Cell death and cell death responses in liver disease: Mechanisms and clinical relevance

Gastroenterology

Volumn 147, Issue 4, 2014, Pages 765-783.e4

  Luedde, Tom ^a   Kaplowitz, Neil ^b   Schwabe, Robert F ^c  

^a UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^c Och Spine at New York Presbyterian Hospitals   (United States)

Author keywords

Alcoholic Liver Disease; Apoptosis; DILI Caspases; Hepatitis NASH Clinical; Necrosis Necroptosis; Necrosome DAMP Viral; RIP3 RIP Kinases; Trial Hepatocellular Carcinoma

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; BILE ACID; BIOLOGICAL MARKER; CARBAMOYL PHOSPHATE SYNTHASE; CASPASE 8; CASPASE 8 INHIBITOR; CYTOCHROME C; DEATH RECEPTOR 5; FAS ANTIGEN; FLICE INHIBITORY PROTEIN; GALACTOSAMINE; GAMMA GLUTAMYLTRANSFERASE; HIGH MOBILITY GROUP B1 PROTEIN; I KAPPA B KINASE GAMMA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; K 18; MICRORNA; PROTEIN P53; REACTIVE OXYGEN METABOLITE; STRESS ACTIVATED PROTEIN KINASE; TUMOR NECROSIS FACTOR RECEPTOR;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; APOPTOSIS; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; AUTOPHAGY; B CELL LYMPHOMA; CELL AGING; CELL CYCLE ARREST; CELL DEATH; CELL ORGANELLE; CELL POPULATION; CELL PROLIFERATION; CELL REGENERATION; CELL SWELLING; CHOLESTASIS; CHRONIC LIVER DISEASE; CLINICAL STUDY; DISEASE COURSE; DRUG INDUCED DISEASE; ENDOPLASMIC RETICULUM STRESS; FATTY LIVER; FIBROGENESIS; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; GENE DELETION; HEPATITIS; HUMAN; LIVER CANCER; LIVER CARCINOGENESIS; LIVER CELL; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER DISEASE; LIVER FIBROSIS; LIVER FUNCTION; LIVER NECROSIS; LIVER REGENERATION; MITOCHONDRIAL PERMEABILITY; MITOCHONDRION SWELLING; NECROPTOSIS; NONHUMAN; OXIDATIVE PHOSPHORYLATION; PRIORITY JOURNAL; REGULATORY MECHANISM; STELLATE CELL; UNFOLDED PROTEIN RESPONSE; VIRUS HEPATITIS; ANIMAL; LIVER; LIVER DISEASES; METABOLISM; NECROSIS; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; BIOMARKERS; HEPATOCYTES; HUMANS; LIVER; LIVER DISEASES; NECROSIS; SIGNAL TRANSDUCTION;

EID: 84919465499     PISSN: 00165085     EISSN: 15280012     Source Type: Journal    
DOI: 10.1053/j.gastro.2014.07.018     Document Type: Review

References (256)

1. G. Fattovich, N. Olivari, and M. Pasino Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years Gut 57 2008 84 90
2. U.H. Iloeje, H.I. Yang, and J. Su Predicting cirrhosis risk based on the level of circulating hepatitis B viral load Gastroenterology 130 2006 678 686
3. D.I. Tai, S.M. Lin, and I.S. Sheen Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time Hepatology 49 2009 1859 1867
4. T.C. Tseng, C.J. Liu, and H.C. Yang High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load Gastroenterology 142 2012 1140 1149.e3 quiz e13-e14
5. M.G. Ghany, D.E. Kleiner, and H. Alter Progression of fibrosis in chronic hepatitis C Gastroenterology 124 2003 97 104
6. C.K. Hui, T. Belaye, and K. Montegrande A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase J Hepatol 38 2003 511 517
7. M. Wiese, F. Berr, and M. Lafrenz Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany: a 20-year multicenter study Hepatology 32 2000 91 96
8. M. Wiese, J. Fischer, and M. Lobermann Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection Hepatology 59 2014 49 57
9. D.N. Amarapurka, A.D. Amarapurkar, and N.D. Patel Nonalcoholic steatohepatitis (NASH) with diabetes: predictors of liver fibrosis Ann Hepatol 5 2006 30 33
10. P. Angulo, J.C. Keach, and K.P. Batts Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis Hepatology 30 1999 1356 1362
11. S. McPherson, E. Henderson, and A.D. Burt Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease J Hepatol 60 2014 1055 1062
12. J.J. Feld, H. Dinh, and T. Arenovich Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome Hepatology 42 2005 53 62
13. T.H. Lee, W.R. Kim, and J.T. Benson Serum aminotransferase activity and mortality risk in a United States community Hepatology 47 2008 880 887
14. H.C. Kim, C.M. Nam, and S.H. Jee Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study BMJ 328 2004 983
15. C.E. Ruhl, and J.E. Everhart Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population Gastroenterology 136 2009 477 485.e11
16. G.K. Michalopoulos, and M. DeFrances Liver regeneration Adv Biochem Eng Biotechnol 93 2005 101 134
17. A. Columbano, G.M. Ledda-Columbano, and P.P. Coni Occurrence of cell death (apoptosis) during the involution of liver hyperplasia Lab Invest 52 1985 670 675
18. A. Benedetti, A.M. Jezequel, and F. Orlandi Preferential distribution of apoptotic bodies in acinar zone 3 of normal human and rat liver J Hepatol 7 1988 319 324
