent data in Crigler–Najjar type II fell on the regression line. Data such as these suggested that Gilbert syndrome and the two Crigler–Najjar syndromes might all reflect mutations with quantitatively differing effects on a single gene, designated at the time bilirubin-UDP-glucuronosyltransferase. (Adapted from [146] with permission from Elsevier.)

Figure 5.10

Observed ranges of plasma radiobilirubin disappearance curves in patients with Gilbert syndrome and in healthy young adult volunteers. The average curve for each group was calculated by computer from the mean values, for the group, of the intercompartmental rate constants (λ) of a compartmental model of bilirubin metabolism. The groups do not overlap for the first 16 hours after injection. Estimates of bilirubin clearance (

C

BR

), calculated from the areas under the curves, were reduced to one third of normal in Gilbert syndrome patients. (Reproduced from [120] with permission from the American College of Physicians. ©American College of Physicians.)

Figure 5.11

Liver biopsy in Dubin–Johnson syndrome showing coarsely granular pigment most pronounced in the centrilobular region. Hematoxylin and eosin, original × 240. (Courtesy of the late Dr. Kamal G. Ishak, Armed Forces Institute of Pathology.)

Figure 5.12

Urinary coproporphyrin in Dubin–Johnson and Rotor syndromes. The orange bars represent the percentage of total urinary coproporphyrin excreted as coproporphyrin I. The blue bars represent total urinary coproporphyrin excretion. Vertical bars represent ± standard error of the mean. Total urinary coproporphyrin excretion is normal to slightly increased in the Dubin–Johnson syndrome (DJS) with a markedly elevated proportion of coproporphyrin I (approximately 80%). Both variables are markedly elevated in Rotor syndrome. Thus, with respect to urinary coproporphyrin excretion, the two disorders are distinct. Results in obligate heterozygotes (DJS hetero, Rotor hetero) lie intermediate between results in normal individuals and in individuals manifesting the respective disorder. (Reproduced from [241] with permission from Elsevier.)

Chapter 6

Figure 6.1

The Masson trichrome stains type I collagen blue, revealing zone 3 fibrosis in this case of alcoholic liver disease. An occluded terminal hepatic venule can be seen in the center of the field.

Figure 6.2

The Movat pentachrome stain shows a partially occluded outflow vein in this case of alcoholic cirrhosis. The elastic tissue in the wall of the vein is black, whereas mucopolysaccharides in the hypertrophied intima are pale blue, and collagen in the cirrhotic scars is yellow-green.

Figure 6.3

The reticulin stain shows the black-staining type III collagen fibers that support the liver cell plates. A terminal hepatic venule in the center of the field is surrounded by collapsed reticulin, indicating zone 3 necrosis.

Figure 6.4

The periodic acid–Schiff (PAS) stain after diastase digestion to remove glycogen demonstrates the presence of lipofuscin and other cell debris in Kupffer cells in acute hepatocellular injury.

Figure 6.5

Globules of α

1

-antitrypsin are strongly PAS-positive and diastase resistant.

Figure 6.6

The Prussian blue stain for iron demonstrates hemosiderin (blue granules) and also brings out the green color of bile and the golden-brown color of lipofuscin.

Figure 6.7

The rhodanine stain demonstrates copper as brick-red granules in liver cells in this case of Wilson disease.

Figure 6.8

The Victoria blue stain shows cells containing large amounts of hepatitis B surface antigen in a chronic carrier.

Figure 6.9

The oil red O stain of a frozen section shows microvesicular fat in acute fatty liver of pregnancy.

Figure 6.10

Immunostain with a cocktail of monoclonal antibodies that react with cytokeratin types 7, 8, 18, and 19. There is strongly positive staining of the bile duct in the center of the portal area and the ductular cells at the edge, whereas hepatocytes stain only weakly.

Figure 6.11

Immunostain with polyclonal antibodies to carcinoembryonic antigen demonstrates dark-staining bile canaliculi between hepatocytes.

Figure 6.12

Immunostain with antibody to ubiquitin demonstrates dark-staining Mallory–Denk bodies (arrows) in liver cells in alcoholic hepatitis.

Figure 6.13

Immunostains for hepatitis B antigens. (Top) Antibody to hepatitis B surface antigen (HBsAg) shows variable amounts of antigen in the cytoplasm of hepatocytes. (Bottom) Antibody to hepatitis B core antigen (HBcAg) shows antigen in the nuclei of liver cells with replicative virus.

Figure 6.14

Portal macrophages in the center of field (A) contain talc crystals, which are birefringent and easily visualized with polarizing microscopy (B).

Figure 6.15

Deposits of protoporphyrin are birefringent and appear red in polarized light. Larger deposits show a characteristic Maltese cross.

Figure 6.16

Hepatocytes undergoing apoptosis (arrows) become shrunken, angulated and darker than their neighbors, lose their nuclei and begin to fragment, forming acidophilic bodies.

Figure 6.17

High magnification of an acidophilic body that has been extruded from the liver cell plate into a sinusoid. Most of the degenerated nucleus of the dead hepatocyte remains.

Figure 6.18

Cellular degeneration and death with apoptotic bodies (arrows) and ballooning (B).

Figure 6.19

Ballooning degeneration. The hepatocytes are swollen and pale. A cluster of inflammatory cells (“focal necrosis”) in the center of the field shows the position where a hepatocyte has disappeared from the tissue (arrow).

Figure 6.20

Coagulative necrosis in a case of ischemic injury. The cytoplasm of the necrotic cells is eosinophilic and granular, and the nuclei have disappeared.

Figure 6.21

Active necroinflammatory injury with regenerating liver cells, recognizable by enlarged nuclei, prominent nucleoli, and binucleate liver cells (arrows). Clusters of hypertrophied Kupffer cells (K) are present at sites of liver cell dropout.

Figure 6.22

The PAS stain after diastase digestion demonstrates clusters of hypertrophied, lipofuscin-filled Kupffer cells (dark staining) at the sites of liver cell dropout.

Figure 6.23

Acute viral hepatitis. Note acinar disarray, apoptosis, and focal necrosis, Kupffer cell hypertrophy, and lymphocytic infiltrate.

Figure 6.24

Acute hepatitis A, showing marked portal inflammation with extension into the adjacent parenchyma (interface hepatitis), mimicking the appearance of chronic hepatitis. Inset shows plasma cells in the portal inflammation.

Figure 6.25

Infectious mononucleosis hepatitis. There is a prominent sinusoidal mononuclear cell infiltrate along with the hepatocellular injury of an acute hepatitis.

Figure 6.26

Cytomegalovirus infection in an immunodeficient host. The large cell in the center of the field has a characteristic intranuclear inclusion and many small cytoplasmic inclusions.

Figure 6.27