Molecular Pathology of Liver Diseases (eBook)

Satdarshan (Paul) Singh Monga, M.D. is Director: the Division of Experimental Pathology and Associate Professor of Pathology and Medicine, University of Pittsburgh, Pittsburgh, PA

Chapter 1: Gross and Cellular Anatomy of the Liver 26
Gross Anatomy of the Liver 26
Cellular Anatomy of the Liver 28
References 29
Chapter 2: Liver Zonation 30
Introduction 30
The Liver Lobule, the Zonated Unit of the Liver 30
Metabolic Zonal Functions 30
Possible Mechanisms for Zonation 33
The Wnt/b(Beta)-Catenin Pathway 33
b(Beta)-Catenin, A Master Signaling Molecule Orchestrating Metabolic Zonation in the Liver 33
The Consequences of Disrupting Zonation 34
Establishment of Liver Zonation by b(Beta)-Catenin and Wnts 34
b(Beta)-Catenin and Hepatocyte Proliferation 35
Integration of b(Beta)-Catenin Signaling with Other Regulators of Zonal Liver Functions 35
Hnf4 a(Alpha) Is a Liver-Enriched Factor Specializing b(Beta)-Catenin Transcriptome 36
Conclusion 36
References 37
Chapter 3: Hepatocytes 40
Introduction 40
Hepatocyte Structure 40
Polarity 40
Ultrastructive 41
Isolation and Culture of Hepatocytes 41
Hepatocyte Functional Characterization 42
Epithelial to Mesenchymal Transitions of Hepatocytes 45
Alternative Production of Hepatocytes from Stem Cells 46
Hepatocyte Cell Lines 46
Conclusions and Future Perspectives 47
References 47
Chapter 4: Biliary Epithelial Cells 50
Introduction 50
Anion Transport and pHi Maintenance 51
Mechanism Involved in Anion Transport and pHi Maintenance 52
Regulatory Factors 54
Hormones 54
Other Factors 54
BEC Primary Cilium 54
Immune System and Cell Defenses 55
Mechanism Involved in BEC Immune Regulation and Defense 55
Antigen Presenting Cell Capabilities 55
Adhesion Molecules 55
Secretion in Response to Cytokines and Chemokines 57
Stress, Apoptosis and Senescence-Related Changes 57
Responses to Oxidative Stress and Senescence-Related Changes 58
SPRR2A 58
Other Defense Systems Against Pathogens 58
Immunoglobulin 58
Toll-Like Receptors 59
Antimicrobial Molecules 59
Trefoil Factor Family 59
BEC Proliferation and Wound Healing 59
Crosstalk Between Proliferating BEC and Other Liver Cells 60
Epithelial-Mesenchymal Transition 60
Common Intracellular Signaling Pathways Mediating BEC Proliferation 61
cAMP/PKA/ERK1/2 61
PI3K/AKT 62
IP3R/Ca2+/PKC 62
Receptor Tyrosine Kinase (RTK)/Ras/MEK/ERK1/2 and STAT3 62
Factors Regulating BEC Proliferation 62
Extracellular Matrix 62
Bile Acids 63
Hormones 63
Neuropeptides 63
Cytokines and Growth Factors (Reviewed in [18, 259]) 64
Future Directions 65
References 66
Chapter 5: Stellate Cells 75
History, Location, and Morphological Characteristics of Stellate Cells 75
Origin of Stellate Cells 76
Isolation and Culture of HSCs 76
Activation and Proliferation of Stellate Cells 78
Retinoids 79
Soluble Mediators 79
Reactive Oxygen Species 80
Platelet-Derived Growth Factor and Endothelin-1 80
Transforming Growth Factor-b(beta) 81
Hepatic Fibrosis and Stellate Cells 82
Extracellular Matrix 83
Reactive Oxygen Species 83
Transforming Growth Factor-b(beta) 83
Endothelin 84
Renin-Angiotensin System 84
Other Mediators 85
Adipocytokines 85
Hepatitis Virus C 85
Regulation of Sinusoidal Blood Flow by Stellate Cells 85
Role in Hepatic Growth, Inflammation, and Immune Regulation 87
Selective Elimination of HSCs as Therapeutic Strategy 90
Inhibitors of Endogenously Produced Substances 90
Inhibitors of Signaling Pathways Associated with Activation and Fibrogenic Activity of HSCs 91
Summary and Perspective 91
References 91
Chapter 6: Kupffer Cells 102
Origin, Location, and Life Span of Kupffer Cells 102
Isolation and Culture of Kupffer Cells 102
Phagocytosis and Clearance Functions of Kupffer Cells 103
Activation of Kupffer Cells 104
Role in Liver Regeneration 107
Role in Ischemia/Reperfusion Injury 107
Role in Alcohol-Induced Liver Injury 108
Role in Non-alcoholic Fatty Liver Disease 109
Role in Regulation of Immune System 109
Summary and Perspectives 110
References 110
Chapter 7: Sinusoidal Endothelial Cells 117
The Liver Lobule, Microcirculation, and the Sinusoidal Endothelial Cell 117
Organization of Cells Relative to the Liver Sinusoidal Endothelial Cell 120
Fenestrations: Function and Regulation of the Liver Sieve 122
Other Novel Functions of LSEC 123
Repopulation and Derivation of LSEC and their Role in Diseases 123
Study In Vitro: Isolation and Culture of Liver LSEC 124
References 125
Chapter 8: Hepatic Carbohydrate Metabolism 128
Introduction 128
Hepatic Glucose Uptake, Glycogen and Lipid Synthesis 128
Regulation of Hepatic Glucose Production 129
Direct and Indirect Effects of Insulin on the Liver 129
Transcriptional Regulation of Gluconeogenic Enzymes 130
The Role of Growth Hormone and Insulin-Like Growth Factor in Carbohydrate Metabolism 131
Glucocorticoids and Hepatic Carbohydrate Metabolism 132
Glucose Homeostasis in Liver Disease 133
Insulin Resistance, the Common Link in Metabolic Syndrome, Nonalcoholic Fatty Liver Disease, and Hepatogenous Diabetes 133
Role of IRS1/2 133
Intracellular Activators of Inflammatory Pathways 133
Inflammatory Pathways Involved in Insulin Resistance 133
Adipokines 134
Adiponectin 134
Leptin 135
Resistin 135
Tumor Necrosis Factor-a 136
IL-6 136
Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis 136
Hepatitis C and Diabetes 137
Hepatogenous Diabetes 137
Summary 138
References 138
Chapter 9: Hepatic Protein Metabolism 143
Introduction 143
Protein Ingestion and Metabolism to Urea 143
Urinary Excretion of Urea Accounts for 70–80% of its Production 143
Intestinal Microbial Urea Recycling in Ruminants 144
Ammonia Excretion 144
Digestibility of Dietary Proteins 144
Intestinal Ammonia Production from Glutamine 144
Role of Intestine in Ammonia Production 145
Hepatic Ammonia Detoxification 145
Sources of Hepatic Urea Synthesis 145
Zonation of Ammonia-Metabolizing Enzymes and Transporters 146
Amino-Acid Transport into the Liver 146
