A critical review of endpoints for non-cirrhotic NASH therapeutic trials

Journal of Hepatology

Volumn 68, Issue 2, 2018, Pages 353-361

  Ratziu, Vlad ^a  

^a PITIÉ SALPÊTRIÈRE HOSPITAL   (France)

Author keywords

Fibrosis; Magnetic resonance imaging; NASH; Randomised controlled trials; Steatohepatitis; Steatosis; Trial outcomes

Indexed keywords

ALCOHOL LIVER CIRRHOSIS; ANTIINFLAMMATORY ACTIVITY; HISTOPATHOLOGY; HUMAN; LIVER FIBROSIS; NONALCOHOLIC FATTY LIVER; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; VALIDITY; BIOASSAY; CLINICAL TRIAL (TOPIC); COMPLICATION; DISEASE EXACERBATION; DISEASE MANAGEMENT; LIVER CIRRHOSIS; PROCEDURES; PROGNOSIS; STANDARDS;

CLINICAL TRIALS AS TOPIC; DISEASE MANAGEMENT; DISEASE PROGRESSION; ENDPOINT DETERMINATION; HUMANS; LIVER CIRRHOSIS; NON-ALCOHOLIC FATTY LIVER DISEASE; PROGNOSIS;

EID: 85038889162     PISSN: 01688278     EISSN: 16000641     Source Type: Journal    
DOI: 10.1016/j.jhep.2017.12.001     Document Type: Review

References (93)

