, Volume 79, Issue 9, pp 903–927 | Cite as

Fibrosis in Chronic Liver Disease: An Update on Diagnostic and Treatment Modalities

  • Paul Manka
  • Amos Zeller
  • Wing-Kin SynEmail author
Leading Article


Fibrosis is a common outcome of most chronic inflammatory diseases, characterized by the accumulation of excessive extracellular matrix components. Individuals with progressive liver fibrosis develop cirrhosis, are at risk of developing liver cancer, and may succumb to liver failure. Although a number of specific therapies for different diseases have been developed and successfully used, for example, direct antiviral agents in treatment for hepatitis C, effective and specific antifibrotic therapies are still not available. Liver biopsy remains the gold standard of staging liver fibrosis. However, transient elastography is increasingly being used in clinical trials and in hepatology clinics as part of standard-of-care evaluation because it is easy to use. Magnetic resonance (MR)-elastography is most accurate in evaluating fibrosis stage but is costly and time consuming and thus not readily available. Recent advances, however, have been made in areas of diagnostic and therapeutic modalities, with an increasing number of potential drugs currently in phase II and III trials, particularly in the field of non-alcoholic steatohepatitis-related liver fibrosis. These new drugs target multiple pathways involved in the pathogenesis of chronic liver disease, and we anticipate that some of them may soon be approved for use in patients.



The figures were created with “Biological illustration” ( by Servier, used under Creative Commons Attribution 3.0 Unported License, and modified by Paul Manka.

Compliance with Ethical Standards

Conflcit of interest

PM reports personal fees (for a presentation) and non-financial support from Intercept Pharmaceuticals. WKS is a (site) principal investigator for Genfit, Intercept, and Conatus clinical trials. AZ certifies that he has no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interests (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.


  1. 1.
    Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line Sci Transl Med. 2013;5:167sr1. Scholar
  2. 2.
    Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18. Scholar
  3. 3.
    Trautwein C, Friedman SL, Schuppan D, Pinzani M. Hepatic fibrosis: concept to treatment. J Hepatol. 2015;62:S15–24. Scholar
  4. 4.
    Adams LA, Lindor KD. Nonalcoholic fatty liver disease. Ann Epidemiol. 2007;17:863–9. Scholar
  5. 5.
    Kanwal F, Kramer JR, Duan Z, Yu X, White D, El-Serag HB. Trends in the burden of nonalcoholic fatty liver disease in a United States Cohort of Veterans. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2016;14(301–308):e1–2. Scholar
  6. 6.
    Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest. 2017;127:55–64. Scholar
  7. 7.
    Schuppan D, Afdhal NH. Liver cirrhosis. Lancet Lond. Engl. 2008;371:838–51. Scholar
  8. 8.
    Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–40. Scholar
  9. 9.
    Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJP, Benyon C, Iredale JP. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem. 2002;277:11069–76. Scholar
  10. 10.
    Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatol Baltim Md. 2003;38:1449–57. Scholar
  11. 11.
    Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatol Baltim Md. 1981;1:431–5.Google Scholar
  12. 12.
    Group TMFC. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatol. Baltim. Md. 1994;20:15–20.Google Scholar
  13. 13.
    Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, Feng Z-Z, Reddy KR, Schiff ER. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614–8. Scholar
  14. 14.
    Pandey N, John S. Liver biopsy. In: StatPearls, StatPearls Publishing, Treasure Island (FL). 2018. Accessed 17 April 2019.
  15. 15.
    Guido M, Rugge M. Liver biopsy sampling in chronic viral hepatitis. Semin Liver Dis. 2004;24:89–97. Scholar
  16. 16.
    Denzer U, Arnoldy A, Kanzler S, Galle PR, Dienes HP, Lohse AW. Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications. J Clin Gastroenterol. 2007;41:103–10. Scholar
  17. 17.
    Sandrin L, Fourquet B, Hasquenoph J-M, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705–13.Google Scholar
  18. 18.
    Jung KS, Kim SU. Clinical applications of transient elastography. Clin Mol Hepatol. 2012;18:163–73. Scholar
  19. 19.
    Obara N, Ueno Y, Fukushima K, Nakagome Y, Kakazu E, Kimura O, Wakui Y, Kido O, Ninomiya M, Kogure T, Inoue J, Kondo Y, Shiina M, Iwasaki T, Yamamoto T, Shimosegawa T. Transient elastography for measurement of liver stiffness measurement can detect early significant hepatic fibrosis in Japanese patients with viral and nonviral liver diseases. J Gastroenterol. 2008;43:720–8. Scholar
  20. 20.
    Sini M, Sorbello O, Civolani A, Liggi M, Demelia L. Non-invasive assessment of hepatic fibrosis in a series of patients with Wilson’s Disease. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2012;44:487–91. Scholar
  21. 21.
    Corpechot C, El Naggar A, Poujol-Robert A, Ziol M, Wendum D, Chazouillères O, de Lédinghen V, Dhumeaux D, Marcellin P, Beaugrand M, Poupon R. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatol Baltim Md. 2006;43:1118–24. Scholar
  22. 22.
    Kwok R, Tse Y-K, Wong GL-H, Ha Y, Lee AU, Ngu MC, Chan HL-Y, Wong VW-S. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease–the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther. 2014;39:254–69. Scholar
  23. 23.
    Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, Moscarella S, Boddi V, Petrarca A, Laffi G, Marra F, Pinzani M. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatol Baltim Md. 2008;47:380–4. Scholar
  24. 24.
    Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography (FibroScan(®)) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease—where do we stand? World J Gastroenterol. 2016;22:7236–51. Scholar
  25. 25.
    Giannini EG, Zaman A, Ceppa P, Mastracci L, Risso D, Testa R. A simple approach to noninvasively identifying significant fibrosis in chronic hepatitis C patients in clinical practice. J Clin Gastroenterol. 2006;40:521–7.Google Scholar
  26. 26.
    Borsoi Viana MSV, Takei K, Collarile Yamaguti DC, Guz B, Strauss E. Use of AST platelet ratio index (APRI Score) as an alternative to liver biopsy for treatment indication in chronic hepatitis C. Ann Hepatol. 2009;8:26–31.Google Scholar
  27. 27.
    Calès P, Oberti F, Michalak S, Hubert-Fouchard I, Rousselet M-C, Konaté A, Gallois Y, Ternisien C, Chevailler A, Lunel F. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatol Baltim Md. 2005;42:1373–81. Scholar
  28. 28.
    Guéchot J, Trocmé C, Renversez J-C, Sturm N, Zarski J-P. ANRS HC EP 23 Fibrostar Study Group, Independent validation of the Enhanced Liver Fibrosis (ELF) score in the ANRS HC EP 23 Fibrostar cohort of patients with chronic hepatitis C. Clin Chem Lab Med. 2012;50:693–9. Scholar
  29. 29.
    Calès P, Boursier J, Oberti F, Moal V, Fouchard Hubert I, Bertrais S, Hunault G, Rousselet MC, Multicentric groups (SNIFF, ANRS HC 23). A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis. Hepatol Commun. 2018;2:455–66. Scholar
  30. 30.
