Practical Hepatic Pathology: A Diagnostic Approach

Cover
Serier Page
Practical Hepatic Pathology: A Diagnostic Approach
Copyright
Dedication
Contributors
Series Preface
Preface
Acknowledgments
Pattern-Based Approach to Diagnosis
Virtual Slide Box
Section I: Basic Concepts in Liver Pathology
1 - Microscopic Anatomy, Basic Terms, and Elemental Lesions
Parenchymal Architecture and Tissue Organization
Assessing Parenchymal Architecture in a Biopsy
Absence of Portal Tracts
Fragmentation
Subcapsular Parenchyma
Portal Tracts
Bile Ducts
Hepatic Arteries
Portal Veins
Hepatic Veins
Lobular Parenchyma
Hepatocytes
Intralobular Biliary Channels
Sinusoids
Disse Space
Electron Microscopy
Hepatocytes
Sinusoidal Lining Cells
Disse Space
Utility of Electron Microscopy in Routine Diagnostic Practice
Basic Terms and Elemental Lesions
Structural
Inflammation, Cell Damage, and Necrosis
Intracellular Pathology
Biliary Lesions
Sinusoidal Lesions
References
Section II: Clinical, Laboratory, and Radiologic Features of Liver Disease
2 - Clinical Features of Liver Disease
Definitions and Synonyms
Acute Liver Disease
Etiology
Clinical Manifestations
Treatment and Prognosis
Acute Liver Failure
Subacute Liver Failure
Chronic Liver Disease
Etiology
Assessing the Severity of Cirrhosis
Clinical Signs (Stigmata) of Chronic Liver Disease
Complications of Liver Cirrhosis
Variceal Bleeding
Ascites
Spontaneous Bacterial Peritonitis
Hepatorenal Syndrome
Hepatic Encephalopathy
Hepatopulmonary Syndrome
Portopulmonary Hypertension
References
3 - Laboratory Tests in Liver Disease
Liver Tests
Transaminases
“Biliary” Enzymes
Measures of Coagulation
Other Tests
Approach to Evaluation of Abnormal Liver Tests
Laboratory Investigation of Acute Liver Injury
Laboratory Investigation of Chronic Liver Disease
Laboratory Investigation of Liver Disease in Pregnancy
Laboratory Investigation of Liver Abnormalities in Systemic Diseases and Disease of Other Organs
Connective Tissue Diseases
Endocrine Disorders
Infectious Diseases
Neoplastic Diseases
Cardiac Diseases
Gastrointestinal Diseases
References
4 - Investigative Imaging of the Liver
Commonly Used Imaging Modalities
Imaging of Liver Tumors
Hemangioma
Focal Nodular Hyperplasia
Hepatocellular Adenoma
Hepatocellular Carcinoma
Metastases
Cholangiocarcinoma
Imaging of Diffuse Liver Disease
Hepatic Steatosis
Hepatic Fibrosis and Cirrhosis
Contrast-Enhanced Sonography
Transient Elastography
Magnetic Resonance Elastography
Summary
Section III: Liver Diseases of Childhood
5 - Liver Diseases of Childhood
Neonatal Cholestasis
Incidence and Demographics
Role of Liver Biopsy in Neonatal Cholestasis
Biliary Atresia
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Pathology
Macroscopic Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Neonatal (Giant Cell) Hepatitis
Clinical Manifestations
Pathology
Differential Diagnosis
Treatment and Prognosis
Alagille Syndrome
Incidence and Demographics
Molecular Genetics
Clinical Manifestations
Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Primary Sclerosing Cholangitis
Incidence and Demographics
Clinical Manifestations
Radiologic Findings
Microscopic Pathology
Diagnosis
Treatment and Prognosis
Sclerosing Cholangitis Due to Langerhans Cell Histiocytosis
Microscopic Pathology
Molecular Pathology
Treatment and Prognosis
Neonatal Sclerosing Cholangitis
References
Section IV: Metabolic Diseases of the Liver
6 - Medical Genetics and Biochemistry in Diagnosis and Management
Clinical Approach
Approach to Biochemical and Genetic Investigation
Collection, Storage, and Shipping of Specimens
Methodologies Involved in Biochemical and Genetic Testing
Tandem Mass Spectrometry
Methodologies Used for Specific Biochemical Compounds
Amino Acids
Organic Acids
Proteins
Enzymes
DNA
Very Long Chain Fatty Acids and Related Molecules
Treatment and Management
Newborn Screening–Related Disorders
Other Metabolic Liver Diseases
Mitochondrial Disorders
Genetic Counseling
References
7 - Histologic Patterns of Metabolic Liver Diseases
Handling Liver Biopsy Specimens for Suspected Metabolic Disease
Analysis and Reporting of Liver Biopsy Specimens for Suspected Metabolic Disease
Histologic Patterns of Metabolic Liver Disease
Metabolic Diseases with Normal Liver Histology
Metabolic Diseases with an Inflammatory Pattern
Metabolic Diseases with Prominent Lobular Cholestasis
Bile Ductules Versus Ducts in Metabolic Disease
Metabolic Diseases with a Steatotic Pattern
Pathology
Diagnosis
Pathology
Diagnosis
Reye Syndrome
Urea Cycle Defects
Clinical Manifestations
Pathology
Diagnosis
Citrin Deficiency
Galactosemia
