Chapter 105
Hepatic Fibrosis and Cirrhosis
Don C Rockey,
Don C Rockey
Medical University of South Carolina, Charleston, SC, USA
Search for more papers by this authorDon C Rockey,
Don C Rockey
Medical University of South Carolina, Charleston, SC, USA
Search for more papers by this authorBook Editor(s):Daniel K. Podolsky MD,
Michael Camilleri MD,
J. Gregory Fitz MD FAASLD,
Anthony N. Kalloo MD,
Fergus Shanahan MD,
Timothy C. Wang MD,
Daniel K. Podolsky MD
President, University of Texas Southwestern Medical Center, Professor of Internal Medicine, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA
Search for more papers by this authorMichael Camilleri MD
Executive Dean for Development, Atherton and Winifred W. Bean Professor, Professor of Medicine, Physiology and Pharmacology, Distinguished Investigator, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorJ. Gregory Fitz MD FAASLD
Executive Vice President for Academic Aff airs and Provost, University of Texas Southwestern Medical Center, Dean, Professor of Internal Medicine, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA
Search for more papers by this authorAnthony N. Kalloo MD
Professor of Medicine, Johns Hopkins University School of Medicine, Director, Division of Gastroenterology & Hepatology, Johns Hopkins Hospital, Baltimore, MD, USA
Search for more papers by this authorFergus Shanahan MD
Professor and Chair, Department of Medicine, Director, Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland
Search for more papers by this authorTimothy C. Wang MD
Chief, Division of Digestive and Liver Diseases, Silberberg Professor of Medicine, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorFirst published: 27 November 2015
Summary
This chapter reviews multiple aspects of hepatic fibrosis, including its pathophysiologic mechanisms, natural history, clinical features, current and future tools for diagnosing fibrosis, as well as emerging antifibrotic therapies. Stellate cells are the predominant cell type involved in the fibrogenic response. During and as part of the activation process, stellate cells exhibit a variety of properties. These include fibrogenesis, proliferation, cellular contractility, motility, cytokine synthesis, chemotaxis, matrix degradation, retinoid loss, and proinflammatory responses. Stellate cell activation is accompanied by depletion of retinoid (vitamin A) droplets. Percutaneous liver biopsy has historically been considered to be the gold standard for assessment of fibrosis and cirrhosis. In many forms of liver disease, treatment of the underlying inciting lesion leads to improvement in fibrosis, even in patients with histological cirrhosis. Angiogenic pathways appear to be important in fibrosis, and represent an attractive therapeutic target.
References
- Henderson N.C., Arnold T.D., Katamura Y., et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013; 19: 1617.
- Hillebrandt S., Goos C., Matern S., et al. Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15. Gastroenterology 2002; 123: 2041.
- Iredale J.P., Benyon R.C., Pickering J., et al. Mechanisms of spontaneous resolution of rat liver fibrosis. HSC apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102: 538.
- Lee Y.A., Wallace M.C., Friedman S.L. Pathobiology of liver fibrosis: a translational success story. Gut 2015; 64: 830.
- Liaw Y.F., Sung J.J., Chow W.C., et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521.
- Maher J.J., McGuire R.F. ECM gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo. J Clin Invest 1990; 86: 1641.
- Rockey D.C., Bell P.D., Hill J.A. Fibrosis – a common pathway to organ injury and failure. N Engl J Med 2015; 372: 1138.
- Rockey D.C., Housset C.N., Friedman S.L. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 1993; 92: 1795.
- Seki E., De Minicis S., Osterreicher C.H., et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007; 13: 132.
- Shafiei M.S., Rockey D.C. The role of integrin-linked kinase in liver wound healing. J Biol Chem 2006; 281: 24863.
- Shi Z., Wakil A.E., Rockey D.C. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci U S A 1997; 94: 10663.
- Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 1980; 66: 303.
- Rockey DC, Bell PD, Hill JA. Fibrosis: a common pathway of organ injury and failure. NEJM 2015; 372: 1138.
- Schuppan D, Ruehl M, Somasundaram R, et al. Matrix as modulator of stellate cell and hepatic fibrogenesis. Semin Liver Dis 2001; 21: 351.
- Jarnagin WR, Rockey DC, Koteliansky VE, et al. Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol 1994; 127: 2037.
- Bedossa P, Ferlicot S, Paradis V, et al. Dystroglycan expression in hepatic stellate cells: role in liver fibrosis. Lab Invest 2002; 82: 1053.
- Arthur MJ, Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2000; 279: G245.
- Iredale JP. Stellate cell behavior during resolution of liver injury. Semin Liver Dis 2001; 21: 427.
- Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88: 125.
- Maher JJ, McGuire RF. Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo. J Clin Invest 1990; 86: 1641.
- Rockey DC. Hepatic fibrosis, stellate cells, and portal hypertension. Clin Liver Dis 2006; 10: 459, vii-viii.