19. G.K. Michalopoulos, and M.C. DeFrances Liver regeneration Science 276 1997 60 66
20. H. Yanai, A. Matsuda, and J. An Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection Proc Natl Acad Sci U S A 110 2013 20699 20704
21. J.P. Iredale, R.C. Benyon, and J. Pickering Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors J Clin Invest 102 1998 538 549
22. M. Miura Active participation of cell death in development and organismal homeostasis Dev Growth Differ 53 2011 125 136
23. M. Adachi, S. Suematsu, and T. Kondo Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver Nat Genet 11 1995 294 300
24. H. Ashida, H. Mimuro, and M. Ogawa Cell death and infection: a double-edged sword for host and pathogen survival J Cell Biol 195 2011 931 942
25. J.F. Kerr, A.H. Wyllie, and A.R. Currie Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics Br J Cancer 26 1972 239 257
26. N.N. Danial, and S.J. Korsmeyer Cell death: critical control points Cell 116 2004 205 219
27. A. Linkermann, and D.R. Green Necroptosis N Engl J Med 370 2014 455 465
28. N.I. Walker, B.V. Harmon, and G.C. Gobe Patterns of cell death Methods Achiev Exp Pathol 13 1988 18 54
29. N. Festjens, T. Vanden Berghe, and P. Vandenabeele Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response Biochim Biophys Acta 1757 2006 1371 1387
30. A. Kaczmarek, P. Vandenabeele, and D.V. Krysko Necroptosis: the release of damage-associated molecular patterns and its physiological relevance Immunity 38 2013 209 223
31. J.J. Lemasters, T.P. Theruvath, and Z. Zhong Mitochondrial calcium and the permeability transition in cell death Biochim Biophys Acta 1787 2009 1395 1401
32. C.P. Baines, R.A. Kaiser, and N.H. Purcell Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death Nature 434 2005 658 662
33. T. Nakagawa, S. Shimizu, and T. Watanabe Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death Nature 434 2005 652 658
34. H. Malhi, G.J. Gores, and J.J. Lemasters Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43 2006 S31 S44
35. B.K. Gunawan, Z.X. Liu, and D. Han c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity Gastroenterology 131 2006 165 178
36. Y. Masubuchi, C. Suda, and T. Horie Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice J Hepatol 42 2005 110 116
37. T.P. Theruvath, Z. Zhong, and P. Pediaditakis Minocycline and N-methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition Hepatology 47 2008 236 246
38. P.C. Waldmeier, K. Zimmermann, and T. Qian Cyclophilin D as a drug target Curr Med Chem 10 2003 1485 1506
39. J.J. Lemasters Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis Gastroenterology 129 2005 351 360
40. A. Ramachandran, M.R. McGill, and Y. Xie Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice Hepatology 58 2013 2099 2108
41. S. Roychowdhury, M.R. McMullen, and S.G. Pisano Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury Hepatology 57 2013 1773 1783
42. A.A. Nanji, and S. Hiller-Sturmhofel Apoptosis and necrosis: two types of cell death in alcoholic liver disease Alcohol Health Res World 21 1997 325 330
43. D. Joka, K. Wahl, and S. Moeller Prospective biopsy-controlled evaluation of cell death biomarkers for prediction of liver fibrosis and nonalcoholic steatohepatitis Hepatology 55 2012 455 464
44. A.E. Feldstein, A. Canbay, and P. Angulo Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis Gastroenterology 125 2003 437 443
45. A. Linkermann, J.H. Brasen, and M. Darding Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury Proc Natl Acad Sci U S A 110 2013 12024 12029
46. K. Kon, J.S. Kim, and H. Jaeschke Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes Hepatology 40 2004 1170 1179
47. J.J. Lemasters, A.L. Nieminen, and T. Qian The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy Biochim Biophys Acta 1366 1998 177 196
48. S.J. Martin, and D.R. Green Protease activation during apoptosis: death by a thousand cuts? Cell 82 1995 349 352
49. E.M. Creagh, H. Conroy, and S.J. Martin Caspase-activation pathways in apoptosis and immunity Immunol Rev 193 2003 10 21
50. W.A. Faubion, M.E. Guicciardi, and H. Miyoshi Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas J Clin Invest 103 1999 137 145
51. H. Bantel, and K. Schulze-Osthoff Apoptosis in hepatitis C virus infection Cell Death Differ 10 suppl 1 2003 S48 S58
52. R. Fischer, T. Baumert, and H.E. Blum Hepatitis C virus infection and apoptosis World J Gastroenterol 13 2007 4865 4872
53. S. Natori, C. Rust, and L.M. Stadheim Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis J Hepatol 34 2001 248 253