Hereditary Fructose Intolerance
Lysosomal Storage Disorders
Pathology
Diagnosis
Acid Lipase Deficiency
Niemann-Pick Disease, Type C
Cystinosis
Diagnosis
Bile Acid Synthetic Defects
Peroxisomal Diseases
Clinical Manifestations
Pathology
Diagnosis
Pathology
Diagnosis
Genetic Hemolytic Disorders
Genetic Metabolic Diseases of Unknown Etiology
References
8 - Liver in Wilson Disease
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Pathology
Gross Pathology
Microscopic Features
Grading and Staging
Ancillary Diagnostic Studies
Differential Diagnosis
Other Disorders of Hepatic Copper Accumulation
Genetics
Treatment and Prognosis
References
9 - Liver Disease in Alpha-1 Antitrypsin Deficiency
Terminology
Incidence and Demographics
Clinical Manifestations and Natural History of Liver Disease
PiZZ
PiMZ
The “S” Allele
Microscopic Pathology
Intracytoplasmic Globules
Pathology of PiZZ
Pathology of PiMZ
Pathology of the “S” Variant
Ultrastructural Pathology
Differential Diagnosis
Diagnosis
Genetics and Molecular Pathology
Treatment and Prognosis
References
10 - Liver Disease in Cystic Fibrosis
Incidence and Demographics
Genetics
Pathophysiology
Clinical Manifestations of Hepatobiliary Disease
Microscopic Pathology
Steatosis
Neonatal Cholestasis
Focal Biliary Cirrhosis
Multilobular Cirrhosis
Large Bile Duct Disease
Diagnostic Studies
Therapy
References
11 - Liver Disease in Iron Overload
Iron Homeostasis
HFE
Hepcidin and Ferroportin
Hepcidin Deficiency/Hepcidin Resistance
Hepcidin Excess/Ferroportin Deficiency
Microscopic Pathology
Iron Pigment
Patterns of Iron Deposition
Parenchymal Iron Overload
Hereditary Hemochromatosis Types 1, 2A, 2B, and 3
Microscopic Pathology
Hereditary Hemochromatosis Type 4 (Ferroportin Gain-of-Function Mutations)
Hereditary Aceruloplasminemia
Dyserythropoietic Syndromes
Iron Overload Associated with Alpha-1-Antitrypsin Deficiency
Mesenchymal Iron Overload
Hereditary Hemochromatosis Type 4 (Ferroportin Loss-of-Function Mutations)
Miscellaneous Disorders
Microscopic Pathology
Mixed Parenchymal-Mesenchymal Iron Overload
Genetic Causes
African Iron Overload and Hepatic Iron Overload in African Americans
Porphyria Cutanea Tarda
Nongenetic Causes
Dysmetabolic Iron Overload Syndrome
Alcoholic Liver Disease
Nonalcoholic Fatty Liver Disease
Chronic Viral Hepatitis
Differential Diagnosis of Severe Iron Overload in Cirrhosis
Genetic/Hereditary Causes
Advanced Fibrosis/Cirrhosis
Spur Cell Anemia in Cirrhosis
Alcoholic Liver Disease
Role of Liver Biopsy
Differential Diagnosis
Iron-Free Foci
Histologic Grading of Iron Deposition
Histologic Effects of Chelation Therapy
Effect on Stainable Iron
Effect on Fibrosis
Ancillary Diagnostic Studies
Hepatic Iron Concentration
Hepatic Iron Index
References
12 - Nonalcoholic Fatty Liver Disease
Definitions and Synonyms
Incidence and Demographics
Clinical Manifestations
Radiology
Gross Pathology
Microscopic Pathology
Steatosis
Steatohepatitis
Inflammation
Other Features
Fibrosis
Variations in Children
Special Stains
Grading and Staging
Differential Diagnosis
Alcoholic Liver Disease
Nonalcoholic Fatty Liver Disease with Concurrent Liver Disease
Nonalcoholic Fatty Liver Disease Outside the Context of Metabolic Syndrome
Drug-Induced Fatty Liver Disease
Abnormalities of Lipid Metabolism
Nutritional Causes
Total Parenteral Nutrition
Starvation and Dietary Effects
Celiac Disease
Chronic Liver Diseases
Hepatitis C Virus Infection
Wilson Disease
Ancillary Diagnostic Tests
Genetics
Treatment and Prognosis
References
Section V: Infectious Diseases of the Liver
13 - Acute Viral Hepatitis
Histologic Patterns of Injury in Acute Viral Hepatitis
Acute “Lobular” Hepatitis (Prototypical Acute Hepatitis)
Gross Pathology
Microscopic Pathology
Clinicopathologic Course Related to Special Patterns of Hepatic Necrosis and Regeneration
Histologic Clues to the Causative Virus
Hepatitis A
Hepatitis E
Hepatitis B
Hepatitis C
Other Viruses Causing Acute Hepatitis
Hepatitis D (Delta) Virus
Clinical Manifestations and Natural History
Pathology
Herpesviruses
Epstein-Barr Virus
Liver Disease Caused by Epstein-Barr Virus. Primary EBV infection occurring in children is largely asymptomatic or minimally sym...
Pathology. The most remarkable histopathologic feature of EBV-related hepatitis is the presence of a dense lymphocytic inflammat...
Diagnosis. Diagnosis of infectious mononucleosis is established by the detection of heterophilic antibodies to EBV by the Monosp...
Cytomegalovirus
Liver Disease Caused by Cytomegalovirus. CMV is the most common cause of congenital infection and is reported in 0.2% to 2.2% of...