- Li Z, Dranoff JA, Chan EP, et al. Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 2007; 46: 1246.
- Kisseleva T, Uchinami H, Feirt N, et al. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol 2006; 45: 429.
- Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112: 1776.
- Kaimori A, Potter J, Kaimori JY, et al. Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 2007; 282: 22089.
- Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 1980; 66: 303.
- Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J 1991; 5: 271.
- Schuppan D. Structure of the extracellular matrix in normal and fibrotic liver: collagens and glycoproteins. Semin Liver Dis 1990; 10: 1.
- Rockey DC, Boyles JK, Gabbiani G, et al. Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture. J Submicrosc Cytol Pathol 1992; 24: 193.
- Hinz B. Masters and servants of the force: the role of matrix adhesions in myofibroblast force perception and transmission. Eur J Cell Biol 2006; 85: 175.
- Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003; 200: 500.
- Wake K, Sato T. Intralobular heterogeneity of perisinusoidal stellate cells in porcine liver. Cell Tissue Res 1993; 273: 227.
- Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med 2000; 21: 49.
- Urtasun R, Lopategi A, George J, et al. Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin alpha(V)beta(3) engagement and PI3K/pAkt/NFkappaB signaling. Hepatology 2012; 55: 594.
- Mormone E, Lu Y, Ge X, et al. Fibromodulin, an oxidative stress-sensitive proteoglycan, regulates the fibrogenic response to liver injury in mice. Gastroenterology 2012; 142: 612.
- Sancho P, Mainez J, Crosas-Molist E, et al. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS ONE 2012; 7: e45285.
- Dunning S, Ur Rehman A, Tiebosch MH, et al. Glutathione and antioxidant enzymes serve complementary roles in protecting activated hepatic stellate cells against hydrogen peroxide-induced cell death. Biochim Biophys Acta 2013; 1832: 2027.
- Jiang JX, Torok NJ. Liver Injury and the Activation of the Hepatic Myofibroblasts. Curr Pathobiol Rep 2013; 1: 215.
- Cui W, Matsuno K, Iwata K, et al. NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation. Hepatology 2011; 54: 949.
- Pellicoro A, Ramachandran P, Iredale JP, et al. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 2014; 14: 181.
- Presser LD, McRae S, Waris G. Activation of TGF-beta1 promoter by hepatitis C virus-induced AP-1 and Sp1: role of TGF-beta1 in hepatic stellate cell activation and invasion. PLoS ONE 2013; 8: e56367.
- Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007; 13: 1324.
- Guo J, Loke J, Zheng F, et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 2009; 49: 960.
- Canbay A, Taimr P, Torok N, et al. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest 2003; 83: 655.
- Lee TF, Lin YL, Huang YT. Kaerophyllin inhibits hepatic stellate cell activation by apoptotic bodies from hepatocytes. Liver Int 2011; 31: 618.
- Canbay A, Higuchi H, Bronk SF, et al. Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis. Gastroenterology 2002; 123: 1323.
- Schnabl B, Purbeck CA, Choi YH, et al. Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 2003; 37: 653.
- Krizhanovsky V, Yon M, Dickins RA, et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134: 657.
- Kong X, Feng D, Wang H, et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012; 56: 1150.
- Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 2008; 48: 920.
- LeCouter J, Moritz DR, Li B, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003; 299: 890.
- Olaso E, Salado C, Egilegor E, et al. Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. Hepatology 2003; 37: 674.
- Yoshiji H, Kuriyama S, Yoshii J, et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 2003; 52: 1347.
- Mann J, Mann DA. Transcriptional regulation of hepatic stellate cells. Adv Drug Deliv Rev 2009; 61: 497.
- De Minicis S, Seki E, Uchinami H, et al. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology 2007; 132: 1937.
- Friedman SL. Transcriptional regulation of stellate cell activation. J Gastroenterol Hepatol 2006; 21(Suppl 3): S79.
- Marra F, Efsen E, Romanelli RG, et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 2000; 119: 466.
- Miyahara T, Schrum L, Rippe R, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 2000; 275: 35715.
- Yang L, Chan CC, Kwon OS, et al. Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2006; 291: G902.
- Fiorucci S, Antonelli E, Rizzo G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004; 127: 1497.
- Hellemans K, Verbuyst P, Quartier E, et al. Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids. Hepatology 2004; 39: 97.
- Beaven SW, Wroblewski K, Wang J, et al. Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease. Gastroenterology 2011; 140: 1052.
- Paik YH, Schwabe RF, Bataller R, et al. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 2003; 37: 1043.
- Rippe RA, Schrum LW, Stefanovic B, et al. NF-kappaB inhibits expression of the alpha1(I) collagen gene. DNA Cell Biol 1999; 18: 751.
- Smart DE, Green K, Oakley F, et al. JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation. Hepatology 2006; 44: 1432.
- Ghiassi-Nejad Z, Hernandez-Gea V, Woodrell C, et al. Reduced hepatic stellate cell expression of Kruppel-like factor 6 tumor suppressor isoforms amplifies fibrosis during acute and chronic rodent liver injury. Hepatology 2013; 57: 786.