    M.L. al et, Enhanced liver fibrosis test as a reliable tool for assessing fibrosis in non-alcoholic fatty liver disease in a clinical setting. - PubMed - NCBI, (n.d.). Accessed 17April 2019.
  31. 31.
    European Association for Study of Liver. Asociacion Latinoamericana para el Estudio del Higado, EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63:237–64. Scholar
  32. 32.
    Calès P, Veillon P, Konaté A, Mathieu E, Ternisien C, Chevailler A, Godon A, Gallois Y, Joubaud F, Hubert-Fouchard I, Oberti F, Réaud S, Hunault G, Mauriat F, Lunel-Fabiani F. Reproducibility of blood tests of liver fibrosis in clinical practice. Clin Biochem. 2008;41:10–8. Scholar
  33. 33.
    Poynard T, Munteanu M, Deckmyn O, Ngo Y, Drane F, Messous D, Castille JM, Housset C, Ratziu V, Imbert-Bismut F. Applicability and precautions of use of liver injury biomarker FibroTest. A reappraisal at 7 years of age. BMC Gastroenterol. 2011;11:39. Scholar
  34. 34.
    Leroy V, Monier F, Bottari S, Trocme C, Sturm N, Hilleret M-N, Morel F, Zarski J-P. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid. Am J Gastroenterol. 2004;99:271–9.Google Scholar
  35. 35.
    Boursier J, de Ledinghen V, Zarski J-P, Fouchard-Hubert I, Gallois Y, Oberti F, Calès P. multicentric groups from SNIFF 32, VINDIAG 7, and ANRS/HC/EP23 FIBROSTAR studies, Comparison of eight diagnostic algorithms for liver fibrosis in hepatitis C: new algorithms are more precise and entirely noninvasive. Hepatol Baltim Md. 2012;55:58–67. Scholar
  36. 36.
    Calès P, Boursier J, Lebigot J, de Ledinghen V, Aubé C, Hubert I, Oberti F. Liver fibrosis diagnosis by blood test and elastography in chronic hepatitis C: agreement or combination? Aliment Pharmacol Ther. 2017;45:991–1003. Scholar
  37. 37.
    Huwart L, Peeters F, Sinkus R, Annet L, Salameh N, ter Beek LC, Horsmans Y, Van Beers BE. Liver fibrosis: non-invasive assessment with MR elastography. NMR Biomed. 2006;19:173–9. Scholar
  38. 38.
    Ichikawa S, Motosugi U, Morisaka H, Sano K, Ichikawa T, Tatsumi A, Enomoto N, Matsuda M, Fujii H, Onishi H. Comparison of the diagnostic accuracies of magnetic resonance elastography and transient elastography for hepatic fibrosis. Magn Reson Imaging. 2015;33:26–30. Scholar
  39. 39.
    Cui J, Ang B, Haufe W, Hernandez C, Verna EC, Sirlin CB, Loomba R. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study. Aliment Pharmacol Ther. 2015;41:1271–80. Scholar
  40. 40.
    Huwart L, Sempoux C, Vicaut E, Salameh N, Annet L, Danse E, Peeters F, ter Beek LC, Rahier J, Sinkus R, Horsmans Y, Van Beers BE. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008;135:32–40. Scholar
  41. 41.
    Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T, Yamanaka T, Wada K, Saito S, Nakajima A. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;150:626–637.e7. Scholar
  42. 42.
    Wang J, Malik N, Yin M, Smyrk TC, Czaja AJ, Ehman RL, Venkatesh SK. Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis. World J Gastroenterol. 2017;23:859–68. Scholar
  43. 43.
    Eaton JE, Dzyubak B, Venkatesh SK, Smyrk TC, Gores GJ, Ehman RL, LaRusso NF, Gossard AA, Lazaridis KN. Performance of magnetic resonance elastography in primary sclerosing cholangitis. J Gastroenterol Hepatol. 2016;31:1184–90. Scholar
  44. 44.
    Kennedy P, Wagner M, Castéra L, Hong CW, Johnson CL, Sirlin CB, Taouli B. Quantitative elastography methods in liver disease: current evidence and future directions. Radiology. 2018;286:738–63. Scholar
  45. 45.
    D’Ambrosio R, Aghemo A, Rumi MG, Ronchi G, Donato MF, Paradis V, Colombo M, Bedossa P. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatol Baltim Md. 2012;56:532–43. Scholar
  46. 46.
    Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling M-H, Albrecht J. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122:1303–13.Google Scholar
  47. 47.
    Glass LM, Dickson RC, Anderson JC, Suriawinata AA, Putra J, Berk BS, Toor A. Total body weight loss of ≥ 10% is associated with improved hepatic fibrosis in patients with non-alcoholic steatohepatitis. Dig Dis Sci. 2015;60:1024–30. Scholar
  48. 48.
    Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with non-alcoholic steatohepatitis: a randomized, prospective trial. Hepatol Baltim Md. 2009;49:80–6. Scholar
  49. 49.
    Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, Fava JL, Wing RR. Randomized controlled trial testing the effects of weight loss on non-alcoholic steatohepatitis. Hepatol Baltim Md. 2010;51:121–9. Scholar
  50. 50.
    Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. Liver fibrosis, but no other histologic features is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–397.e10. Scholar
  51. 51.
    Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M, Fischer L, Ratziu V. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contem. Clin Trials. 2016;47:356–65. Scholar
  52. 52.
    Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, Heymann F, Kalthoff S, Lefebvre E, Eulberg D, Luedde T, Marx G, Strassburg CP, Roskams T, Trautwein C, Tacke F. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatol Baltim Md. 2016;64:1667–82. Scholar
  53. 53.
    Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147:577–594.e1. Scholar
  54. 54.
    Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, Chou H-L, Hashiguchi T, Plato C, Poulin D, Richards T, Yoneyama H, Jenkins H, Wolfgang G, Friedman SL. Antifibrotic effects of the dual CCR54/CCR54 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11:e0158156. Scholar
  55. 55.
    Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, Liepelt A, Lefebvre E, Luedde T, Hellerbrand C, Weiskirchen R, Longerich T, Costa IG, Anstee QM, Trautwein C, Tacke F. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018;67:1270–83. Scholar
  56. 56.
    Abdelmalek MF, Lanthier N, Chojkier M, Kluwe J, Fowell AJ, Yuan J, Nicandro JP, Seyedkazemi S, Fischer L, Goodman ZD, Harrison SA. Cenicriviroc treatment over 2 years results in clinically meaningful and sustained improvement in fibrosis in adults with nonalcoholic steatohepatitis and severe liver fibrosis (Abstract 2274). Hepatology. 2018;68:184–1353. Scholar
  57. 57.
    Matsukawa J, Matsuzawa A, Takeda K, Ichijo H. The ASK1-MAP kinase cascades in mammalian stress response. J Biochem (Tokyo). 2004;136:261–5. Scholar
  58. 58.
    Yamamoto E, Dong Y-F, Kataoka K, Yamashita T, Tokutomi Y, Matsuba S, Ichijo H, Ogawa H, Kim-Mitsuyama S. Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition. Hypertens Dallas TX. 2008;1979(52):573–80. Scholar
  59. 59.
