Molecular mechanism and treatment of viral hepatitis-related liver fibrosis

International Journal of Molecular Sciences

Volumn 15, Issue 6, 2014, Pages 10578-10604

  Su, Tung Hung ^a,b   Kao, Jia Horng ^a,b   Liu, Chun Jen ^a,b,c  

^a NATIONAL TAIWAN UNIVERSITY   (Taiwan)

^b NATIONAL TAIWAN UNIVERSITY HOSPITAL   (Taiwan)

^c Taiwan Liver Disease Consortium (TLC)   (Taiwan)

Author keywords

Antiviral therapy; Hepatic stellate cells; Hepatitis b; Hepatitis c; Hepatocellular carcinoma; Interferon; Macrophage; Molecular target agent; Myofibroblast; Nucleos(t)ide analogs

Indexed keywords

ADEFOVIR DIPIVOXIL; ANGIOTENSIN RECEPTOR ANTAGONIST; ATORVASTATIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENTECAVIR; FRESOLIMUMAB; HOST FACTOR; IMMUNOMODULATING AGENT; LAMIVUDINE; MICRORNA; NINTEDANIB; PIOGLITAZONE; PIRFENIDONE; PLATELET DERIVED GROWTH FACTOR; PRM 151; SAR 156597; SIMTUZUMAB; SORAFENIB; STATIN (PROTEIN); STX 100; TELBIVUDINE; TENOFOVIR; TRALOKINUMAB; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; ANTIVIRUS AGENT; PROTEIN KINASE INHIBITOR;

ANGIOGENESIS; ANTIVIRAL THERAPY; AUTOPHAGY; CELL PROLIFERATION; DISEASE COURSE; ENDOTHELIUM CELL; EPIGENETICS; FIBROGENESIS; FIBROSING ALVEOLITIS; FOCAL GLOMERULOSCLEROSIS; GENE MUTATION; GENOTYPE; HEPATITIS B; HEPATITIS C; HUMAN; INFLAMMATION; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; MACROPHAGE; MEMBRANE VESICLE; METABOLIC REGULATION; MYELOFIBROSIS; MYOFIBROBLAST; NATURAL KILLER CELL; NATURAL KILLER T CELL; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POLARIZATION; REMISSION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STELLATE CELL; T LYMPHOCYTE; VIRUS HEPATITIS; VIRUS LOAD; CD4+ T LYMPHOCYTE; COMPLICATION; CYTOLOGY; HEPATITIS, VIRAL, HUMAN; IMMUNOLOGY; METABOLISM;

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; ANTIVIRAL AGENTS; CD4-POSITIVE T-LYMPHOCYTES; HEPATIC STELLATE CELLS; HEPATITIS, VIRAL, HUMAN; HUMANS; LIVER CIRRHOSIS; MICRORNAS; PROTEIN KINASE INHIBITORS;

EID: 84902330457     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms150610578     Document Type: Review

References (148)