Ammonia Transport into the Liver 147
pH and Ammonia Detoxification 147
Ammonia Detoxification in the Compromised Liver 147
Conclusions 148
References 148
Chapter 10: Hepatic Lipid Metabolism 151
Introduction 151
Sources and Synthesis of Fatty Acids 151
Hepatic Uptake of Plasma NEFAs Released by Adipose Tissue and Hydrolysis of Circulating Triglyceride-Rich Lipoproteins 151
Chylomicron Remnants 152
Hepatic Cytoplasmic Lipid Droplet Stores 153
De Novo Lipogenesis 154
Very Low Density Lipoprotein Assembly and Secretion 154
Fatty Acid Oxidation 155
Mitochondrial b-Oxidation 155
Peroxisomal b-Oxidation 156
Microsomal w-Oxidation 157
Fatty Acid a-Oxidation 157
Ketogenesis 158
Regulation of Hepatic Lipid Metabolism: Clues from Knockout Mouse Models 158
Regulation of Hepatic Lipogenesis 158
Regulation of Fatty Acid Oxidation 159
MicroRNAs in the Regulation of Lipid Metabolism 160
Summary 161
References 161
Chapter 11: Detoxification Functions of the Liver 165
Introduction 165
Major DMEs in the Liver 166
Cytochrome P450 166
CYP450 Isoforms 167
CYP1A2 167
CYP2B Family 168
CYP2C Family 168
CYP2D6 168
CYP2E1 168
CYP3A4 Family 168
CYP4A11 168
Regulation of DME Expression 169
Zone Specific Expression of CYP450 169
Flavin Monooxygenase 169
DMES Involved in Conjugation Reactions 169
Glucuronidation 170
Sulfation 171
Glutathione Conjugation 171
Acetylation 171
Methylation 172
Amino Acid Conjugation 172
Role of Transporters as a Detoxification System in the Liver 172
Basolateral (Sinusoidal) Excretion 173
ABCC3 (MRP3) 173
ABCC4 (MRP4) 173
ABCC5 (MRP5) and ABCC6 (MRP6) 174
Canalicular (Biliary) Excretion 174
ABCB1 (MDR1 or P-Glycoprotein or Pgp) 174
ABCB4/MDR3 174
ABCB11 (BSEP) 174
ABCC2 (MRP2) 175
ABCG2/BCRP 175
ABCG5 and ABCG8 176
Drug Uptake Transporters in Detoxification 176
SLC10A1 Na+/Taurocholate Co-Transporting Polypeptide
Organic Anion Transporting Polypeptides (SLC21/SLCO/OATP) 176
Conclusion 177
References 177
Chapter 12: Bile Acid Metabolism 182
Introduction 182
Bile Acid Metabolism 182
Bile Acid Structures 182
Bile Acid Synthesis in the Liver 183
Bile Acid Biotransformation 184
Enterohepatic Circulation of Bile Acids 185
Regulation of Bile Acid Metabolism 185
Regulation by Bile Acid Receptors 186
Regulation by Cell Signaling Pathways 187
PKC 188
Proinflammatory Cytokines 188
Growth Factor and Insulin Signaling 188
Role of Bile Acids in Metabolic Regulation 188
Bile Acids Regulate Lipid Metabolism 188
Bile Acids Regulate Glucose Metabolism 189
Bile Acids Regulate Energy Metabolism 189
Molecular Pathology of the Enterohepatic System 190
Metabolic Defects in Bile Acid Metabolism 190
Defects in Bile Acid Synthesis 190
Defects in Bile Acid Conjugation 191
Cholestatic Liver Diseases 191
Hereditary Cholestatic Diseases 191
Acquired Cholestasis 191
Obstructive Cholestasis 191
Bile Acids as Therapeutic Agents 192
Bile Acid Displacement and Replacement 192
FXR Agonists for Cholestasis, Gallstone, Fatty Liver and Cardiovascular Disease 192
References 192
Chapter 13: Liver Development 198
Introduction 198
Inducing the Hepatic Domain in Foregut Endoderm 198
Fate Mapping of Liver Precursors: Where to Hepatoblasts Come from? 198
From Endoderm to Hepatoblasts: Inductive Signals 199
From Endoderm to Hepatoblasts: Intrinsic Factors 199
Defining the Liver Field: Lineage Segregation Within the Foregut Endoderm 201
Constructing the Liver Bud 202
A Transcription Factor Network Controls the Formation of the Hepatic Primordium 202
Expanding the Liver Primodium 203
Summary 204
References 204
chapter 14: Transcriptional Control of Hepatocyte Differentiation 207
Introduction 207
Evolution of Studies on Transcriptional Regulation In Liver 207
The Transcriptional Environment in the Adult Liver 208
Liver Enriched Factors 208
Phase 1: Prehepatic Expression and Developmental Competence 208
Phase 2: Establishment of Definitive Hepatic Structures 215
Phase 3: Establishment of a Constitutive Phenotype 216
Phase 4: Dynamic Gene Regulation in the Mature Liver 217
Repression and the Oncofetal Paradigm 220
Closing 221
References 222
Chapter 15: Bile Duct Development and Biliary Differentiation 226
Introduction 226
Development of the Intrahepatic Bile Ducts 226
Markers of Cholangiocyte Differentiation 226
Biliary Cells Differentiate Near the Portal Vein 227
Transcriptional Network Initiating Intrahepatic Biliary Differentiation 228
Intrahepatic Bile Duct Morphogenesis: A Multistep Process 229
Cell-Cell Signaling and Intrahepatic Bile Duct Development 231
Gene Regulation and Intrahepatic Bile Duct Development 231
Development of the Extrahepatic Biliary Tract 232
Lessons from Developmental Diseases of the Biliary Tract 233
Bile Duct Paucity 233
Ciliopathies 233
Ductal Plate Malformations 234
Diseases of the Extrahepatic biliary Tract 234
Conclusions 234
References 234
Chapter 16: Hepatic Progenitors in Development and Transplantation 238
High Regenerative Potential of the Liver 238
Role of YAP in Molecular Regulation of Liver Mass 238
Hepatocyte Transplantation into the Regenerating Liver 239
Special Animal Models to Repopulate the Liver by Transplanted Hepatocytes 239
Progenitor (“Oval”) Cells for Liver Repopulation 241
Transplantation of “Oval Cells” 242
Properties of Stem and Progenitor Cells Relevant to Liver Reconstitution/Repopulation 243
Hepatic Stem Cells in the Developing Liver 244
Liver Repopulation Using Fetal Liver Stem/Progenitor Cells 244
Liver Repopulation by Extrahepatic and Embryonic Stem Cells 245
Induced Pluripotent Stem Cells 246
Human “Oval Cells” and Stem Cells 246
Xenorepopulation Models 247
Future Horizons 247
References 250
Chapter 17: Adult Liver Stem Cells 255
Introduction 255
History of Liver Stem-Like Progenitor Cell Biology 255
Essential Properties of Stem-Like Progenitor Cells 256
Stem-Like Progenitor Cells of the Adult Liver 256
Unipotential Liver Stem-Like Progenitor Cells: Differentiated Hepatocytes and Biliary Epithelial Cells 258