54. K.S. Ravichandran Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways Immunity 35 2011 445 455
55. D.R. Gude, S.E. Alvarez, and S.W. Paugh Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal FASEB J 22 2008 2629 2638
56. M.R. Elliott, F.B. Chekeni, and P.C. Trampont Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance Nature 461 2009 282 286
57. S.P. Cullen, C.M. Henry, and C.J. Kearney Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells Mol Cell 49 2013 1034 1048
58. S.J. Martin, C.M. Henry, and S.P. Cullen A perspective on mammalian caspases as positive and negative regulators of inflammation Mol Cell 46 2012 387 397
59. C.F. Chen, W.C. Lee, and H.I. Yang Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma Gastroenterology 141 2011 1240 1248 1248.e1-2
60. M.H. Lee, H.I. Yang, and S.N. Lu Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study J Clin Oncol 28 2010 4587 4593
61. J.C. Martinou, and R.J. Youle Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics Dev Cell 21 2011 92 101
62. T. Takehara, T. Tatsumi, and T. Suzuki Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses Gastroenterology 127 2004 1189 1197
63. B. Vick, A. Weber, and T. Urbanik Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes Hepatology 49 2009 627 636
64. A. Weber, R. Boger, and B. Vick Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice Hepatology 51 2010 1226 1236
65. G.C. Shore, F.R. Papa, and S.A. Oakes Signaling cell death from the endoplasmic reticulum stress response Curr Opin Cell Biol 23 2011 143 149
66. C.M. Greene, and N.G. McElvaney Z alpha-1 antitrypsin deficiency and the endoplasmic reticulum stress response World J Gastrointest Pharmacol Ther 1 2010 94 101
67. T. Asselah, I. Bieche, and A. Mansouri In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C J Pathol 221 2010 264 274
68. E. Merquiol, D. Uzi, and T. Mueller HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response PLoS One 6 2011 e24660
69. U. Ozcan, E. Yilmaz, and L. Ozcan Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes Science 313 2006 1137 1140
70. S.C. Cazanave, and G.J. Gores Mechanisms and clinical implications of hepatocyte lipoapoptosis Clin Lipidol 5 2010 71 85
71. R.G. Holzer, E.J. Park, and N. Li Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation Cell 147 2011 173 184
72. M. Sharma, F. Urano, and A. Jaeschke Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes J Hepatol 56 2012 192 198
73. C. Guichard, G. Amaddeo, and S. Imbeaud Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma Nat Genet 44 2012 694 698
74. J.R. Muppidi, J. Tschopp, and R.M. Siegel Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction Immunity 21 2004 461 465
75. Y. Akazawa, and G.J. Gores Death receptor-mediated liver injury Semin Liver Dis 27 2007 327 338
76. J. Ogasawara, R. Watanabe-Fukunaga, and M. Adachi Lethal effect of the anti-Fas antibody in mice Nature 364 1993 806 809
77. P.R. Galle, W.J. Hofmann, and H. Walczak Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage J Exp Med 182 1995 1223 1230
78. C. Scaffidi, S. Fulda, and A. Srinivasan Two CD95 (APO-1/Fas) signaling pathways EMBO J 17 1998 1675 1687
79. H. Wajant The Fas signaling pathway: more than a paradigm Science 296 2002 1635 1636
80. R. Reinehr, and D. Haussinger CD95 death receptor and epidermal growth factor receptor (EGFR) in liver cell apoptosis and regeneration Arch Biochem Biophys 518 2012 2 7
81. R.F. Schwabe, and D.A. Brenner Mechanisms of liver injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways Am J Physiol Gastrointest Liver Physiol 290 2006 G583 G589
82. G. Tang, Y. Minemoto, and B. Dibling Inhibition of JNK activation through NF-kappaB target genes Nature 414 2001 313 317
83. S. Win, T.A. Than, and D. Han c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice J Biol Chem 286 2011 35071 35078
84. M. Karin, and A. Lin NF-kappaB at the crossroads of life and death Nat Immunol 3 2002 221 227
85. D. Wallach, E.E. Varfolomeev, and N.L. Malinin Tumor necrosis factor receptor and Fas signaling mechanisms Annu Rev Immunol 17 1999 331 367
86. R.F. Schwabe, H. Uchinami, and T. Qian Differential requirement for c-Jun NH2-terminal kinase in TNFalpha- and Fas-mediated apoptosis in hepatocytes FASEB J 18 2004 720 722
87. R.F. Schwabe, C.A. Bradham, and T. Uehara c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration Hepatology 37 2003 824 832
88. M. Leist, F. Gantner, and I. Bohlinger Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest J Immunol 153 1994 1778 1788
89. T. Luedde, U. Assmus, and T. Wustefeld Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury J Clin Invest 115 2005 849 859
