Monga Molecular Pathology of Liver Diseases

1. Auflage 2010
ISBN: 978-1-4419-7107-4
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 5, 931 Seiten

Reihe: Molecular Pathology Library

Cellular and Molecular Pathology of the Liver is extensive, complex and ranges from the understanding the basic molecular mechanisms that dictate everything from liver homeostasis to liver disease. Molecular Pathology of the liver is complicated due to some of the important functions inherent and unique to the Liver, including its innate ability to regenerate and the multitude of functions it plays for the wellbeing of an organism. With all this in mind, Molecular Pathology of Liver Diseases is organized in different sections, which will coherently and cohesively present the molecular basis of hepatic physiology and pathology. The first two sections are key to understanding the liver anatomy and physiology at a cellular level and go on to define the molecular mechanics in various liver cell types. These sections also cover the existing paradigms in liver development, regeneration and growth. The next section is key to understanding the Molecular Pathology unique to liver diseases and associated phenotypes. The final sections are geared towards the existing knowledge of the molecular basis of many common and uncommon liver diseases in both neoplastic and non-neoplastic areas including pathologies associated with intra-hepatic and extra-hepatic biliary tree. Thus, this textbook is a one-stop reference for comprehending the molecular mechanisms of hepatic pathobiology. It is clearly unique in its format, readability and information and thus will be an asset to many in the field of Pathology and other disciplines.

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

Autoren/Hrsg.

Monga, Satdarshan P. S.

Inhaltsverzeichnis

1;Chapter 1: Gross and Cellular Anatomy of the Liver;26
1.1;Gross Anatomy of the Liver;26
1.2;Cellular Anatomy of the Liver;28
1.3;References;29
2;Chapter 2: Liver Zonation;30
2.1;Introduction;30
2.2;The Liver Lobule, the Zonated Unit of the Liver;30
2.3;Metabolic Zonal Functions;30
2.4;Possible Mechanisms for Zonation;33
2.5;The Wnt/b(Beta)-Catenin Pathway;33
2.6;b(Beta)-Catenin, A Master Signaling Molecule Orchestrating Metabolic Zonation in the Liver;33
2.7;The Consequences of Disrupting Zonation;34
2.8;Establishment of Liver Zonation by b(Beta)-Catenin and Wnts;34
2.9;b(Beta)-Catenin and Hepatocyte Proliferation;35
2.10;Integration of b(Beta)-Catenin Signaling with Other Regulators of Zonal Liver Functions;35
2.11;Hnf4 a(Alpha) Is a Liver-Enriched Factor Specializing b(Beta)-Catenin Transcriptome;36
2.12;Conclusion;36
2.13;References;37
3;Chapter 3: Hepatocytes;40
3.1;Introduction;40
3.2;Hepatocyte Structure;40
3.2.1;Polarity;40
3.2.2;Ultrastructive;41
3.3;Isolation and Culture of Hepatocytes;41
3.4;Hepatocyte Functional Characterization;42
3.5;Epithelial to Mesenchymal Transitions of Hepatocytes;45
3.6;Alternative Production of Hepatocytes from Stem Cells;46
3.6.1;Hepatocyte Cell Lines;46
3.7;Conclusions and Future Perspectives;47
3.8;References;47
4;Chapter 4: Biliary Epithelial Cells;50
4.1;Introduction;50
4.2;Anion Transport and pHi Maintenance;51
4.2.1;Mechanism Involved in Anion Transport and pHi Maintenance;52
4.2.2;Regulatory Factors;54
4.2.2.1;Hormones;54
4.2.2.2;Other Factors;54
4.2.2.3;BEC Primary Cilium;54
4.3;Immune System and Cell Defenses;55
4.3.1;Mechanism Involved in BEC Immune Regulation and Defense;55
4.3.2;Antigen Presenting Cell Capabilities;55
4.3.3;Adhesion Molecules;55
4.3.4;Secretion in Response to Cytokines and Chemokines;57
4.3.5;Stress, Apoptosis and Senescence-Related Changes;57
4.3.5.1;Responses to Oxidative Stress and Senescence-Related Changes;58
4.3.5.2;SPRR2A;58
4.3.6;Other Defense Systems Against Pathogens;58
4.3.6.1;Immunoglobulin;58
4.3.6.2;Toll-Like Receptors;59
4.3.6.3;Antimicrobial Molecules;59
4.3.6.4;Trefoil Factor Family;59
4.4;BEC Proliferation and Wound Healing;59
4.4.1;Crosstalk Between Proliferating BEC and Other Liver Cells;60
4.4.2;Epithelial-Mesenchymal Transition;60
4.4.3;Common Intracellular Signaling Pathways Mediating BEC Proliferation;61
4.4.3.1;cAMP/PKA/ERK1/2;61
4.4.3.2;PI3K/AKT;62
4.4.3.3;IP3R/Ca2+/PKC;62
4.4.3.4;Receptor Tyrosine Kinase (RTK)/Ras/MEK/ERK1/2 and STAT3;62
4.4.4;Factors Regulating BEC Proliferation;62
4.4.4.1;Extracellular Matrix;62
4.4.4.2;Bile Acids;63
4.4.4.3;Hormones;63
4.4.4.4;Neuropeptides;63
4.4.4.5;Cytokines and Growth Factors (Reviewed in [18, 259]);64
4.5;Future Directions;65
4.6;References;66
5;Chapter 5: Stellate Cells;75
5.1;History, Location, and Morphological Characteristics of Stellate Cells;75
5.2;Origin of Stellate Cells;76
5.3;Isolation and Culture of HSCs;76
5.4;Activation and Proliferation of Stellate Cells;78
5.4.1;Retinoids;79
5.4.2;Soluble Mediators;79
5.4.3;Reactive Oxygen Species;80
5.4.4;Platelet-Derived Growth Factor and Endothelin-1;80
5.4.5;Transforming Growth Factor-b(beta);81
5.5;Hepatic Fibrosis and Stellate Cells;82
5.5.1;Extracellular Matrix;83
5.5.2;Reactive Oxygen Species;83
5.5.3;Transforming Growth Factor-b(beta);83
5.5.4;Endothelin;84
5.5.5;Renin-Angiotensin System;84
5.5.6;Other Mediators;85
5.5.7;Adipocytokines;85
5.5.8;Hepatitis Virus C;85
5.6;Regulation of Sinusoidal Blood Flow by Stellate Cells;85
5.7;Role in Hepatic Growth, Inflammation, and Immune Regulation;87
5.8;Selective Elimination of HSCs as Therapeutic Strategy;90
5.8.1;Inhibitors of Endogenously Produced Substances;90
5.8.2;Inhibitors of Signaling Pathways Associated with Activation and Fibrogenic Activity of HSCs;91
5.9;Summary and Perspective;91
5.10;References;91
6;Chapter 6: Kupffer Cells;102
6.1;Origin, Location, and Life Span of Kupffer Cells;102
6.2;Isolation and Culture of Kupffer Cells;102
6.3;Phagocytosis and Clearance Functions of Kupffer Cells;103
6.4;Activation of Kupffer Cells;104
6.5;Role in Liver Regeneration;107
6.5.1;Role in Ischemia/Reperfusion Injury;107
6.5.2;Role in Alcohol-Induced Liver Injury;108
6.5.3;Role in Non-alcoholic Fatty Liver Disease;109
6.5.4;Role in Regulation of Immune System;109
6.6;Summary and Perspectives;110
6.7;References;110
7;Chapter 7: Sinusoidal Endothelial Cells;117
7.1;The Liver Lobule, Microcirculation, and the Sinusoidal Endothelial Cell;117
7.2;Organization of Cells Relative to the Liver Sinusoidal Endothelial Cell;120
7.3;Fenestrations: Function and Regulation of the Liver Sieve;122
7.4;Other Novel Functions of LSEC;123
7.5;Repopulation and Derivation of LSEC and their Role in Diseases;123
7.6;Study In Vitro: Isolation and Culture of Liver LSEC;124
7.7;References;125
8;Chapter 8: Hepatic Carbohydrate Metabolism;128
8.1;Introduction;128
8.2;Hepatic Glucose Uptake, Glycogen and Lipid Synthesis;128
8.3;Regulation of Hepatic Glucose Production;129
8.4;Direct and Indirect Effects of Insulin on the Liver;129
8.5;Transcriptional Regulation of Gluconeogenic Enzymes;130
8.6;The Role of Growth Hormone and Insulin-Like Growth Factor in Carbohydrate Metabolism;131
8.7;Glucocorticoids and Hepatic Carbohydrate Metabolism;132
8.8;Glucose Homeostasis in Liver Disease;133
8.8.1;Insulin Resistance, the Common Link in Metabolic Syndrome, Nonalcoholic Fatty Liver Disease, and Hepatogenous Diabetes;133