Unipotential Liver Stem-Like Progenitor Cells: Small Hepatocyte Progenitor Cells 258
Multipotential Liver Stem-Like Progenitor Cells: Oval Cells 260
Liver Stem-Like Progenitor Cells from Extrahepatic Tissues 261
Liver from Progenitor Cells of the Bone Marrow 261
Liver from Stem-Like Progenitor Cells of the Pancreas 262
Liver from Neural Stem Cell Cultures 262
Human Liver Stem-Like Progenitor Cells 263
Evidence for Liver Stem-Like Progenitor Cells in Humans 263
Liver from Bone Marrow Stem-Like Progenitor Cells in Humans 263
Isolation and Culture of Adult Liver Stem-Like Progenitor Cells 263
Early Studies of Propagable Liver Epithelial Cells 264
Rat Liver Epithelial Stem-Like Progenitor Cells: Oval Cell Lines 264
Rat Liver Epithelial Stem-Like Progenitor Cells: The WB-F344 Cell Line 264
Stem-Like Progenitor Cells from the Human Liver 264
Evidence for the Multipotential Differentiation of Adult Liver Stem-Like Progenitor Cells In Vivo 265
Hepatocytic Differentiation by Transplanted WB-F344 Rat Liver Stem Cells 265
Multipotential Differentiation of Adult Liver Stem Cells in Culture 266
Hepatocytic Differentiation of Oval Cells In Vitro 266
Hepatocytic Differentiation by RLE-13 Rat Liver Epithelial Cells in Culture 267
Hepatocytic Differentiation of WB-F344 Rat Liver Stem-Like Progenitor Cells in Culture 267
Stem-Like Progenitor Cell Responses in Liver Injury and Repair 267
References 267
Chapter 18: Liver Regeneration 273
General Considerations 273
How Much Liver Does the Body Need? Is There a “Hepatostat”? 274
Liver Regeneration After PHx 275
Histologic Changes and Cellular Proliferation Kinetics 275
Extracellular Matrix 276
Signals Associated with Hepatocyte Mitogenesis 276
Mitogenic Growth Factors 276
HGF and Its Receptor (cMET) 277
EGF, TGFa(alpha) and the EGFR Ligand Family of Proteins 277
Intracellular Signaling Events 278
Auxiliary Mitogens 278
TNF a(alpha) 278
Interleukin 6 279
Bile Acids 279
Norepinephrine 279
Insulin 280
Termination of Liver Regeneration 280
Transforming Growth Factor Beta 1 (TGFb(beta)1) 280
Extracellular Matrix 281
Glypican 3 282
Yes-Associated Protein 282
Exchange of Growth Regulatory Signals Between Hepatic Cell Types During Liver Regeneration 282
Clinical Implications of Liver Regeneration 283
Generation of Growth Enhancing or Inhibitory Signals as Part of the Inflammatory Process 283
Effects of Viruses and Toxins on the Capacity of Hepatocytes to Replicate 284
Cirrhosis as a Chronic Regeneration Process 284
Overall Conclusions 285
References 285
Chapter 19: Senescent Liver 291
Introduction 291
Liver Functions and Age 291
Morphological Changes in Senescent Liver 292
HCV Infections and Nonalcoholic Fatty Liver Diseases Are the Major Risk Factors for Hepatocellular Carcinoma in Elderly 293
Aging Reduces Regenerative Capacity of the Liver 293
Telomere Shortening in Senescent Liver and Its Possible Contribution to the Inhibition of Liver Proliferation in Elderly 294
Epigenetic Silencing of Liver Regeneration in Old Mice 295
Signal Transduction Pathways Which Change Epigenetic Control in Livers of Old Mice 295
Additional Alterations that Might Contribute to the Decline of Proliferation in Senescent Liver 297
Liver Surgery and Liver Transplantation in Elderly 298
Development of Approaches to Improve Liver Regeneration and Graft Survival in Older Patients 298
Concluding Remarks 299
References 299
Chapter 20: Signaling Pathways in the Liver 303
Introduction 303
b(Beta)-Catenin Signaling 303
ERBB/EGFR Family 304
Hepatocyte Growth Factor (HGF) Signaling 305
Hedgehog Signaling 306
JAK/STAT Pathway 307
MAP Kinase Pathway 308
Notch Signaling 309
PDGF/PDGFR Signaling 309
Peroxisome-Proliferator-Activated Receptors (PPARs) 310
PI3-Kinase/AKT Pathway 310
TGFb Signaling 311
TNFa/NFkB Signaling 312
Conclusion 313
References 313
Chapter 21: Hepatocyte Transplantation 320
Introduction 320
Indications for Human Hepatocyte Transplantation 320
Hepatocyte Preparation: Source, Isolation, and Quality 322
Cell Sources for Human Hepatocyte Transplantation 322
Hepatocyte Isolation and Storage 323
Assessment of Hepatocyte Quality for Transplantation 324
Hepatocyte Transplantation: Location and Engraftment 324
Posttransplantation Hepatocyte Engraftment and Immune Response 326
Overview of Current Clinical Experience 327
Conclusions 327
References 328
Chapter 22: Hepatic Tissue Engineering 331
Introduction 331
Current Treatments for Liver Failure 331
Cell-Based Therapies 331
Cell Sourcing 332
Mature Hepatocytes 333
Stem Cells and Progenitor Populations 334
Reprogrammed Adult Cells 335
In Vitro Platforms and Applications 335
2-D Culture Platforms 336
3-D Spheroid Culture 336
Bioreactor Cultures 337
Microtechnology Tools 337
Application of In Vitro Liver Models: Studying Liver Pathophysiology 338
Implantable Engineered Tissue Constructs 339
Scaffold Properties 339
Material and Chemical Modifications 339
Porosity 340
3-D Architecture 341
Cell-Sourcing for Implantable Liver Tissues 342
Mature Hepatocytes Versus Hepatic Progenitor Cells 342
Cell–Cell Interactions 342
Clinical Translation for Human Therapy 343
Assessment in Animal Models 343
Integration with Host Tissue Vasculature and Biliary System 343
Immune Response 344
Conclusion 344
References 344
Chapter 23: Hepatic Gene Therapy 353
Introduction 353
Liver in Gene Therapy 353
Liver: A Major Target Organ in Gene Therapy 353
Understanding Biological Functions of the Liver: Rare Monogenic Diseases as Targets for Hepatic Gene Therapy 354
Understanding Molecular Pathogenesis of Diseases: More Common Diseases as Targets for Hepatic Gene Therapy 354
Understanding Liver Immunology: A Key to Successful Hepatic Gene Therapy 354
Vectors and Methods for Hepatic Gene Transfer and Their Mechanism of Action 357
Barriers in Hepatic Gene Therapy 357
Adenoviral Vectors 358
Adeno-associated Virus Vectors 359
Retroviral Vectors 360
Lentiviral Vectors 361
Non-viral Vectors 362