Pathology. Congenital CMV infection may lead to neonatal hepatitis, which is discussed in Chapter 5. Histologically, there is po...
Diagnosis. Diagnosis can be made by histology, viral cultures, or serologic tests that detect antibodies or viral proteins. Sero...
Human Herpesvirus 6
Herpes Zoster
Herpes Simplex Virus Types 1 and 2
Pathology. The histologic findings are distinctive, with randomly distributed, patchy areas of coagulative necrosis that demonst...
Adenovirus
Pathology
Diagnosis
Parvovirus
Icteric Hemorrhagic Fevers
Yellow Fever Virus
Liver Disease Caused by Yellow Fever Virus. After 4 to 5 days of incubation, the patient presents with fever, headache, diffuse ...
Pathology. The major histologic finding is hemorrhagic hepatocyte necrosis, which is predominantly midzonal (zone 2) but may be ...
Diagnosis. Besides epidemiologic and clinical symptoms compatible with yellow fever, serologic enzyme immunoassay must detect Ig...
Vaccination and Viscerotropic Disease. The presence of only one serotype of the yellow fever virus enabled the successful develo...
Dengue Virus
Liver Involvement in Severe Dengue Virus Infections. Severe forms of DENV infection demonstrate high level of viremia leading to...
Pathology. A wide spectrum of hepatic histologic changes has been noted in dengue. This comprises fatty change (microvesicular),...
Diagnosis
Ebola and Marburg Viruses
Arenaviruses
Hantavirus
References
14 - Hepatitis B
Incidence and Demographics
Molecular Virology
Natural History and Clinical Manifestations
Treatment
Role of Liver Biopsy in Management of Hepatitis B
Microscopic Pathology of Chronic Hepatitis B
Portal Changes and Interface Hepatitis
Lobular Inflammation, Apoptosis, and Necrosis
Ground-Glass Cells and Sanded Nuclei
Large Cell and Small Cell Changes
Fibrosis and Architectural Distortion
Immunohistochemical Stains for Viral Antigens in Chronic Hepatitis B
Differential Diagnosis of Chronic Hepatitis B
Chronic Hepatitis C
Other Chronic Hepatitides
Other Chronic Liver Diseases
Ground-Glass Cells
Practical Approach in Evaluating Liver Biopsy Specimens from Patients with Chronic Hepatitis B
References
15 - Hepatitis C
Incidence and Demographics
Molecular Virology
Natural History and Clinical Manifestations
Treatment
Role of Liver Biopsy in Management of Hepatitis C
Microscopic Pathology of Chronic Hepatitis C
Portal Changes and Interface Hepatitis
Lobular Inflammation, Apoptosis, and Necrosis
Steatosis and Other Cytoplasmic Changes of Hepatocytes
Large Cell Change and Small Cell Change
Fibrosis and Architectural Distortion
Differential Diagnosis of Chronic Hepatitis C
Chronic Hepatitides
Hereditary Metabolic Disorders
Chronic Biliary Diseases
Steatohepatitis
Malignant Lymphoma
Practical Approach in Evaluating Liver Biopsy Specimens from Patients with Chronic Hepatitis C
References
16 - Chronic Hepatitis: Grading and Staging
Need for Grading and Staging
General Principles of Grading and Staging
Grading and Staging Systems
Histologic Activity Index
Grading Systems
Scheuer System
Batts and Ludwig System
Ishak System
METAVIR Algorithm
Staging Systems
Scheuer System
Ishak System
METAVIR System
Which Is the Best Grading and Staging System
Limitations of the Liver Biopsy in Grading and Staging: Sampling Error
Limitations of Semiquantitative Scoring: Interobserver Variability
Semiquantitative Scoring versus Morphometric Analysis
Noninvasive Non–Biopsy-Based Staging Systems
References
17 - Human Immunodeficiency Virus Infection of the Liver
Pattern of Reactivity of the Reticuloendothelial System
Basic Liver Reactivity Pattern to Human Immunodeficiency Virus Infection
Visceral Leishmaniasis
Hemophagocytic Lymphohistiocytosis
Cholangiopathy Pattern
Steatosis Pattern
Chronic Hepatitis Pattern
Coinfection With Human Immunodeficiency Virus and Hepatitis C Virus
Coinfection With Human Immunodeficiency Virus and Hepatitis B Virus
Hepatitis Pattern With Multifocal Parenchymal Necrosis
Cytomegalovirus
Herpesvirus
Toxoplasmosis
Pneumocystis Infection
Granulomatous Inflammation Pattern
Mycobacterial Infections
Mycoses
Pattern of Bacterial Infections With Abscess Formation
Fibrogenic Pattern
Vascular Lesions
Peliosis
Bacillary Angiomatosis
Nodular Regenerative Hyperplasia
Mitochondriopathy Pattern
Acute Hepatitis and Cholestatic Hepatitis
Human Immunodeficiency Virus–Associated Neoplasia
Kaposi Sarcoma
Acquired Immunodeficiency Syndrome–Associated Lymphomas
References
18 - Nonviral Infections of the Liver
Bacterial Infections
Liver in Sepsis
Pathology
Pyogenic Abscess
Salmonellosis
Pathogenesis
Liver Disease in Salmonellosis
Diagnosis
Brucellosis
Liver Involvement in Brucellosis
Diagnosis
Legionellosis
Actinomycosis
Liver Involvement in Actinomycosis
Syphilis
Leptospirosis
Clinical Manifestations
Pathogenesis
Pathology
Rickettsial Infections
Rocky Mountain Spotted Fever
Liver Disease in Rocky Mountain Spotted Fever
Q Fever
Liver Involvement in Q Fever
Chlamydial Infection
Mycobacterial and Fungal Infections
Protozoal Infections
Amebiasis
Life Cycle in Relation to Liver Disease
Pathology
Diagnosis
Visceral Leishmaniasis (Kala-azar)
Life Cycle and Pathogenesis in Relation to Liver Disease
Pathology
Diagnosis
Visceral Leishmaniasis in Acquired Immunodeficiency Syndrome