1. Wynn, T.A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 2008, 214, 199-210.
2. Friedman, S.L. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008, 134, 1655-1669.
3. Friedman, S.L.; Sheppard, D.; Duffield, J.S.; Violette, S. Therapy for fibrotic diseases: Nearing the starting line. Sci. Transl. Med. 2013, 5, 167sr161.
4. Mallat, A.; Lotersztajn, S. Cellular mechanisms of tissue fibrosis. 5. Novel insights into liver fibrosis. Am. J. Physiol. 2013, 305, C789-C799.
5. Wynn, T.A.; Ramalingam, T.R. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat. Med. 2012, 18, 1028-1040.
6. Zeisberg, M.; Yang, C.; Martino, M.; Duncan, M.B.; Rieder, F.; Tanjore, H.; Kalluri, R. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem. 2007, 282, 23337-23347.
7. Scholten, D.; Osterreicher, C.H.; Scholten, A.; Iwaisako, K.; Gu, G.; Brenner, D.A.; Kisseleva, T. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 2010, 139, 987-998.
8. Taura, K.; Miura, K.; Iwaisako, K.; Osterreicher, C.H.; Kodama, Y.; Penz-Osterreicher, M.; Brenner, D.A. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 2010, 51, 1027-1036.
9. Mederacke, I.; Hsu, C.C.; Troeger, J.S.; Huebener, P.; Mu, X.; Dapito, D.H.; Pradere, J.P.; Schwabe, R.F. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 2013, 4, 2823.
10. Tacke, F.; Weiskirchen, R. Update on hepatic stellate cells: Pathogenic role in liver fibrosis and novel isolation techniques. Expert Rev. Gastroenterol. Hepatol. 2012, 6, 67-80.
11. Shirakami, Y.; Lee, S.A.; Clugston, R.D.; Blaner, W.S. Hepatic metabolism of retinoids and disease associations. Biochim. Biophys. Acta 2012, 1821, 124-136.
12. Rockey, D.C. Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin. Liver Dis. 2001, 21, 337-349.
13. Eckardt, K.U.; Pugh, C.W.; Meier, M.; Tan, C.C.; Ratcliffe, P.J.; Kurtz, A. Production of erythropoietin by liver cells in vivo and in vitro. Ann. N. Y. Acad. Sci. 1994, 718, 50-60.
14. Leyland, H.; Gentry, J.; Arthur, M.J.; Benyon, R.C. The plasminogen-activating system in hepatic stellate cells. Hepatology 1996, 24, 1172-1178.
15. Bachem, M.G.; Meyer, D.; Melchior, R.; Sell, K.M.; Gressner, A.M. Activation of rat liver perisinusoidal lipocytes by transforming growth factors derived from myofibroblastlike cells. A potential mechanism of self perpetuation in liver fibrogenesis. J. Clin. Investig. 1992, 89, 19-27.
16. Iredale, J.P.; Thompson, A.; Henderson, N.C. Extracellular matrix degradation in liver fibrosis: Biochemistry and regulation. Biochim. Biophys. Acta 2013, 1832, 876-883.
17. Seki, E.; de Minicis, S.; Osterreicher, C.H.; Kluwe, J.; Osawa, Y.; Brenner, D.A.; Schwabe, R.F. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 2007, 13, 1324-1332.
18. De Minicis, S.; Seki, E.; Uchinami, H.; Kluwe, J.; Zhang, Y.; Brenner, D.A.; Schwabe, R.F. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology 2007, 132, 1937-1946.
19. + monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009, 50, 261-274.
20. Karlmark, K.R.; Zimmermann, H.W.; Roderburg, C.; Gassler, N.; Wasmuth, H.E.; Luedde, T.; Trautwein, C.; Tacke, F. The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 2010, 52, 1769-1782.
21. Seki, E.; de Minicis, S.; Gwak, G.Y.; Kluwe, J.; Inokuchi, S.; Bursill, C.A.; Llovet, J.M.; Brenner, D.A.; Schwabe, R.F. CCR1 and CCR5 promote hepatic fibrosis in mice. J. Clin. Investig. 2009, 119, 1858-1870.
22. Winau, F.; Hegasy, G.; Weiskirchen, R.; Weber, S.; Cassan, C.; Sieling, P.A.; Modlin, R.L.; Liblau, R.S.; Gressner, A.M.; Kaufmann, S.H. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 2007, 26, 117-129.
23. Ichikawa, S.; Mucida, D.; Tyznik, A.J.; Kronenberg, M.; Cheroutre, H. Hepatic stellate cells function as regulatory bystanders. J. Immunol. 2011, 186, 5549-5555.
24. Inagaki, Y.; Okazaki, I. Emerging insights into transforming growth factor β Smad signal in hepatic fibrogenesis. Gut 2007, 56, 284-292.
25. Kitani, A.; Fuss, I.; Nakamura, K.; Kumaki, F.; Usui, T.; Strober, W. Transforming growth factor (TGF)-β1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-β1-mediated fibrosis. J. Exp. Med. 2003, 198, 1179-1188.