Hydrodynamics-Based In Vivo Transfection Method 364
Transposon and Phage Integrase-Based Approaches: Sleeping Beauty Transposon and Phic31 Integrase Systems 365
Gene Repair and Gene-Targeting-Based Approaches 366
RNA Interference-Based Approach 367
Preclinical and Clincal Applications of Hepatic Gene Therapy 367
Hemophilia 367
Inborn Errors of Metabolism 368
Liver Fibrosis 369
Ischemia-Reperfusion Injury 370
Diabetes 370
Viral Hepatits 371
Liver Cancers 372
Conclusions 373
References 373
Chapter 24: Liver Cell Death 382
Introduction 382
Overview of Apoptosis 382
The Extracellular Pathway 384
The BCL-2 Family of Apoptosis Regulators 384
The Mitochondrial/Intracellular Pathway 386
Lysosomes 386
Endoplasmic Reticulum 386
Overview of Necrosis 388
The Mitochondria in Necrosis 388
Molecular Mediators of Apoptosis 389
Fas 389
TRAIL 390
TNF-Alpha 390
JNK 391
Conclusion 392
References 392
Chapter 25: Macroautophagy 397
Introduction 397
Basic Biology of Autophagy 397
Morphological Studies of Macroautophagy 397
Molecular Machinery of Macroautophagy 398
The Physiological Role of Autophagy in Hepatocytes 400
Autophagy in Protein Metabolism 400
Glycogen Autophagy and Glucose Homeostasis 400
Autophagy in Lipid Metabolism 400
The Pathobiological Role of Autophagy in Liver Diseases 401
Autophagy in Alpha-1-Antitrypsin Deficiency 401
Autophagy in Hypofibrinogenemia 401
Autophagy in Alcoholic Liver Disease 402
Autophagy in Hepatic Carcinogenesis and Liver Cancer 402
Conclusion 403
References 403
Chapter 26: Hepatic Ischemia/Reperfusion Injury 405
Introduction 405
Warm Ischemia/Reperfusion Injury 405
Oxidant Stress 405
Transcription Factors 406
NF-kB 406
AP-1 408
JAK-STAT Pathway 408
Peroxisome Proliferator-Activated Receptors 409
Proinflammatory and Anti-inflammatory Mediators 409
Proinflammatory 410
IL-12 410
TNFa 410
IL-1 410
Chemokines 410
Platelet Activating Factor 410
TLR4 Ligands 411
Anti-inflammatory 411
IL-6 411
SLPI 411
Heme Oxygenase 411
Nitric Oxide 412
Lymphocytes 412
Neutrophil-Mediated Liver Injury 412
Recovery from Warm Ischemia/Reperfusion 413
Time Course and Cell Cycle Control 413
Chemokine Participation 413
Cold Ischemia–Reperfusion Injury 414
Sinusoidal Endothelial Cell (Sec) Apoptosis 414
Increased Platelet Adhesion 414
Recovery and Regeneration 414
Decreased Liver Regeneration 414
References 415
Chapter 27: Inflammation and Liver Injury 419
Introduction 419
Cells in the Liver and Inflammatory Response 419
Immune Cells in the Liver 419
Monocytes/Macrophages 419
Dendritic Cells 420
Neutrophils 421
NK and NKT Cells 421
Regulatory T Cells 421
Th17 Cells 421
Bone Marrow-Derived Stem Cells 422
Signaling Pathways and Liver Inflammation 422
Sensing Danger Signals 422
Toll-Like Receptors (TLRs) 424
Helicase Receptors 424
NLRs and the Inflammasome 425
Intracellular Signaling Molecules 425
Apoptotic Pathways 425
Nuclear Receptors 426
B7 Family Members of Cell Surface Molecules 426
Liver Injury and Mediators of Inflammation 426
Oxidative Stress 426
Chemokines 427
Inflammatory and Immunoregulatory Cytokines 427
Adipokines 428
The Impact of Chronic Inflammation on the Liver 428
Inflammation and Fibrosis 428
Inflammation and Liver Cancer 428
Future Directions 428
References 429
Chapter 28: Oxidative Stress and Liver Injury 434
Introduction 434
Oxidative Stress and Signaling Pathways 434
Mitogen-Activated Protein Kinases 434
The RAS-RAF-MEK-ERK Pathway 435
The SAPK/JNK Pathway 436
The p38 Pathway 436
The BMK1 Signaling Pathway 437
Crosstalk Between the MAPK Signaling Pathways in Oxidative Stress 437
Nuclear Factor kB 437
Oxidative Stress and Liver Injury 438
Oxidative Stress and Acute Liver Injury: Acetominophen-Induced Oxidative Stress 438
Oxidative Stress and Chronic Liver Injury 438
Nonalcoholic Fatty Liver Disease 438
Alcoholic Liver Disease 439
Future Perspectives 439
References 440
Chapter 29: Fatty Liver 443
Introduction 443
What is Fatty Liver Disease? 443
What are the Causes of Fatty Liver Disease? 443
Histological Features of Fatty Liver Disease 444
Overview of the Molecular Pathogenesis of Fatty Liver Disease 444
Physiologic Effects of Insulin Relevant to Liver Metabolism 446
Role of Insulin Resistance in the Development of Fatty Liver 446
Cross Talk Between the Liver and other Organs in Fatty Liver Disease 446
Role of Signaling Pathways of Inflammation, Proinflammatory Cytokines and Adipokines 447
Overview of Lipid Handling in the Liver 447
Fatty Acid Uptake by the Liver 447
De Novo Lipogenesis 447
Oxidation of Fatty Acids 447
Export of Lipids from the Liver 448
Liver Transcription Factors and Nuclear Receptors 448
PPAR Family 448
ChREBP and SREBP 448
LXR 449
PXR, CAR, and FXR 449
Oxidative Stress and Lipid Peroxidation 449
Dysfunction of Intracellular Organelle in Fatty Liver Disease 449
Recent Advances 450
MicroRNA and Fatty Liver Disease 450
Endocannabinoids 450
Autophagy 450
References 450
Chapter 30: Hepatic Fibrosis and Cirrhosis 454
Introduction 454
Epidemiology and Etiology 454
Fibrosis Scoring Systems 455
Matrix Proteins of the Normal and Fibrotic Liver 456
Collagens in the Liver 457
Other Matrix Proteins Important in Fibrosis 459
The Cellular Source of Matrix Proteins: Myofibroblasts 460
The Cellular Source of Matrix Proteins: Nonmyofibroblastic Contributors 460
Stem Cells and Progenitor Cells in Fibrosis 461
Mediators of Fibrosis Progression 461
Progression from Fibrosis to Cirrhosis 463
Matrix Degradation 463
Regression 464
Clinical Features of Fibrosis and Cirrhosis 464
Fibrosis and Cirrhosis in the Future 465
References 465
Chapter 31: Biliary Cirrhosis 472
Introduction 472
Historical Perspectives 472
Evidence That BDE Mediate Biliary Cirrhosis 473
Evidence That Portal Fibroblasts/Myofibroblasts Mediate Biliary Cirrhosis 473
Secretion of Cytokines and Regulation of Portal Fibroblasts by Bile Duct Epithelia 473
Portal Fibroblasts as Regulators of Purinergic Signaling in Bile Duct Epithelia 474