    Budas G, Karnik S, Jonnson T, Shafizadeh T, Watkins S, Breckenridge D, Tumas D. Reduction of liver steatosis and fibrosis with an ask1 inhibitor in a murine model of nash is accompanied by improvements in cholesterol, bile acid and lipid metabolism. J Hepatol. 2016;64:S170. Scholar
  60. 60.
    Wang P-X, Ji Y-X, Zhang X-J, Zhao L-P, Yan Z-Z, Zhang P, Shen L-J, Yang X, Fang J, Tian S, Zhu X-Y, Gong J, Zhang X, Wei Q-F, Wang Y, Li J, Wan L, Xie Q, She Z-G, Wang Z, Huang Z, Li H. Targeting CASP8 and FADD-like apoptosis regulator ameliorates non-alcoholic steatohepatitis in mice and nonhuman primates. Nat Med. 2017;23:439–49. Scholar
  61. 61.
    Xiang M, Wang P-X, Wang A-B, Zhang X-J, Zhang Y, Zhang P, Mei F-H, Chen M-H, Li H. Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis. J Hepatol. 2016;64:1365–77. Scholar
  62. 62.
    Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, Diehl AM, Djedjos CS, Han L, Myers RP, Subramanian GM, McHutchison JG, Goodman ZD, Afdhal NH, Charlton MR, GS-US-384-1497 Investigators. The ASK1 inhibitor selonsertib in patients with non-alcoholic steatohepatitis: a randomized, phase 2 trial. Hepatol Baltim Md. 2017. Scholar
  63. 63.
    Nakagawa H, Hirata Y, Takeda K, Hayakawa Y, Sato T, Kinoshita H, Sakamoto K, Nakata W, Hikiba Y, Omata M, Yoshida H, Koike K, Ichijo H, Maeda S. Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase. Hepatol Baltim Md. 2011;54:185–95. Scholar
  64. 64.
    Kagan HM, Li W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem. 2003;88:660–72. Scholar
  65. 65.
    Issa R, Zhou X, Constandinou CM, Fallowfield J, Millward-Sadler H, Gaca MDA, Sands E, Suliman I, Trim N, Knorr A, Arthur MJP, Benyon RC, Iredale JP. Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology. 2004;126:1795–808.Google Scholar
  66. 66.
    Liu SB, Ikenaga N, Peng Z-W, Sverdlov DY, Greenstein A, Smith V, Schuppan D, Popov Y. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J Off Publ Fed Am Soc Exp Biol. 2016;30:1599–609. Scholar
  67. 67.
    Kagan HM. Lysyl oxidase: mechanism, regulation and relationship to liver fibrosis. Pathol Res Pract. 1994;190:910–9. Scholar
  68. 68.
    Vadasz Z, Kessler O, Akiri G, Gengrinovitch S, Kagan HM, Baruch Y, Izhak OB, Neufeld G. Abnormal deposition of collagen around hepatocytes in Wilson’s disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 2005;43:499–507. Scholar
  69. 69.
    Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, Garcia CA, Velayo AC, Jorgensen B, Biermann D, Tsai D, Green J, Zaffryar-Eilot S, Holzer A, Ogg S, Thai D, Neufeld G, Van Vlasselaer P, Smith V. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16:1009–17. Scholar
  70. 70.
    Muir AJ, Levy C, Janssen HLA, Montano-Loza AJ, Shiffman ML, Caldwell S, Luketic V, Ding D, Jia C, McColgan BJ, McHutchison JG, Subramanian GM, Myers RP, Manns M, Chapman R, Afdhal NH, Goodman Z, Eksteen B, Bowlus CL, GS-US-321-0102 Investigators. Simtuzumab for primary sclerosing cholangitis: phase 2 study results with insights on the natural history of the disease. Hepatol Baltim Md. 2018. Scholar
  71. 71.
    Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, Carreras MC, Poderoso JJ, Gores GJ. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver IntOff J Int Assoc Study Liver. 2015;35:953–66. Scholar
  72. 72.
    Eguchi A, Koyama Y, Wree A, Johnson CD, Nakamura R, Povero D, Kneiber D, Tameda M, Contreras P, Spada A, Feldstein AE. Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation. J Mol Med Berl Ger. 2018;96:575–83. Scholar
  73. 73.
    Pockros PJ, Schiff ER, Shiffman ML, McHutchison JG, Gish RG, Afdhal NH, Makhviladze M, Huyghe M, Hecht D, Oltersdorf T, Shapiro DA. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatol Baltim Md. 2007;46:324–9. Scholar
  74. 74.
    Shiffman ML, Pockros P, McHutchison JG, Schiff ER, Morris M, Burgess G. 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. 2010;31:969–78. Scholar
  75. 75.
    LP37 : A placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases. Journal of Hepatology, (n.d.). Accessed 3 Jan 2019.
  76. 76.
    Shiffman M, Freilich B, Vuppalanchi R, Watt K, Chan JL, Spada A, Hagerty DT, Schiff E. Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2019;49:64–73. Scholar
  77. 77.
    Garcia-Tsao G, Fuchs M, Shiffman M, Borg BB, Pyrsopoulos N, Shetty K, Gallegos-Orozco JF, Reddy KR, Feyssa E, Chan JL, Yamashita M, Robinson JM, Spada AP, Hagerty DT, Bosch J. Emricasan (IDN-6556) lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. Hepatol Baltim Md. 2018. Scholar
  78. 78.
    Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, Cheng JT, Cave M, Khaderi SA, Massoud O, Pyrsopoulos N, Park JS, Robinson JM, Yamashita M, Spada AP, Chan JL, Hagerty DT. Emricasan Improves Liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2018. Scholar
  79. 79.
    Yang R-Y, Rabinovich GA, Liu F-T. Galectins: structure, function and therapeutic potential. Expert Rev Mol Med. 2008;10:15. Scholar
  80. 80.
    Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009;230:160–71. Scholar
  81. 81.
    Forsman H, Islander U, Andréasson E, Andersson A, Onnheim K, Karlström A, Sävman K, Magnusson M, Brown KL, Karlsson A. Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis. Arthritis Rheum. 2011;63:445–54. Scholar
  82. 82.
    Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP, Iredale JP, Haslett C, Simpson KJ, Sethi T. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci USA. 2006;103:5060–5. Scholar
  83. 83.
    Iacobini C, Menini S, Ricci C, Blasetti Fantauzzi C, Scipioni A, Salvi L, Cordone S, Delucchi F, Serino M, Federici M, Pricci F, Pugliese G. Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver. J Hepatol. 2011;54:975–83. Scholar
  84. 84.
    Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel M-I, Friedman SL. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One. 2013;8:e75361. Scholar
  85. 85.
    Flores-Contreras L, Sandoval-Rodríguez AS, Mena-Enriquez MG, Lucano-Landeros S, Arellano-Olivera I, Alvarez-Álvarez A, Sanchez-Parada MG, Armendáriz-Borunda J. Treatment with pirfenidone for two years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C. BMC Gastroenterol. 2014;14:131. Scholar
  86. 86.
    Di Sario A, Bendia E, Svegliati Baroni G, Ridolfi F, Casini A, Ceni E, Saccomanno S, Marzioni M, Trozzi L, Sterpetti P, Taffetani S, Benedetti A. Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production. J Hepatol. 2002;37:584–91.Google Scholar
  87. 87.