26. Akpolat, N.; Yahsi, S.; Godekmerdan, A.; Demirbag, K.; Yalniz, M. Relationship between serum cytokine levels and histopathological changes of liver in patients with hepatitis B. World J. Gastroenterol. 2005, 11, 3260-3263.
27. Kamal, S.M.; Turner, B.; He, Q.; Rasenack, J.; Bianchi, L.; Al Tawil, A.; Nooman, A.; Massoud, M.; Koziel, M.J.; Afdhal, N.H. Progression of fibrosis in hepatitis C with and without schistosomiasis: Correlation with serum markers of fibrosis. Hepatology 2006, 43, 771-779.
28. Liu, Y.; Wen, X.M.; Lui, E.L.; Friedman, S.L.; Cui, W.; Ho, N.P.; Li, L.; Ye, T.; Fan, S.T.; Zhang, H. Therapeutic targeting of the PDGF and TGF-β-signaling pathways in hepatic stellate cells by PTK787/ZK22258. Lab. Investig. 2009, 89, 1152-1160.
29. Parsons, C.J.; Takashima, M.; Rippe, R.A. Molecular mechanisms of hepatic fibrogenesis. J. Gastroenterol. Hepatol. 2007, 22, S79-S84.
30. Wick, G.; Grundtman, C.; Mayerl, C.; Wimpissinger, T.F.; Feichtinger, J.; Zelger, B.; Sgonc, R.; Wolfram, D. The immunology of fibrosis. Ann. Rev. Immunol. 2013, 31, 107-135.
31. Shi, J.; Aisaki, K.; Ikawa, Y.; Wake, K. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am. J. Pathol. 1998, 153, 515-525.
32. Popov, Y.; Sverdlov, D.Y.; Bhaskar, K.R.; Sharma, A.K.; Millonig, G.; Patsenker, E.; Krahenbuhl, S.; Krahenbuhl, L.; Schuppan, D. Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am. J. Physiol. 2010, 298, G323-G334.
33. Atabai, K.; Jame, S.; Azhar, N.; Kuo, A.; Lam, M.; McKleroy, W.; Dehart, G.; Rahman, S.; Xia, D.D.; Melton, A.C. et al. MFGE8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J. Clin. Investig. 2009, 11 9, 3713-3722.
34. Sica, A.; Invernizzi, P.; Mantovani, A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 2014, 59, 2034-2042.
35. Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958-969.
36. Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 2003, 3, 23-35.
37. Lee, C.G.; Homer, R.J.; Zhu, Z.; Lanone, S.; Wang, X.; Koteliansky, V.; Shipley, J.M.; Gotwals, P.; Noble, P.; Chen, Q. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β1. J. Exp. Med. 2001, 194, 809-821.
38. Pradere, J.P.; Kluwe, J.; de Minicis, S.; Jiao, J.J.; Gwak, G.Y.; Dapito, D.H.; Jang, M.K.; Guenther, N.D.; Mederacke, I.; Friedman, R. et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013, 58, 1461-1473.
39. Chu, P.S.; Nakamoto, N.; Ebinuma, H.; Usui, S.; Saeki, K.; Matsumoto, A.; Mikami, Y.; Sugiyama, K.; Tomita, K.; Kanai, T. et al. C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. Hepatology 2013, 58, 337-350.
40. Heymann, F.; Hammerich, L.; Storch, D.; Bartneck, M.; Huss, S.; Russeler, V.; Gassler, N.; Lira, S.A.; Luedde, T.; Trautwein, C. et al. Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice. Hepatology 2012, 55, 898-909.
41. Aoyama, T.; Inokuchi, S.; Brenner, D.A.; Seki, E. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology 2010, 52, 1390-1400.
42. Fallowfield, J.A.; Mizuno, M.; Kendall, T.J.; Constandinou, C.M.; Benyon, R.C.; Duffield, J.S.; Iredale, J.P. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 2007, 178, 5288-5295.
43. Jiao, J.; Sastre, D.; Fiel, M.I.; Lee, U.E.; Ghiassi-Nejad, Z.; Ginhoux, F.; Vivier, E.; Friedman, S.L.; Merad, M.; Aloman, C. Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression. Hepatology 2012, 55, 244-255.
44. Liu, Y.; Meyer, C.; Muller, A.; Herweck, F.; Li, Q.; Mullenbach, R.; Mertens, P.R.; Dooley, S.; Weng, H.L. IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β-independent Smad signaling. J. Immunol. 2011, 187, 2814-2823.
45. Tan, Z.; Qian, X.; Jiang, R.; Liu, Q.; Wang, Y.; Chen, C.; Wang, X.; Ryffel, B.; Sun, B. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J. Immunol. 2013, 191, 1835-1844.
46. Lemmers, A.; Moreno, C.; Gustot, T.; Marechal, R.; Degre, D.; Demetter, P.; de Nadai, P.; Geerts, A.; Quertinmont, E.; Vercruysse, V. et al. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 2009, 49, 646-657.