Secretion of Cytokines and Regulation of Portal Fibroblasts by Bile Duct Epithelia 475
Lingering Questions and Future Directions 475
References 476
Chapter 32: Cholestasis 479
Introduction 479
Molecular Principles of Bile Formation as Basis for Understanding Cholestasis 479
Genetic Causes of Cholestasis 481
Acquired Changes in Hepatobiliary Transport and Metabolism in Cholestasis 483
Cytoskeletal and Other Hepatocellular Changes in Cholestasis 485
Summary and Conclusions 486
References 487
Chapter 33: Portal Hypertension 488
Introduction 488
Normal Physiology of Portal Circulation 488
Anatomy 488
Sinusoidal Microenvironment 488
Causes of Portal Hypertension 489
Common Causes 489
Cirrhosis 489
Extrahepatic Portal Vein Thrombosis 489
Schistosomiasis 489
Idiopathic Portal Hypertension 489
Less Common Causes 490
Nodular Regenerative Hyperplasia 490
Partial Nodular Transformation of the Liver 490
Sarcoidosis 490
Splanchnic Arteriovenous Fistula 490
Mechanical Factors in Pathophysiology of Portal Hypertension 490
Vascular Basis of Portal Hypertension 491
Intrahepatic Vasoconstriction/Impaired Responsiveness to Vasodilation 491
Increased Vascular Tone of Sinusoids 491
Endothelial Dysfunction 491
Oxidative Stress 491
Inflammation 492
Hepatic Stellate Cell 492
Decreased Production of Nitric Oxide 493
Background 493
Mechanism of Action 493
Inadequate Nitric Oxide 493
HSC Resistance to NO-Mediated Relaxation 493
Potential NO Therapy 493
Increased Vasoconstrictor Activity 494
Increased Endothelin Activity 494
Splanchic Vasodilation 494
Role of NO 494
NO-Independent Mechanisms of Splanchnic Arteriolar Relaxation 495
Collateral Vessel Flow 495
Conclusions 496
References 496
Chapter 34: Nonalcoholic Fatty Liver Disease 501
Introduction 501
Overview of Nonalcoholic Fatty Liver Disease 501
Development of Hepatic Steatosis 501
Abnormal Lipid Metabolism 501
Increased DNL in the Liver 501
Increased Lipolysis of Adipose Tissue 502
Impaired Fatty-Acid Metabolism 502
Altered Insulin Signaling 503
Endocannabinoids Signaling 504
MicroRNA Signaling and Its Emerging Role in Lipid Metabolism 504
Mechanism of Cell Injury 505
FFA-Induced Cellular Lipotoxicity: A Manifestation of Oxidative Stress and Mitochondrial Dysfunction 505
Endoplasmic Reticulum Stress and the Unfolded Protein Response 506
Mechanism of Cell Injury: Interactions Between Macrophages and Adipocytes 507
Innate Immunity, Role of Cytokines and Adipokines 507
Molecular Basis of Fibrosis 508
Hepatic Stellate Cell Activation 508
Genetic Polymorphisms 509
Summary 509
References 509
Chapter 35: Alcoholic Liver Disease 512
Introduction 512
Primer on the Histopathology of Alcoholic Liver Disease 512
Molecular Pathology of ALD 512
Microarrays and Global Changes in Gene Expression 513
Microarray Analysis in Animal Studies 513
Microarrays of Tissue Cultures Treated with Ethanol 517
Microarray Studies on Human ALD 517
Single Signaling Pathways 518
Mechanisms Involved in Ethanol-Induced Fatty Liver 519
Role of the Proteasome in ALD 520
Mallory-Denk body Pathogenesis 521
Microarray Analysis of Liver Forming MDBs 522
Ethanol-Induced Fibrosis of the Liver 522
Innate Immunity and Fibrosis 523
Epigenetic Changes in the Stellate Cells 523
Genetic Polymorphism Predisposition to ALD 523
References 524
Chapter 36: Viral Hepatitis A 528
Introduction 528
History 528
Virology 528
Classification 528
Structure 528
Physiochemical Characteristics 528
Morphology 529
Genome Organization 529
Genome and Proteins 529
In Vitro Culture, Virus–Cell Interactions, and Replication Cycle 531
Genomic Variability of HAV 533
Recombination in HAV 533
Quasispecies Nature and Evolution of HAV 533
Antigenicity and Serotype 534
Host Range 534
Epidemiology 534
Modes of Transmission 534
Person to Person 535
Foodborne and Waterborne 535
Blood-Borne 535
Vertical 535
Specific Groups and Settings 535
Child Care Centers, Schools, and Institutions 535
Users of Illicit Drugs 536
Homosexuality 536
Transfusions and Other Health Care Settings 536
International Travel 536
Foodborne and Waterborne 536
Incidence and Prevalence and Worldwide Disease Patterns 536
Pathogenesis 538
Incubation Period 538
Viral Replication 538
Pathogenesis and Natural History of HAV Infection 539
Immune Response 540
Pathology 541
Clinical Features 541
Symptoms 541
Complications 542
Prolonged Cholestatic Hepatitis 542
Relapsing Hepatitis A 542
Coinfection of HAV with Other Hepatotropic Viruses 542
Acute HEV Superinfection in Patients with Cirrhosis 543
Fulminant Hepatic Failure 543
Other Complications 543
Diagnosis and Detection of HAV 543
Approaches to HAV Detection 543
Detection of HAV-Specific Antibodies 543
Virus or Viral Component Detection 544
Laboratory Diagnosis 544
Detection from Water and Food 545
Therapy and General Management 545
Prevention 546
General Measures 546
Passive Immunoprophylaxis 546
Active Immunoprophylaxis 547
Summary, Conclusions, and Directions for the Future 548
References 548
Chapter 37: Viral Hepatitis B 554
Introduction 554
Natural History and Pathogenesis 555
HBV Vaccine 555
Hepatocellular Carcinoma 556
HBX and the Pathogenesis of HCC 556
Immune Mediated Pathogenesis of HCC 557
HBV DNA Integration and HCC 559
HBX and Epigenetic Mechanisms of HCC 560
HBx Overcomes Apoptosis in Chronic Infection 561
HBX and Innate Immunity 563
HBX and Senescence 563
Conclusions and Prospects 564
References 565
Chapter 38: Viral Hepatitis C 569
Introduction 569
Natural History of Chronic Hepatitis C 569
Immunopathogenesis of Hepatitis C 570
Immune Contribution to Liver Injury 570
Role of Adaptive Immune Responses 570
CD8+ Cytotoxic T Cells 570
T Helper and Treg Cells 571
Dendritic Cells 572
Innate Immunity 572
NK, NT and NKT Cells 572
Cytokines and Chemokines 573
Metabolic Consequences of HCV Infection 574
Steatosis and Insulin Resistance 574
Mechanisms of HCV-Induced Steatosis 574
Defects in Lipoprotein Assembly and Export 575
Alterations in Lipid Synthesis 575