8.8.1.1;Role of IRS1/2;133
8.8.1.2;Intracellular Activators of Inflammatory Pathways;133
8.8.1.3;Inflammatory Pathways Involved in Insulin Resistance;133
8.8.1.4;Adipokines;134
8.8.1.5;Adiponectin;134
8.8.1.6;Leptin;135
8.8.1.7;Resistin;135
8.8.1.8;Tumor Necrosis Factor-a;136
8.8.1.9;IL-6;136
8.8.2;Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis;136
8.8.3;Hepatitis C and Diabetes;137
8.8.4;Hepatogenous Diabetes;137
8.9;Summary;138
8.10;References;138
9;Chapter 9: Hepatic Protein Metabolism;143
9.1;Introduction;143
9.2;Protein Ingestion and Metabolism to Urea;143
9.3;Urinary Excretion of Urea Accounts for 70–80% of its Production;143
9.4;Intestinal Microbial Urea Recycling in Ruminants;144
9.5;Ammonia Excretion;144
9.6;Digestibility of Dietary Proteins;144
9.7;Intestinal Ammonia Production from Glutamine;144
9.8;Role of Intestine in Ammonia Production;145
9.9;Hepatic Ammonia Detoxification;145
9.10;Sources of Hepatic Urea Synthesis;145
9.11;Zonation of Ammonia-Metabolizing Enzymes and Transporters;146
9.12;Amino-Acid Transport into the Liver;146
9.13;Ammonia Transport into the Liver;147
9.14;pH and Ammonia Detoxification;147
9.15;Ammonia Detoxification in the Compromised Liver;147
9.16;Conclusions;148
9.17;References;148
10;Chapter 10: Hepatic Lipid Metabolism;151
10.1;Introduction;151
10.2;Sources and Synthesis of Fatty Acids;151
10.2.1;Hepatic Uptake of Plasma NEFAs Released by Adipose Tissue and Hydrolysis of Circulating Triglyceride-Rich Lipoproteins;151
10.2.2;Chylomicron Remnants;152
10.2.3;Hepatic Cytoplasmic Lipid Droplet Stores;153
10.2.4;De Novo Lipogenesis;154
10.3;Very Low Density Lipoprotein Assembly and Secretion;154
10.4;Fatty Acid Oxidation;155
10.4.1;Mitochondrial b-Oxidation;155
10.4.2;Peroxisomal b-Oxidation;156
10.4.3;Microsomal w-Oxidation;157
10.4.4;Fatty Acid a-Oxidation;157
10.4.5;Ketogenesis;158
10.5;Regulation of Hepatic Lipid Metabolism: Clues from Knockout Mouse Models;158
10.5.1;Regulation of Hepatic Lipogenesis;158
10.5.2;Regulation of Fatty Acid Oxidation;159
10.5.3;MicroRNAs in the Regulation of Lipid Metabolism;160
10.6;Summary;161
10.7;References;161
11;Chapter 11: Detoxification Functions of the Liver;165
11.1;Introduction;165
11.2;Major DMEs in the Liver;166
11.2.1;Cytochrome P450;166
11.2.2;CYP450 Isoforms;167
11.2.2.1;CYP1A2;167
11.2.2.2;CYP2B Family;168
11.2.2.3;CYP2C Family;168
11.2.2.4;CYP2D6;168
11.2.2.5;CYP2E1;168
11.2.2.6;CYP3A4 Family;168
11.2.2.7;CYP4A11;168
11.2.3;Regulation of DME Expression;169
11.2.4;Zone Specific Expression of CYP450;169
11.2.5;Flavin Monooxygenase;169
11.3;DMES Involved in Conjugation Reactions;169
11.3.1;Glucuronidation;170
11.3.2;Sulfation;171
11.3.3;Glutathione Conjugation;171
11.3.4;Acetylation;171
11.3.5;Methylation;172
11.3.6;Amino Acid Conjugation;172
11.4;Role of Transporters as a Detoxification System in the Liver;172
11.4.1;Basolateral (Sinusoidal) Excretion;173
11.4.1.1;ABCC3 (MRP3);173
11.4.1.2;ABCC4 (MRP4);173
11.4.1.3;ABCC5 (MRP5) and ABCC6 (MRP6);174
11.4.2;Canalicular (Biliary) Excretion;174
11.4.2.1;ABCB1 (MDR1 or P-Glycoprotein or Pgp);174
11.4.2.2;ABCB4/MDR3;174
11.4.2.3;ABCB11 (BSEP);174
11.4.2.4;ABCC2 (MRP2);175
11.4.2.5;ABCG2/BCRP;175
11.4.2.6;ABCG5 and ABCG8;176
11.4.3;Drug Uptake Transporters in Detoxification;176
11.4.3.1;SLC10A1; Na+/Taurocholate Co-Transporting Polypeptide;176
11.4.3.2;Organic Anion Transporting Polypeptides (SLC21/SLCO/OATP);176
11.5;Conclusion;177
11.6;References;177
12;Chapter 12: Bile Acid Metabolism;182
12.1;Introduction;182
12.2;Bile Acid Metabolism;182
12.2.1;Bile Acid Structures;182
12.2.2;Bile Acid Synthesis in the Liver;183
12.2.3;Bile Acid Biotransformation;184
12.2.4;Enterohepatic Circulation of Bile Acids;185
12.3;Regulation of Bile Acid Metabolism;185
12.3.1;Regulation by Bile Acid Receptors;186
12.3.2;Regulation by Cell Signaling Pathways;187
12.3.2.1;PKC;188
12.3.2.2;Proinflammatory Cytokines;188
12.3.2.3;Growth Factor and Insulin Signaling;188
12.4;Role of Bile Acids in Metabolic Regulation;188
12.4.1;Bile Acids Regulate Lipid Metabolism;188
12.4.2;Bile Acids Regulate Glucose Metabolism;189
12.4.3;Bile Acids Regulate Energy Metabolism;189
12.5;Molecular Pathology of the Enterohepatic System;190
12.5.1;Metabolic Defects in Bile Acid Metabolism;190
12.5.1.1;Defects in Bile Acid Synthesis;190
12.5.1.2;Defects in Bile Acid Conjugation;191
12.5.2;Cholestatic Liver Diseases;191
12.5.2.1;Hereditary Cholestatic Diseases;191
12.5.2.2;Acquired Cholestasis;191
12.5.2.3;Obstructive Cholestasis;191
12.6;Bile Acids as Therapeutic Agents;192
12.6.1;Bile Acid Displacement and Replacement;192
12.6.2;FXR Agonists for Cholestasis, Gallstone, Fatty Liver and Cardiovascular Disease;192
12.7;References;192
13;Chapter 13: Liver Development;198
13.1;Introduction;198
13.2;Inducing the Hepatic Domain in Foregut Endoderm;198
13.2.1;Fate Mapping of Liver Precursors: Where to Hepatoblasts Come from?;198
13.2.2;From Endoderm to Hepatoblasts: Inductive Signals;199
13.2.3;From Endoderm to Hepatoblasts: Intrinsic Factors;199
13.2.4;Defining the Liver Field: Lineage Segregation Within the Foregut Endoderm;201
13.3;Constructing the Liver Bud;202
13.3.1;A Transcription Factor Network Controls the Formation of the Hepatic Primordium;202
13.3.2;Expanding the Liver Primodium;203
13.4;Summary;204
13.5;References;204
14;chapter 14: Transcriptional Control of Hepatocyte Differentiation;207
14.1;Introduction;207
14.2;Evolution of Studies on Transcriptional Regulation In Liver;207
14.3;The Transcriptional Environment in the Adult Liver;208
14.4;Liver Enriched Factors;208
14.4.1;Phase 1: Prehepatic Expression and Developmental Competence;208
14.4.2;Phase 2: Establishment of Definitive Hepatic Structures;215
14.4.3;Phase 3: Establishment of a Constitutive Phenotype;216
14.4.4;Phase 4: Dynamic Gene Regulation in the Mature Liver;217
14.5;Repression and the Oncofetal Paradigm;220
14.6;Closing;221
14.7;References;222
15;Chapter 15: Bile Duct Development and Biliary Differentiation;226
15.1;Introduction;226
15.2;Development of the Intrahepatic Bile Ducts;226
15.2.1;Markers of Cholangiocyte Differentiation;226
15.2.2;Biliary Cells Differentiate Near the Portal Vein;227
15.2.3;Transcriptional Network Initiating Intrahepatic Biliary Differentiation;228
15.2.4;Intrahepatic Bile Duct Morphogenesis: A Multistep Process;229
15.2.5;Cell-Cell Signaling and Intrahepatic Bile Duct Development;231
15.2.6;Gene Regulation and Intrahepatic Bile Duct Development;231
15.2.7;Development of the Extrahepatic Biliary Tract;232
15.2.8;Lessons from Developmental Diseases of the Biliary Tract;233
15.2.8.1;Bile Duct Paucity;233
15.2.8.2;Ciliopathies;233
15.2.8.3;Ductal Plate Malformations;234
15.2.8.4;Diseases of the Extrahepatic biliary Tract;234
15.3;Conclusions;234
15.4;References;234
16;Chapter 16: Hepatic Progenitors in Development and Transplantation;238
16.1;High Regenerative Potential of the Liver;238
16.2;Role of YAP in Molecular Regulation of Liver Mass;238
16.3;Hepatocyte Transplantation into the Regenerating Liver;239
16.4;Special Animal Models to Repopulate the Liver by Transplanted Hepatocytes;239
16.5;Progenitor (“Oval”) Cells for Liver Repopulation;241
16.6;Transplantation of “Oval Cells”;242