47. Meng, F.; Wang, K.; Aoyama, T.; Grivennikov, S.I.; Paik, Y.; Scholten, D.; Cong, M.; Iwaisako, K.; Liu, X.; Zhang, M. et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012, 143, 765-776.
48. Krizhanovsky, V.; Yon, M.; Dickins, R.A.; Hearn, S.; Simon, J.; Miething, C.; Yee, H.; Zender, L.; Lowe, S.W. Senescence of activated stellate cells limits liver fibrosis. Cell 2008, 134, 657-667.
49. Xie, G.; Wang, X.; Wang, L.; Wang, L.; Atkinson, R.D.; Kanel, G.C.; Gaarde, W.A.; Deleve, L.D. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012, 142, 918-927.
50. Ding, B.S.; Cao, Z.; Lis, R.; Nolan, D.J.; Guo, P.; Simons, M.; Penfold, M.E.; Shido, K.; Rabbany, S.Y.; Rafii, S. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 2014, 505, 97-102.
51. Taura, K.; de Minicis, S.; Seki, E.; Hatano, E.; Iwaisako, K.; Osterreicher, C.H.; Kodama, Y.; Miura, K.; Ikai, I.; Uemoto, S. et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 2008, 135, 1729-1738.
52. Novo, E.; Cannito, S.; Zamara, E.; Valfre di Bonzo, L.; Caligiuri, A.; Cravanzola, C.; Compagnone, A.; Colombatto, S.; Marra, F.; Pinzani, M. et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am. J. Pathol. 2007, 170, 1942-1953.
53. Rosmorduc, O.; Housset, C. Hypoxia: A link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. Semin. Liver Dis. 2010, 30, 258-270.
54. She, H.; Xiong, S.; Hazra, S.; Tsukamoto, H. Adipogenic transcriptional regulation of hepatic stellate cells. J. Biol. Chem. 2005, 280, 4959-4967.
55. Chen, A.; Tang, Y.; Davis, V.; Hsu, F.F.; Kennedy, S.M.; Song, H.; Turk, J.; Brunt, E.M.; Newberry, E.P.; Davidson, N.O. Liver fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet-induced nonalcoholic fatty liver disease. Hepatology 2013, 57, 2202-2212.
56. Chen, Y.; Choi, S.S.; Michelotti, G.A.; Chan, I.S.; Swiderska-Syn, M.; Karaca, G.F.; Xie, G.; Moylan, C.A.; Garibaldi, F.; Premont, R. et al. Hedgehog controls hepatic stellate cell fate by regulating metabolism. Gastroenterology 2012, 143, 1319-1329.
57. Hernandez-Gea, V.; Ghiassi-Nejad, Z.; Rozenfeld, R.; Gordon, R.; Fiel, M.I.; Yue, Z.; Czaja, M.J.; Friedman, S.L. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 2012, 142, 938-946.
58. Roderburg, C.; Urban, G.W.; Bettermann, K.; Vucur, M.; Zimmermann, H.; Schmidt, S.; Janssen, J.; Koppe, C.; Knolle, P.; Castoldi, M. et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2011, 53, 209-218.
59. Lakner, A.M.; Steuerwald, N.M.; Walling, T.L.; Ghosh, S.; Li, T.; McKillop, I.H.; Russo, M.W.; Bonkovsky, H.L.; Schrum, L.W. Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis. Hepatology 2012, 56, 300-310.
60. Ogawa, T.; Enomoto, M.; Fujii, H.; Sekiya, Y.; Yoshizato, K.; Ikeda, K.; Kawada, N. MicroRNA-221/222 up-regulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut 2012, 61, 1600-1609.
61. Tsukamoto, H.; Zhu, N.L.; Asahina, K.; Mann, D.A.; Mann, J. Epigenetic cell fate regulation of hepatic stellate cells. Hepatol. Res. 2011, 41, 675-682.
62. Zeybel, M.; Hardy, T.; Wong, Y.K.; Mathers, J.C.; Fox, C.R.; Gackowska, A.; Oakley, F.; Burt, A.D.; Wilson, C.L.; Anstee, Q.M. et al. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat. Med. 2012, 18, 1369-1377.
63. Lemoinne, S.; Thabut, D.; Housset, C.; Moreau, R.; Valla, D.; Boulanger, C.M.; Rautou, P.E. The emerging roles of microvesicles in liver diseases. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 350-361.
64. Kornek, M.; Popov, Y.; Libermann, T.A.; Afdhal, N.H.; Schuppan, D. Human T cell microparticles circulate in blood of hepatitis patients and induce fibrolytic activation of hepatic stellate cells. Hepatology 2011, 53, 230-242.
65. Szabo, G.; Bala, S. MicroRNAs in liver disease. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 542-552.
66. Witek, R.P.; Yang, L.; Liu, R.; Jung, Y.; Omenetti, A.; Syn, W.K.; Choi, S.S.; Cheong, Y.; Fearing, C.M.; Agboola, K.M. et al. Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells. Gastroenterology 2009, 136, 320-330.