Malaria
Life Cycle and Pathogenesis
Clinical Manifestations
Pathology
Diagnosis
Parasitic Infections
Ascariasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Visceral Larva Migrans/Toxocariasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Capillariasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Strongyloidiasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Schistosomiasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Pentastomiasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Fascioliasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Clonorchiasis and Opisthorchiasis
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
Hydatid Cyst
Life Cycle in Relation to Liver Disease
Clinical Manifestations
Pathology
Diagnosis
References
Section VI: Granulomatous Diseases of the Liver
19 - Hepatic Granulomas: Differential Diagnosis
Histologic Patterns of Hepatic Granulomas
Epithelioid Granulomas
Suppurative Granulomas (Granulomas with Central Microabscess)
Microgranulomas
Lipogranulomas
Foamy Macrophage Aggregates
Fibrin-Ring Granulomas
Specific Granulomatous Diseases
Tuberculosis
Pathology
Diagnosis
Other Mycobacteria
Brucellosis
Pathology
Diagnosis
Q-Fever
Pathology
Diagnosis
Systemic Mycoses
Candidiasis
Pathology
Diagnosis
Histoplasmosis
Pathology
Other Mycoses
Parasitic Infections
Other Infectious Agents
Molecular Methods in Paraffin-Embedded Tissues for Detection of Microorganisms
Sarcoidosis
Pathology
Drug-Induced Granulomas
Pathology
Diagnosis
Neoplasia-Associated Granulomas
Idiopathic Hepatic Granulomas
References
20 - Hepatic Sarcoidosis
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
References
Section VII: Autoimmune Hepatitis
21 - Autoimmune Hepatitis and Overlap Syndromes
Definitions and Synonyms
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Microscopic Pathology
Portal Changes and Interface Hepatitis
Lobular Inflammation and Damage
Cholestasis
Fibrosis
Overlap Syndromes
Overlap with Primary Biliary Cholangitis
Overlap with Primary Sclerosing Cholangitis
Grading and Staging of Autoimmune Hepatitis
Differential Diagnosis
Acute or Chronic Viral Hepatitis
Celiac Disease
Drug-Induced Liver Injury
Hereditary Metabolic Diseases
Primary Biliary Cholangitis
Genetics
Treatment and Prognosis
References
Section VIII: Drug- and Toxin-Induced Liver Injury
22 - Metabolism of Drugs and Xenobiotics
General Considerations in Drug Metabolism
Factors Affecting Bioavailability of Drugs
Enzyme Induction and Inhibition
Enzyme Polymorphisms
Disease States
Clinically Significant Drug-Metabolizing Enzymes and Transporters
Cytochrome P450 Enzymes
CYP1A2
CYP2B6
CYP2C
CYP2D6
CYP3A
Conjugating Enzymes
Drug Transporters/Phase III Enzymes
Role of Drug Metabolism in Drug-Induced Liver Injury
Alcohol Use and Risk of Drug-Induced Liver Injury
References
23 - Liver Injury Due to Drugs and Herbal Agents
Brief Historical Overview
Incidence and Demographics
Clinical Manifestations
Microscopic Pathology
Necroinflammatory Patterns (Figures 23.1 to 23.8)
Cholestatic Patterns (Figures 23.9 to 23.15)
Steatotic Patterns (Figures 23.16 to 23.19)
Vascular Injury Patterns (Figures 23.20 to 23.22)
Pigments and Other Cytoplasmic Changes
Neoplasms
Grading and Staging
Differential Diagnosis
Establishing Causality
Ancillary Diagnostic Studies
Genetics
Treatment and Prognosis
Figure Acknowledgments
References
24 - Alcohol-Induced Liver Disease
Incidence and Demographics
Clinical Manifestations
Noninvasive Assessment of Alcoholic Liver Disease
Blood Tests
Imaging Studies
Gross Pathology
Microscopic Pathology
Alcoholic Fatty Liver
Alcoholic Steatohepatitis
Cirrhosis
Histologic Variants
Portal Tract Changes
Iron Overload
Other Changes in Hepatocytes
Grading and Staging
Role of Liver Biopsy
Focal Liver Lesions in Alcoholic Liver Disease
Hepatocellular Carcinoma
Other Focal Lesions
Differential Diagnosis
Classical Histologic Features of Alcoholic Liver Disease
Other Histologic Variants of Alcoholic Liver Disease
Interactions with Other Liver Diseases
Genetics
Treatment and Prognosis
References
Section IX: Disorders of the Bile Ducts, Bile Formation, and Secretion
25 - Fibrocystic Liver Diseases
Ductal Plate
Ductal Plate Malformation
von Meyenburg Complex (Microhamartoma, Biliary Hamartoma)
Polycystic Liver
Autosomal Dominant Polycystic Kidney Disease
Autosomal Dominant Polycystic Liver Disease
Clinical Manifestations
Macroscopic Pathology
Microscopic Pathology
Treatment
Solitary (Nonparasitic) Bile Duct Cysts
Autosomal Recessive Polycystic Kidney Disease/Congenital Hepatic Fibrosis
Clinical Manifestations
Macroscopic Pathology
Microscopic Pathology
Treatment
Caroli Disease
Clinical Manifestations
Macroscopic Pathology
Microscopic Pathology
Treatment
Choledochal Cysts
Clinical Manifestations
Macroscopic Pathology
Microscopic Pathology
Treatment
References
26 - Primary Biliary Cholangitis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Liver Enzymes and Immunoglobulins
Autoantibodies
Antimitochondrial Antibodies
Antinuclear Antibodies
Other Autoantibodies
Radiologic Features
Pathology
Gross Pathology
Microscopic Pathology
Nonsuppurative Cholangitis. Nonsuppurative cholangitis is the hallmark of PBC.17,18 However, the distribution is heterogeneous e...