16.7;Properties of Stem and Progenitor Cells Relevant to Liver Reconstitution/Repopulation;243
16.8;Hepatic Stem Cells in the Developing Liver;244
16.9;Liver Repopulation Using Fetal Liver Stem/Progenitor Cells;244
16.10;Liver Repopulation by Extrahepatic and Embryonic Stem Cells;245
16.11;Induced Pluripotent Stem Cells;246
16.12;Human “Oval Cells” and Stem Cells;246
16.13;Xenorepopulation Models;247
16.14;Future Horizons;247
16.15;References;250
17;Chapter 17: Adult Liver Stem Cells;255
17.1;Introduction;255
17.2;History of Liver Stem-Like Progenitor Cell Biology;255
17.3;Essential Properties of Stem-Like Progenitor Cells;256
17.4;Stem-Like Progenitor Cells of the Adult Liver;256
17.4.1;Unipotential Liver Stem-Like Progenitor Cells: Differentiated Hepatocytes and Biliary Epithelial Cells;258
17.4.2;Unipotential Liver Stem-Like Progenitor Cells: Small Hepatocyte Progenitor Cells;258
17.4.3;Multipotential Liver Stem-Like Progenitor Cells: Oval Cells;260
17.4.4;Liver Stem-Like Progenitor Cells from Extrahepatic Tissues;261
17.4.4.1;Liver from Progenitor Cells of the Bone Marrow;261
17.4.4.2;Liver from Stem-Like Progenitor Cells of the Pancreas;262
17.4.4.3;Liver from Neural Stem Cell Cultures;262
17.5;Human Liver Stem-Like Progenitor Cells;263
17.5.1;Evidence for Liver Stem-Like Progenitor Cells in Humans;263
17.5.2;Liver from Bone Marrow Stem-Like Progenitor Cells in Humans;263
17.6;Isolation and Culture of Adult Liver Stem-Like Progenitor Cells;263
17.6.1;Early Studies of Propagable Liver Epithelial Cells;264
17.6.2;Rat Liver Epithelial Stem-Like Progenitor Cells: Oval Cell Lines;264
17.6.3;Rat Liver Epithelial Stem-Like Progenitor Cells: The WB-F344 Cell Line;264
17.6.4;Stem-Like Progenitor Cells from the Human Liver;264
17.7;Evidence for the Multipotential Differentiation of Adult Liver Stem-Like Progenitor Cells In Vivo;265
17.7.1;Hepatocytic Differentiation by Transplanted WB-F344 Rat Liver Stem Cells;265
17.8;Multipotential Differentiation of Adult Liver Stem Cells in Culture;266
17.8.1;Hepatocytic Differentiation of Oval Cells In Vitro;266
17.8.2;Hepatocytic Differentiation by RLE-13 Rat Liver Epithelial Cells in Culture;267
17.8.3;Hepatocytic Differentiation of WB-F344 Rat Liver Stem-Like Progenitor Cells in Culture;267
17.9;Stem-Like Progenitor Cell Responses in Liver Injury and Repair;267
17.10;References;267
18;Chapter 18: Liver Regeneration;273
18.1;General Considerations;273
18.1.1;How Much Liver Does the Body Need? Is There a “Hepatostat”?;274
18.2;Liver Regeneration After PHx;275
18.2.1;Histologic Changes and Cellular Proliferation Kinetics;275
18.2.2;Extracellular Matrix;276
18.2.3;Signals Associated with Hepatocyte Mitogenesis;276
18.2.3.1;Mitogenic Growth Factors;276
18.2.4;HGF and Its Receptor (cMET);277
18.2.5;EGF, TGFa(alpha) and the EGFR Ligand Family of Proteins;277
18.2.5.1;Intracellular Signaling Events;278
18.2.5.2;Auxiliary Mitogens;278
18.2.6;TNF a(alpha);278
18.2.7;Interleukin 6;279
18.2.8;Bile Acids;279
18.2.9;Norepinephrine;279
18.2.10;Insulin;280
18.2.11;Termination of Liver Regeneration;280
18.2.11.1;Transforming Growth Factor Beta 1 (TGFb(beta)1);280
18.2.11.2;Extracellular Matrix;281
18.2.11.3;Glypican 3;282
18.2.11.4;Yes-Associated Protein;282
18.2.12;Exchange of Growth Regulatory Signals Between Hepatic Cell Types During Liver Regeneration;282
18.3;Clinical Implications of Liver Regeneration;283
18.3.1;Generation of Growth Enhancing or Inhibitory Signals as Part of the Inflammatory Process;283
18.3.2;Effects of Viruses and Toxins on the Capacity of Hepatocytes to Replicate;284
18.3.3;Cirrhosis as a Chronic Regeneration Process;284
18.4;Overall Conclusions;285
18.5;References;285
19;Chapter 19: Senescent Liver;291
19.1;Introduction;291
19.2;Liver Functions and Age;291
19.3;Morphological Changes in Senescent Liver;292
19.4;HCV Infections and Nonalcoholic Fatty Liver Diseases Are the Major Risk Factors for Hepatocellular Carcinoma in Elderly;293
19.5;Aging Reduces Regenerative Capacity of the Liver;293
19.6;Telomere Shortening in Senescent Liver and Its Possible Contribution to the Inhibition of Liver Proliferation in Elderly;294
19.7;Epigenetic Silencing of Liver Regeneration in Old Mice;295
19.8;Signal Transduction Pathways Which Change Epigenetic Control in Livers of Old Mice;295
19.9;Additional Alterations that Might Contribute to the Decline of Proliferation in Senescent Liver;297
19.10;Liver Surgery and Liver Transplantation in Elderly;298
19.11;Development of Approaches to Improve Liver Regeneration and Graft Survival in Older Patients;298
19.12;Concluding Remarks;299
19.13;References;299
20;Chapter 20: Signaling Pathways in the Liver;303
20.1;Introduction;303
20.2;b(Beta)-Catenin Signaling;303
20.3;ERBB/EGFR Family;304
20.4;Hepatocyte Growth Factor (HGF) Signaling;305
20.5;Hedgehog Signaling;306
20.6;JAK/STAT Pathway;307
20.7;MAP Kinase Pathway;308
20.8;Notch Signaling;309
20.9;PDGF/PDGFR Signaling;309
20.10;Peroxisome-Proliferator-Activated Receptors (PPARs);310
20.11;PI3-Kinase/AKT Pathway;310
20.12;TGFb Signaling;311
20.13;TNFa/NFkB Signaling;312
20.14;Conclusion;313
20.15;References;313
21;Chapter 21: Hepatocyte Transplantation;320
21.1;Introduction;320
21.2;Indications for Human Hepatocyte Transplantation;320
21.3;Hepatocyte Preparation: Source, Isolation, and Quality;322
21.3.1;Cell Sources for Human Hepatocyte Transplantation;322
21.3.2;Hepatocyte Isolation and Storage;323
21.3.3;Assessment of Hepatocyte Quality for Transplantation;324
21.4;Hepatocyte Transplantation: Location and Engraftment;324
21.5;Posttransplantation Hepatocyte Engraftment and Immune Response;326
21.6;Overview of Current Clinical Experience;327
21.7;Conclusions;327
21.8;References;328
22;Chapter 22: Hepatic Tissue Engineering;331
22.1;Introduction;331
22.2;Current Treatments for Liver Failure;331
22.2.1;Cell-Based Therapies;331
22.3;Cell Sourcing;332
22.3.1;Mature Hepatocytes;333
22.3.2;Stem Cells and Progenitor Populations;334
22.3.3;Reprogrammed Adult Cells;335
22.4;In Vitro Platforms and Applications;335
22.4.1;2-D Culture Platforms;336
22.4.2;3-D Spheroid Culture;336
22.4.3;Bioreactor Cultures;337
22.4.4;Microtechnology Tools;337
22.4.5;Application of In Vitro Liver Models: Studying Liver Pathophysiology;338
22.5;Implantable Engineered Tissue Constructs;339
22.5.1;Scaffold Properties;339
22.5.2;Material and Chemical Modifications;339
22.5.3;Porosity;340
22.5.4;3-D Architecture;341
22.5.5;Cell-Sourcing for Implantable Liver Tissues;342
22.5.6;Mature Hepatocytes Versus Hepatic Progenitor Cells;342
22.5.7;Cell–Cell Interactions;342
22.5.8;Clinical Translation for Human Therapy;343
22.5.9;Assessment in Animal Models;343
22.5.10;Integration with Host Tissue Vasculature and Biliary System;343
22.5.11;Immune Response;344
22.6;Conclusion;344
22.7;References;344
23;Chapter 23: Hepatic Gene Therapy;353
23.1;Introduction;353
23.2;Liver in Gene Therapy;353
23.2.1;Liver: A Major Target Organ in Gene Therapy;353
23.2.2;Understanding Biological Functions of the Liver: Rare Monogenic Diseases as Targets for Hepatic Gene Therapy;354
23.2.3;Understanding Molecular Pathogenesis of Diseases: More Common Diseases as Targets for Hepatic Gene Therapy;354
23.2.4;Understanding Liver Immunology: A Key to Successful Hepatic Gene Therapy;354