67. Iredale, J.P.; Benyon, R.C.; Pickering, J.; McCullen, M.; Northrop, M.; Pawley, S.; Hovell, C.; Arthur, M.J. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Investig. 1998, 102, 538-549.
68. Kisseleva, T.; Cong, M.; Paik, Y.; Scholten, D.; Jiang, C.; Benner, C.; Iwaisako, K.; Moore-Morris, T.; Scott, B.; Tsukamoto, H. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl. Acad. Sci. USA 2012, 109, 9448-9453.
69. Troeger, J.S.; Mederacke, I.; Gwak, G.Y.; Dapito, D.H.; Mu, X.; Hsu, C.C.; Pradere, J.P.; Friedman, R.A.; Schwabe, R.F. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 2012, 143, 1073-1083.
70. Kisseleva, T.; Brenner, D.A. Anti-fibrogenic strategies and the regression of fibrosis. Best Pract. Res. Clin. Gastroenterol. 2011, 25, 305-317.
71. Chang, C.Y.; Martin, P.; Fotiadu, A.; Hytiroglou, P. A patient with chronic hepatitis B and regression of fibrosis during treatment. Semin. Liver Dis. 2010, 30, 296-301.
72. Duffield, J.S.; Forbes, S.J.; Constandinou, C.M.; Clay, S.; Partolina, M.; Vuthoori, S.; Wu, S.; Lang, R.; Iredale, J.P. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Investig. 2005, 11 5, 56-65.
73. Kenny-Walsh, E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N. Engl. J. Med. 1999, 340, 1228-1233.
74. Wiese, M.; Berr, F.; Lafrenz, M.; Porst, H.; Oesen, U. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in germany: A 20-year multicenter study. Hepatology 2000, 32, 91-96.
75. Poynard, T.; Bedossa, P.; Opolon, P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997, 349, 825-832.
76. Ghany, M.G.; Strader, D.B.; Thomas, D.L.; Seeff, L.B. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology 2009, 49, 1335-1374.
77. Everhart, J.E.; Wright, E.C.; Goodman, Z.D.; Dienstag, J.L.; Hoefs, J.C.; Kleiner, D.E.; Ghany, M.G.; Mills, A.S.; Nash, S.R.; Govindarajan, S. et al. Prognostic value of Ishak fibrosis stage: Findings from the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology 2010, 51, 585-594.
78. Thein, H.H.; Yi, Q.; Dore, G.J.; Krahn, M.D. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: A meta-analysis and meta-regression. Hepatology 2008, 48, 418-431.
79. Hui, C.K.; Leung, N.; Yuen, S.T.; Zhang, H.Y.; Leung, K.W.; Lu, L.; Cheung, S.K.; Wong, W.M.; Lau, G.K. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology 2007, 46, 395-401.
80. Hui, C.K.; Leung, N.; Shek, T.W.; Yao, H.; Lee, W.K.; Lai, J.Y.; Lai, S.T.; Wong, W.M.; Lai, L.S.; Poon, R.T. et al. Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology 2007, 46, 690-698.
81. Kao, J.H.; Chen, P.J.; Lai, M.Y.; Chen, D.S. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000, 11 8, 554-559.
82. Kao, J.H.; Wu, N.H.; Chen, P.J.; Lai, M.Y.; Chen, D.S. Hepatitis B genotypes and the response to interferon therapy. J. Hepatol. 2000, 33, 998-1002.
83. Iloeje, U.H.; Yang, H.I.; Su, J.; Jen, C.L.; You, S.L.; Chen, C.J. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006, 130, 678-686.
84. Chen, C.J.; Yang, H.I.; Su, J.; Jen, C.L.; You, S.L.; Lu, S.N. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006, 295, 65-73.
85. Yang, H.C.; Chen, C.L.; Shen, Y.C.; Peng, C.Y.; Liu, C.J.; Tseng, T.C.; Su, T.H.; Chuang, W.L.; Yu, M.L.; Dai, C.Y. et al. Distinct evolution and predictive value of hepatitis B virus precore and basal core promoter mutations in interferon-induced hepatitis B e antigen seroconversion. Hepatology 2013, 57, 934-943.
86. Tseng, T.C.; Liu, C.J.; Yang, H.C.; Chen, C.L.; Yang, W.T.; Tsai, C.S.; Kuo, S.F.; Verbree, F.C.; Su, T.H.; Wang, C.C. et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut 2014, doi:10.1136/gutjnl-2014-306977.
87. Martin-Vilchez, S.; Sanz-Cameno, P.; Rodriguez-Munoz, Y.; Majano, P.L.; Molina-Jimenez, F.; Lopez-Cabrera, M.; Moreno-Otero, R.; Lara-Pezzi, E. The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells. Hepatology 2008, 47, 1872-1883.
88. Guo, G.H.; Tan, D.M.; Zhu, P.A.; Liu, F. Hepatitis B virus X protein promotes proliferation and up-regulates TGF-β1 and CTGF in human hepatic stellate cell line, LX-2. Hepatobiliary Pancreat. Dis. Int. 2009, 8, 59-64.