- Shi Z, Rockey DC. Interferon-gamma-mediated inhibition of serum response factor-dependent smooth muscle-specific gene expression. J Biol Chem 2010; 285: 32415.
- Weiskirchen R, Moser M, Weiskirchen S, et al. LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1. Biochem J 2001; 359: 485.
- Kalinichenko VV, Bhattacharyya D, Zhou Y, et al. Foxf1 +/− mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology 2003; 37: 107.
- Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008; 456: 980.
- Liu G, Friggeri A, Yang Y, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med 2010; 207: 1589.
- Chau BN, Xin C, Hartner J, et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med 2012; 4: 121ra18.
- Roderburg C, Urban GW, Bettermann K, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2010.
- Li J, Ghazwani M, Zhang Y, et al. miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J Hepatol 2013; 58: 522.
- Sun X, He Y, Ma TT, et al. Participation of miR-200a in TGF-beta1-mediated hepatic stellate cell activation. Mol Cell Biochem 2014; 388: 11.
- Roderburg C, Luedde M, Vargas Cardenas D, et al. miR-133a mediates TGF-beta-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis. J Hepatol 2013; 58: 736.
- He Y, Huang C, Zhang SP, et al. The potential of microRNAs in liver fibrosis. Cell Signal 2012; 24: 2268.
- Wells RG. Fibrogenesis. V. TGF-beta signaling pathways. Am J Physiol Gastrointest Liver Physiol 2000; 279: G845.
- Gressner AM, Weiskirchen R, Breitkopf K, et al. Roles of tgf-Beta in hepatic fibrosis. Front Biosci 2002; 7: D793.
- Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115: 209.
- Rockey DC. Translating an understanding of the pathogenesis of hepatic fibrosis to novel therapies. Clin Gastroenterol Hepatol 2013; 11: 224.
- Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front Biosci 2002; 7: d1720.
- Rockey DC, Fouassier L, Chung JJ, et al. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998; 27: 472.
- Pinzani M, Milani S, De Franco R, et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 1996; 110: 534.
- Marra F, Grandaliano G, Valente AJ, et al. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 1995; 22: 780.
- Rosenbaum J, Blazejewski S, Preaux AM, et al. Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts. Gastroenterology 1995; 109: 1986.
- Pinzani M, Abboud HE, Aron DC. Secretion of insulin-like growth factor-I and binding proteins by rat liver fat-storing cells: regulatory role of platelet-derived growth factor. Endocrinology 1990; 127: 2343.
- Moles A, Tarrats N, Fernandez-Checa JC, et al. Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential. Hepatology 2009; 49: 1297.
- Yang L, Stimpson SA, Chen L, et al. Effectiveness of the PPARgamma agonist, GW570, in liver fibrosis. Inflamm Res 2010; 59: 1061.
- Sun WY, Song Y, Hu SS, et al. Depletion of beta-arrestin2 in hepatic stellate cells reduces cell proliferation via ERK pathway. J Cell Biochem 2013; 114: 1153.
- Rockey DC, Housset CN, Friedman SL. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 1993; 92: 1795.
- Rockey DC. Vascular mediators in the injured liver. Hepatology 2003; 37: 4.
- Housset C, Rockey DC, Bissell DM. Endothelin receptors in rat liver: lipocytes as a contractile target for endothelin 1. Proc Natl Acad Sci U S A 1993; 90: 9266.
- Rockey DC, Chung JJ. Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. J Clin Invest 1995; 95: 1199.
- Rockey DC, Weymouth N, Shi Z. Smooth muscle alpha actin (Acta2) and myofibroblast function during hepatic wound healing. PLoS ONE 2013; 8: e77166.
- Melton AC, Soon RK Jr, Park JG, et al. Focal adhesion disassembly is an essential early event in hepatic stellate cell chemotaxis. Am J Physiol Gastrointest Liver Physiol 2007; 293: G1272.
- Marra F. Chemokines in liver inflammation and fibrosis. Front Biosci 2002; 7: d1899.
- Ohata M, Yamauchi M, Takeda K, et al. RAR and RXR expression by Kupffer cells. Exp Mol Pathol 2000; 68: 13.
- Schwabe RF, Bataller R, Brenner DA. Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 2003; 285: G949.
- Gaca MD, Zhou X, Benyon RC. Regulation of hepatic stellate cell proliferation and collagen synthesis by proteinase-activated receptors. J Hepatol 2002; 36: 362.
- Bataller R, Paik YH, Lindquist JN, et al. Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 2004; 126: 529.
- Efsen E, Grappone C, DeFranco RM, et al. Up-regulated expression of fractalkine and its receptor CX3CR1 during liver injury in humans. J Hepatol 2002; 37: 39.