23.3;Vectors and Methods for Hepatic Gene Transfer and Their Mechanism of Action;357
23.3.1;Barriers in Hepatic Gene Therapy;357
23.3.2;Adenoviral Vectors;358
23.3.3;Adeno-associated Virus Vectors;359
23.3.4;Retroviral Vectors;360
23.3.5;Lentiviral Vectors;361
23.3.6;Non-viral Vectors;362
23.3.7;Hydrodynamics-Based In Vivo Transfection Method;364
23.3.8;Transposon and Phage Integrase-Based Approaches: Sleeping Beauty Transposon and Phic31 Integrase Systems;365
23.3.9;Gene Repair and Gene-Targeting-Based Approaches;366
23.3.10;RNA Interference-Based Approach;367
23.4;Preclinical and Clincal Applications of Hepatic Gene Therapy;367
23.4.1;Hemophilia;367
23.4.2;Inborn Errors of Metabolism;368
23.4.3;Liver Fibrosis;369
23.4.4;Ischemia-Reperfusion Injury;370
23.4.5;Diabetes;370
23.4.6;Viral Hepatits;371
23.4.7;Liver Cancers;372
23.5;Conclusions;373
23.6;References;373
24;Chapter 24: Liver Cell Death;382
24.1;Introduction;382
24.2;Overview of Apoptosis;382
24.3;The Extracellular Pathway;384
24.4;The BCL-2 Family of Apoptosis Regulators;384
24.5;The Mitochondrial/Intracellular Pathway;386
24.6;Lysosomes;386
24.7;Endoplasmic Reticulum;386
24.8;Overview of Necrosis;388
24.9;The Mitochondria in Necrosis;388
24.10;Molecular Mediators of Apoptosis;389
24.10.1;Fas;389
24.10.2;TRAIL;390
24.10.3;TNF-Alpha;390
24.10.4;JNK;391
24.11;Conclusion;392
24.12;References;392
25;Chapter 25: Macroautophagy;397
25.1;Introduction;397
25.2;Basic Biology of Autophagy;397
25.2.1;Morphological Studies of Macroautophagy;397
25.2.2;Molecular Machinery of Macroautophagy;398
25.3;The Physiological Role of Autophagy in Hepatocytes;400
25.3.1;Autophagy in Protein Metabolism;400
25.3.2;Glycogen Autophagy and Glucose Homeostasis;400
25.3.3;Autophagy in Lipid Metabolism;400
25.4;The Pathobiological Role of Autophagy in Liver Diseases;401
25.4.1;Autophagy in Alpha-1-Antitrypsin Deficiency;401
25.4.2;Autophagy in Hypofibrinogenemia;401
25.4.3;Autophagy in Alcoholic Liver Disease;402
25.4.4;Autophagy in Hepatic Carcinogenesis and Liver Cancer;402
25.5;Conclusion;403
25.6;References;403
26;Chapter 26: Hepatic Ischemia/Reperfusion Injury;405
26.1;Introduction;405
26.2;Warm Ischemia/Reperfusion Injury;405
26.2.1;Oxidant Stress;405
26.2.2;Transcription Factors;406
26.2.2.1;NF-kB;406
26.2.2.2;AP-1;408
26.2.2.3;JAK-STAT Pathway;408
26.2.2.4;Peroxisome Proliferator-Activated Receptors;409
26.2.3;Proinflammatory and Anti-inflammatory Mediators;409
26.2.3.1;Proinflammatory;410
26.2.3.1.1;IL-12;410
26.2.3.1.2;TNFa;410
26.2.3.1.3;IL-1;410
26.2.3.1.4;Chemokines;410
26.2.3.1.5;Platelet Activating Factor;410
26.2.3.1.6;TLR4 Ligands;411
26.2.3.2;Anti-inflammatory;411
26.2.3.2.1;IL-6;411
26.2.3.2.2;SLPI;411
26.2.3.2.3;Heme Oxygenase;411
26.2.3.2.4;Nitric Oxide;412
26.2.4;Lymphocytes;412
26.2.5;Neutrophil-Mediated Liver Injury;412
26.3;Recovery from Warm Ischemia/Reperfusion;413
26.3.1;Time Course and Cell Cycle Control;413
26.3.2;Chemokine Participation;413
26.4;Cold Ischemia–Reperfusion Injury;414
26.4.1;Sinusoidal Endothelial Cell (Sec) Apoptosis;414
26.4.2;Increased Platelet Adhesion;414
26.5;Recovery and Regeneration;414
26.5.1;Decreased Liver Regeneration;414
26.6;References;415
27;Chapter 27: Inflammation and Liver Injury;419
27.1;Introduction;419
27.2;Cells in the Liver and Inflammatory Response;419
27.2.1;Immune Cells in the Liver;419
27.2.2;Monocytes/Macrophages;419
27.2.3;Dendritic Cells;420
27.2.4;Neutrophils;421
27.2.5;NK and NKT Cells;421
27.2.6;Regulatory T Cells;421
27.2.6.1;Th17 Cells;421
27.2.7;Bone Marrow-Derived Stem Cells;422
27.3;Signaling Pathways and Liver Inflammation;422
27.3.1;Sensing Danger Signals;422
27.3.2;Toll-Like Receptors (TLRs);424
27.3.3;Helicase Receptors;424
27.3.4;NLRs and the Inflammasome;425
27.3.5;Intracellular Signaling Molecules;425
27.3.6;Apoptotic Pathways;425
27.3.7;Nuclear Receptors;426
27.3.8;B7 Family Members of Cell Surface Molecules;426
27.4;Liver Injury and Mediators of Inflammation;426
27.4.1;Oxidative Stress;426
27.4.2;Chemokines;427
27.4.3;Inflammatory and Immunoregulatory Cytokines;427
27.4.4;Adipokines;428
27.5;The Impact of Chronic Inflammation on the Liver;428
27.5.1;Inflammation and Fibrosis;428
27.5.2;Inflammation and Liver Cancer;428
27.6;Future Directions;428
27.7;References;429
28;Chapter 28: Oxidative Stress and Liver Injury;434
28.1;Introduction;434
28.2;Oxidative Stress and Signaling Pathways;434
28.2.1;Mitogen-Activated Protein Kinases;434
28.2.1.1;The RAS-RAF-MEK-ERK Pathway;435
28.2.1.2;The SAPK/JNK Pathway;436
28.2.1.3;The p38 Pathway;436
28.2.2;The BMK1 Signaling Pathway;437
28.2.2.1;Crosstalk Between the MAPK Signaling Pathways in Oxidative Stress;437
28.2.3;Nuclear Factor kB;437
28.3;Oxidative Stress and Liver Injury;438
28.3.1;Oxidative Stress and Acute Liver Injury: Acetominophen-Induced Oxidative Stress;438
28.4;Oxidative Stress and Chronic Liver Injury;438
28.4.1;Nonalcoholic Fatty Liver Disease;438
28.4.2;Alcoholic Liver Disease;439
28.5;Future Perspectives;439
28.6;References;440
29;Chapter 29: Fatty Liver;443
29.1;Introduction;443
29.2;What is Fatty Liver Disease?;443
29.3;What are the Causes of Fatty Liver Disease?;443
29.4;Histological Features of Fatty Liver Disease;444
29.5;Overview of the Molecular Pathogenesis of Fatty Liver Disease;444
29.5.1;Physiologic Effects of Insulin Relevant to Liver Metabolism;446
29.5.2;Role of Insulin Resistance in the Development of Fatty Liver;446
29.5.3;Cross Talk Between the Liver and other Organs in Fatty Liver Disease;446
29.6;Role of Signaling Pathways of Inflammation, Proinflammatory Cytokines and Adipokines;447
29.6.1;Overview of Lipid Handling in the Liver;447
29.6.1.1;Fatty Acid Uptake by the Liver;447
29.6.1.2;De Novo Lipogenesis;447
29.6.1.3;Oxidation of Fatty Acids;447
29.6.1.4;Export of Lipids from the Liver;448
29.6.2;Liver Transcription Factors and Nuclear Receptors;448
29.6.2.1;PPAR Family;448
29.6.2.2;ChREBP and SREBP;448
29.6.2.3;LXR;449
29.6.2.4;PXR, CAR, and FXR;449
29.6.3;Oxidative Stress and Lipid Peroxidation;449
29.6.4;Dysfunction of Intracellular Organelle in Fatty Liver Disease;449
29.6.5;Recent Advances;450
29.6.5.1;MicroRNA and Fatty Liver Disease;450
29.6.5.2;Endocannabinoids;450
29.6.5.3;Autophagy;450
29.7;References;450
30;Chapter 30: Hepatic Fibrosis and Cirrhosis;454
30.1;Introduction;454
30.2;Epidemiology and Etiology;454
30.3;Fibrosis Scoring Systems;455
30.4;Matrix Proteins of the Normal and Fibrotic Liver;456
30.5;Collagens in the Liver;457
30.6;Other Matrix Proteins Important in Fibrosis;459
30.7;The Cellular Source of Matrix Proteins: Myofibroblasts;460
30.8;The Cellular Source of Matrix Proteins: Nonmyofibroblastic Contributors;460
30.9;Stem Cells and Progenitor Cells in Fibrosis;461
30.10;Mediators of Fibrosis Progression;461
30.11;Progression from Fibrosis to Cirrhosis;463
30.12;Matrix Degradation;463
30.13;Regression;464
30.14;Clinical Features of Fibrosis and Cirrhosis;464
30.15;Fibrosis and Cirrhosis in the Future;465
30.16;References;465
31;Chapter 31: Biliary Cirrhosis;472
31.1;Introduction;472
31.2;Historical Perspectives;472
31.3;Evidence That BDE Mediate Biliary Cirrhosis;473
31.4;Evidence That Portal Fibroblasts/Myofibroblasts Mediate Biliary Cirrhosis;473