90. T. Luedde, N. Beraza, and V. Kotsikoris Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma Cancer Cell 11 2007 119 132
91. T. Luedde, J. Heinrichsdorff, and R. De Lorenzi IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver Proc Natl Acad Sci U S A 105 2008 9733 9738
92. J.M. Schattenberg, T. Zimmermann, and M. Worns Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo J Hepatol 55 2011 1272 1280
93. T. Vanden Berghe, A. Linkermann, and S. Jouan-Lanhouet Regulated necrosis: the expanding network of non-apoptotic cell death pathways Nat Rev Mol Cell Biol 15 2014 135 147
94. J. Han, C.Q. Zhong, and D.W. Zhang Programmed necrosis: backup to and competitor with apoptosis in the immune system Nat Immunol 12 2011 1143 1149
95. Y.S. Cho, S. Challa, and D. Moquin Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation Cell 137 2009 1112 1123
96. S. He, L. Wang, and L. Miao Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha Cell 137 2009 1100 1111
97. N. Holler, R. Zaru, and O. Micheau Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule Nat Immunol 1 2000 489 495
98. D.W. Zhang, J. Shao, and J. Lin RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis Science 325 2009 332 336
99. W.J. Kaiser, J.W. Upton, and A.B. Long RIP3 mediates the embryonic lethality of caspase-8-deficient mice Nature 471 2011 368 372
100. Z. Wang, H. Jiang, and S. Chen The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways Cell 148 2012 228 243
101. Z. Cai, S. Jitkaew, and J. Zhao Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis Nat Cell Biol 16 2014 55 65
102. X. Chen, W. Li, and J. Ren Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death Cell Res 24 2014 105 121
103. H. Wang, L. Sun, and L. Su Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3 Mol Cell 54 2014 133 146
104. M. Luedde, M. Lutz, and N. Carter RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction Cardiovasc Res 103 2014 206 216
105. M. Vucur, F. Reisinger, and J. Gautheron RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation Cell Rep 4 2013 776 790
106. M. Sharma, V. Gadang, and A. Jaeschke Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity Mol Pharmacol 82 2012 1001 1007
107. M.C. Bonnet, D. Preukschat, and P.S. Welz The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation Immunity 35 2011 572 582
108. P.S. Welz, A. Wullaert, and K. Vlantis FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation Nature 477 2011 330 334
109. A.M. Choi, S.W. Ryter, and B. Levine Autophagy in human health and disease N Engl J Med 368 2013 651 662
110. W.X. Ding, M. Li, and X. Chen Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice Gastroenterology 139 2010 1740 1752
111. M. Amir, E. Zhao, and L. Fontana Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation Cell Death Differ 20 2013 878 887
112. H.M. Ni, A. Bockus, and N. Boggess Activation of autophagy protects against acetaminophen-induced hepatotoxicity Hepatology 55 2012 222 232
113. M.J. Czaja, W.X. Ding, and T.M. Donohue Jr. Functions of autophagy in normal and diseased liver Autophagy 9 2013 1131 1158
114. R. Singh, S. Kaushik, and Y. Wang Autophagy regulates lipid metabolism Nature 458 2009 1131 1135
115. H. Higuchi, S.F. Bronk, and Y. Takikawa The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis J Biol Chem 276 2001 38610 38618
116. E.B. Alabraba, V. Lai, and L. Boon Coculture of human liver macrophages and cholangiocytes leads to CD40-dependent apoptosis and cytokine secretion Hepatology 47 2008 552 562
117. K. Harada, S. Ozaki, and M.E. Gershwin Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis Hepatology 26 1997 1399 1405
118. K. Takeda, Y. Kojima, and K. Ikejima Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease Proc Natl Acad Sci U S A 105 2008 10895 10900
119. Y. Ueno, M. Ishii, and K. Yahagi Fas-mediated cholangiopathy in the murine model of graft versus host disease Hepatology 31 2000 966 974
120. X. Xia, S. Demorrow, and H. Francis Cholangiocyte injury and ductopenic syndromes Semin Liver Dis 27 2007 401 412
121. W. Gao, R.C. Bentley, and J.F. Madden Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation Hepatology 27 1998 1652 1660
122. P.M. Huet, M.R. Nagaoka, and G. Desbiens Sinusoidal endothelial cell and hepatocyte death following cold ischemia-warm reperfusion of the rat liver Hepatology 39 2004 1110 1119
123. I.N. Crispe, T. Dao, and K. Klugewitz The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev 174 2000 47 62
124. O. Takeuchi, and S. Akira Pattern recognition receptors and inflammation Cell 140 2010 805 820
125. P. Matzinger The danger model: a renewed sense of self Science 296 2002 301 305