- Kobayashi S, Seki S, Kawada N, et al. Apoptosis of T cells in the hepatic fibrotic tissue of the rat: a possible inducing role of hepatic myofibroblast-like cells. Cell Tissue Res 2003; 311: 353.
- Shi Z, Wakil AE, Rockey DC. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci U S A 1997; 94: 10663.
- Safadi R, Ohta M, Alvarez CE, et al. Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. Gastroenterology 2004; 127: 870.
- Gao B, Radaeva S, Jeong WI. Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis. Expert Rev Gastroenterol Hepatol 2007; 1: 173.
- Holt AP, Haughton EL, Lalor PF, et al. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 2009; 136: 705.
- Zhan S, Chan CC, Serdar B, et al. Fibronectin stimulates endothelin-1 synthesis in rat hepatic myofibroblasts via a Src/ERK-regulated signaling pathway. Gastroenterology 2009; 136: 2345.
- Tsukamoto H. Redox regulation of cytokine expression in Kupffer cells. Antioxid Redox Signal 2002; 4: 741.
- Muro AF, Moretti FA, Moore BB, et al. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med 2008; 177: 638.
- Border WA, Noble NA, Yamamoto T, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 1992; 360: 361.
- Vogel W, Gish GD, Alves F, et al. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997; 1: 13.
- Ikeda K, Wang LH, Torres R, et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J Biol Chem 2002; 277: 19206.
- Olaso E, Ikeda K, Eng FJ, et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 2001; 108: 1369.
- Luo Z, Liu H, Sun X, et al. RNA interference against discoidin domain receptor 2 ameliorates alcoholic liver disease in rats. PLoS ONE 2013; 8: e55860.
- Racine-Samson L, Rockey DC, Bissell DM. The role of alpha1beta1 integrin in wound contraction. A quantitative analysis of liver myofibroblasts in vivo and in primary culture. J Biol Chem 1997; 272: 30911.
- Levine D, Rockey DC, Milner TA, et al. Expression of the integrin alpha8beta1 during pulmonary and hepatic fibrosis. Am J Pathol 2000; 156: 1927.
- Gao R, Brigstock DR. Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin alpha(v)beta(3) and heparan sulfate proteoglycan. J Biol Chem 2004; 279: 8848.
- Zhou X, Murphy FR, Gehdu N, et al. Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem 2004; 279: 23996.
- Henderson NC, Arnold TD, Katamura Y, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013; 19: 1617.
- Shafiei MS, Rockey DC. The role of integrin-linked kinase in liver wound healing. J Biol Chem 2006; 281: 24863.
- Shafiei MS, Rockey DC. The function of integrin-linked kinase in normal and activated stellate cells: implications for fibrogenesis in wound healing. Lab Invest 2012; 92: 305.
- Gaca MD, Pickering JA, Arthur MJ, et al. Human and rat hepatic stellate cells produce stem cell factor: a possible mechanism for mast cell recruitment in liver fibrosis. J Hepatol 1999; 30: 850.
- Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis 2001; 21: 397.
- Saiman Y, Agarwal R, Hickman DA, et al. CXCL12 induces hepatic stellate cell contraction through a calcium independent pathway. Am J Physiol Gastrointest Liver Physiol 2013.
- Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102: 538.
- Sohara N, Znoyko I, Levy MT, et al. Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate. J Hepatol 2002; 37: 214.
- Preaux AM, D'Ortho MP, Bralet MP, et al. Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2. Hepatology 2002; 36: 615.
- Li L, Tao J, Davaille J, et al. 15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. J Biol Chem 2001; 276: 38152.
- Thoen LF, Guimaraes EL, Grunsven LA. Autophagy: a new player in hepatic stellate cell activation. Autophagy 2012; 8: 126.
- Thoen LF, Guimaraes EL, Dolle L, et al. A role for autophagy during hepatic stellate cell activation. J Hepatol 2011; 55: 1353.
- Hernndez-Gea V, Friedman SL. Autophagy fuels tissue fibrogenesis. Autophagy 2012; 8: 849.
- Hernandez-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 2012; 142: 938.
- Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095.
- Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013; 369: 448.
- Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013; 59: 160.
- Neff GW, Duncan CW, Schiff ER. The current economic burden of cirrhosis. Gastroenterol Hepatol 2011; 7: 661.
- El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142: 1264.
- Poynard T, Mathurin P, Lai CL, et al. A comparison of fibrosis progression in chronic liver diseases. J Hepatol 2003; 38: 257.
- 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.
- Thein HH, Yi Q, Dore GJ, et al. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008; 48: 418.
- Huang H, Shiffman ML, Friedman S, et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007; 46: 297.
- Konerman MA, Mehta SH, Sutcliffe CG, et al. Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: prospective analysis of 435 liver biopsy pairs. Hepatology 2013.
- Yilmaz N, Shiffman ML, Stravitz RT, et al. A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C virus following liver transplantation. Liver Transpl 2007; 13: 975.
- Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J Hepatol 2013; 58: 1028.