    Aoudjehane L, Boelle P-Y, Bisch G, Delelo R, Paye F, Scatton O, Housset C, Becquart J, Calmus Y, Conti F. Development of an in vitro model to test antifibrotic drugs on primary human liver myofibroblasts. Lab Investig J Tech Methods Pathol. 2016;96:672–9. Scholar
  88. 88.
    Xiang X-H, Jiang T-P, Zhang S, Song J, Li X, Yang J-Y, Zhou S. Pirfenidone inhibits proliferation, arrests the cell cycle, and downregulates heat shock protein-47 and collagen type I in rat hepatic stellate cells in vitro. Mol Med Rep. 2015;12:309–14. Scholar
  89. 89.
    Komiya C, Tanaka M, Tsuchiya K, Shimazu N, Mori K, Furuke S, Miyachi Y, Shiba K, Yamaguchi S, Ikeda K, Ochi K, Nakabayashi K, Hata K-I, Itoh M, Suganami T, Ogawa Y. Antifibrotic effect of pirfenidone in a mouse model of human non-alcoholic steatohepatitis. Sci Rep. 2017;7:44754. Scholar
  90. 90.
    Verma N, Kumar P, Mitra S, Taneja S, Dhooria S, Das A, Duseja A, Dhiman RK, Chawla Y. Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: case report and mini-review of the literature. Hepatol Commun. 2018;2:142–7. Scholar
  91. 91.
    Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y. FXR, a multipurpose nuclear receptor. Trends Biochem Sci. 2006;31:572–80. Scholar
  92. 92.
    Teodoro JS, Rolo AP, Palmeira CM. Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol Metab TEM. 2011;22:458–66. Scholar
  93. 93.
    Trivedi PJ, Hirschfield GM, Gershwin ME. Obeticholic acid for the treatment of primary biliary cirrhosis. Expert Rev Clin Pharmacol. 2016;9:13–26. Scholar
  94. 94.
    Lindor KD. Farnesoid X receptor agonists for primary biliary cirrhosis. Curr Opin Gastroenterol. 2011;27:285–8. Scholar
  95. 95.
    Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol. 2009;51:380–8. Scholar
  96. 96.
    Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, Orlandi S, Pellicciari R, Morelli A. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology. 2004;127:1497–512.Google Scholar
  97. 97.
    Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L, Orlandi S, Pruzanski M, Morelli A, Pellicciari R. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther. 2005;314:584–95. Scholar
  98. 98.
    Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L, Morelli A, Pruzanski M, Pellicciari R. Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther. 2005;315:58–68. Scholar
  99. 99.
    Renga B, Mencarelli A, Migliorati M, Cipriani S, D’Amore C, Distrutti E, Fiorucci S. SHP-dependent and -independent induction of peroxisome proliferator-activated receptor-γ by the bile acid sensor farnesoid X receptor counter-regulates the pro-inflammatory phenotype of liver myofibroblasts. Inflamm Res Off J Eur Histamine Res Soc Al. 2011;60:577–87. Scholar
  100. 100.
    Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51:771–84. Scholar
  101. 101.
    Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, Halilbasic E, Stöger U, Arrese M, Pizarro M, Solís N, Carrasco G, Caligiuri A, Sombetzki M, Reisinger E, Tsybrovskyy O, Zatloukal K, Denk H, Jaeschke H, Pinzani M, Trauner M. Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol. 2009;175:2392–405. Scholar
  102. 102.
    Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Elst IV, Windmolders P, Vanuytsel T, Nevens F, Laleman W. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatol Baltim Md. 2014;59:2286–98. Scholar
  103. 103.
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E. NASH Clinical Research Network, Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet Lond Engl. 2015;385:956–65. Scholar
  104. 104.
    Combination Obeticholic Acid (OCA) and Statins for Monitoring of Lipids (CONTROL) - Study Results -, (n.d.). Accessed 4 Jan 2019.
  105. 105.
    Halegoua-DeMarzio D, Thuluvath P, Abdelmalek MF, Van Biene C, Shringarpure R, MacConell L. Obeticholic acid was safe and well tolerated in patients with nash and compensated cirrhosis: a secondary analysis of the CONTROL Study (Abstract#0071). Hepatology. 2018;68:1–183. Scholar
  106. 106.
    Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB, Mutnick D, Bursulaya B, Schmeits J, Wu X, Bao D, Zoll J, Kim Y, Groessl T, McNamara P, Seidel HM, Molteni V, Liu B, Phimister A, Joseph SB, Laffitte B. Discovery of tropifexor (LJN452), a highly potent non-bile acid fxr agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem. 2017;60:9960–73. Scholar
  107. 107.
    Sanyal AP, Lopez Patricia, Lawitz Eric, Kim Won, Huang Jee-Fu, Andreone Pietro, Goh Boon Bee George, Chen Yi-Cheng, Ratziu Vlad, Kim Yoon Jun, Ryan Marno, Weltman Martin, Andreas Geier, Loeffler Juergen, Schaefer Felicity, Vaidyanathan Sujata. Clifford brass, tropifexor (TXR), an FXR agonist for the treatment of nash-interim results from first two parts of phase 2b study flight-FXR (LB-23). Hepatology. 2018;68:1444A–71A. Scholar
  108. 108.
    Patel K, Harrison SA, Trotter JF, Herring R, Rojter SE, Kayali Z, Shiffman ML, Freilich BL, Lawitz EJ, Harting E, Nguyen T, Chung C. The nonsteroidal FXR agonist GS-9674 leads to significant reductions in hepatic steatosis, serum bile acids, and liver biochemistry in a phase 2, randomized, placebo-controlled trial of patients with NASH (Abstract 736). Hepatology. 2018;68:184–1353. Scholar
  109. 109.
    Liles JT, Karnik S, Hambruch E, Kremoser C, Birkel M, Watkins WJ, Tumas D, Breckenridge D, French D. Fxr Agonism by Gs-9674 Decreases Steatosis and Fibrosis in a Murine Model of Nash. J Hepatol. 2016;64:S169. Scholar
  110. 110.
    Schaap FG, Trauner M, Jansen PLM. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11:55–67. Scholar
  111. 111.
    Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, Stewart TA. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143:1741–7. Scholar
  112. 112.
    Alvarez-Sola G, Uriarte I, Latasa MU, Fernandez-Barrena MG, Urtasun R, Elizalde M, Barcena-Varela M, Jiménez M, Chang HC, Barbero R, Catalán V, Rodríguez A, Frühbeck G, Gallego-Escuredo JM, Gavaldà-Navarro A, Villarroya F, Rodriguez-Ortigosa CM, Corrales FJ, Prieto J, Berraondo P, Berasain C, Avila MA. Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut. 2017;66:1818–28. Scholar
  113. 113.
    Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan J-P, Stinson J, Stewart T, French DM. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol. 2002;160:2295–307. Scholar
  114. 114.
    Uriarte I, Latasa MU, Carotti S, Fernandez-Barrena MG, Garcia-Irigoyen O, Elizalde M, Urtasun R, Vespasiani-Gentilucci U, Morini S, de Mingo A, Mari M, Corrales FJ, Prieto J, Berasain C, Avila MA. Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer. 2015;136:2469–75. Scholar
  115. 115.
    Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu J-Y, Yang H, Humphrey M, Ding X, Arora T, Learned RM, DePaoli AM, Tian H, Ling L. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res. 2014;74:3306–16. Scholar
  116. 116.
    Zhou M, Yang H, Learned RM, Tian H, Ling L. Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nat Commun. 2017;8:15433. Scholar
  117. 117.
    Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, Kugelmas M, Bashir MR, Jaros MJ, Ling L, Rossi SJ, DePaoli AM, Loomba R. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. 2018;391:1174–85. Scholar
  118. 118.
    Tanaka N, Aoyama T, Kimura S, Gonzalez FJ. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther. 2017;179:142–57. Scholar
  119. 119.
    Toyama T, Nakamura H, Harano Y, Yamauchi N, Morita A, Kirishima T, Minami M, Itoh Y, Okanoue T. PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats. Biochem Biophys Res Commun. 2004;324:697–704. Scholar
  120. 120.
    Chen L, Li L, Chen J, Li L, Zheng Z, Ren J, Qiu Y. Oleoylethanolamide, an endogenous PPAR-α ligand, attenuates liver fibrosis targeting hepatic stellate cells. Oncotarget. 2015;6:42530–40.Google Scholar
  121. 121.
    Bahar R, Wong KA, Liu CH, Bowlus CL. Update on new drugs and those in development for the treatment of primary biliary cholangitis. Gastroenterol Hepatol. 2018;14:154–63.Google Scholar
  122. 122.
    Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol. 2001;21:1840–5.Google Scholar
  123. 123.
    Nakajima T, Tanaka N, Kanbe H, Hara A, Kamijo Y, Zhang X, Gonzalez FJ, Aoyama T. Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in mice: a novel peroxisome proliferator-activated receptor alpha-independent mechanism. Mol Pharmacol. 2009;75:782–92. Scholar
  124. 124.
    Iwaisako K, Haimerl M, Paik Y-H, Taura K, Kodama Y, Sirlin C, Yu E, Yu RT, Downes M, Evans RM, Brenner DA, Schnabl B. Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist. Proc Natl Acad Sci USA. 2012;109:E1369–76. Scholar
  125. 125.
    Kostadinova R, Montagner A, Gouranton E, Fleury S, Guillou H, Dombrowicz D, Desreumaux P, Wahli W. GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation. Cell Biosci. 2012;2:34. Scholar
  126. 126.
    Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee QM, Hum D, Hanf R, Roudot A, Megnien S, Staels B, Sanyal A, GOLDEN-505 Investigator Study Group, Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–1159.e5. Scholar
  127. 127.
    Miyahara T, Schrum L, Rippe R, Xiong S, Yee HF, Motomura K, Anania FA, Willson TM, Tsukamoto H. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem. 2000;275:35715–22. Scholar
  128. 128.
    Bae M-A, Rhee SD, Jung WH, Ahn JH, Song B-J, Cheon HG. Selective inhibition of activated stellate cells and protection from carbon tetrachloride-induced liver injury in rats by a new PPARgamma agonist KR62776. Arch Pharm Res. 2010;33:433–42. Scholar
  129. 129.
    McHutchison J, Goodman Z, Patel K, Makhlouf H, Rodriguez-Torres M, Shiffman M, Rockey D, Husa P, Chuang W-L, Levine R, Jonas M, Theodore D, Brigandi R, Webster A, Schultz M, Watson H, Stancil B, Gardner S, Farglitizar Study Investigators. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology. 2010;138:1365–73. (1373.e1–2).Google Scholar
  130. 130.
    Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307. Scholar
  131. 131.
    Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: a Randomized Trial. Ann Intern Med. 2016;165:305–15. Scholar
  132. 132.
    Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, Austin AS, Freeman JG, Morgan L, Webber J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with non-alcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84. Scholar
  133. 133.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR. NASH CRN, Pioglitazone, vitamin E, or placebo for non-alcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85. Scholar
  134. 134.
    Xu P, Zhang Y, Liu Y, Yuan Q, Song L, Liu M, Liu Z, Yang Y, Li J, Li D, Ren G. Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-β/smad2/3 and NF-κB signaling pathways. Toxicol Appl Pharmacol. 2016;290:43–53. Scholar
  135. 135.
    Fisher FM, Chui PC, Nasser IA, Popov Y, Cunniff JC, Lundasen T, Kharitonenkov A, Schuppan D, Flier JS, Maratos-Flier E. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology. 2014;147:1073–1083.e6. Scholar
  136. 136.
    Harrison S, Moussa S, Bashir M, Alkhouri N, Frias J, Baum S, et al. MGL-3196, a selective thyroid hormone receptor-beta agonist significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy study. J Hepatol. 2018;68:S38. Scholar
  137. 137.
    Luo Y, Krupinski J, Gao S, Charles E, Christian R. BMS-986036, a PEGylated fibroblast growth factor 21 analogue, reduces fibrosis and Pro-C3 in a mouse model of non-alcoholic steatohepatitis. J Hepatol. 2018;68:S396–7. Scholar
  138. 138.
    Zinker B, Boehm S, Gao S, He A, Strassle B, Morin P, Christian R, Krupinski J. Effects of a PEGylated fibroblast growth factor 21 variant on steatosis, inflammation, and fibrosis in a mouse model of non-alcoholic steatohepatitis. J Hepatol. 2018;68:S390. Scholar
  139. 139.
    Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS, Christian R. Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obes Silver Spring Md. 2019;27:41–9. Scholar
  140. 140.
    Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, Lawitz EJ, Halegoua-DeMarzio D, Kundu S, Noviello S, Luo Y, Christian R. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Lond Engl. 2019;392:2705–17. Scholar
  141. 141.
    Leikin-Frenkel A, Gonen A, Shaish A, Goldiner I, Leikin-Gobbi D, Konikoff FM, Harats D, Gilat T. Fatty acid bile acid conjugate inhibits hepatic stearoyl coenzyme A desaturase and is non-atherogenic. Arch Med Res. 2010;41:397–404. Scholar
  142. 142.
    Enoch HG, Catalá A, Strittmatter P. Mechanism of rat liver microsomal stearyl-CoA desaturase. Studies of the substrate specificity, enzyme-substrate interactions, and the function of lipid. J Biol Chem. 1976;251:5095–103.Google Scholar
  143. 143.
    Allen B, Mato JM, Craig Amanda, Fernandez-Ramos D, Lopitz-Otsoa F, Hayardeny L, Villanueva A, Friedman Scott L. Aramchol downregulates SCD1 and induces pparg in hepatic stellate cells to attenuate cellular activation and fibrogenesis (Abstract #738). Hepatology. 2018;68:184–1353. Scholar
  144. 144.
    Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R, FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with non-alcoholic fatty liver disease. Clin Gastroenterol Hepatol Off Cli. Pract J Am Gastroenterol Assoc. 2014;12:2085–2091.e1. Scholar
  145. 145.