Ductular Reaction. Ductular reaction often accompanies the bile duct injury and results from metaplasia of periportal hepatocyte...
Bile Duct Loss and Ductopenia. Bile duct loss and ductopenia occur with disease progression, primarily involving the small intra...
Portal Inflammation
Hepatic Parenchymal Changes
Encroachment of the Limiting Plate. The inflammatory cells often spill over from the portal tract into the adjacent parenchyma (...
Cholate Stasis. This finding becomes more prominent with disease progression but may not be seen in all cases on needle biopsies...
Copper Deposition. Copper is excreted in the bile and copper accumulation occurs in the liver in chronic cholestasis of any etio...
Keratin7 Expression. Periportal hepatocytes may strongly express K7 by immunohistochemistry, reflecting acquisition of a biliary...
Cholestasis. Although biochemical cholestasis is present early in the disease, cholestasis at the morphologic level occurs years...
Fibrosis. Progressive ductular reaction and cholate stasis is accompanied by fibrosis. In early stages, periportal fibrosis may ...
Diagnosis
Staging
Differential Diagnosis
Mechanical Large Bile Duct Obstruction
Primary Sclerosing Cholangitis
Adverse Drug Reaction
Autoimmune Hepatitis
Viral Hepatitis
Granulomatous Inflammation
Treatment and Prognosis
Variants and Special Diagnostic Considerations
Antimitochondrial Antibody–Negative Primary Biliary Cholangitis
Asymptomatic Patients with Positive Antimitochondrial Antibody
Primary Biliary Cholangitis–Autoimmune Hepatitis Overlap Syndrome
Recurrent Primary Biliary Cholangitis in Allograft Liver
Nodular Regenerative Hyperplasia
References
27 - Primary Sclerosing Cholangitis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Large (Hilar/Parahilar) Bile Ducts
Small (Septal/Interlobular) Bile Ducts
Small Peripheral Portal Tracts
Parenchymal Changes
Gallbladder
Grading of Primary Sclerosing Cholangitis
Differential Diagnosis
Primary Biliary Cholangitis
Autoimmune Hepatitis
Immunoglobulin G4–Related Sclerosing Cholangitis
Hepatolithiasis and Recurrent Pyogenic Cholangitis
Secondary Sclerosing Cholangitis
Other Chronic Liver Diseases
Dominant Stricture
Genetics
Treatment and Prognosis
Secondary (Acquired) Sclerosing Cholangitis
References
28 - Loss of Intrahepatic Bile Ducts
Microscopic Pathology of Loss of Intrahepatic Bile Ducts
Pitfalls in Microscopic Diagnosis
Liver Diseases Leading to Loss of Intrahepatic Bile Ducts
Primary Biliary Cholangitis
Microscopic Pathology
Primary Sclerosing Cholangitis
Microscopic Pathology
Secondary Sclerosing Cholangitis
Sarcoidosis
Acute and Chronic Liver Allograft Rejection
Microscopic Pathology
Recurrent Primary Biliary Cholangitis and Primary Sclerosing Cholangitis in Liver Allografts
Graft-versus-Host Disease
Acute Graft-versus-Host Disease
Chronic Graft-versus-Host Disease
Microscopic Pathology
Ischemic Cholangiopathy
Microscopic Pathology
Drug-Induced Loss of Intrahepatic Bile Ducts
Microscopic Pathology
Idiopathic Adulthood Ductopenia
References
29A - Intrahepatic Cholestasis
Transporter Proteins
Basolateral (Sinusoidal) Membrane Transporters
Apical (Canalicular) Membrane Transporters
Bile Salt Export Pump (ABCB11)
Multidrug Resistance 1 (ABCB1)
Multidrug Resistance 3 Phospholipid Transporter (ABCB4)
Multidrug Resistance 2 (ABCC2)
Hepatic Basolateral ABC-Transporter Proteins
Electroneutral Anion Exchanger
Other Hepatocyte Transporters
Bile Acids
Bile Acid Functions
Bile Acid Signaling
Enterohepatic Circulation of Bile
Cholangiocyte Modification of Bile
Ileal Transport of Bile Acids
29B - Intrahepatic Cholestasis
Progressive Familial Intrahepatic Cholestasis
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations (Table 29B.2)
Laboratory Findings
Microscopic Findings
PFIC-1
PFIC-2
PFIC-3
Immunohistochemistry
Electron Microscopy
Treatment (see Table 29B.2)
Miscellaneous Causes of “Low-GGT” Intrahepatic Cholestasis
Miscellaneous Causes of “High-GGT” Intrahepatic Cholestasis
Differential Diagnosis
“Benign” Recurrent Intrahepatic Cholestasis
Etiopathogenesis
Clinical Manifestations
Microscopic Findings
Treatment
Intrahepatic Cholestasis of Pregnancy
Etiopathogenesis
Clinical Manifestations
Microscopic Findings
Treatment
Disorders of Bilirubin Metabolism
Crigler-Najjar and Gilbert Syndromes
Dubin-Johnson Syndrome
Rotor Syndrome
References
Section X: Vascular Disorders of the Liver
30 - Vascular Disorders of the Liver
Differential Diagnosis of Sinusoidal Congestion
Budd-Chiari Syndrome