- Hillebrandt S, Wasmuth HE, Weiskirchen R, et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet 2005; 37: 835.
- Hillebrandt S, Goos C, Matern S, et al. Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15. Gastroenterology 2002; 123: 2041.
- Patton HM, Patel K, Behling C, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol 2004; 40: 484.
- Fartoux L, Poujol-Robert A, Guechot J, et al. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut 2005; 54: 1003.
- Perumalswami P, Kleiner DE, Lutchman G, et al. Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology 2006; 43: 780.
- Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002; 35: 1522.
- Lindh M, Horal P, Dhillon AP, et al. Hepatitis B virus DNA levels, precore mutations, genotypes and histological activity in chronic hepatitis B. J Viral Hepat 2000; 7: 258.
- Merican I, Guan R, Amarapuka D, et al. Chronic hepatitis B virus infection in Asian countries. J Gastroenterol Hepatol 2000; 15: 1356.
- Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130: 678.
- Kobayashi M, Arase Y, Ikeda K, et al. Clinical characteristics of patients infected with hepatitis B virus genotypes A, B, and C. J Gastroenterol 2002; 37: 35.
- Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003; 348: 800.
- Farci P, Roskams T, Chessa L, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 2004; 126: 1740.
- Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521.
- Lee MH, Yang HI, Liu J, et al. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology 2013; 58: 546.
- Raynard B, Balian A, Fallik D, et al. Risk factors of fibrosis in alcohol-induced liver disease. Hepatology 2002; 35: 635.
- Tian C, Stokowski RP, Kershenobich D, et al. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42: 21.
- Falck-Ytter Y, Younossi ZM, Marchesini G, et al. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001; 21: 17.
- Dam-Larsen S, Becker U, Franzmann MB, et al. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol 2009; 44: 1236.
- Argo CK, Northup PG, Al-Osaimi AM, et al. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009; 51: 371.
- Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis 2010; 28: 162.
- Sobesky R, Mathurin P, Charlotte F, et al. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view. The Multivirc Group. Gastroenterology 1999; 116: 378.
- Poynard T, Ratziu V, Charlotte F, et al. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. J Hepatol 2001; 34: 730.
- Rockey DC, Bissell DM. Noninvasive measures of liver fibrosis. Hepatology 2006; 43: S113.
- Chalasani N, Imperiale TF, Ismail A, et al. Predictors of large esophageal varices in patients with cirrhosis. Am J Gastroenterol 1999; 94: 3285.
- Giannini E, Risso D, Botta F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 2003; 163: 218.
- Sheth SG, Flamm SL, Gordon FD, et al. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998; 93: 44.
- Giannini E, Testa R. Noninvasive diagnosis of fibrosis: the truth is rarely pure and never simple. Hepatology 2003; 38: 1312, author reply 3.
- Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002; 36: 986.
- Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38: 518.
- Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol 2004; 3: 8.
- Patel K, Gordon SC, Jacobson I, et al. Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients. J Hepatol 2004; 41: 935.
- Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004; 127: 1704.
- Parkes J, Roderick P, Harris S, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut 2010; 59: 1245.
- Dev A, White I, Symonds W, et al. Serum proteomic analysis in hepatitis C patients with and without fibrosis. J Hepatol 2005.
- Callewaert N, Van Vlierberghe H, Van Hecke A, et al. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med 2004; 10: 429.
- Wells RG. The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol 2005; 39: S158.
- Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep 2009; 11: 120.
- Rockey DC. Noninvasive assessment of liver fibrosis and portal hypertension with transient elastography. Gastroenterology 2008; 134: 8.
- Beljaars L, Meijer DK, Poelstra K. Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis. Front Biosci 2002; 7: e214.
- Giannini EG, Fasoli A, Borro P, et al. 13C-galactose breath test and 13C-aminopyrine breath test for the study of liver function in chronic liver disease. Clin Gastroenterol Hepatol 2005; 3: 279.
- Testa R, Caglieris S, Risso D, et al. Monoethylglycinexylidide formation measurement as a hepatic function test to assess severity of chronic liver disease. Am J Gastroenterol 1997; 92: 2268.
- Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology 2009; 49: 1017.
- Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97: 2614.
- Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic Fatty liver disease. Gastroenterology 2005; 128: 1898.
- D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44: 217.
- Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646.
- Wiesner RH, McDiarmid SV, Kamath PS, et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl 2001; 7: 567.
- Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33: 464.
- Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007; 133: 481.
- Ripoll C, Lastra P, Rincon D, et al. Comparison of MELD, HVPG, and their changes to predict clinically relevant endpoints in cirrhosis. Scand J Gastroenterol 2012; 47: 204.
- Durand F, Valla D. Assessment of prognosis of cirrhosis. Semin Liver Dis 2008; 28: 110.
- Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997; 112: 463.
- Lyles T, Elliott A, Rockey DC. A risk scoring system to predict in-hospital mortality in patients with cirrhosis presenting with upper gastrointestinal bleeding. J Clin Gastroenterol 2014; 48: 712.