31.5;Secretion of Cytokines and Regulation of Portal Fibroblasts by Bile Duct Epithelia;473
31.6;Portal Fibroblasts as Regulators of Purinergic Signaling in Bile Duct Epithelia;474
31.7;Secretion of Cytokines and Regulation of Portal Fibroblasts by Bile Duct Epithelia;475
31.8;Lingering Questions and Future Directions;475
31.9;References;476
32;Chapter 32: Cholestasis;479
32.1;Introduction;479
32.2;Molecular Principles of Bile Formation as Basis for Understanding Cholestasis;479
32.3;Genetic Causes of Cholestasis;481
32.4;Acquired Changes in Hepatobiliary Transport and Metabolism in Cholestasis;483
32.5;Cytoskeletal and Other Hepatocellular Changes in Cholestasis;485
32.6;Summary and Conclusions;486
32.7;References;487
33;Chapter 33: Portal Hypertension;488
33.1;Introduction;488
33.2;Normal Physiology of Portal Circulation;488
33.2.1;Anatomy;488
33.2.2;Sinusoidal Microenvironment;488
33.3;Causes of Portal Hypertension;489
33.3.1;Common Causes;489
33.3.1.1;Cirrhosis;489
33.3.1.2;Extrahepatic Portal Vein Thrombosis;489
33.3.1.3;Schistosomiasis;489
33.3.1.4;Idiopathic Portal Hypertension;489
33.3.2;Less Common Causes;490
33.3.2.1;Nodular Regenerative Hyperplasia;490
33.3.2.2;Partial Nodular Transformation of the Liver;490
33.3.2.3;Sarcoidosis;490
33.3.2.4;Splanchnic Arteriovenous Fistula;490
33.4;Mechanical Factors in Pathophysiology of Portal Hypertension;490
33.5;Vascular Basis of Portal Hypertension;491
33.5.1;Intrahepatic Vasoconstriction/Impaired Responsiveness to Vasodilation;491
33.5.1.1;Increased Vascular Tone of Sinusoids;491
33.5.1.2;Endothelial Dysfunction;491
33.5.1.2.1;Oxidative Stress;491
33.5.1.2.2;Inflammation;492
33.5.1.3;Hepatic Stellate Cell;492
33.5.1.4;Decreased Production of Nitric Oxide;493
33.5.1.4.1;Background;493
33.5.1.4.2;Mechanism of Action;493
33.5.1.4.3;Inadequate Nitric Oxide;493
33.5.1.4.4;HSC Resistance to NO-Mediated Relaxation;493
33.5.1.4.5;Potential NO Therapy;493
33.5.1.5;Increased Vasoconstrictor Activity;494
33.5.1.5.1;Increased Endothelin Activity;494
33.5.2;Splanchic Vasodilation;494
33.5.2.1;Role of NO;494
33.5.2.2;NO-Independent Mechanisms of Splanchnic Arteriolar Relaxation;495
33.5.3;Collateral Vessel Flow;495
33.6;Conclusions;496
33.7;References;496
34;Chapter 34: Nonalcoholic Fatty Liver Disease;501
34.1;Introduction;501
34.1.1;Overview of Nonalcoholic Fatty Liver Disease;501
34.2;Development of Hepatic Steatosis;501
34.2.1;Abnormal Lipid Metabolism;501
34.2.1.1;Increased DNL in the Liver;501
34.2.1.2;Increased Lipolysis of Adipose Tissue;502
34.2.1.3;Impaired Fatty-Acid Metabolism;502
34.2.2;Altered Insulin Signaling;503
34.2.3;Endocannabinoids Signaling;504
34.2.4;MicroRNA Signaling and Its Emerging Role in Lipid Metabolism;504
34.3;Mechanism of Cell Injury;505
34.3.1;FFA-Induced Cellular Lipotoxicity: A Manifestation of Oxidative Stress and Mitochondrial Dysfunction;505
34.3.2;Endoplasmic Reticulum Stress and the Unfolded Protein Response;506
34.3.3;Mechanism of Cell Injury: Interactions Between Macrophages and Adipocytes;507
34.3.4;Innate Immunity, Role of Cytokines and Adipokines;507
34.4;Molecular Basis of Fibrosis;508
34.4.1;Hepatic Stellate Cell Activation;508
34.5;Genetic Polymorphisms;509
34.6;Summary;509
34.7;References;509
35;Chapter 35: Alcoholic Liver Disease;512
35.1;Introduction;512
35.2;Primer on the Histopathology of Alcoholic Liver Disease;512
35.3;Molecular Pathology of ALD;512
35.3.1;Microarrays and Global Changes in Gene Expression;513
35.3.1.1;Microarray Analysis in Animal Studies;513
35.3.1.2;Microarrays of Tissue Cultures Treated with Ethanol;517
35.3.1.3;Microarray Studies on Human ALD;517
35.3.2;Single Signaling Pathways;518
35.3.3;Mechanisms Involved in Ethanol-Induced Fatty Liver;519
35.3.4;Role of the Proteasome in ALD;520
35.3.4.1;Mallory-Denk body Pathogenesis;521
35.3.4.2;Microarray Analysis of Liver Forming MDBs;522
35.3.5;Ethanol-Induced Fibrosis of the Liver;522
35.3.5.1;Innate Immunity and Fibrosis;523
35.3.5.2;Epigenetic Changes in the Stellate Cells;523
35.3.6;Genetic Polymorphism Predisposition to ALD;523
35.4;References;524
36;Chapter 36: Viral Hepatitis A;528
36.1;Introduction;528
36.2;History;528
36.3;Virology;528
36.3.1;Classification;528
36.3.2;Structure;528
36.3.2.1;Physiochemical Characteristics;528
36.3.2.2;Morphology;529
36.3.3;Genome Organization;529
36.3.3.1;Genome and Proteins;529
36.3.3.2;In Vitro Culture, Virus–Cell Interactions, and Replication Cycle;531
36.3.3.3;Genomic Variability of HAV;533
36.3.3.4;Recombination in HAV;533
36.3.3.5;Quasispecies Nature and Evolution of HAV;533
36.3.3.6;Antigenicity and Serotype;534
36.4;Host Range;534
36.5;Epidemiology;534
36.5.1;Modes of Transmission;534
36.5.1.1;Person to Person;535
36.5.1.2;Foodborne and Waterborne;535
36.5.1.3;Blood-Borne;535
36.5.1.4;Vertical;535
36.5.2;Specific Groups and Settings;535
36.5.2.1;Child Care Centers, Schools, and Institutions;535
36.5.2.2;Users of Illicit Drugs;536
36.5.2.3;Homosexuality;536
36.5.2.4;Transfusions and Other Health Care Settings;536
36.5.2.5;International Travel;536
36.5.2.6;Foodborne and Waterborne;536
36.5.3;Incidence and Prevalence and Worldwide Disease Patterns;536
36.6;Pathogenesis;538
36.6.1;Incubation Period;538
36.6.2;Viral Replication;538
36.6.3;Pathogenesis and Natural History of HAV Infection;539
36.7;Immune Response;540
36.8;Pathology;541
36.9;Clinical Features;541
36.9.1;Symptoms;541
36.9.2;Complications;542
36.9.2.1;Prolonged Cholestatic Hepatitis;542
36.9.2.2;Relapsing Hepatitis A;542
36.9.2.3;Coinfection of HAV with Other Hepatotropic Viruses;542
36.9.2.4;Acute HEV Superinfection in Patients with Cirrhosis;543
36.9.2.5;Fulminant Hepatic Failure;543
36.9.2.6;Other Complications;543
36.10;Diagnosis and Detection of HAV;543
36.10.1;Approaches to HAV Detection;543
36.10.1.1;Detection of HAV-Specific Antibodies;543
36.10.1.2;Virus or Viral Component Detection;544
36.10.2;Laboratory Diagnosis;544
36.10.3;Detection from Water and Food;545
36.11;Therapy and General Management;545
36.12;Prevention;546
36.12.1;General Measures;546
36.12.2;Passive Immunoprophylaxis;546
36.12.3;Active Immunoprophylaxis;547
36.13;Summary, Conclusions, and Directions for the Future;548
36.14;References;548
37;Chapter 37: Viral Hepatitis B;554
37.1;Introduction;554
37.2;Natural History and Pathogenesis;555
37.3;HBV Vaccine;555
37.4;Hepatocellular Carcinoma;556
37.5;HBX and the Pathogenesis of HCC;556
37.6;Immune Mediated Pathogenesis of HCC;557
37.7;HBV DNA Integration and HCC;559
37.8;HBX and Epigenetic Mechanisms of HCC;560
37.9;HBx Overcomes Apoptosis in Chronic Infection;561
37.10;HBX and Innate Immunity;563
37.11;HBX and Senescence;563
37.12;Conclusions and Prospects;564
37.13;References;565
38;Chapter 38: Viral Hepatitis C;569
38.1;Introduction;569
38.2;Natural History of Chronic Hepatitis C;569
38.3;Immunopathogenesis of Hepatitis C;570
38.3.1;Immune Contribution to Liver Injury;570
38.3.2;Role of Adaptive Immune Responses;570
38.3.2.1;CD8+ Cytotoxic T Cells;570
38.3.2.2;T Helper and Treg Cells;571
38.3.2.3;Dendritic Cells;572
38.3.3;Innate Immunity;572
38.3.3.1;NK, NT and NKT Cells;572
38.3.3.2;Cytokines and Chemokines;573
38.4;Metabolic Consequences of HCV Infection;574
38.4.1;Steatosis and Insulin Resistance;574
38.4.2;Mechanisms of HCV-Induced Steatosis;574