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Congestive Hepatopathy
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Sinusoidal Obstruction Syndrome/Veno-occlusive Disease
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Sickle Cell Disease
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Preeclampsia
Etiopathogenesis
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Hemolysis, Elevated Liver Enzymes and Low Platelets (HELLP) Syndrome
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Portal Vein Thrombosis
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Idiopathic Noncirrhotic Portal Hypertension
Obliterative Portal Venopathy
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Nodular Regenerative Hyperplasia
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Diseases of the Hepatic Artery
Ischemic Hepatitis
Etiopathogenesis
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Microscopic Pathology
Treatment and Prognosis
Amyloidosis
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
References
Section XI: Tumors and Tumor-like Lesions of the Liver
31 - Premalignant and Early Malignant Hepatocellular Lesions in Chronic Hepatitis/Cirrhosis
Clinical Setting and Target Population: Surveillance
Nomenclature
Dysplastic Foci
Dysplastic Nodules
Small Hepatocellular Carcinoma
Dysplastic Nodules as Hepatocellular Carcinoma Precursors
Natural History of Premalignant Lesions
Dysplastic Nodules and Early Hepatocellular Carcinoma: Role of Imaging
Premalignant and Early Malignant Hepatocellular Nodules in Daily Clinical Practice
Basic Histopathologic Features (Elementary Lesions)
Parenchymal Changes
Nonparenchymal Changes
Key Diagnostic Points
Stromal Invasion
Biomarkers
Nodule in Nodule
Liver Biopsy
Diagnostic Criteria in Liver Biopsy
Nodule Management
References
32 - Benign Hepatocellular Tumors
Definitions and Synonyms
Focal Nodular Hyperplasia
Hepatocellular Adenoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Focal Nodular Hyperplasia
Ultrasonography and Contrast-Enhanced Ultrasound
Magnetic Resonance Imaging
Hepatocellular Adenoma
Ultrasonography and Contrast-Enhanced Ultrasound
Magnetic Resonance Imaging
Differential Diagnosis
Gross Pathology
Microscopic Pathology
Focal Nodular Hyperplasia
Hepatocellular Adenoma
Genotype-Phenotype Classification of Hepatocellular Adenoma
HNF1α-Inactivated Hepatocellular Adenoma
β-Catenin–Activated Hepatocellular Adenoma
Inflammatory Hepatocellular Adenoma
Hepatocellular Adenoma, Not Otherwise Specified
Immunohistochemistry
Histologic Variants
Differential Diagnosis
Genetics
HNF1α-Inactivated Hepatocellular Adenoma: HNF1A Gene
β-Catenin–Activated Hepatocellular Adenoma: CTNNB1 Gene
Inflammatory Hepatocellular Adenoma
Telomerase Reverse Transcriptase Promoter
Treatment
Focal Nodular Hyperplasia
Hepatocellular Adenoma
References
33 - Hepatocellular Carcinoma
Epidemiology and Risk Factors
Hepatotropic Viruses
Other Etiologic Factors
Clinical Manifestations
Gross Pathology
Microscopic Pathology
Tumor Cells
Growth Patterns
Immunohistochemistry
Histologic Variants
Fibrolamellar Hepatocellular Carcinoma
Clear Cell Hepatocellular Carcinoma
Steatohepatitic Hepatocellular Carcinoma
Sarcomatoid Hepatocellular Carcinoma
Sclerosing Hepatocellular Carcinoma
Grading and Other Prognostic Factors
Differential Diagnosis
Molecular Genetics
Natural History and Treatment
References
34 - Benign and Malignant Tumors of Bile Ducts
Benign Tumors or Tumor-like Lesions
Solitary Bile Duct Cyst
Clinical Manifestations
Pathology
Differential Diagnosis
Ciliated Hepatic Foregut Cyst
Clinical Manifestations
Pathology
Differential Diagnosis
Bile Duct Hamartoma
Clinical Manifestations
Radiologic Features
Pathology
Gross Pathology. On gross examination, bile duct hamartomas are small, ranging from 2 to 5 mm in diameter. They are usually mult...
Microscopic Pathology. Microscopically, bile duct hamartomas are composed of a variable number of ductal structures embedded in ...
Differential Diagnosis
Adenocarcinoma. Bile duct hamartomas need to be distinguished from malignant neoplasms in the liver such as metastatic adenocarc...
Peribiliary Gland Hamartoma. Benign lesions that can be confused with bile duct hamartomas are peribiliary gland hamartomas (see...
Prognosis
Peribiliary Gland Hamartoma (Bile Duct Adenoma)
Clinical Manifestations
Radiologic Features
Pathology
Gross Pathology. Grossly, peribiliary gland hamartoma is a round or ovoid, well-demarcated but not encapsulated lesion that is u...