- Rockey DC. Antifibrotic therapy in chronic liver disease. Clin Gastroenterol Hepatol 2005; 3: 95.
- Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996; 98: 1381.
- Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol 2012; 56: 1171.
- Crespo-Leiro MG, Robles O, Paniagua MJ, et al. Reversal of cardiac cirrhosis following orthotopic heart transplantation. Am J Transplant 2008; 8: 1336.
- Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 2004; 40: 646.
- El-Husseini R, Kaplan MM. Reversal of portal hypertension in a patient with primary biliary cirrhosis: disappearance of esophageal varices and thrombocytopenia. Am J Gastroenterol 2004; 99: 1859.
- Hammel P, Couvelard A, O'Toole D, et al. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 2001; 344: 418.
- Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 2000; 124: 1599.
- Dufour JF, DeLellis R, Kaplan MM. Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med 1997; 127: 981.
- Kweon YO, Goodman ZD, Dienstag JL, et al. Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol 2001; 35: 749.
- Chang TT, Liaw YF, Wu SS, 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: 866.
- Marcellin P, Gane E, Buti M, 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.
- Liaw YF. Reversal of cirrhosis: an achievable goal of hepatitis B antiviral therapy. J Hepatol 2013; 59: 880.
- Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000; 132: 517.
- Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122: 1303.
- Mallet V, Gilgenkrantz H, Serpaggi J, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008; 149: 399.
- Powell LW, Kerr JF. Reversal of "cirrhosis" in idiopathic haemochromatosis following long-term intensive venesection therapy. Australas Ann Med 1970; 19: 54.
- Blumberg RS, Chopra S, Ibrahim R, et al. Primary hepatocellular carcinoma in idiopathic hemochromatosis after reversal of cirrhosis. Gastroenterology 1988; 95: 1399.
- Sorensen TI, Orholm M, Bentsen KD, et al. Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet 1984; 2: 241.
- Berhe N, Myrvang B, Gundersen SG. Reversibility of schistosomal periportal thickening/fibrosis after praziquantel therapy: a twenty-six month follow-up study in Ethiopia. Am J Trop Med Hyg 2008; 78: 228.
- Ozaslan E. Drug-induced autoimmune hepatitis: an easily reversible type of liver fibrosis? Hepatology 2011; 53: 370.
- Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007; 132: 1746.
- Roberts S, Gordon A, McLean C, et al. Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis. Clin Gastroenterol Hepatol 2007; 5: 932.
- Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38: 343.
- Czaja AJ. Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39: 385.
- Ramond MJ, Poynard T, Rueff B, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992; 326: 507.
- Spahr L, Rubbia-Brandt L, Pugin J, et al. Rapid changes in alcoholic hepatitis histology under steroids: correlation with soluble intercellular adhesion molecule-1 in hepatic venous blood. J Hepatol 2001; 35: 582.
- Rambaldi A, Saconato HH, Christensen E, et al. Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther 2008; 27: 1167.
- Cohen SM, Ahn J. Review article: the diagnosis and management of alcoholic hepatitis. Aliment Pharmacol Ther 2009; 30: 3.
- Nelson DR, Tu Z, Soldevila-Pico C, et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 2003; 38: 859.
- Tilg H, Jalan R, Kaser A, et al. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis. J Hepatol 2003; 38: 419.
- Boetticher NC, Peine CJ, Kwo P, et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 2008; 135: 1953.
- Parker R, Armstrong MJ, Corbett C, et al. Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Aliment Pharmacol Ther 2013; 37: 845.
- Schaff Z, Lapis K, Szende B, et al. The effect of D-penicillamine on CCl4-induced experimental liver cirrhosis. Exp Pathol 1991; 43: 111.
- Bodenheimer HC Jr, Schaffner F, Sternlieb I, et al. A prospective clinical trial of D-penicillamine in the treatment of primary biliary cirrhosis. Hepatology 1985; 5: 1139.
- Dickson ER, Fleming TR, Wiesner RH, et al. Trial of penicillamine in advanced primary biliary cirrhosis. N Engl J Med 1985; 312: 1011.
- Aithal GP, Haugk B, Das S, et al. Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified? Aliment Pharmacol Ther 2004; 19: 391.
- Hendrickse MT, Rigney E, Giaffer MH, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial [see comments]. Gastroenterology 1999; 117: 400.
- Bach N, Bodian C, Bodenheimer H, et al. Methotrexate therapy for primary biliary cirrhosis. Am J Gastroenterol 2003; 98: 187.
- Lieber CS, Weiss DG, Groszmann R, et al. Veterans affairs cooperative study of polyenylphosphatidylcholine in alcoholic liver disease. Alcohol Clin Exp Res 2003; 27: 1765.
- Jia JD, Bauer M, Cho JJ, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1. J Hepatol 2001; 35: 392.