126. G.Y. Chen, and G. Nunez Sterile inflammation: sensing and reacting to damage Nat Rev Immunol 10 2010 826 837
127. K.L. Rock, J.J. Lai, and H. Kono Innate and adaptive immune responses to cell death Immunol Rev 243 2011 191 205
128. M.T. Lotze, H.J. Zeh, and A. Rubartelli The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity Immunol Rev 220 2007 60 81
129. P. Scaffidi, T. Misteli, and M.E. Bianchi Release of chromatin protein HMGB1 by necrotic cells triggers inflammation Nature 418 2002 191 195
130. A. Tsung, R. Sahai, and H. Tanaka The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion J Exp Med 201 2005 1135 1143
131. B. McDonald, K. Pittman, and G.B. Menezes Intravascular danger signals guide neutrophils to sites of sterile inflammation Science 330 2010 362 366
132. P. Kubes, and W.Z. Mehal Sterile inflammation in the liver Gastroenterology 143 2012 1158 1172
133. R. Hoque, M.A. Sohail, and S. Salhanick P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice Am J Physiol Gastrointest Liver Physiol 302 2012 G1171 G1179
134. A.B. Imaeda, A. Watanabe, and M.A. Sohail Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome J Clin Invest 119 2009 305 314
135. T. Pusterla, J. Nemeth, and I. Stein Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice Hepatology 58 2013 363 373
136. T. McHedlidze, M. Waldner, and S. Zopf Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis Immunity 39 2013 357 371
137. J. Li, N. Razumilava, and G.J. Gores Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation J Clin Invest 124 2014 3241 3251
138. C.K. Argo, P.G. Northup, and A.M. Al-Osaimi Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis J Hepatol 51 2009 371 379
139. H. Bantel, A. Lugering, and J. Heidemann Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury Hepatology 40 2004 1078 1087
140. I. Mederacke, C.C. Hsu, and J.S. Troeger Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology Nat Commun 4 2013 2823
141. J.S. Duffield, S.J. Forbes, and C.M. Constandinou Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair J Clin Invest 115 2005 56 65
142. J.P. Pradere, J. Kluwe, and S. De Minicis Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice Hepatology 58 2013 1461 1473
143. E. Seki, S. De Minicis, and C.H. Osterreicher TLR4 enhances TGF-beta signaling and hepatic fibrosis Nat Med 13 2007 1324 1332
144. A. Canbay, A. Feldstein, and E. Baskin-Bey The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse J Pharmacol Exp Ther 308 2004 1191 1196
145. Q.M. Anstee, D. Concas, and H. Kudo Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis J Hepatol 53 2010 542 550
146. J. Gautheron, M. Vucur, and F. Reisinger A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis EMBO Mol Med 6 2014 1062 1074
147. A. Canbay, P. Taimr, and N. Torok Apoptotic body engulfment by a human stellate cell line is profibrogenic Lab Invest 83 2003 655 663
148. J.X. Jiang, K. Mikami, and S. Venugopal Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways J Hepatol 51 2009 139 148
149. S.S. Zhan, J.X. Jiang, and J. Wu Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo Hepatology 43 2006 435 443
150. A. Canbay, A.E. Feldstein, and H. Higuchi Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression Hepatology 38 2003 1188 1198
151. S. Maeda, H. Kamata, and J.L. Luo IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis Cell 121 2005 977 990
152. K. Bettermann, M. Vucur, and J. Haybaeck TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer Cancer Cell 17 2010 481 496
153. H. Hikita, T. Kodama, and S. Shimizu Bak deficiency inhibits liver carcinogenesis: a causal link between apoptosis and carcinogenesis J Hepatol 57 2012 92 100
154. W. Qiu, X. Wang, and B. Leibowitz PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice Hepatology 54 2011 1249 1258
155. C. Liedtke, J.M. Bangen, and J. Freimuth Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury Gastroenterology 141 2011 2176 2187
156. Y. Nakamoto, S. Kaneko, and H. Fan Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-fas ligand antibody therapy J Exp Med 196 2002 1105 1111
157. H. Wang, O. Bloom, and M. Zhang HMG-1 as a late mediator of endotoxin lethality in mice Science 285 1999 248 251
158. W. Beerheide, Y.J. Tan, and E. Teng Downregulation of proapoptotic proteins Bax and Bcl-X(S) in p53 overexpressing hepatocellular carcinomas Biochem Biophys Res Commun 273 2000 54 61
159. Y.H. Shi, W.X. Ding, and J. Zhou Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence Hepatology 48 2008 497 507
160. W. Sieghart, D. Losert, and S. Strommer Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy J Hepatol 44 2006 151 157