Effects on Fatty Acid Uptake and Oxidation 575
Mechanisms of HCV-Induced Insulin Resistance 576
Mechanisms of HCV-Induced Oxidative Stress 576
Fibrogenesis 577
Effects of HCV on Cell Cycle Regulation and Growth Control 577
HCV-Induced Alteration of the Cell Cycle Control 578
HCV Effects on p53 578
HCV Effects on Rb 578
HCV and Cdks 578
HCV Alterations of Proliferation Signaling Pathways 579
PI3K/Akt 579
MAP Kinases 579
Wnt/b-Catenin Pathway 580
TGF-b and Epithelial to Mesenchymal Transition 580
HCV and DNA Repair 580
Conclusions and Perspectives 580
References 581
Chapter 39: Viral Hepatitis D 589
Introduction 589
Pathology in Patients 591
Pathology in Experimental Animals 591
Pathogenesis in Cultured Cells 592
Analogy to Plant Viroids 593
Prevention 593
Treatment 593
Summary and Outlook 593
References 594
Chapter 40: Viral Hepatitis E 596
Introduction 596
History 596
Virology 596
Classification 596
Structure 596
Physiochemical Characteristics 596
Morphology 596
Genome Organization 597
Genome and Proteins 597
Replication Cycle 599
Genomic Variability of HEV 600
Distribution of HEV Genotypes 600
Quasispecies Nature and Evolution of HEV 601
Serotypes and Antigenicity 602
Animal Models and In Vitro Culture 602
Epidemiology 602
Incidence and Prevalence and Worldwide Disease Patterns 602
HEV in Endemic Regions 602
HEV in Nonendemic Regions 603
Modes of Transmission 604
Specific Groups and Settings 605
Persons Having Contact with Swine and Untreated Waste Water 605
HIV-Infected Persons 605
Transfusions and Other Health Care Settings 605
HEV Infection as a Zoonosis 605
Pathogenesis 606
Incubation Period 606
Viral Replication 606
Pathogenesis 607
Immune Response 608
Pathology 608
Clinical Features 609
Symptoms 609
Anicteric Hepatitis and Asymptomatic Infection 610
Chronicity 610
Complications 610
Prolonged Cholestatic Hepatitis 610
Fulminant Hepatic Failure 610
Acute HEV Superinfection in Patients with Cirrhosis 611
Pregnant Women 611
Coinfection of HEV with Other Hepatotropic Viruses 612
Other Complications 612
Autochthonous HEV in Developed Countries 612
Clinical Significance of HEV Genotype 612
Diagnosis and Detection of HEV 613
Approaches to HEV Detection 613
Virus or Viral Component Detection 613
Serological Assays 613
Laboratory Diagnosis 613
Differential Diagnosis 614
Natural History 614
Therapy and General Management 614
Prevention 614
General Measures 614
Passive Immunoprophylaxis 614
Active Immunoprophylaxis 615
Summary, Conclusions, and Directions for the Future 616
References 616
Chapter 41: Autoimmune Hepatitis 622
Introduction 622
Types of Autoimmune Hepatitis 623
Determinants of Antigen Selection and Recognition 624
Nature of the Antigen-Binding Groove 625
Genetic Determinants of the Antigen-Binding Groove 625
Antigen Selection and Presentation 625
Diverse Susceptibility Alleles for Type 1 Autoimmune Hepatitis 625
Protective Genetic Factors for Type 1 Autoimmune Hepatitis 626
Genetic Associations with Type 2 Autoimmune Hepatitis 626
Antigen Recognition 627
Candidate Autoantigens 627
Disturbances in Immunocyte Activation 628
Disturbances in Immunocyte Differentiation 628
Factors Influencing the Intensity of the Immune Response 629
“Gene Dosing” 629
Modifying Cell Populations 630
Chemo-Attractant Molecules 631
Programmed Cell Death (Apoptosis) 632
Nonspecific Factors Influencing the Clinical Phenotype 632
Conclusions 633
References 633
Chapter 42: Toxicant-Induced Liver Injury 639
Introduction 639
Mode of Cell Death During Drug Hepatotoxicity 639
Intracellular Signaling Mechanisms of Drug-Induced Cell Death 640
Protein Binding Hypothesis 640
Lipid Peroxidation 641
Mitochondrial Dysfunction 641
Mitochondrial Oxidant Stress 641
Nuclear DNA Damage 643
Initiation of Mitochondrial Dysfunction 643
Drug Hepatotoxicity and Innate Immunity 644
Kupffer Cells 644
Natural Killer and NKT Cells 644
Polymorphonuclear Leukocytes (Neutrophils) 644
Neutrophils and Kupffer Cells in Regeneration 645
Sterile Inflammation and Drug Hepatotoxicity 645
Idiosyncratic Drug-Induced Liver Injury 646
Summary 647
References 647
Chapter 43: Wilson’s Disease 652
Introduction 652
Copper Metabolism and the Pathogenesis of Wilson Disease 652
Copper Toxicity 653
Pathology 654
Epidemiology 656
Diagnosis 656
Treatment 657
References 659
Chapter 44: Hemochromatosis 661
Introduction 661
Iron Deposition Patterns in Hemochromatosis 662
Overview of Iron Metabolism 662
Liver Iron Transport 662
Transferrin-Bound Iron Uptake 662
High-Affinity Uptake: Transferrin Receptor 1 662
Low-Affinity Uptake: Transferrin Receptor 2 663
Non-Transferrin Bound Iron Uptake 663
Iron Release 663
HFE and Liver Iron Transport 664
Liver Iron Transport in Hereditary Hemochromatosis 664
Hepcidin is a Central Regulator of Iron Homeostasis 664
Iron and Oxidative Stress 666
Lipid Peroxidation 667
DNA and Protein Damage 667
Iron, ROS, and Cell Signaling 667
Immune Responses in Hemochromatosis 668
The Role of Iron in Fibrogenesis 668
References 669
Chapter 45: Glycogen Storage Diseases 673
Introduction 673
Etiology 673
Types of Glycogen Storage Diseases 673
Clinical Features of GSDS 673
Type 1 GSD 673
Type II GSD 674
Type III GSD 675
Type IV GSD 675
Type V and VII GSD 675
Type VI and IX GSD 675
Type VIII and X GSD 675
Molecular Mechanisms 675
References 677
Chapter 46: a1-Antitrypsin Deficiency 678
Introduction 678
AT Structure 679
The Protease Inhibitor System for Classification of Structural Variants of AT 679
Function of AT 680
Biosynthesis of AT 681
Clearance and Tissue Distribution of AT 681
Mechanism for Decreased Serum levels of AT and Fate of Mutant AT in PIZZ Individuals 682
Pathogenesis of Liver Injury in PIZZ Individuals 683
Mechanism of Liver-Cell Injury in AT deficiency 686
Mechanism of Hepatic Carcinogenesis in AT Deficiency 687
Liver Disease: Clinical Manifestations 688
Diagnosis 689
Treatment 689
References 690
Chapter 47: Hepatic Artery Diseases 696