38.4.2.1;Defects in Lipoprotein Assembly and Export;575
38.4.2.2;Alterations in Lipid Synthesis;575
38.4.2.3;Effects on Fatty Acid Uptake and Oxidation;575
38.4.3;Mechanisms of HCV-Induced Insulin Resistance;576
38.4.4;Mechanisms of HCV-Induced Oxidative Stress;576
38.4.5;Fibrogenesis;577
38.5;Effects of HCV on Cell Cycle Regulation and Growth Control;577
38.5.1;HCV-Induced Alteration of the Cell Cycle Control;578
38.5.1.1;HCV Effects on p53;578
38.5.1.2;HCV Effects on Rb;578
38.5.1.3;HCV and Cdks;578
38.5.2;HCV Alterations of Proliferation Signaling Pathways;579
38.5.2.1;PI3K/Akt;579
38.5.2.2;MAP Kinases;579
38.5.2.3;Wnt/b-Catenin Pathway;580
38.5.2.4;TGF-b and Epithelial to Mesenchymal Transition;580
38.5.3;HCV and DNA Repair;580
38.6;Conclusions and Perspectives;580
38.7;References;581
39;Chapter 39: Viral Hepatitis D;589
39.1;Introduction;589
39.2;Pathology in Patients;591
39.3;Pathology in Experimental Animals;591
39.4;Pathogenesis in Cultured Cells;592
39.5;Analogy to Plant Viroids;593
39.6;Prevention;593
39.7;Treatment;593
39.8;Summary and Outlook;593
39.9;References;594
40;Chapter 40: Viral Hepatitis E;596
40.1;Introduction;596
40.2;History;596
40.3;Virology;596
40.3.1;Classification;596
40.3.2;Structure;596
40.3.2.1;Physiochemical Characteristics;596
40.3.2.2;Morphology;596
40.3.3;Genome Organization;597
40.3.3.1;Genome and Proteins;597
40.3.3.2;Replication Cycle;599
40.3.3.3;Genomic Variability of HEV;600
40.3.3.4;Distribution of HEV Genotypes;600
40.3.3.5;Quasispecies Nature and Evolution of HEV;601
40.3.3.6;Serotypes and Antigenicity;602
40.3.3.7;Animal Models and In Vitro Culture;602
40.4;Epidemiology;602
40.4.1;Incidence and Prevalence and Worldwide Disease Patterns;602
40.4.1.1;HEV in Endemic Regions;602
40.4.1.2;HEV in Nonendemic Regions;603
40.4.2;Modes of Transmission;604
40.4.3;Specific Groups and Settings;605
40.4.3.1;Persons Having Contact with Swine and Untreated Waste Water;605
40.4.3.2;HIV-Infected Persons;605
40.4.3.3;Transfusions and Other Health Care Settings;605
40.4.3.4;HEV Infection as a Zoonosis;605
40.5;Pathogenesis;606
40.5.1;Incubation Period;606
40.5.2;Viral Replication;606
40.5.3;Pathogenesis;607
40.6;Immune Response;608
40.7;Pathology;608
40.8;Clinical Features;609
40.8.1;Symptoms;609
40.8.2;Anicteric Hepatitis and Asymptomatic Infection;610
40.8.3;Chronicity;610
40.8.4;Complications;610
40.8.4.1;Prolonged Cholestatic Hepatitis;610
40.8.4.2;Fulminant Hepatic Failure;610
40.8.4.3;Acute HEV Superinfection in Patients with Cirrhosis;611
40.8.4.4;Pregnant Women;611
40.8.4.5;Coinfection of HEV with Other Hepatotropic Viruses;612
40.8.4.6;Other Complications;612
40.8.5;Autochthonous HEV in Developed Countries;612
40.8.6;Clinical Significance of HEV Genotype;612
40.9;Diagnosis and Detection of HEV;613
40.9.1;Approaches to HEV Detection;613
40.9.1.1;Virus or Viral Component Detection;613
40.9.1.2;Serological Assays;613
40.9.2;Laboratory Diagnosis;613
40.9.3;Differential Diagnosis;614
40.10;Natural History;614
40.11;Therapy and General Management;614
40.12;Prevention;614
40.12.1;General Measures;614
40.12.2;Passive Immunoprophylaxis;614
40.12.3;Active Immunoprophylaxis;615
40.13;Summary, Conclusions, and Directions for the Future;616
40.14;References;616
41;Chapter 41: Autoimmune Hepatitis;622
41.1;Introduction;622
41.2;Types of Autoimmune Hepatitis;623
41.3;Determinants of Antigen Selection and Recognition;624
41.3.1;Nature of the Antigen-Binding Groove;625
41.3.2;Genetic Determinants of the Antigen-Binding Groove;625
41.3.3;Antigen Selection and Presentation;625
41.3.4;Diverse Susceptibility Alleles for Type 1 Autoimmune Hepatitis;625
41.3.5;Protective Genetic Factors for Type 1 Autoimmune Hepatitis;626
41.3.6;Genetic Associations with Type 2 Autoimmune Hepatitis;626
41.3.7;Antigen Recognition;627
41.4;Candidate Autoantigens;627
41.5;Disturbances in Immunocyte Activation;628
41.6;Disturbances in Immunocyte Differentiation;628
41.7;Factors Influencing the Intensity of the Immune Response;629
41.7.1;“Gene Dosing”;629
41.7.2;Modifying Cell Populations;630
41.7.3;Chemo-Attractant Molecules;631
41.7.4;Programmed Cell Death (Apoptosis);632
41.8;Nonspecific Factors Influencing the Clinical Phenotype;632
41.9;Conclusions;633
41.10;References;633
42;Chapter 42: Toxicant-Induced Liver Injury;639
42.1;Introduction;639
42.2;Mode of Cell Death During Drug Hepatotoxicity;639
42.3;Intracellular Signaling Mechanisms of Drug-Induced Cell Death;640
42.3.1;Protein Binding Hypothesis;640
42.3.2;Lipid Peroxidation;641
42.3.3;Mitochondrial Dysfunction;641
42.3.4;Mitochondrial Oxidant Stress;641
42.3.5;Nuclear DNA Damage;643
42.3.6;Initiation of Mitochondrial Dysfunction;643
42.4;Drug Hepatotoxicity and Innate Immunity;644
42.4.1;Kupffer Cells;644
42.4.2;Natural Killer and NKT Cells;644
42.4.3;Polymorphonuclear Leukocytes (Neutrophils);644
42.4.4;Neutrophils and Kupffer Cells in Regeneration;645
42.5;Sterile Inflammation and Drug Hepatotoxicity;645
42.6;Idiosyncratic Drug-Induced Liver Injury;646
42.7;Summary;647
42.8;References;647
43;Chapter 43: Wilson’s Disease;652
43.1;Introduction;652
43.2;Copper Metabolism and the Pathogenesis of Wilson Disease;652
43.3;Copper Toxicity;653
43.4;Pathology;654
43.5;Epidemiology;656
43.6;Diagnosis;656
43.7;Treatment;657
43.8;References;659
44;Chapter 44: Hemochromatosis;661
44.1;Introduction;661
44.2;Iron Deposition Patterns in Hemochromatosis;662
44.3;Overview of Iron Metabolism;662
44.4;Liver Iron Transport;662
44.5;Transferrin-Bound Iron Uptake;662
44.5.1;High-Affinity Uptake: Transferrin Receptor 1;662
44.5.2;Low-Affinity Uptake: Transferrin Receptor 2;663
44.6;Non-Transferrin Bound Iron Uptake;663
44.7;Iron Release;663
44.8;HFE and Liver Iron Transport;664
44.9;Liver Iron Transport in Hereditary Hemochromatosis;664
44.10;Hepcidin is a Central Regulator of Iron Homeostasis;664
44.11;Iron and Oxidative Stress;666
44.12;Lipid Peroxidation;667
44.13;DNA and Protein Damage;667
44.14;Iron, ROS, and Cell Signaling;667
44.15;Immune Responses in Hemochromatosis;668
44.16;The Role of Iron in Fibrogenesis;668
44.17;References;669
45;Chapter 45: Glycogen Storage Diseases;673
45.1;Introduction;673
45.2;Etiology;673
45.3;Types of Glycogen Storage Diseases;673
45.3.1;Clinical Features of GSDS;673
45.3.1.1;Type 1 GSD;673
45.3.1.2;Type II GSD;674
45.3.1.3;Type III GSD;675
45.3.1.4;Type IV GSD;675
45.3.1.5;Type V and VII GSD;675
45.3.1.6;Type VI and IX GSD;675
45.3.1.7;Type VIII and X GSD;675
45.4;Molecular Mechanisms;675
45.5;References;677
46;Chapter 46: a1-Antitrypsin Deficiency;678
46.1;Introduction;678
46.2;AT Structure;679
46.3;The Protease Inhibitor System for Classification of Structural Variants of AT;679
46.4;Function of AT;680
46.5;Biosynthesis of AT;681
46.6;Clearance and Tissue Distribution of AT;681
46.7;Mechanism for Decreased Serum levels of AT and Fate of Mutant AT in PIZZ Individuals;682
46.8;Pathogenesis of Liver Injury in PIZZ Individuals;683
46.9;Mechanism of Liver-Cell Injury in AT deficiency;686
46.10;Mechanism of Hepatic Carcinogenesis in AT Deficiency;687
46.11;Liver Disease: Clinical Manifestations;688
46.12;Diagnosis;689
46.13;Treatment;689
46.14;References;690
47;Chapter 47: Hepatic Artery Diseases;696
47.1;Introduction;696