161. T. Takehara, X. Liu, and J. Fujimoto Expression and role of Bcl-xL in human hepatocellular carcinomas Hepatology 34 2001 55 61
162. A. Arzumanyan, H.M. Reis, and M.A. Feitelson Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma Nat Rev Cancer 13 2013 123 135
163. V. Hernandez-Gea, S. Toffanin, and S.L. Friedman Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma Gastroenterology 144 2013 512 527
164. D.H. Dapito, A. Mencin, and G.Y. Gwak Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4 Cancer Cell 21 2012 504 516
165. T. Luedde, and R.F. Schwabe NF-kappaB in the liver - linking injury, fibrosis and hepatocellular carcinoma Nat Rev Gastroenterol Hepatol 8 2011 108 118
166. E. Pikarsky, R.M. Porat, and I. Stein NF-kappaB functions as a tumour promoter in inflammation-associated cancer Nature 431 2004 461 466
167. S. Inokuchi, T. Aoyama, and K. Miura Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis Proc Natl Acad Sci U S A 107 2010 844 849
168. M.C. Kew Serum aminotransferase concentration as evidence of hepatocellular damage Lancet 355 2000 591 592
169. M. Botros, and K.A. Sikaris The De Ritis ratio: the test of time Clin Biochem Rev 34 2013 117 130
170. S. Liangpunsakul, R. Qi, and D.W. Crabb Relationship between alcohol drinking and aspartate aminotransferase:alanine aminotransferase (AST: ALT) ratio, mean corpuscular volume (MCV), gamma-glutamyl transpeptidase (GGT), and apolipoprotein A1 and B in the U.S. population J Stud Alcohol Drugs 71 2010 249 252
171. N.O. Ku, and M.B. Omary Effect of mutation and phosphorylation of type I keratins on their caspase-mediated degradation J Biol Chem 276 2001 26792 26798
172. A. Eguchi, A. Wree, and A.E. Feldstein Biomarkers of liver cell death J Hepatol 60 2014 1063 1074
173. G. Musso, R. Gambino, and M. Cassader Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity Ann Med 43 2011 617 649
174. A.E. Feldstein, N. Alkhouri, and R. De Vito Serum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children Am J Gastroenterol 108 2013 1526 1531
175. M. Tsutsui, N. Tanaka, and M. Kawakubo Serum fragmented cytokeratin 18 levels reflect the histologic activity score of nonalcoholic fatty liver disease more accurately than serum alanine aminotransferase levels J Clin Gastroenterol 44 2010 440 447
176. V.J. Lavallard, S. Bonnafous, and S. Patouraux Serum markers of hepatocyte death and apoptosis are non invasive biomarkers of severe fibrosis in patients with alcoholic liver disease PLoS One 6 2011 e17599
177. M.T. Lotze, and K.J. Tracey High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal Nat Rev Immunol 5 2005 331 342
178. D.J. Antoine, R.E. Jenkins, and J.W. Dear Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity J Hepatol 56 2012 1070 1079
179. K. Wang, S. Zhang, and B. Marzolf Circulating microRNAs, potential biomarkers for drug-induced liver injury Proc Natl Acad Sci U S A 106 2009 4402 4407
180. D.J. Antoine, J.W. Dear, and P.S. Lewis Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital Hepatology 58 2013 777 787
181. J. Trebicka, E. Anadol, and N. Elfimova Hepatic and serum levels of miR-122 after chronic HCV-induced fibrosis J Hepatol 58 2013 234 239
182. C. Roderburg, G.W. Urban, and K. Bettermann Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis Hepatology 53 2011 209 218
183. C. Roderburg, M. Luedde, and D. Vargas Cardenas miR-133a mediates TGF-beta-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis J Hepatol 58 2013 736 742
184. C. Roderburg, T. Mollnow, and B. Bongaerts Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis PLoS One 7 2012 e32999
185. S.V. Weerasinghe, Y.J. Jang, and R.J. Fontana Carbamoyl phosphate synthatase-1 (CPS1) is a rapid turnover biomarker in mouse and human acute liver injury Am J Physiol Gastrointest Liver Physiol 307 2014 G355 G364
186. N. Hanawa, M. Shinohara, and B. Saberi Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury J Biol Chem 283 2008 13565 13577
187. M.J. Smilkstein, G.L. Knapp, and K.W. Kulig Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) N Engl J Med 319 1988 1557 1562
188. K.J. Heard Acetylcysteine for acetaminophen poisoning N Engl J Med 359 2008 285 292
189. R. Keays, P.M. Harrison, and J.A. Wendon Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial BMJ 303 1991 1026 1029
190. N. Kaplowitz, and L. DeLeve Drug-induced liver injury: introduction and overview N. Kaplowitz, Drug-induced liver injury 3rd ed 2013 Elsevier San Diego, CA 3 14
191. J. Karkhanis, E.C. Verna, and M.S. Chang Steroid use in acute liver failure Hepatology 59 2014 612 621