Microscopic Pathology. Histologically, peribiliary gland hamartoma is composed of tubules and acini, which are lined by a single...
Differential Diagnosis
Mucinous Cystic Neoplasm
Clinical Manifestations
Radiologic Features
Pathology
Gross Pathology. Grossly, these cystic neoplasms are typically large, ranging in size from several centimeters to more than 20 c...
Microscopic Pathology. Microscopically, the locules are lined by a columnar epithelium that is almost always mucinous (Fig. 34.7...
Differential Diagnosis
Ciliated Hepatic Foregut Cysts and Solitary Bile Duct Cysts. These are usually small, asymptomatic, and incidental findings. The...
Cystic Variant of Intraductal Papillary Neoplasm. It may be challenging to distinguish mucinous cystic neoplasm from a cystic va...
Cystadenocarcinoma and Cystic Cholangiocarcinoma. It may be difficult to determine if a cystadenocarcinoma represents malignant ...
Intraductal Papillary Neoplasm of Bile Duct
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Pathology
Gross Pathology. Grossly, the bile ducts involved are variably dilated. Papillary and fragile tumors are present on the inner su...
Microscopic Pathology. IPNB shares many features with IPMN of the pancreas. Similar to IPMN, the involved ducts are dilated, con...
Differential Diagnosis
Mucinous Cystic Neoplasm. IPNB may mimic mucinous cystic neoplasm, particularly when the former becomes cystic; however, the lac...
Biliary Dysplasia (Biliary Intraepithelial Neoplasia). Caution should be practiced to discriminate IPNB from biliary dysplasia o...
Malignant Tumors
Cholangiocarcinoma
Clinical Manifestations
Radiologic Features
Pathology
Gross Pathology. CCs are generally firm, gray-white to tan tumors (Fig. 34.15). They may present as a single mass with or withou...
Microscopic Pathology. Microscopically, CC may mimic metastatic adenocarcinoma from any site; thus, thorough clinical and imagin...
Differential Diagnosis
Benign Biliary Tumors. Typical features of CC are the complex cribriform glands, nuclear pleomorphism, hyperchromasia, mitotic f...
Hepatocellular Carcinoma. Although mucin is not always present, its presence can help distinguish CC from HCC. Immunohistochemic...
Metastatic Adenocarcinoma. Although to some extent immunohistochemistry may help to distinguish CC from metastatic carcinoma fro...
Epithelioid Hemangioendothelioma. Epithelioid hemangioendothelioma can be misdiagnosed as ICC because its intracytoplasmic vascu...
Combined Hepatocellular-Cholangiocarcinoma. Combined hepatocellular-cholangiocarcinoma (HCC-CC), also known as mixed tumor or he...
References
35 - Liver Tumors of Childhood
Epithelial Tumors
Hepatoblastoma
Incidence and Demographics
Clinical Manifestations
Current Classification
Radiologic Features and Gross Pathology
Microscopic Pathology
Pathology of Treated Hepatoblastoma
Staging of Pediatric Liver Tumors
Variants of Hepatoblastoma and Tumors Probably Related to Hepatoblastoma
Genetics and Molecular Pathology
Treatment and Prognosis
Pleomorphic and Anaplastic Hepatoblastoma, Hepatoblastoma with Hepatocellular Carcinoma–Like Features, and Transitional Liver Ce...
Clinical Manifestations
Radiologic Features and Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Fibrolamellar Hepatocellular Carcinoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Microscopic Pathology
Differential Diagnosis
Genetics and Molecular Pathology
Treatment and Prognosis
Hepatocellular Carcinoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Microscopic Pathology
Differential Diagnosis
Genetics and Molecular Pathology
Treatment and Prognosis
Liver Cell Adenoma
Focal Nodular Hyperplasia
Other Rare Malignant Epithelial Tumors
Mesenchymal Tumors
Hamartoma of the Liver
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Microscopic Pathology
Differential Diagnosis
Genetics and Molecular Pathology
Treatment and Prognosis
Undifferentiated (Embryonal) Sarcoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Microscopic Pathology
Differential Diagnosis
Genetics and Molecular Pathology
Treatment and Prognosis
Hepatobiliary Rhabdomyosarcoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Histopathology
Differential Diagnosis
Treatment and Prognosis
Malignant Extrarenal Rhabdoid Tumor
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Microscopic Pathology
Differential Diagnosis
Genetics and Molecular Pathology
Treatment and Prognosis
Vascular Tumors
Infantile Hemangioma
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Histopathology
Differential Diagnosis
Treatment and Prognosis
Epithelioid Hemangioendothelioma
Pediatric Angiosarcoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features and Gross Pathology
Microscopic Pathology
Treatment and Prognosis
Tumors of the Perivascular Epithelioid Cell
References
36 - Miscellaneous Liver Tumors and Tumor-like Lesions
Cavernous Hemangioma
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Epithelioid Hemangioendothelioma
Brief Historical Overview
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Angiosarcoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Lymphangioma
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Angiomyolipoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Focal Fatty Change
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Lymphoma
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Hepatosplenic T-Cell Lymphoma
Incidence and Demographics