Introduction 696
Hepatic Artery Aneurysms 696
Prevalence and Etiology 696
Clinical Features 697
Diagnosis 697
Treatment and Outcome 698
Hepatic Artery Thrombosis 698
Prevalence and Etiology 698
Early Hepatic Artery Thrombosis 698
A Role for the Hemostatic System? 699
Late Hepatic Artery Thrombosis 699
A Role for the Hemostatic System? 700
Clinical Features 700
Early Hepatic Artery Thrombosis 700
Late Hepatic Artery Thrombosis 700
Diagnosis 700
Early Hepatic Artery Thrombosis 700
Late Hepatic Artery Thrombosis 700
Treatment and Possible Prophylactic Options 701
Early Hepatic Artery Thrombosis 701
Late Hepatic Artery Thrombosis 701
References 701
Chapter 48: Hepatic Venous Outflow Obstruction 704
Introduction 704
Congestive Hepatopathy 705
Clinical Features 706
Laboratory Findings 706
Pathology 707
Diagnosis 707
Treatment and Prognosis 707
Constrictive Pericarditis 708
Budd-Chiari Syndrome 708
Epidemiology 708
Classification and Etiology 708
Myeloproliferative Disorders or Prothrombotic Conditions 709
Pathogenesis and Pathophysiology 709
Pathology 710
Clinical and Laboratory Findings 710
Prognosis and Survival 711
Diagnosis 712
Real-Time and Doppler Ultrasonography 712
Computed Tomography 712
Venography 712
Liver Biopsy 713
Differential Diagnosis 713
Treatment 714
Medical Therapy 714
Restoration of Hepatic Blood Flow 715
Veno-Occlusive Disease (Sinusoidal Obstruction Syndrome) 715
Clinical Presentation 716
Risk Factors 716
Histology and Pathophysiology 716
Treatment 716
Conclusion 716
References 717
Chapter 49: Primary Biliary Cirrhosis 720
Introduction and Clinical Features 720
Sex Factors and PBC 720
PBC Immunobiology 722
Antimitochondrial Antibodies 722
Antinuclear Antibodies 723
Autoreactive T Cells 723
Innate Immune Cells 723
T Regulatory Cells 725
Individual Susceptibility to PBC 725
Genetic Considerations in PBC 725
Association Studies 726
Environmental Considerations in PBC 727
Infectious Agents and PBC 728
Chemicals and PBC 728
PBC Animal Models 729
The Resulting Pathogenesis of PBC 729
Open Issues in PBC Pathogenesis 730
References 730
Chapter 50: Primary Sclerosing Cholangitis 735
Introduction 735
Clinical Features 735
Epidemiology 735
Pathophysiology 735
Genetic Factors 736
Clinical Manifestations 736
Biochemical Features 736
Serologic Features 737
Radiographic Features 737
Histologic Features 738
Disease-Modifying Treatments 738
Ursodeoxycholic Acid 738
Immunosuppressive Agents 738
Other Agents 739
Combination Therapy 739
Innovative Approaches to Medical Therapy 739
Endoscopic Therapy 739
Biliary Surgery 740
Liver Transplantation 740
Disease-Related Malignancy 740
Cholangiocarcinoma 740
Hepatocellular Carcinoma 741
Colonic Dysplasia and Carcinoma 741
Gallbladder Neoplasia 741
Conclusions 741
References 742
Chapter 51: Biliary Atresia 747
Introduction 747
Epidemiology 747
Clinical Features 747
At Presentation 747
During Progression of Disease 748
Recognizable Phenotypes of Disease 748
Perinatal Form of Biliary Atresia 748
Embryonic Form of Biliary Atresia 748
Cystic Variant of Biliary Atresia 748
Diagnosis 749
Laboratory Studies 749
Radiological Studies 749
Histopathology 749
Exploratory Laparotomy and Cholangiography 750
Pathogenesis of Disease 750
Defect in Morphogenesis 750
Defect in Fetal/Prenatal Circulation 751
Exposure to Environmental Toxins 752
Viral Infection 752
Immune-Mediated Injury 752
Human Studies 752
Animal Studies 753
Treatment 754
Portoenterostomy 754
Medical Treatment Following Portoenterostomy 754
Complications and Sequelae 755
Long-Term Outcome and Liver Transplantation 755
Long-Term Outcome 755
Liver Transplantation 755
References 756
Chapter 52: Benign Liver Tumors 761
Introduction 761
Focal Nodular Hyperplasia 761
Clinical and Pathological Characteristics 761
Epigenetic and Genetic Features in FNH 761
Signaling Pathways Altered in FNH 762
Hepatocellular Adenomas 763
Clinical and Pathological Features of HCA 763
First Subtype of Adenoma: HNF1a Inactivated HCA (H-HCA) 763
Second Subtype of Adenoma: b-Catenin Activated Adenomas (bHCA) 763
Third Subtype of Adenoma: Inflammatory Adenoma (IHCA) 764
Conclusion 764
References 765
Chapter 53: Hepatoblastoma 768
Introduction 768
Etiological Factors and Associated Conditions 768
Presentation, Clinical Staging and Treatment 769
Pathological Classification 770
Epithelial Types 770
Mixed Epithelial and Mesenchymal Types 771
Immunohistochemical Markers for HB Diagnosis and Prognosis 771
Genetic Alterations in Hepatoblastoma 772
Mutational Activation of b-Catenin 775
Oncogenic Pathways in HB 776
Molecular Classification of Hepatoblastoma 777
Conclusion 778
References 778
Chapter 54: Hepatocyte Growth, Proliferation and Experimental Carcinogenesis 782
Introduction 782
Autonomy and Timing of the Proliferative Process in Liver Hyperplasia 785
Spatial Distribution of Replicating Hepatocytes 785
Liver Ploidy 786
Gene Expression During Liver Hyperplasia 787
Immediate Early Genes/Transcription Factors 787
Termination of Liver Hyperplasia 790
Potential Efficacy of Primary Mitogens in the Context of Liver Regeneration in the Elderly and Living Related Transplantation 790
Cell Proliferation and Hepatocarcinogenesis 792
Genetically Engineered Models 795
C-Met 795
WNT-b/Catenin 796
C-Myc 796
C-Jun 797
P53 797
Why Experimental Carcinogenesis is Still Important 798
Conclusions and Perspectives 798
References 799
Chapter 55: Stem Cells and Liver Cancer 805
Liver Cancer Stem Cells 805
Immortality 805
Rat Hepatomas 805
Human HCC 806
Tumor Transplantation 807
Resistance to Therapy 807
Radiation Therapy of Morris Hepatomas 808
Nature of Therapy-Resistant Cells 808
Markers of LCSC 808
Stem Cell Transcription Factors 808
Cell Surface Markers 809
Side Population Cells 809
Summary 809
The Stem Cell Origin of Liver Cancer 809
Experimental Chemical Hepatocarcinogenesis 809
Dedifferentiation 810
Oval Cells 810
Blocked Ontogeny 810