89. Liu, X.; Zhu, S.T.; You, H.; Cong, M.; Liu, T.H.; Wang, B.E.; Jia, J.D. Hepatitis B virus infects hepatic stellate cells and affects their proliferation and expression of collagen type I. Chin. Med. J. 2009, 122, 1455-1461.
90. Jin, Z.; Sun, R.; Wei, H.; Gao, X.; Chen, Y.; Tian, Z. Accelerated liver fibrosis in hepatitis B virus transgenic mice: Involvement of natural killer T cells. Hepatology 2011, 53, 219-229.
91. Zhao, J.; Zhang, Z.; Luan, Y.; Zou, Z.; Sun, Y.; Li, Y.; Jin, L.; Zhou, C.; Fu, J.; Gao, B. et al. Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology 2014, 59, 1331-1342.
92. Gutierrez-Reyes, G.; Gutierrez-Ruiz, M.C.; Kershenobich, D. Liver fibrosis and chronic viral hepatitis. Arch. Med. Res. 2007, 38, 644-651.
93. Silini, E.; Bottelli, R.; Asti, M.; Bruno, S.; Candusso, M.E.; Brambilla, S.; Bono, F.; Iamoni, G.; Tinelli, C.; Mondelli, M.U. et al. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a case-control study. Gastroenterology 1996, 111, 199-205.
94. Bruno, S.; Crosignani, A.; Maisonneuve, P.; Rossi, S.; Silini, E.; Mondelli, M.U. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: A seventeen-year prospective cohort study. Hepatology 2007, 46, 1350-1356.
95. Hisada, M.; Chatterjee, N.; Kalaylioglu, Z.; Battjes, R.J.; Goedert, J.J. Hepatitis C virus load and survival among injection drug users in the United States. Hepatology 2005, 42, 1446-1452.
96. Lee, M.H.; Yang, H.I.; Lu, S.N.; Jen, C.L.; Yeh, S.H.; Liu, C.J.; Chen, P.J.; You, S.L.; Wang, L.Y.; Chen, W.J. et al. Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: Long-term predictors from a community-based cohort study. J. Clin. Oncol. 2010, 28, 4587-4593.
97. Weng, H.L.; Liu, Y.; Chen, J.L.; Huang, T.; Xu, L.J.; Godoy, P.; Hu, J.H.; Zhou, C.; Stickel, F.; Marx, A. et al. The etiology of liver damage imparts cytokines transforming growth factor β1 or interleukin-13 as driving forces in fibrogenesis. Hepatology 2009, 50, 230-243.
98. Huang, H.; Shiffman, M.L.; Friedman, S.; Venkatesh, R.; Bzowej, N.; Abar, O.T.; Rowland, C.M.; Catanese, J.J.; Leong, D.U.; Sninsky, J.J. et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007, 46, 297-306.
99. Marcolongo, M.; Young, B.; dal Pero, F.; Fattovich, G.; Peraro, L.; Guido, M.; Sebastiani, G.; Palu, G.; Alberti, A. A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology 2009, 50, 1038-1044.
100. Lauer, G.M.; Walker, B.D. Hepatitis C virus infection. N. Engl. J. Med. 2001, 345, 41-52.
101. Tsukuma, H.; Hiyama, T.; Tanaka, S.; Nakao, M.; Yabuuchi, T.; Kitamura, T.; Nakanishi, K.; Fujimoto, I.; Inoue, A.; Yamazaki, H. et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N. Engl. J. Med. 1993, 328, 1797-1801.
102. Chen, C.L.; Yang, H.I.; Yang, W.S.; Liu, C.J.; Chen, P.J.; You, S.L.; Wang, L.Y.; Sun, C.A.; Lu, S.N.; Chen, D.S. et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: A follow-up study in Taiwan. Gastroenterology 2008, 135, 111-121.
103. Bruno, S.; Zuin, M.; Crosignani, A.; Rossi, S.; Zadra, F.; Roffi, L.; Borzio, M.; Redaelli, A.; Chiesa, A.; Silini, E.M. et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: A long-term prospective study. Am. J. Gastroenterol. 2009, 104, 1147-1158.
104. European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J. Hepatol. 2012, 57, 167-185.
105. Chang, T.T.; Liaw, Y.F.; Wu, S.S.; Schiff, E.; Han, K.H.; Lai, C.L.; Safadi, R.; Lee, S.S.; Halota, W.; Goodman, Z. et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010, 52, 886-893.
106. Marcellin, P.; Gane, E.; Buti, M.; Afdhal, N.; Sievert, W.; Jacobson, I.M.; Washington, M.K.; Germanidis, G.; Flaherty, J.F.; Schall, R.A. et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: A 5-year open-label follow-up study. Lancet 2013, 381, 468-475.
107. Chang, X.M.; Chang, Y.; Jia, A. Effects of interferon-alpha on expression of hepatic stellate cell and transforming growth factor-beta1 and alpha-smooth muscle actin in rats with hepatic fibrosis. World J. Gastroenterol. 2005, 11, 2634-2636.