- Lieber CS, Leo MA, Cao Q, et al. Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons. J Clin Gastroenterol 2003; 37: 336.
- Rambaldi A, Jacobs BP, Iaquinto G, et al. Milk thistle for alcoholic and/or hepatitis B or C liver diseases – a systematic cochrane hepato-biliary group review with meta-analyses of randomized clinical trials. Am J Gastroenterol 2005; 100: 2583.
- Brown KE, Poulos JE, Li L, et al. Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload. Am J Physiol 1997; 272: G116.
- Houglum K, Venkataramani A, Lyche K, et al. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology 1997; 113: 1069.
- Hasegawa T, Yoneda M, Nakamura K, et al. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001; 15: 1667.
- Mezey E, Potter J, Rennie-Tankersley L, et al. A randomized placebo controlled trial of vitamin E in alcoholic hepatitis. J Hepatol 2004; 40: 40.
- Stewart S, Prince M, Bassendine M, et al. A trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol 2002; 36(S): 16.
- Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675.
- Song BJ, Rockey DC. Status of research on vitamin D supplementation in treating or preventing liver fibrosis. Liver Int 2013; 33: 653.
- Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98: 2485.
- Ahmad A, Afroz N, Gupta UD, et al. Vitamin B supplement alleviates N′-nitrosodimethylamine-induced hepatic fibrosis in rats. Pharm Biol 2014; PMID:24405044.
- Sakaida I, Tsuchiya M, Kawaguchi K, et al. Herbal medicine Inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol 2003; 38: 762.
- Shimizu I, Ma YR, Mizobuchi Y, et al. Effects of Sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats [see comments]. Hepatology 1999; 29: 149.
- Zhang XL, Liu L, Jiang HQ. Salvia miltiorrhiza monomer IH764-3 induces hepatic stellate cell apoptosis via caspase-3 activation. World J Gastroenterol 2002; 8: 515.
- Chen ZX, Zhang SJ, Lao SX, et al. He Jie Tang in the treatment of chronic hepatitis B patients. World J Gastroenterol 2005; 11: 6638.
- Wang BE. Treatment of chronic liver diseases with traditional Chinese medicine. J Gastroenterol Hepatol 2000; 15(Suppl): E67.
- Navarro VJ, Seeff LB. Liver injury induced by herbal complementary and alternative medicine. Clin Liver Dis 2013; 17: 715, x.
- Lu SC, Tsukamoto H, Mato JM. Role of abnormal methionine metabolism in alcoholic liver injury. Alcohol 2002; 27: 155.
- Anonymous. The results of a randomized double blind controlled trial evaluating malotilate in primary biliary cirrhosis. A European multicentre study group. J Hepatol 1993; 17: 227.
- Kaplan MM, DeLellis RA, Wolfe HJ. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 1997; 126: 682.
- Kaplan MM, Cheng S, Price LL, et al. A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results. Hepatology 2004; 39: 915.
- Mato JM, Camara J, Fernandez de Paz J, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol 1999; 30: 1081.
- Rambaldi A, Gluud C. Meta-analysis of propylthiouracil for alcoholic liver disease – a Cochrane Hepato-Biliary Group Review. Liver 2001; 21: 398.
- Nava-Ocampo AA, Suster S, Muriel P. Effect of colchiceine and ursodeoxycholic acid on hepatocyte and erythrocyte membranes and liver histology in experimentally induced carbon tetrachloride cirrhosis in rats. Eur J Clin Invest 1997; 27: 77.
- Stiehl A. Ursodeoxycholic acid in the treatment of primary sclerosing cholangitis. Ann Med 1994; 26: 345.
- Combes B, Carithers RL Jr, Maddrey WC, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1995; 22: 759.
- Jacquemin E, Hermans D, Myara A, et al. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology 1997; 25: 519.
- Lindblad A, Glaumann H, Strandvik B. A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease. Hepatology 1998; 27: 166.
- Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999; 354: 1053.
- Poupon RE, Bonnand AM, Chretien Y, et al. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology 1999; 29: 1668.
- Degott C, Zafrani ES, Callard P, et al. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology 1999; 29: 1007.
- Poupon RE, Lindor KD, Pares A, et al. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 2003; 39: 12.
- Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004; 39: 770.
- Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011; 54: 1011.
- Rudic JS, Poropat G, Krstic MN, et al. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2012;(12):CD000551.
- Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst Rev 2012;(10):CD000222.
- Rockey DC, Maher JJ, Jarnagin WR, et al. Inhibition of rat hepatic lipocyte activation in culture by interferon-gamma. Hepatology 1992; 16: 776.
- Rockey DC, Chung JJ. Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: implications for treatment of hepatic fibrosis. J Investig Med 1994; 42: 660.
- Muir AJ, Sylvestre PB, Rockey DC. Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection. J Viral Hepat 2006; 13: 322.
- Pockros PJ, Jeffers L, Afdhal N, et al. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology 2007; 45: 569.