192. B. Rehermann Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells Nat Med 19 2013 859 868
193. P.A. Knolle, and R. Thimme Hepatic immune regulation and its involvement in viral hepatitis infection Gastroenterology 146 2014 1193 1207
194. M.I. Kafrouni, G.R. Brown, and D.L. Thiele Virally infected hepatocytes are resistant to perforin-dependent CTL effector mechanisms J Immunol 167 2001 1566 1574
195. J.M. Pawlotsky New hepatitis C therapies: the toolbox, strategies, and challenges Gastroenterology 146 2014 1176 1192
196. S.J. Scaglione, and A.S. Lok Effectiveness of hepatitis B treatment in clinical practice Gastroenterology 142 2012 1360 1368.e1
197. L. Mollica, F. De Marchis, and A. Spitaleri Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities Chem Biol 14 2007 431 441
198. M.P. Manns, H. Wedemeyer, and A. Singer Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks J Viral Hepat 19 2012 537 546
199. K. Cusi Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications Gastroenterology 142 2012 711 725.e6
200. G. Vernon, A. Baranova, and Z.M. Younossi Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults Aliment Pharmacol Ther 34 2011 274 285
201. J.C. Cohen, J.D. Horton, and H.H. Hobbs Human fatty liver disease: old questions and new insights Science 332 2011 1519 1523
202. D. Schuppan, and Y.O. Kim Evolving therapies for liver fibrosis J Clin Invest 123 2013 1887 1901
203. W. Cao, C. Zhao, and C. Shen Cytokeratin 18, alanine aminotransferase, platelets and triglycerides predict the presence of nonalcoholic steatohepatitis PLoS One 8 2013 e82092
204. R.P. Witek, W.C. Stone, and F.G. Karaca Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis Hepatology 50 2009 1421 1430
205. M. Hatting, G. Zhao, and F. Schumacher Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents Hepatology 57 2013 2189 2201
206. J. Wu, Z. Huang, and J. Ren Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis Cell Res 23 2013 994 1006
207. K. Newton, X. Sun, and V.M. Dixit Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4 Mol Cell Biol 24 2004 1464 1469
208. R.K. Soon Jr., J.S. Yan, and J.P. Grenert Stress signaling in the methionine-choline-deficient model of murine fatty liver disease Gastroenterology 139 2010 1730 1739 1739.e1
209. H. Malhi, E.M. Kropp, and V.F. Clavo C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis J Biol Chem 288 2013 18624 18642
210. K. Tomita, G. Tamiya, and S. Ando Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice Gut 55 2006 415 424
211. S.C. Cazanave, J.L. Mott, and S.F. Bronk Death receptor 5 signaling promotes hepatocyte lipoapoptosis J Biol Chem 286 2011 39336 39348
212. P. Mathurin, A. Hollebecque, and L. Arnalsteen Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease Gastroenterology 137 2009 532 540
213. D.L. Diab, L. Yerian, and P. Schauer Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients Clin Gastroenterol Hepatol 6 2008 1249 1254
214. M.A. Burza, S. Romeo, and A. Kotronen Long-term effect of bariatric surgery on liver enzymes in the Swedish Obese Subjects (SOS) study PLoS One 8 2013 e60495
215. R. Belfort, S.A. Harrison, and K. Brown A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis N Engl J Med 355 2006 2297 2307
216. V. Ratziu, M.Y. Sheikh, and A.J. Sanyal A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis Hepatology 55 2012 419 428
217. N. Chalasani, Z. Younossi, and J.E. Lavine The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology Gastroenterology 142 2012 1592 1609
218. J.E. Lavine, J.B. Schwimmer, and M.L. Van Natta Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial JAMA 305 2011 1659 1668
219. A.J. Sanyal, N. Chalasani, and K.V. Kowdley Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis N Engl J Med 362 2010 1675 1685
220. S. Mudaliar, R.R. Henry, and A.J. Sanyal Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease Gastroenterology 145 2013 574 582.e1
221. B. Gao, and R. Bataller Alcoholic liver disease: pathogenesis and new therapeutic targets Gastroenterology 141 2011 1572 1585
222. Y.H. Ni, M.H. Chang, and L.M. Huang Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination Ann Intern Med 135 2001 796 800
223. M.H. Chang, C.J. Chen, and M.S. Lai Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group N Engl J Med 336 1997 1855 1859
224. M. Ziol, M. Tepper, and M. Lohez Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis J Hepatol 34 2001 254 260
225. J. Altamirano, and R. Bataller Alcoholic liver disease: pathogenesis and new targets for therapy Nat Rev Gastroenterol Hepatol 8 2011 491 501
226. Y. Adachi, L.E. Moore, and B.U. Bradford Antibiotics prevent liver injury in rats following long-term exposure to ethanol Gastroenterology 108 1995 218 224