108. Weng, H.; Mertens, P.R.; Gressner, A.M.; Dooley, S. IFN-γ abrogates profibrogenic TGF-β signaling in liver by targeting expression of inhibitory and receptor Smads. J. Hepatol. 2007, 46, 295-303.
109. Shiratori, Y.; Imazeki, F.; Moriyama, M.; Yano, M.; Arakawa, Y.; Yokosuka, O.; Kuroki, T.; Nishiguchi, S.; Sata, M.; Yamada, G. et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann. Intern. Med. 2000, 132, 517-524.
110. Mallet, V.; Gilgenkrantz, H.; Serpaggi, J.; Verkarre, V.; Vallet-Pichard, A.; Fontaine, H.; Pol, S. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann. Intern. Med. 2008, 149, 399-403.
111. Lok, A.S.; McMahon, B.J. Chronic hepatitis B: Update 2009. Hepatology 2009, 50, 661-662.
112. Ghany, M.G.; Nelson, D.R.; Strader, D.B.; Thomas, D.L.; Seeff, L.B. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011, 54, 1433-1444.
113. Liaw, Y.F.; Sung, J.J.; Chow, W.C.; Farrell, G.; Lee, C.Z.; Yuen, H. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med. 2004, 351, 1521-1531.
114. Papatheodoridis, G.V.; Lampertico, P.; Manolakopoulos, S.; Lok, A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: A systematic review. J. Hepatol. 2010, 53, 348-356.
115. Hosaka, T.; Suzuki, F.; Kobayashi, M.; Seko, Y.; Kawamura, Y.; Sezaki, H.; Akuta, N.; Suzuki, Y.; Saitoh, S.; Arase, Y. et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2012, 58, 98-107.
116. Wong, G.L.; Chan, H.L.; Mak, C.W.; Lee, S.K.; Ip, Z.M.; Lam, A.T.; Iu, H.W.; Leung, J.M.; Lai, J.W.; Lo, A.O. et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology 2013, 58, 1537-1547.
117. Zoutendijk, R.; Reijnders, J.G.; Zoulim, F.; Brown, A.; Mutimer, D.J.; Deterding, K.; Hofmann, W.P.; Petersen, J.; Fasano, M.; Buti, M. et al. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut 2013, 62, 760-765.
118. Poynard, T.; McHutchison, J.; Manns, M.; Trepo, C.; Lindsay, K.; Goodman, Z.; Ling, M.H.; Albrecht, J. Impact of pegylated interferon -2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002, 122, 1303-1313.
119. Hung, C.H.; Lee, C.M.; Lu, S.N.; Wang, J.H.; Hu, T.H.; Tung, H.D.; Chen, C.H.; Chen, W.J.; Changchien, C.S. Long-term effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. J. Viral Hepat. 2006, 13, 409-414.
120. Bruno, S.; Stroffolini, T.; Colombo, M.; Bollani, S.; Benvegnu, L.; Mazzella, G.; Ascione, A.; Santantonio, T.; Piccinino, F.; Andreone, P. et al. Sustained virological response to interferon is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 2007, 45, 579-587.
121. Bruno, S.; Crosignani, A.; Facciotto, C.; Rossi, S.; Roffi, L.; Redaelli, A.; de Franchis, R.; Almasio, P.L.; Maisonneuve, P. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology 2010, 51, 2069-2076.
122. Fernandez-Rodriguez, C.M.; Alonso, S.; Martinez, S.M.; Forns, X.; Sanchez-Tapias, J.M.; Rincon, D.; Rodriguez-Caravaca, G.; Barcena, R.; Serra, M.A.; Romero-Gomez, M. et al. Peginterferon plus ribavirin and sustained virological response in HCV-related cirrhosis: Outcomes and factors predicting response. Am. J. Gastroenterol. 2010, 105, 2164-2172.
123. Roberts, S.; Gordon, A.; McLean, C.; Pedersen, J.; Bowden, S.; Thomson, K.; Angus, P. Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis. Clin. Gastroenterol. Hepatol. 2007, 5, 932-937.
124. Noureddin, M.; Ghany, M.G. Editorial: Treatment of patients with HCV-related cirrhosis with peginterferon and ribavirin: Swinging the pendulum toward treatment. Am. J. Gastroenterol. 2010, 105, 2174-2176.
125. Velosa, J.; Serejo, F.; Marinho, R.; Nunes, J.; Gloria, H. Eradication of hepatitis C virus reduces the risk of hepatocellular carcinoma in patients with compensated cirrhosis. Dig. Dis. Sci. 2011, 56, 1853-1861.
126. Morgan, R.L.; Baack, B.; Smith, B.D.; Yartel, A.; Pitasi, M.; Falck-Ytter, Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: A meta-analysis of observational studies. Ann. Intern. Med. 2013, 158, 329-337.
127. Trebicka, J.; Hennenberg, M.; Odenthal, M.; Shir, K.; Klein, S.; Granzow, M.; Vogt, A.; Dienes, H.P.; Lammert, F.; Reichen, J. et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J. Hepatol. 2010, 53, 702-712.