- Hazra S, Xiong S, Wang J, et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem 2004; 279: 11392.
- Shafiei MS, Shetty S, Scherer PE, et al. Adiponectin regulation of stellate cell activation via PPARgamma-dependent and -independent mechanisms. Am J Pathol 2011; 178: 2690.
- McHutchison J, Goodman Z, Patel K, et al. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology 2010; 138: 1365, 73 e1-2.
- Rodriguez L, Cerbon-Ambriz J, Munoz ML. Effects of colchicine and colchiceine in a biochemical model of liver injury and fibrosis. Arch Med Res 1998; 29: 109.
- Kaplan MM, Alling DW, Zimmerman HJ, et al. A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med 1986; 315: 1448.
- Kershenobich D, Vargas F, Garcia-Tsao G, et al. Colchicine in the treatment of cirrhosis of the liver. N Engl J Med 1988; 318: 1709.
- Morgan TR, Weiss DG, Nemchausky B, et al. Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival. Gastroenterology 2005; 128: 882.
- Rambaldi A, Gluud C. Colchicine for alcoholic and non-alcoholic liver fibrosis or cirrhosis. Liver 2001; 21: 129.
- Novobrantseva TI, Akinc A, Borodovsky A, et al. Delivering silence: advancements in developing siRNA therapeutics. Curr Opin Drug Discov Devel 2008; 11: 217.
- Vaishnaw AK, Gollob J, Gamba-Vitalo C, et al. A status report on RNAi therapeutics. Silence 2011; 1: 14.
- Bisht S, Khan MA, Bekhit M, et al. A polymeric nanoparticle formulation of curcumin (NanoCurc) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest 2011; 91: 1383.
- van Beuge MM, Prakash J, Lacombe M, et al. Reduction of fibrogenesis by selective delivery of a Rho kinase inhibitor to hepatic stellate cells in mice. J Pharmacol Exp Ther 2011; 337: 628.
- Isaka Y, Brees DK, Ikegaya K, et al. Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med 1996; 2: 418.
- George J, Roulot D, Koteliansky VE, et al. In vivo inhibition of rat stellate cell activation by soluble TGF beta type II receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad Sci U S A 1999; 96: 12719.
- Yata Y, Gotwals P, Koteliansky V, et al. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-beta soluble receptor: implications for antifibrotic therapy. Hepatology 2002; 35: 1022.
- Gonzalo T, Beljaars L, van de Bovenkamp M, et al. Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. J Pharmacol Exp Ther 2007; 321: 856.
- Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science 2012; 336: 1262.
- Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012; 590: 447.
- Schnabl B, Brenner DA. Interactions Between the Intestinal Microbiome and Liver Diseases. Gastroenterology 2014.
- Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology 2014; 59: 328.
- Gomez-Hurtado I, Santacruz A, Peiro G, et al. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoS ONE 2011; 6: e23037.
- Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012; 21: 504.
- Zhu L, Baker SS, Gill C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57: 601.
- Yamaguchi Y, Takihara T, Chambers RA, et al. A peptide derived from endostatin ameliorates organ fibrosis. Sci Transl Med 2012; 4: 136ra71.
- Jiang X, Tsitsiou E, Herrick SE, et al. MicroRNAs and the regulation of fibrosis. FEBS J 2010; 277: 2015.
- Sekiya Y, Ogawa T, Yoshizato K, et al. Suppression of hepatic stellate cell activation by microRNA-29b. Biochem Biophys Res Commun 2011; 412: 74.
- Lakner AM, Steuerwald NM, Walling TL, et al. Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis. Hepatology 2012; 56: 300.
- Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010; 16: 1009.
- Lopez B, Gonzalez A, Hermida N, et al. Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects. Am J Physiol Heart Circ Physiol 2010; 299: H1.
- Li J, Zhang Y, Kuruba R, et al. Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells. Mol Pharmacol 2011; 80: 191.
- Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 574.
- Xu W, Hellerbrand C, Kohler UA, et al. The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis. Lab Invest 2008; 88: 1068.
- Kim IH, Kim DG, Hao P, et al. Anti-fibrotic effects of L-2-oxothiazolidine-4-carboxylic acid via modulation of nuclear factor erythroid 2-related factor 2 in rats. BMB Rep 2012; 45: 348.
- Zhao XY, Zeng X, Li XM, et al. Pirfenidone inhibits carbon tetrachloride- and albumin complex-induced liver fibrosis in rodents by preventing activation of hepatic stellate cells. Clin Exp Pharmacol Physiol 2009; 36: 963.
- Titos E, Claria J, Planaguma A, et al. Inhibition of 5-lipoxygenase induces cell growth arrest and apoptosis in rat Kupffer cells: implications for liver fibrosis. FASEB J 2003; 17: 1745.
- King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083.
- Zein CO, Yerian LM, Gogate P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54: 1610.
- Van Wagner LB, Koppe SW, Brunt EM, et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 2011; 10: 277.