Alpha-Fetoprotein: A Marker for Early Cellular Events in Chemical Hepatocarcinogenesis 811
Choline Deficiency (CD) 812
Cyclic N-2 Acetylaminofluorene 812
Solt-Farber Model 812
Diethylnitrosamine 813
Liver-Cell Lineage and HCC 813
Mouse Hepatoblastomas 813
Human Hepatoblastoma 814
Human Hepatocellular Carcinoma 814
Summary and Conclusions 815
References 815
Chapter 56: Primary Hepatocellular Carcinoma 820
Introduction 820
Epidemiology 820
Etiology and Risk Factors 820
Genomics and Carcinogenesis 821
Mutations and Chromosomal Aberrations in HCC 821
Genomic Changes in HCC 821
Frequent Mutations in HCC 821
Genetic Alterations Specific to Etiological Factors 822
HBV 822
Aflatoxin B1 822
Vinyl Chloride 822
MicroRNAs 822
Telomeres and Telomerase 822
Cell Signaling in HCC 823
p53 Pathway 823
WNT/b-Catenin Pathway 824
Sonic Hedgehog Signaling 824
Inflammation and HCC 825
Inflammatory Pathways in HCC 825
NFkB 825
IL-6 and JAK-STAT3 Signaling 825
Liver Stem Cells 826
Angiogenesis in HCC 827
Cellular Actors of Angiogenesis 827
Modes of Tumor Vascularization 828
Vascular Characteristics of HCC 828
Angiogenic Pathways in HCC 828
VEGF Signaling 828
Angiopoietin 829
Notch-Deltalike Ligand 4 (D114) 829
(Tumor)Cell–Matrix Interactions 829
HCC Classification 830
Edmondson and Steiner Grading 830
HCC Signature – Molecular Profiling of HCC 830
Therapeutic Considerations 831
References 831
Chapter 57: Fibrolamellar Hepatocellular Carcinoma 838
Epidemiology and Clinical Features 838
Imaging Characteristics 839
Etiology 839
Pathologic Features 839
Gross Features 839
Microscopic Features 840
Histochemistry 840
Immunohistochemistry 840
Ultrastructural Features 841
Differential Diagnosis 841
Conventional HCC 841
Adenocarcinoma (Cholangiocarcinoma or Metastatic Adenocarcinoma) 841
Neuroendocrine Tumors 841
Angiomyolipoma 842
Melanoma 842
Other 842
Genetic Features 842
Natural History and Treatment 843
Prognosis and Survival 843
References 844
Chapter 58: Biology of Metastatic Liver Tumors 847
Introduction 847
The Metastatic Cascade 847
Histology of Metastatic Carcinomas 849
Phenotypic Plasticity of Cancer Cells 850
Tumor Microenvironment 850
Tumor Dormancy 851
Investigative Models of Liver Metastases 852
Conclusions 853
References 853
Chapter 59: Cholangiocarcinoma 855
Introduction 855
The Process of Cholangiocarcinogenesis 855
Genetic Alterations 856
K-ras and p53 856
NKG2D 856
Activation-Induced Cytidine Deaminase 857
Cellular Senescence 857
Epigenetic Dysregulation 857
DNA Methylation 857
p16INK4A 857
Ras Association Domain Family 1A 857
Human mutL Homologue 1 859
Other Hyper-Methylated Genes 859
Histone Modifications 859
Molecular Cellular Pathways 859
Initiation of the Malignant Process 859
IL-6 and Mcl-1 859
Transforming Growth Factor-b 861
DCP4/Smad4 861
c-Met/Hepatocyte Growth Factor 861
ErbB-2 861
Glutathione 861
COX-2 862
Nitric Oxide 862
Bile Acids 862
Apoptosis and Cholangiocarcinoma 863
Invasion and Progression of Cholangiocarcinoma 863
Epithelial-to-Mesenchymal Transition of Cholangiocarcinoma Cells 864
MicroRNA and Cholangiocarcinoma 864
Molecular Differences Between Intra and Extrahepatic CC 865
Conclusion 865
References 865
Chapter 60: Neoplasms of Extrahepatic Bile Ducts 869
Epidemiology 869
Risk Factors 869
Primary Sclerosing Cholangitis and Ulcerative Colitis 869
Congenital Biliary Cyst Disease and Abnormal Choledochal-pancreatic Duct Junction 869
Hepatolithiasis 870
Infections 870
Miscellaneous 870
Histogenesis 870
Flat Biliary Dysplasia (Biliary Intraepithelial Neoplasia) 870
Intraductal Papillary Neoplasms of Bile Ducts 871
General Anatomic-Clinical Consideration 871
Molecular and Genetic Alteration 872
Cell Cycle Proteins 873
Tumor Suppressor Genes 873
Cell Adhesion Proteins 874
Mucin-Related Glycoproteins 874
Matrix Proteins 875
Miscellaneous 875
Summary 876
References 876
Chapter 61: Neoplasms of the Gallbladder 879
Epidemiology 879
Risk Factors 879
Gallstones 879
Diet and Obesity 879
Pollutants and Environmental Factors 879
Gender 879
Bile Infections 880
Porcelain Gallbladder 880
Anomalous Pancreaticobiliary Ductal Junction 880
Histogenesis – Precancers 880
Metaplasia-Dysplasia-Carcinoma Sequence (Flat Dysplasia Intraepithelial Neoplasia)
Adenoma-Carcinoma Sequence (Mass-Forming Preinvasive Neoplasia) 881
General Considerations for Invasive Carcinoma 882
Molecular Genetic Alterations in Neoplastic Lesions 882
Oncogenes 882
K-ras 882
p21/CDKN1A 883
C-erb-B2 883
Cyclin D1 and Cyclin E 883
Tumor Suppressor Genes 883
TP53 883
p16/CDKN2/INK4 883
Fragile Histidine Triad Gene 884
Other Tumor Suppressor Genes 884
Microsatellite Instability (MSI) 884
Adhesion Molecules 884
Cadherin-catenin Complex 884
ICAM-1/CD54 885
CD44 885
CD99 (Mic2) 885
CEA 885
NCAM/CD56 885
Epigenetic Alterations 886
Genetic Susceptibility, Polymorphisms, and Biomarkers 886
Inflammation and Molecular Carcinogenesis 886
Mitochondrial DNA Mutations (mt DNA) 886
Inducible Nitric Oxide Synthase (iNOS) 887
Cyclooxigenase-2 (COX-2) 887
Others Genes 887
Angiogenesis and Vascular Endothelial Growth Factor (VEGF) 887
hTERT/Telomere Aging and GBC 888
Conclusion 888
References 888
Chapter 62: Current and Future Methods for Diagnosis of Neoplastic Liver Disease 894
Introduction 894
Case Presentations 894
Case 1 894
Clinical Background 894
Radiologic Assessment 894
Pathologic Assessment 894
Case 2 894
Clinical Background 894
Radiologic Assessment 895
Pathologic Assessment 895
Radiologic Approaches to Diagnosing Neoplastic Liver Disease 895
Pathologic Assessment of Neoplastic Liver Disease 897
Current Methods in Obtaining Liver Tissue for Diagnosis 897
Current Methods in the Diagnosis of Liver Diseases and Tumors 897
Molecular Pathology Assessment of Neoplastic Liver Disease 900
Molecular Evaluation of Neoplastic Liver Diseases 900
MicroRNAS 900
MicroRNAS and Neoplastic Liver Diseases 901
Cancers of Unknown Primary 901
Molecular Applications for Targeted Therapy in Neoplastic Liver Disease 901
References 902