128. Abbas, G.; Silveira, M.G.; Lindor, K.D. Hepatic fibrosis and the renin-angiotensin system. Am. J. Ther. 2011, 18, e202-e208.
129. Zhang, W.; Wu, R.; Zhang, F.; Xu, Y.; Liu, B.; Yang, Y.; Zhou, H.; Wang, L.; Wan, K.; Xiao, X. et al. Thiazolidinediones improve hepatic fibrosis by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in rats with non-alcoholic steatohepatitis. Clin. Exp. Pharmacol. Physiol. 2012, 39, 1026-1033.
130. Wilhelm, S.M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M. et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004, 64, 7099-7109.
131. Chang, Y.S.; Adnane, J.; Trail, P.A.; Levy, J.; Henderson, A.; Xue, D.; Bortolon, E.; Ichetovkin, M.; Chen, C.; McNabola, A. et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother. Pharmacol. 2007, 59, 561-574.
132. Calvisi, D.F.; Ladu, S.; Gorden, A.; Farina, M.; Conner, E.A.; Lee, J.S.; Factor, V.M.; Thorgeirsson, S.S. Ubiquitous activation of Ras and Jak/STAT pathways in human HCC. Gastroenterology 2006, 130, 1117-1128.
133. Semela, D.; Dufour, J.F. Angiogenesis and hepatocellular carcinoma. J. Hepatol. 2004, 41, 864-880.
134. Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; de Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 2008, 359, 378-390.
135. Cheng, A.L.; Kang, Y.K.; Chen, Z.; Tsao, C.J.; Qin, S.; Kim, J.S.; Luo, R.; Feng, J.; Ye, S.; Yang, T.S. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009, 10, 25-34.
136. Bruix, J.; Sherman, M. Management of hepatocellular carcinoma: an update. Hepatology 2011, 53, 1020-1022.
137. Wang, Y.; Gao, J.; Zhang, D.; Zhang, J.; Ma, J.; Jiang, H. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J. Hepatol. 2010, 53, 132-144.
138. Hong, F.; Chou, H.; Fiel, M.I.; Friedman, S.L. Antifibrotic activity of sorafenib in experimental hepatic fibrosis: Refinement of inhibitory targets, dosing, and window of efficacy in vivo. Dig. Dis. Sci. 2013, 58, 257-264.
139. Barry-Hamilton, V.; Spangler, R.; Marshall, D.; McCauley, S.; Rodriguez, H.M.; Oyasu, M.; Mikels, A.; Vaysberg, M.; Ghermazien, H.; Wai, C. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 2010, 16, 1009-1017.
140. Di Sario, A.; Bendia, E.; Svegliati Baroni, G.; Ridolfi, F.; Casini, A.; Ceni, E.; Saccomanno, S.; Marzioni, M.; Trozzi, L.; Sterpetti, P. et al. Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production. J. Hepatol. 2002, 37, 584-591.
141. Noble, P.W.; Albera, C.; Bradford, W.Z.; Costabel, U.; Glassberg, M.K.; Kardatzke, D.; King, T.E., Jr.; Lancaster, L.; Sahn, S.A.; Szwarcberg, J. et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials. Lancet 2011, 377, 1760-1769.
142. King, T.E., Jr.; Bradford, W.Z.; Castro-Bernardini, S.; Fagan, E.A.; Glaspole, I.; Glassberg, M.K.; Gorina, E.; Hopkins, P.M.; Kardatzke, D.; Lancaster, L. et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2083-2092.
143. Duffield, J.S.; Lupher, M.L., Jr. PRM-151 (recombinant human serum amyloid P/pentraxin 2) for the treatment of fibrosis. Drug News Perspect. 2010, 23, 305-315.
144. Richeldi, L.; Costabel, U.; Selman, M.; Kim, D.S.; Hansell, D.M.; Nicholson, A.G.; Brown, K.K.; Flaherty, K.R.; Noble, P.W.; Raghu, G. et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2011, 365, 1079-1087.
145. Richeldi, L.; du Bois, R.M.; Raghu, G.; Azuma, A.; Brown, K.K.; Costabel, U.; Cottin, V.; Flaherty, K.R.; Hansell, D.M.; Inoue, Y. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2071-2082.
146. Li, G.; Xie, Q.; Shi, Y.; Li, D.; Zhang, M.; Jiang, S.; Zhou, H.; Lu, H.; Jin, Y. Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats. J. Gene Med. 2006, 8, 889-900.
147. Sato, Y.; Murase, K.; Kato, J.; Kobune, M.; Sato, T.; Kawano, Y.; Takimoto, R.; Takada, K.; Miyanishi, K.; Matsunaga, T. et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat. Biotechnol. 2008, 26, 431-442.
148. Moreno, M.; Gonzalo, T.; Kok, R.J.; Sancho-Bru, P.; van Beuge, M.; Swart, J.; Prakash, J.; Temming, K.; Fondevila, C.; Beljaars, L. et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 2010, 51, 942-952.