227. H. Kono, I. Rusyn, and M. Yin NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease J Clin Invest 106 2000 867 872
228. T. Uesugi, M. Froh, and G.E. Arteel Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice Hepatology 34 2001 101 108
229. A. Louvet, S. Naveau, and M. Abdelnour The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids Hepatology 45 2007 1348 1354
230. N.C. Boetticher, C.J. Peine, and P. Kwo A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis Gastroenterology 135 2008 1953 1960
231. E. Nguyen-Khac, T. Thevenot, and M.A. Piquet Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis N Engl J Med 365 2011 1781 1789
232. H.B. El-Serag Hepatocellular carcinoma N Engl J Med 365 2011 1118 1127
233. M.F. Yuen, H.J. Yuan, and D.K. Wong Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications Gut 54 2005 1610 1614
234. G.A. Michelotti, M.V. Machado, and A.M. Diehl NAFLD, NASH and liver cancer Nat Rev Gastroenterol Hepatol 10 2013 656 665
235. European Association for the Study of the Liver EASL clinical practice guidelines: Management of chronic hepatitis B virus infection J Hepatol 57 2012 167 185
236. T.R. Morgan Chemoprevention of hepatocellular carcinoma in chronic hepatitis C Recent Results Cancer Res 188 2011 85 99
237. A. Villanueva, V. Hernandez-Gea, and J.M. Llovet Medical therapies for hepatocellular carcinoma: a critical view of the evidence Nat Rev Gastroenterol Hepatol 10 2013 34 42
238. J. Heo, T. Reid, and L. Ruo Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer Nat Med 19 2013 329 336
239. W.M. Lee, L.S. Hynan, and L. Rossaro Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure Gastroenterology 137 2009 856 864 864.e1
240. R.H. Squires, A. Dhawan, and E. Alonso Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial Hepatology 57 2013 1542 1549
241. E. Gabbay, E. Zigmond, and O. Pappo Antioxidant therapy for chronic hepatitis C after failure of interferon: results of phase II randomized, double-blind placebo controlled clinical trial World J Gastroenterol 13 2007 5317 5323
242. P. Gerner, H.G. Posselt, and A. Krahl Vitamin E treatment for children with chronic hepatitis B: a randomized placebo controlled trial World J Gastroenterol 14 2008 7208 7213
243. E.J. Gane, F. Weilert, and D.W. Orr The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients Liver Int 30 2010 1019 1026
244. M.P. Manns, E. Lawitz, and A.I.M. Hoepelman Short term safety, tolerability, pharmacokinetics and preliminary activity of GS-9450, a selective Caspase inhibitor, in patients with chronic HCV infection J Hepatol 52 2010 S114 S115
245. M.L. Shiffman, P. Pockros, and J.G. McHutchison Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor - a randomized placebo-controlled study in patients with chronic hepatitis C Aliment Pharmacol Ther 31 2010 969 978
246. M.A. Jimenez-Luevano, J.M. Lerma-Diaz, and G. Hernandez-Flores Addition of pentoxifylline to pegylated interferon-alpha-2a and ribavirin improves sustained virological response to chronic hepatitis C virus: a randomized clinical trial Ann Hepatol 12 2013 248 255
247. M.P. Manns, H. Wedemeyer, and A. Singer Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks J Viral Hepat 19 2012 537 546
248. E. Akriviadis, R. Botla, and W. Briggs Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial Gastroenterology 119 2000 1637 1648
249. B.K. De, S. Gangopadhyay, and D. Dutta Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial World J Gastroenterol 15 2009 1613 1619
250. S. Stewart, M. Prince, and M. Bassendine A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis J Hepatol 47 2007 277 283
251. C. Moreno, P. Langlet, and A. Hittelet Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial J Hepatol 53 2010 1117 1122
252. P. Mathurin, A. Louvet, and A. Duhamel Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial JAMA 310 2013 1033 1041
253. C.O. Zein, L.M. Yerian, and P. Gogate Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial Hepatology 54 2011 1610 1619
254. V.W. Wong, G.L. Wong, and A.W. Chan Treatment of non-alcoholic steatohepatitis with Phyllanthus urinaria: a randomized trial J Gastroenterol Hepatol 28 2013 57 62
255. A.S. Lee, B.C.Y. Zee, and F.Y. Cheung Randomized phase II study of the X-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC) Am J Clin Oncol 2014 Jun 23 [Epub ahead of print]
256. M. Bitzer, T.M. Ganten, and M.A. Woerns Resminostat in advanced hepatocellular carcinoma (HCC): overall survival subgroup analysis of prognostic factors in the SHELTER trial (abstr) J Clin Oncol 31 suppl 2013 e15088