47.2;Hepatic Artery Aneurysms;696
47.2.1;Prevalence and Etiology;696
47.2.2;Clinical Features;697
47.2.3;Diagnosis;697
47.2.4;Treatment and Outcome;698
47.3;Hepatic Artery Thrombosis;698
47.3.1;Prevalence and Etiology;698
47.3.1.1;Early Hepatic Artery Thrombosis;698
47.3.1.2;A Role for the Hemostatic System?;699
47.3.1.3;Late Hepatic Artery Thrombosis;699
47.3.1.4;A Role for the Hemostatic System?;700
47.3.2;Clinical Features;700
47.3.2.1;Early Hepatic Artery Thrombosis;700
47.3.2.2;Late Hepatic Artery Thrombosis;700
47.3.3;Diagnosis;700
47.3.3.1;Early Hepatic Artery Thrombosis;700
47.3.3.2;Late Hepatic Artery Thrombosis;700
47.3.4;Treatment and Possible Prophylactic Options;701
47.3.4.1;Early Hepatic Artery Thrombosis;701
47.3.4.2;Late Hepatic Artery Thrombosis;701
47.4;References;701
48;Chapter 48: Hepatic Venous Outflow Obstruction;704
48.1;Introduction;704
48.2;Congestive Hepatopathy;705
48.2.1;Clinical Features;706
48.2.2;Laboratory Findings;706
48.2.3;Pathology;707
48.2.4;Diagnosis;707
48.2.5;Treatment and Prognosis;707
48.2.6;Constrictive Pericarditis;708
48.3;Budd-Chiari Syndrome;708
48.3.1;Epidemiology;708
48.3.2;Classification and Etiology;708
48.3.2.1;Myeloproliferative Disorders or Prothrombotic Conditions;709
48.3.3;Pathogenesis and Pathophysiology;709
48.3.4;Pathology;710
48.3.5;Clinical and Laboratory Findings;710
48.3.6;Prognosis and Survival;711
48.3.7;Diagnosis;712
48.3.7.1;Real-Time and Doppler Ultrasonography;712
48.3.7.2;Computed Tomography;712
48.3.7.3;Venography;712
48.3.7.4;Liver Biopsy;713
48.3.8;Differential Diagnosis;713
48.3.9;Treatment;714
48.3.10;Medical Therapy;714
48.3.11;Restoration of Hepatic Blood Flow;715
48.4;Veno-Occlusive Disease (Sinusoidal Obstruction Syndrome);715
48.4.1;Clinical Presentation;716
48.4.2;Risk Factors;716
48.4.3;Histology and Pathophysiology;716
48.4.4;Treatment;716
48.5;Conclusion;716
48.6;References;717
49;Chapter 49: Primary Biliary Cirrhosis;720
49.1;Introduction and Clinical Features;720
49.2;Sex Factors and PBC;720
49.3;PBC Immunobiology;722
49.3.1;Antimitochondrial Antibodies;722
49.3.2;Antinuclear Antibodies;723
49.3.3;Autoreactive T Cells;723
49.3.4;Innate Immune Cells;723
49.3.5;T Regulatory Cells;725
49.4;Individual Susceptibility to PBC;725
49.4.1;Genetic Considerations in PBC;725
49.4.2;Association Studies;726
49.4.3;Environmental Considerations in PBC;727
49.4.4;Infectious Agents and PBC;728
49.4.5;Chemicals and PBC;728
49.5;PBC Animal Models;729
49.6;The Resulting Pathogenesis of PBC;729
49.7;Open Issues in PBC Pathogenesis;730
49.8;References;730
50;Chapter 50: Primary Sclerosing Cholangitis;735
50.1;Introduction;735
50.2;Clinical Features;735
50.2.1;Epidemiology;735
50.2.2;Pathophysiology;735
50.2.3;Genetic Factors;736
50.2.4;Clinical Manifestations;736
50.2.5;Biochemical Features;736
50.2.6;Serologic Features;737
50.2.7;Radiographic Features;737
50.2.8;Histologic Features;738
50.3;Disease-Modifying Treatments;738
50.3.1;Ursodeoxycholic Acid;738
50.3.2;Immunosuppressive Agents;738
50.3.3;Other Agents;739
50.3.4;Combination Therapy;739
50.3.5;Innovative Approaches to Medical Therapy;739
50.3.6;Endoscopic Therapy;739
50.3.7;Biliary Surgery;740
50.3.8;Liver Transplantation;740
50.4;Disease-Related Malignancy;740
50.4.1;Cholangiocarcinoma;740
50.4.2;Hepatocellular Carcinoma;741
50.4.3;Colonic Dysplasia and Carcinoma;741
50.4.4;Gallbladder Neoplasia;741
50.5;Conclusions;741
50.6;References;742
51;Chapter 51: Biliary Atresia;747
51.1;Introduction;747
51.2;Epidemiology;747
51.3;Clinical Features;747
51.3.1;At Presentation;747
51.3.2;During Progression of Disease;748
51.3.3;Recognizable Phenotypes of Disease;748
51.3.3.1;Perinatal Form of Biliary Atresia;748
51.3.3.2;Embryonic Form of Biliary Atresia;748
51.3.3.3;Cystic Variant of Biliary Atresia;748
51.4;Diagnosis;749
51.4.1;Laboratory Studies;749
51.4.2;Radiological Studies;749
51.4.3;Histopathology;749
51.4.4;Exploratory Laparotomy and Cholangiography;750
51.5;Pathogenesis of Disease;750
51.5.1;Defect in Morphogenesis;750
51.5.2;Defect in Fetal/Prenatal Circulation;751
51.5.3;Exposure to Environmental Toxins;752
51.5.4;Viral Infection;752
51.5.5;Immune-Mediated Injury;752
51.5.5.1;Human Studies;752
51.5.5.2;Animal Studies;753
51.6;Treatment;754
51.6.1;Portoenterostomy;754
51.6.2;Medical Treatment Following Portoenterostomy;754
51.7;Complications and Sequelae;755
51.8;Long-Term Outcome and Liver Transplantation;755
51.8.1;Long-Term Outcome;755
51.8.2;Liver Transplantation;755
51.9;References;756
52;Chapter 52: Benign Liver Tumors;761
52.1;Introduction;761
52.2;Focal Nodular Hyperplasia;761
52.2.1;Clinical and Pathological Characteristics;761
52.2.2;Epigenetic and Genetic Features in FNH;761
52.2.3;Signaling Pathways Altered in FNH;762
52.3;Hepatocellular Adenomas;763
52.3.1;Clinical and Pathological Features of HCA;763
52.3.2;First Subtype of Adenoma: HNF1a Inactivated HCA (H-HCA);763
52.3.3;Second Subtype of Adenoma: b-Catenin Activated Adenomas (bHCA);763
52.3.4;Third Subtype of Adenoma: Inflammatory Adenoma (IHCA);764
52.4;Conclusion;764
52.5;References;765
53;Chapter 53: Hepatoblastoma;768
53.1;Introduction;768
53.2;Etiological Factors and Associated Conditions;768
53.3;Presentation, Clinical Staging and Treatment;769
53.4;Pathological Classification;770
53.4.1;Epithelial Types;770
53.4.2;Mixed Epithelial and Mesenchymal Types;771
53.5;Immunohistochemical Markers for HB Diagnosis and Prognosis;771
53.6;Genetic Alterations in Hepatoblastoma;772
53.7;Mutational Activation of b-Catenin;775
53.8;Oncogenic Pathways in HB;776
53.9;Molecular Classification of Hepatoblastoma;777
53.10;Conclusion;778
53.11;References;778
54;Chapter 54: Hepatocyte Growth, Proliferation and Experimental Carcinogenesis;782
54.1;Introduction;782
54.2;Autonomy and Timing of the Proliferative Process in Liver Hyperplasia;785
54.3;Spatial Distribution of Replicating Hepatocytes;785
54.4;Liver Ploidy;786
54.5;Gene Expression During Liver Hyperplasia;787
54.5.1;Immediate Early Genes/Transcription Factors;787
54.6;Termination of Liver Hyperplasia;790
54.7;Potential Efficacy of Primary Mitogens in the Context of Liver Regeneration in the Elderly and Living Related Transplantation;790
54.8;Cell Proliferation and Hepatocarcinogenesis;792
54.9;Genetically Engineered Models;795
54.9.1;C-Met;795
54.9.2;WNT-b/Catenin;796
54.9.3;C-Myc;796
54.9.4;C-Jun;797
54.9.5;P53;797
54.9.6;Why Experimental Carcinogenesis is Still Important;798
54.10;Conclusions and Perspectives;798
54.11;References;799
55;Chapter 55: Stem Cells and Liver Cancer;805
55.1;Liver Cancer Stem Cells;805
55.1.1;Immortality;805
55.1.1.1;Rat Hepatomas;805
55.1.1.2;Human HCC;806
55.1.2;Tumor Transplantation;807
55.1.3;Resistance to Therapy;807
55.1.3.1;Radiation Therapy of Morris Hepatomas;808
55.1.3.2;Nature of Therapy-Resistant Cells;808
55.1.4;Markers of LCSC;808
55.1.4.1;Stem Cell Transcription Factors;808
55.1.4.2;Cell Surface Markers;809
55.1.4.3;Side Population Cells;809
55.1.5;Summary;809
55.2;The Stem Cell Origin of Liver Cancer;809
55.2.1;Experimental Chemical Hepatocarcinogenesis;809
55.2.1.1;Dedifferentiation;810
55.2.1.2;Oval Cells;810
55.2.1.3;Blocked Ontogeny;810
55.2.1.4;Alpha-Fetoprotein: A Marker for Early Cellular Events in Chemical Hepatocarcinogenesis;811