Clinical Manifestations
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Hairy Cell Leukemia
Systemic Mastocytosis
Langerhans Cell Histiocytosis
Inflammatory (Myofibroblastic) Pseudotumor
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Differential Diagnosis
Treatment and Prognosis
Miscellaneous Primary Benign Tumors of the Liver
Miscellaneous Primary Malignant Tumors of the Liver
Common Metastatic Tumors
References
Section XII: Concepts in Liver Pathology
37 - Clinical Aspects of Liver Transplantation
History of Liver Transplantation
Current Trends
Indications in Adults
Hepatitis C
Hepatitis B and Hepatitis A
Nonalcoholic Fatty Liver Disease
Alcoholic Liver Disease
Autoimmune Hepatitis
Cholestatic Liver Disease
Primary Biliary Cholangitis
Primary Sclerosing Cholangitis
Hepatocellular Carcinoma
Acute Liver Failure
Indications in Children
Patient Evaluation
Elderly Patients
Obese Patients
Patients with Substance Abuse
Patients with Comorbidities
Retransplantation
Pediatric Patients
Donor and Allograft Evaluation
Extended Criteria Donors
Physiologic Extended Criteria Donors
Medical History Extended Criteria Donors
Partial Liver Allografts
Liver Allograft Allocation
Organ Matching
Donor and Recipient Operation
Organ Procurement from Deceased Donors
Liver Transplant Operation
Preparation of Allograft
Recipient Hepatectomy
Implantation of Allograft
Closure of Abdomen
Anesthesia
Posttransplant Course
Surgical Complications
Primary Nonfunction
Biliary Complications
Hepatic Outflow Obstruction
Rejection
Infections
Long-Term Renal Failure
Malignancy
Complications in Pediatric Recipients
Posttransplant Immunosuppression
Immunosuppression Agents
Cyclosporine
Tacrolimus
Sirolimus/Everolimus
Mycophenolate Mofetil
Azathioprine
Prednisone
Induction Therapy
Rabbit Antithymocyte Globulin
Alemtuzumab
Daclizumab
Posttransplant Prophylaxis and Treatment of Infections
References
38 - Pathology of Liver Transplantation
Evaluation of Donor Biopsies
Preservation–Reperfusion Injury
Clinical Manifestations
Microscopic Pathology
Differential Diagnosis
Rejection
Terminology
Clinical Manifestations
Microscopic Pathology
Hyperacute Rejection. Liver biopsies are not performed in the majority of cases of hyperacute humoral rejection because of rapid...
Acute Antibody-Mediated Rejection. Histologic features associated with acute AMR consist of endothelial cell hypertrophy, promin...
Cellular Rejection. Cellular rejection occurring in the early posttransplant period (acute cellular rejection) demonstrates a cl...
Chronic Rejection. The ischemic/fibrotic process of chronic rejection affects the bile ducts and the arteries of the liver allog...
Chronic Antibody-Mediated Rejection. Although chronic AMR (cAMR) has not been fully characterized, it has been shown that LT rec...
Treatment
Central Perivenulitis
Recurrent Diseases
Recurrent Hepatitis C
Clinical Considerations
Microscopic Pathology
Differential Diagnosis
Acute Cellular Rejection. The most clinically significant differential diagnostic problem is the distinction of acute cellular r...
Other Conditions. Acute hepatitis C in the allograft has to be distinguished from drug-induced hepatitis. This distinction relie...
Recurrent Hepatitis B
Clinical Considerations
Microscopic Pathology
Differential Diagnosis
Recurrent Autoimmune Hepatitis
Clinical Considerations
Microscopic Pathology
Differential Diagnosis
Recurrent Primary Biliary Cholangitis
Clinical Considerations
Microscopic Pathology
Differential Diagnosis
Recurrent Primary Sclerosing Cholangitis
Clinical Considerations
Microscopic Pathology
Differential Diagnosis
Recurrent Nonalcoholic Steatohepatitis
Clinical Considerations
Microscopic Pathology
Recurrent Alcohol-Related Liver Disease
Clinical Considerations
Microscopic Pathology
De Novo Diseases
Plasma Cell Hepatitis (De Novo Autoimmune Hepatitis)
De Novo Viral Hepatitis
De Novo Idiopathic Chronic Hepatitis
De Novo Malignancy
Posttransplant Lymphoproliferative Disease
Surgical Complications
Biliary Strictures
Microscopic Pathology
Hepatic Artery Thrombosis and Ischemic Cholangitis
Gross and Microscopic Pathology
Infections
Human Herpesvirus 6
Cytomegalovirus
Epstein-Barr Virus
Adenovirus
Microscopic Pathology
Changes in Late Protocol Biopsies
Idiopathic Fibrosis
Nodular Regenerative Hyperplasia
References
Section XIII: Evolving Concepts in Liver Pathology
39 - Biphenotypic Primary Liver Carcinoma
Microscopic Pathology: A Group of Heterogeneous Tumors
Epidemiology and Prognosis
References
40 - Regression of Liver Fibrosis: From Myth to Reality
Mechanisms of Fibrogenesis
Morphologic Patterns of Fibrosis
Regression of Fibrosis
Regression of Cirrhosis
Histologic Assessment of Regression of Fibrosis
Conventional Scoring Systems
Image Analysis Systems
Histologic Assessment of Regression of Cirrhosis
Hepatic Repair Complex
References
41 - Cirrhosis: A Term in Need of a Makeover
What Is Wrong with the Current Concept of Cirrhosis
Cirrhosis Is Not a Homogeneous Disease
Variations in Gross Morphology
Variations in Microscopic Pathology
Clinical Staging and Prognostication of Cirrhosis
Pathologic Staging of Cirrhosis
Regression of Cirrhosis
Histologic Assessment of Regression of Cirrhosis
Is Cirrhosis a Primarily Fibrotic Process
References
Index
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D
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W
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