    Ratziu V, Ladron-De-Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, Harrison SA, Arrese M, Fargion S, Ben-Bashat D, Lackner C, Gorfine T, Kadosh S, Oren R, Loomba R, Sanyal Arun J. One-year results of the global phase 2b randomized placebo -controlled arrest trial of aramchol, a stearoyl CoA desaturase inhibitor, in patients with nash (LB-5). Hepatology. 2018;68:1444A–71A. Scholar
  146. 146.
    Zvibel I, Atias D, Phillips A, Halpern Z, Oren R. Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho. Lab Investig J Tech Methods Pathol. 2010;90:674–84. Scholar
  147. 147.
    Oren R, Dotan I, Papa M, Marravi Y, Aeed H, Barg J, Zeidel L, Bruck R, Halpern Z. Inhibition of experimentally induced cirrhosis in rats by hypothyroidism. Hepatol Baltim Md. 1996;24:419–23. Scholar
  148. 148.
    Bruck R, Weiss S, Traister A, Zvibel I, Aeed H, Halpern Z, Oren R. Induced hypothyroidism accelerates the regression of liver fibrosis in rats. J Gastroenterol Hepatol. 2007;22:2189–94. Scholar
  149. 149.
    Alonso-Merino E, Martín Orozco R, Ruíz-Llorente L, Martínez-Iglesias OA, Velasco-Martín JP, Montero-Pedrazuela A, Fanjul-Rodríguez L, Contreras-Jurado C, Regadera J, Aranda A. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses. Proc Natl Acad Sci USA. 2016;113:E3451–60. Scholar
  150. 150.
    Harrison SA, Bashir M, Frias JP, Alkhouri N, Baum S, Taub R, Moylan CA, Bansal MB, Neuschwander-Tetri BA. In a placebo-controlled 36-week phase 2 trial, treatment with Mgl-3196 compared to placebo results in significant reductions in hepatic fat (MRI-PDFF), liver enzymes, fibrosis biomarkers, atherogenic lipids, and improvement in nash on serial liver biopsy (Abstract #14). Hepatology. 2018;68:184–1353. Scholar
  151. 151.
    Loomba R, Neutel J, Bernard D, Severance R, Mohseni R, Dao M, Saini S, Margaritescu C, Homer K, Tran B, Mancini M, Masamune H, Lian B. VK2809, a novel liver-directed thyroid receptor beta agonist significantly reduces liver fat in patients with non-alcoholic fatty liver disease: a phase 2 randomized, placebo-controlled Trial (LB-4). Hepatology. 2018;68:1444A–71A. Scholar
  152. 152.
    Osterreicher CH, Taura K, De Minicis S, Seki E, Penz-Osterreicher M, Kodama Y, Kluwe J, Schuster M, Oudit GY, Penninger JM, Brenner DA. Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice. Hepatol Baltim Md. 2009;50:929–38. Scholar
  153. 153.
    Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol. 2010;53:273–82. Scholar
  154. 154.
    Kim MY, Baik SK, Park DH, Jang YO, Suk KT, Yea CJ, Lee IY, Kim JW, Kim HS, Kwon SO, Cho MY, Ko SB, Chang SJ, Um SH, Han K-H. Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model. J Gastroenterol. 2008;43:889–96. Scholar
  155. 155.
    Debernardi-Venon W, Martini S, Biasi F, Vizio B, Termine A, Poli G, Brunello F, Alessandria C, Bonardi R, Saracco G, Rizzetto M, Marzano A. AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol. 2007;46:1026–33. Scholar
  156. 156.
    Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatol Baltim Md. 1999;29:334–9. Scholar
  157. 157.
    Baik SK, Park DH, Kim MY, Choi YJ, Kim HS, Lee DK, Kwon SO, Kim YJ, Park JW, Chang SJ. Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol. 2003;38:1150–4. Scholar
  158. 158.
    Heim MH, Jacob L, Beglinger C. The angiotensin II receptor antagonist candesartan is not effective in reducing portal hypertension in patients with cirrhosis. Digestion. 2007;75:122–3. Scholar
  159. 159.
    De BK, Bandyopadhyay K, Das TK, Das D, Biswas PK, Majumdar D, Mandal SK, Ray S, Dasgupta S. Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Am J Gastroenterol. 2003;98:1371–6. Scholar
  160. 160.
    Kim JH, Kim JM, Cho YZ, Na JH, Kim HS, Kim HA, Kang HW, Baik SK, Kwon SO, Cha SH, Kim YJ, Kim MY. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension. Clin Mol Hepatol. 2014;20:376–83. Scholar
  161. 161.
    Kim MY, Cho MY, Baik SK, Jeong PH, Suk KT, Jang YO, Yea CJ, Kim JW, Kim HS, Kwon SO, Yoo BS, Kim JY, Eom MS, Cha SH, Chang SJ. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis—a randomized open-label controlled study, Liver Int. Off J Int Assoc Study Liver. 2012;32:977–87. Scholar
  162. 162.
    Zhu Q, Li N, Li F, Zhou Z, Han Q, Lv J, Sang J, Liu Z. Therapeutic effect of renin angiotensin system inhibitors on liver fibrosis. J Renin Angiotensin Aldosterone Syst. 2016. Scholar
  163. 163.
    Schepke M, Werner E, Biecker E, Schiedermaier P, Heller J, Neef M, Stoffel-Wagner B, Hofer U, Caselmann WH, Sauerbruch T. Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension. Gastroenterology. 2001;121:389–95.Google Scholar
  164. 164.
    Yokohama S, Tokusashi Y, Nakamura K, Tamaki Y, Okamoto S, Okada M, Aso K, Hasegawa T, Aoshima M, Miyokawa N, Haneda M, Yoneda M. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J. Gastroenterol. WJG. 2006;12:322–6. Scholar
  165. 165.
    Terui Y, Saito T, Watanabe H, Togashi H, Kawata S, Kamada Y, Sakuta S. Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatol Baltim Md. 2002;36:1022. Scholar
  166. 166.
    Sookoian S, Fernández MA, Castaño G. Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: a pilot study. World J Gastroenterol. 2005;11:7560–3.Google Scholar
  167. 167.
    Rimola A, Londoño M-C, Guevara G, Bruguera M, Navasa M, Forns X, García-Retortillo M, García-Valdecasas J-C, Rodes J. Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation. 2004;78:686–91.Google Scholar
  168. 168.
    Corey KE, Shah N, Misdraji J, Abu Dayyeh BK, Zheng H, Bhan AK, Chung RT. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int Off J Int Assoc Study Liver. 2009;29:748–53. Scholar
  169. 169.
    Colmenero J, Bataller R, Sancho-Bru P, Domínguez M, Moreno M, Forns X, Bruguera M, Arroyo V, Brenner DA, Ginès P. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol. 2009;297:G726–34. Scholar
  170. 170.
    Abu Dayyeh BK, Yang M, Dienstag JL, Chung RT. The effects of angiotensin blocking agents on the progression of liver fibrosis in the HALT-C Trial cohort. Dig Dis Sci. 2011;56:564–8. Scholar
  171. 171.
    Goh GB, Pagadala MR, Dasarathy J, Unalp-Arida A, Sargent R, Hawkins C, Sourianarayanane A, Khiyami A, Yerian L, Pai R, McCullough AJ, Dasarathy S. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int Off J Int Assoc Study Liver. 2015;35:979–85. Scholar
  172. 172.
    Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, Hasegawa T, Tokusashi Y, Miyokawa N, Nakamura K. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with non-alcoholic steatohepatitis. Hepatol Baltim Md. 2004;40:1222–5. Scholar
  173. 173.
    Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol. 2009;15:942–54.Google Scholar
  174. 174.
    Phung N, Pera N, Farrell G, Leclercq I, Hou JY, George J. Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. Int J Mol Med. 2009;24:171–80.Google Scholar
  175. 175.
    Nan Y-M, Wu W-J, Fu N, Liang B-L, Wang R-Q, Li L-X, Zhao S-X, Zhao J-M, Yu J. Antioxidants vitamin E and 1-aminobenzotriazole prevent experimental non-alcoholic steatohepatitis in mice. Scand J Gastroenterol. 2009;44:1121–31. Scholar
  176. 176.
    Lavine JE. Vitamin E treatment of non-alcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136:734–8.Google Scholar
  177. 177.
    Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther. 2001;15:1667–72.Google Scholar
  178. 178.
    Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatol Baltim Md. 2003;38:413–9. Scholar
  179. 179.
    Yakaryilmaz F, Guliter S, Savas B, Erdem O, Ersoy R, Erden E, Akyol G, Bozkaya H, Ozenirler S. Effects of vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and insulin resistance in patients with non-alcoholic steatohepatitis: results of a pilot study. Intern Med J. 2007;37:229–35. Scholar
  180. 180.
    Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, David E, Rizzetto M, Marchesini G. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in non-alcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082–90. Scholar
  181. 181.
    Vajro P, Mandato C, Franzese A, Ciccimarra E, Lucariello S, Savoia M, Capuano G, Migliaro F. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr. 2004;38:48–55.Google Scholar
  182. 182.
    Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Ünalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of non-alcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–68. Scholar
  183. 183.
    Pietu F, Guillaud O, Walter T, Vallin M, Hervieu V, Scoazec J-Y, Dumortier J. Ursodeoxycholic acid with vitamin E in patients with non-alcoholic steatohepatitis: long-term results. Clin Res Hepatol Gastroenterol. 2012;36:146–55. Scholar
  184. 184.
    Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Atorvastatin and antioxidants for the treatment of non-alcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol. 2011;106:71–7. Scholar
  185. 185.
    Dufour J-F, Oneta CM, Gonvers J-J, Bihl F, Cerny A, Cereda J-M, Zala J-F, Helbling B, Steuerwald M, Zimmermann A. Swiss Association for the Study of the Liver, Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in non-alcoholic steatohepatitis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2006;4:1537–43. Scholar
  186. 186.
    Nobili V, Manco M, Devito R, Ciampalini P, Piemonte F, Marcellini M. Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2006;24:1553–61. Scholar
  187. 187.
    Nobili V, Manco M, Devito R, Di Ciommo V, Comparcola D, Sartorelli MR, Piemonte F, Marcellini M, Angulo P. Lifestyle intervention and antioxidant therapy in children with non-alcoholic fatty liver disease: a randomized, controlled trial. Hepatol Baltim Md. 2008;48:119–28. Scholar
  188. 188.
    Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, Shiffman ML, Clore J, Mills AS. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of non-alcoholic steatohepatitis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2004;2:1107–15.Google Scholar
  189. 189.
    Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with non-alcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485–90. Scholar
  190. 190.
    Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatol Baltim Md. 2018;67:328–57. Scholar
  191. 191.
    Bates J, Hollenback D, Zagorska A, Budas G, Liles JT, Liu H, Liu K, Kusam S, Brockett R, Newstrom D, MIkaelian I, Wang T, Ray AS, Breckenridge D. Combination of ASK1 and ACC inhibitors increases efficacy in rodent models of NASH. Hepatology. 2017;66:149–1185. Scholar
  192. 192.
    Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, Wang L, Harting E, Tarrant JM, McColgan BJ, Chung C, Ray AS, Subramanian GM, Myers RP, Middleton MS, Lai M, Charlton M, Harrison SA. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. 2018;155:1463–1473.e6. Scholar
  193. 193.
    White CA. Nitazoxanide: a new broad spectrum antiparasitic agent. Expert Rev Anti Infect Ther. 2004;2:43–9.Google Scholar
  194. 194.
    Haffizulla J, Hartman A, Hoppers M, Resnick H, Samudrala S, Ginocchio C, Bardin M, Rossignol J-F, US Nitazoxanide Influenza Clinical Study Group. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014;14:609–18. Scholar
  195. 195.
    Korba BE, Montero AB, Farrar K, Gaye K, Mukerjee S, Ayers MS, Rossignol J-F. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antivir Res. 2008;77:56–63. Scholar
  196. 196.
    Rossignol JF, Kabil SM, El-Gohary Y, Elfert A, Keeffe EB. Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther. 2008;28:574–80. Scholar
  197. 197.
    Rossignol J, Elfert A, El–Gohary, Keeffe EB. Improved virologic response in chronic hepatitis C GEnotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology. 2009;136:856–62. Scholar
  198. 198.
    Rossignol J-F, Elfert A, Keeffe EB. Treatment of chronic hepatitis C using a 4-week lead-in with nitazoxanide before peginterferon plus nitazoxanide. J Clin Gastroenterol. 2010;44:504–9. Scholar
  199. 199.
    Belanger C, Foucart C, Negro E, Dubernet M, Hum DW, Staels B, Walczak R. Drug repurposing screen identifies novel small molecule compounds with potent antifibrotic properties. J Hepatol. 2017;66:S605. Scholar
  200. 200.
    Stringer Rowan, Jessie Gu, Pedrosa Marcos C, Woessner Ralph, Ayalasomayajula Surya, Seyedkazemi Star, Chen Jin, Fischer Laurent, Vaidyanathan Sujata, Anstee Quentin M. Tropifexor in combination with cenicriviroc: pharmacokinetics and clinical safety in healthy volunteers PLUS Study design of a phase 2B Trial in patients with nonalcoholic steatohepatitis (Abstract #1739). Hepatology. 2018;68:184–1353. Scholar
  201. 201.
    Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, de Lédinghen V, Marcellin P, Dhumeaux D, Trinchet J-C, Beaugrand M. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatol Baltim Md. 2005;41:48–54. Scholar
  202. 202.
    Arena U, Vizzutti F, Abraldes JG, Corti G, Stasi C, Moscarella S, Milani S, Lorefice E, Petrarca A, Romanelli RG, Laffi G, Bosch J, Marra F, Pinzani M. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut. 2008;57:1288–93. Scholar
  203. 203.
    Nitta Y, Kawabe N, Hashimoto S, Harata M, Komura N, Kobayashi K, Arima Y, Shimazaki H, Nakano T, Murao M, Ichino N, Osakabe K, Aoki H, Hosoe Y, Sugiyama H, Nishikawa T, Yoshioka K. Liver stiffness measured by transient elastography correlates with fibrosis area in liver biopsy in patients with chronic hepatitis C. Hepatol Res Off J Jpn Soc Hepatol. 2009;39:675–84. Scholar
  204. 204.