55.2.1.5;Choline Deficiency (CD);812
55.2.1.6;Cyclic N-2 Acetylaminofluorene;812
55.2.1.7;Solt-Farber Model;812
55.2.1.8;Diethylnitrosamine;813
55.2.2;Liver-Cell Lineage and HCC;813
55.2.2.1;Mouse Hepatoblastomas;813
55.2.2.2;Human Hepatoblastoma;814
55.2.2.3;Human Hepatocellular Carcinoma;814
55.3;Summary and Conclusions;815
55.4;References;815
56;Chapter 56: Primary Hepatocellular Carcinoma;820
56.1;Introduction;820
56.1.1;Epidemiology;820
56.1.2;Etiology and Risk Factors;820
56.2;Genomics and Carcinogenesis;821
56.2.1;Mutations and Chromosomal Aberrations in HCC;821
56.2.1.1;Genomic Changes in HCC;821
56.2.1.2;Frequent Mutations in HCC;821
56.2.1.3;Genetic Alterations Specific to Etiological Factors;822
56.2.1.3.1;HBV;822
56.2.1.3.2;Aflatoxin B1;822
56.2.1.3.3;Vinyl Chloride;822
56.2.2;MicroRNAs;822
56.2.3;Telomeres and Telomerase;822
56.3;Cell Signaling in HCC;823
56.3.1;p53 Pathway;823
56.3.2;WNT/b-Catenin Pathway;824
56.3.3;Sonic Hedgehog Signaling;824
56.3.4;Inflammation and HCC;825
56.3.4.1;Inflammatory Pathways in HCC;825
56.3.4.1.1;NFkB;825
56.3.4.1.2;IL-6 and JAK-STAT3 Signaling;825
56.3.5;Liver Stem Cells;826
56.4;Angiogenesis in HCC;827
56.4.1;Cellular Actors of Angiogenesis;827
56.4.2;Modes of Tumor Vascularization;828
56.4.3;Vascular Characteristics of HCC;828
56.4.4;Angiogenic Pathways in HCC;828
56.4.4.1;VEGF Signaling;828
56.4.4.2;Angiopoietin;829
56.4.4.3;Notch-Deltalike Ligand 4 (D114);829
56.4.4.4;(Tumor)Cell–Matrix Interactions;829
56.5;HCC Classification;830
56.5.1;Edmondson and Steiner Grading;830
56.5.2;HCC Signature – Molecular Profiling of HCC;830
56.6;Therapeutic Considerations;831
56.7;References;831
57;Chapter 57: Fibrolamellar Hepatocellular Carcinoma;838
57.1;Epidemiology and Clinical Features;838
57.2;Imaging Characteristics;839
57.3;Etiology;839
57.4;Pathologic Features;839
57.4.1;Gross Features;839
57.4.2;Microscopic Features;840
57.4.3;Histochemistry;840
57.4.4;Immunohistochemistry;840
57.4.5;Ultrastructural Features;841
57.5;Differential Diagnosis;841
57.5.1;Conventional HCC;841
57.5.2;Adenocarcinoma (Cholangiocarcinoma or Metastatic Adenocarcinoma);841
57.5.3;Neuroendocrine Tumors;841
57.5.4;Angiomyolipoma;842
57.5.5;Melanoma;842
57.5.6;Other;842
57.6;Genetic Features;842
57.7;Natural History and Treatment;843
57.8;Prognosis and Survival;843
57.9;References;844
58;Chapter 58: Biology of Metastatic Liver Tumors;847
58.1;Introduction;847
58.2;The Metastatic Cascade;847
58.3;Histology of Metastatic Carcinomas;849
58.4;Phenotypic Plasticity of Cancer Cells;850
58.5;Tumor Microenvironment;850
58.6;Tumor Dormancy;851
58.7;Investigative Models of Liver Metastases;852
58.8;Conclusions;853
58.9;References;853
59;Chapter 59: Cholangiocarcinoma;855
59.1;Introduction;855
59.2;The Process of Cholangiocarcinogenesis;855
59.3;Genetic Alterations;856
59.3.1;K-ras and p53;856
59.3.2;NKG2D;856
59.3.3;Activation-Induced Cytidine Deaminase;857
59.4;Cellular Senescence;857
59.5;Epigenetic Dysregulation;857
59.5.1;DNA Methylation;857
59.5.2;p16INK4A;857
59.5.3;Ras Association Domain Family 1A;857
59.5.4;Human mutL Homologue 1;859
59.5.5;Other Hyper-Methylated Genes;859
59.5.6;Histone Modifications;859
59.6;Molecular Cellular Pathways;859
59.6.1;Initiation of the Malignant Process;859
59.6.2;IL-6 and Mcl-1;859
59.7;Transforming Growth Factor-b;861
59.7.1;DCP4/Smad4;861
59.7.2;c-Met/Hepatocyte Growth Factor;861
59.7.3;ErbB-2;861
59.7.4;Glutathione;861
59.7.5;COX-2;862
59.7.6;Nitric Oxide;862
59.7.7;Bile Acids;862
59.8;Apoptosis and Cholangiocarcinoma;863
59.9;Invasion and Progression of Cholangiocarcinoma;863
59.10;Epithelial-to-Mesenchymal Transition of Cholangiocarcinoma Cells;864
59.11;MicroRNA and Cholangiocarcinoma;864
59.12;Molecular Differences Between Intra and Extrahepatic CC;865
59.13;Conclusion;865
59.14;References;865
60;Chapter 60: Neoplasms of Extrahepatic Bile Ducts;869
60.1;Epidemiology;869
60.2;Risk Factors;869
60.2.1;Primary Sclerosing Cholangitis and Ulcerative Colitis;869
60.2.2;Congenital Biliary Cyst Disease and Abnormal Choledochal-pancreatic Duct Junction;869
60.2.3;Hepatolithiasis;870
60.2.4;Infections;870
60.2.5;Miscellaneous;870
60.3;Histogenesis;870
60.3.1;Flat Biliary Dysplasia (Biliary Intraepithelial Neoplasia);870
60.3.2;Intraductal Papillary Neoplasms of Bile Ducts;871
60.4;General Anatomic-Clinical Consideration;871
60.5;Molecular and Genetic Alteration;872
60.5.1;Cell Cycle Proteins;873
60.5.2;Tumor Suppressor Genes;873
60.5.3;Cell Adhesion Proteins;874
60.5.4;Mucin-Related Glycoproteins;874
60.5.5;Matrix Proteins;875
60.5.6;Miscellaneous;875
60.6;Summary;876
60.7;References;876
61;Chapter 61: Neoplasms of the Gallbladder;879
61.1;Epidemiology;879
61.2;Risk Factors;879
61.2.1;Gallstones;879
61.2.2;Diet and Obesity;879
61.2.3;Pollutants and Environmental Factors;879
61.2.4;Gender;879
61.2.5;Bile Infections;880
61.2.6;Porcelain Gallbladder;880
61.3;Anomalous Pancreaticobiliary Ductal Junction;880
61.4;Histogenesis – Precancers;880
61.4.1;Metaplasia-Dysplasia-Carcinoma Sequence (Flat Dysplasia; Intraepithelial Neoplasia);881
61.4.2;Adenoma-Carcinoma Sequence (Mass-Forming Preinvasive Neoplasia);881
61.5;General Considerations for Invasive Carcinoma;882
61.6;Molecular Genetic Alterations in Neoplastic Lesions;882
61.6.1;Oncogenes;882
61.6.1.1;K-ras;882
61.6.1.2;p21/CDKN1A;883
61.6.1.3;C-erb-B2;883
61.6.1.4;Cyclin D1 and Cyclin E;883
61.6.2;Tumor Suppressor Genes;883
61.6.2.1;TP53;883
61.6.2.2;p16/CDKN2/INK4;883
61.6.2.3;Fragile Histidine Triad Gene;884
61.6.2.3.1;Other Tumor Suppressor Genes;884
61.6.3;Microsatellite Instability (MSI);884
61.6.4;Adhesion Molecules;884
61.6.4.1;Cadherin-catenin Complex;884
61.6.4.2;ICAM-1/CD54;885
61.6.4.3;CD44;885
61.6.4.4;CD99 (Mic2);885
61.6.4.5;CEA;885
61.6.4.6;NCAM/CD56;885
61.6.5;Epigenetic Alterations;886
61.6.6;Genetic Susceptibility, Polymorphisms, and Biomarkers;886
61.6.7;Inflammation and Molecular Carcinogenesis;886
61.6.7.1;Mitochondrial DNA Mutations (mt DNA);886
61.6.7.2;Inducible Nitric Oxide Synthase (iNOS);887
61.6.7.3;Cyclooxigenase-2 (COX-2);887
61.6.8;Others Genes;887
61.6.8.1;Angiogenesis and Vascular Endothelial Growth Factor (VEGF);887
61.6.8.2;hTERT/Telomere Aging and GBC;888
61.7;Conclusion;888
61.8;References;888
62;Chapter 62: Current and Future Methods for Diagnosis of Neoplastic Liver Disease;894
62.1;Introduction;894
62.2;Case Presentations;894
62.2.1;Case 1;894
62.2.1.1;Clinical Background;894
62.2.1.2;Radiologic Assessment;894
62.2.1.3;Pathologic Assessment;894
62.2.2;Case 2;894
62.2.2.1;Clinical Background;894
62.2.2.2;Radiologic Assessment;895
62.2.2.3;Pathologic Assessment;895
62.3;Radiologic Approaches to Diagnosing Neoplastic Liver Disease;895
62.4;Pathologic Assessment of Neoplastic Liver Disease;897
62.4.1;Current Methods in Obtaining Liver Tissue for Diagnosis;897
62.4.2;Current Methods in the Diagnosis of Liver Diseases and Tumors;897
62.5;Molecular Pathology Assessment of Neoplastic Liver Disease;900
62.5.1;Molecular Evaluation of Neoplastic Liver Diseases;900
62.5.2;MicroRNAS;900
62.5.3;MicroRNAS and Neoplastic Liver Diseases;901
62.5.4;Cancers of Unknown Primary;901
62.5.5;Molecular Applications for Targeted Therapy in Neoplastic Liver Disease;901
62.6;References;902