    Sirli R, Sporea I, Bota S, Popescu A, Cornianu M. A comparative study of non-invasive methods for fibrosis assessment in chronic HCV infection. Hepatol Mon. 2010;10:88–94.Google Scholar
  205. 205.
    Cardoso A-C, Carvalho-Filho RJ, Stern C, Dipumpo A, Giuily N, Ripault M-P, Asselah T, Boyer N, Lada O, Castelnau C, Martinot-Peignoux M, Valla D-C, Bedossa P, Marcellin P. Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C. Liver Int Off J Int Assoc Study Liver. 2012;32:612–21. Scholar
  206. 206.
    Zarski J-P, Sturm N, Guechot J, Paris A, Zafrani E-S, Asselah T, Boisson R-C, Bosson J-L, Guyader D, Renversez J-C, Bronowicki J-P, Gelineau M-C, Tran A, Trocme C, De Ledinghen V, Lasnier E, Poujol-Robert A, Ziegler F, Bourliere M, Voitot H, Larrey D, Rosenthal-Allieri MA, Fouchard Hubert I, Bailly F, Vaubourdolle M, ANRS HCEP 23 Fibrostar Group. Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study. J Hepatol. 2012;56:55–62. Scholar
  207. 207.
    Platon L, Stefanescu H, Feier D, Maniu A, Badea R. Performance of unidimensional transient elastography in staging chronic hepatitis C. Results from a cohort of 1,202 biopsied patients from one single center. J Gastrointest Liver Dis JGLD. 2013;22:157–66.Google Scholar
  208. 208.
    Yoneda M, Thomas E, Sclair SN, Grant TT, Schiff ER. Supersonic shear imaging and transient elastography with the XL probe accurately detect fibrosis in overweight or obese patients with chronic liver disease. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2015;13:1502–1509.e5. Scholar
  209. 209.
    Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Lédinghen V, Beaugrand M. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int Off J Int Assoc Study Liver. 2009;29:242–7. Scholar
  210. 210.
    Zhu X, Wang L-C, Chen E-Q, Chen X-B, Chen L-Y, Liu L, Lei X-Z, Liu C, Tang H. Prospective evaluation of FibroScan for the diagnosis of hepatic fibrosis compared with liver biopsy/AST platelet ratio index and FIB-4 in patients with chronic HBV infection. Dig Dis Sci. 2011;56:2742–9. Scholar
  211. 211.
    Castera L. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease. Best Pract Res Clin Gastroenterol. 2011;25:291–303. Scholar
  212. 212.
    Ogawa E, Furusyo N, Murata M, Ohnishi H, Toyoda K, Taniai H, Ihara T, Ikezaki H, Hayashi T, Kainuma M, Hayashi J. Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis B patients treated with nucleoside analog. Hepatol Res Off J Jpn Soc Hepatol. 2011;41:1178–88. Scholar
  213. 213.
    Chon YE, Choi EH, Song KJ, Park JY, Kim DY, Han K-H, Chon CY, Ahn SH, Kim SU. Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis. PLoS ONE. 2012;7:e44930. Scholar
  214. 214.
    Leung VY, Shen J, Wong VW, Abrigo J, Wong GL, Chim AM, Chu SH, Chan AW, Choi PC, Ahuja AT, Chan HL, Chu WC. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology. 2013;269:910–8. Scholar
  215. 215.
    Degos F, Perez P, Roche B, Mahmoudi A, Asselineau J, Voitot H, Bedossa P. FIBROSTIC study group, Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol. 2010;53:1013–21. Scholar
  216. 216.
    Afdhal NH, Bacon BR, Patel K, Lawitz EJ, Gordon SC, Nelson DR, Challies TL, Nasser I, Garg J, Wei L-J, McHutchison JG. Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2015;13(772–779):e1–3. Scholar
  217. 217.
    Wong VW-S, Vergniol J, Wong GL-H, Foucher J, Chan AW-H, Chermak F, Choi PC-L, Merrouche W, Chu SH-T, Pesque S, Chan HL-Y, de Lédinghen V. Liver stiffness measurement using XL probe in patients with non-alcoholic fatty liver disease. Am J Gastroenterol. 2012;107:1862–71. Scholar
  218. 218.
    Kumar M, Rastogi A, Singh T, Bihari C, Gupta E, Sharma P, Garg H, Kumar R, Bhatia V, Tyagi P, Sarin SK. Analysis of discordance between transient elastography and liver biopsy for assessing liver fibrosis in chronic hepatitis B virus infection. Hepatol Int. 2013;7:134–43. Scholar
  219. 219.
    Cassinotto C, Boursier J, de Lédinghen V, Lebigot J, Lapuyade B, Cales P, Hiriart J-B, Michalak S, Bail BL, Cartier V, Mouries A, Oberti F, Fouchard-Hubert I, Vergniol J, Aubé C. Liver stiffness in non-alcoholic fatty liver disease: a comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatol Baltim Md. 2016;63:1817–27. Scholar
  220. 220.
    Xu Q, Sheng L, Bao H, Chen X, Guo C, Li H, Ma X, Qiu D, Hua J. Evaluation of transient elastography in assessing liver fibrosis in patients with autoimmune hepatitis. J Gastroenterol Hepatol. 2017;32:639–44. Scholar
  221. 221.
    Wai C-T, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS-F. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatol Baltim Md. 2003;38:518–26. Scholar
  222. 222.
    Calès P, Lainé F, Boursier J, Deugnier Y, Moal V, Oberti F, Hunault G, Rousselet MC, Hubert I, Laafi J, Ducluzeaux PH, Lunel F. Comparison of blood tests for liver fibrosis specific or not to NAFLD. J Hepatol. 2009;50:165–73. Scholar
  223. 223.
    Naveau S, Gaudé G, Asnacios A, Agostini H, Abella A, Barri-Ova N, Dauvois B, Prévot S, Ngo Y, Munteanu M, Balian A, Njiké-Nakseu M, Perlemuter G, Poynard T. Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease. Hepatol Baltim Md. 2009;49:97–105. Scholar
  224. 224.
    Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, Kaye P, Burt AD, Ryder SD, Aithal GP, Day CP, Rosenberg WM. Noninvasive markers of fibrosis in non-alcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatol Baltim Md. 2008;47:455–60. Scholar
  225. 225.
    Rosenberg WMC, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, Hubscher S, Roskams T, Pinzani M, Arthur MJP, European Liver Fibrosis Group. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704–13.Google Scholar
  226. 226.
    Casteŕa L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, De Led́inghen V. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of Fibrosis in chronic hepatitis C. Gastroenterology. 2005;128(2):343–50.Google Scholar

Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2019

Authors and Affiliations

  1. 1.Gastroenterology and HepatologyEssen University HospitalEssenGermany
  2. 2.Division of Gastroenterology and Hepatology, Department of MedicineMedical University of South CarolinaCharlestonUSA
  3. 3.Section of GastroenterologyRalph H. Johnson Veterans Affairs Medical CenterCharlestonUSA
  4. 4.Department of Physiology, Faculty of Medicine and NursingUniversity of Basque Country UPV/EHUVizcayaSpain

Personalised recommendations