1. Romero-Gomez, M., Zelber-Sagi, S., Trenell, M., Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 67 (2017), 829–846.
2. Vilar-Gomez, E., Martinez-Perez, Y., Calzadilla-Bertot, L., Torres-Gonzalez, A., Gra-Oramas, B., Gonzalez-Fabian, L., et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149 (2015), 367–378 [e365; quiz e314–e365].
3. Mudaliar, S., Henry, R.R., Sanyal, A.J., Morrow, L., Marschall, H.U., Kipnes, M., 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, 145, 2013, e571.
4. Cariou, B., Hanf, R., Lambert-Porcheron, S., Zair, Y., Sauvinet, V., Noel, B., et al. Dual peroxisome proliferator-activated receptor alpha/delta Agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36 (2013), 2923–2930.
5. Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28 (1985), 412–419.
6. Bonora, E., Targher, G., Alberiche, M., Bonadonna, R.C., Saggiani, F., Zenere, M.B., et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 23 (2000), 57–63.
7. Isokuortti, E., Zhou, Y., Peltonen, M., Bugianesi, E., Clement, K., Bonnefont-Rousselot, D., et al. Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study. Diabetologia 60 (2017), 1873–1882.
8. Hui, J.M., Hodge, A., Farrell, G.C., Kench, J.G., Kriketos, A., George, J., Beyond insulin resistance in NASH: TNF-alpha or adiponectin?. Hepatology 40 (2004), 46–54.
9. Lomonaco, R., Ortiz-Lopez, C., Orsak, B., Webb, A., Hardies, J., Darland, C., et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 55 (2012), 1389–1397.
10. Gastaldelli, A., Harrison, S.A., Belfort-Aguilar, R., Hardies, L.J., Balas, B., Schenker, S., et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 50 (2009), 1087–1093.
11. Belfort, R., Harrison, S.A., Brown, K., Darland, C., Finch, J., Hardies, J., et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355 (2006), 2297–2307.
12. Sanyal, A.J., Chalasani, N., Kowdley, K.V., McCullough, A., Diehl, A.M., Bass, N.M., et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med 362 (2010), 1675–1685.
13. Cusi, K., Orsak, B., Bril, F., Lomonaco, R., Hecht, J., Ortiz-Lopez, C., et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 165 (2016), 305–315.
14. Ratziu, V., Charlotte, F., Bernhardt, C., Giral, P., Halbron, M., Lenaour, G., et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51 (2010), 445–453.
15. Ratziu, V., Giral, P., Jacqueminet, S., Charlotte, F., Hartemann-Heurtier, A., Serfaty, L., et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135 (2008), 100–110.
16. Aithal, G.P., Thomas, J.A., Kaye, P.V., Lawson, A., Ryder, S.D., Spendlove, I., et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135 (2008), 1176–1184.
17. Gastaldelli, A., Harrison, S., Belfort-Aguiar, R., Hardies, J., Balas, B., Schenker, S., et al. Pioglitazone in the treatment of NASH: the role of adiponectin. Aliment Pharmacol Ther 32 (2010), 769–775.
18. Brown, M.S., Goldstein, J.L., Selective vs. total insulin resistance: a pathogenic paradox. Cell Metab 7 (2008), 95–96.
19. Xu, A., Wang, Y., Keshaw, H., Xu, L.Y., Lam, K.S., Cooper, G.J., The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112 (2003), 91–100.
20. Musso, G., Cassader, M., Paschetta, E., Gambino, R., Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med 177 (2017), 633–640.
21. Marra, F., Efsen, E., Romanelli, R.G., Caligiuri, A., Pastacaldi, S., Batignani, G., et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119 (2000), 466–478.
22. Galli, A., Crabb, D., Price, D., Ceni, E., Salzano, R., Surrenti, C., et al. Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology 31 (2000), 101–108.
23. Galli, A., Crabb, D.W., Ceni, E., Salzano, R., Mello, T., Svegliati-Baroni, G., et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122 (2002), 1924–1940.
24. Leclercq, I.A., Sempoux, C., Starkel, P., Horsmans, Y., Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats. Gut 55 (2006), 1020–1029.
25. Ueno, T., Nakamura, A., Nakayama, H., Otabe, S., Yuan, X., Fukutani, T., et al. Adiponectin suppresses endoplasmic reticulum stress in nonalcoholic steatohepatitis. Exp Ther Med 2 (2011), 1035–1040.
26. Musso, G., Cassader, M., De Michieli, F., Rosina, F., Orlandi, F., Gambino, R., Nonalcoholic steatohepatitis vs. steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism. Hepatology 56 (2012), 933–942.
27. Kotronen, A., Westerbacka, J., Bergholm, R., Pietilainen, K.H., Yki-Jarvinen, H., Liver fat in the metabolic syndrome. J Clin Endocrinol Metab 92 (2007), 3490–3497.
28. Yokoo, T., Bydder, M., Hamilton, G., Middleton, M.S., Gamst, A.C., Wolfson, T., et al. Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T. Radiology 251 (2009), 67–76.
29. Meisamy, S., Hines, C.D., Hamilton, G., Sirlin, C.B., McKenzie, C.A., Yu, H., et al. Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology 258 (2011), 767–775.
30. Szczepaniak, L.S., Nurenberg, P., Leonard, D., Browning, J.D., Reingold, J.S., Grundy, S., et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288 (2005), E462–E468.
31. Noureddin, M., Lam, J., Peterson, M.R., Middleton, M., Hamilton, G., Le, T.A., et al. Utility of magnetic resonance imaging vs. histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 58 (2013), 1930–1940.
32. Middleton, M.S., Heba, E.R., Hooker, C.A., Bashir, M.R., Fowler, K.J., Sandrasegaran, K., et al. Agreement between magnetic resonance imaging proton density fat fraction measurements and pathologist-assigned steatosis grades of liver biopsies from adults with nonalcoholic steatohepatitis. Gastroenterology 153 (2017), 753–761.
33. Patel, J., Bettencourt, R., Cui, J., Salotti, J., Hooker, J., Bhatt, A., et al. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Ther Adv Gastroenterol 9 (2016), 692–701.
34. Sanyal, A., Abdelmalek, M.F., Diehl, A.M., Caldwell, S., Shiffman, M.L., Ghalib, R., et al. Efficacy and safety of simtuzumab for the treatment of nonalcoholic steatohepatitis with bridging fibrosis or cirrhosis: results of two phase 2b, dose-ranging, randomized, placebo-controlled trials. J Hepatol, 66, 2017, S54.
35. Harrison, S.A., Abdelmalek, M.F., Trotter, J.F., Paredes, A.H., Arnold, H.L., Kugelmas, M., et al. NGM282, a novel variant of FGF19, significantly reduces hepatic steatosis and key biomarkers of NASH: results of a Phase 2, multicenter, randomized, double-blinded, placebo controlled trial in biopsy-confirmed NASH patients. J Hepatol 66 (2017), S92–S93.
36. Loomba, R., Kayali, Z., Noureddin, M., Ruane, P., Lawitz, E., Gitlin, N., et al. Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 leads to significant improvements in MRI-PDFF in a phase 2, randomized, placebo- controlled trial of patients with NASH. Hepatology, 66, 2017, 1260A.
37. Cusi, K., Chang, Z., Harrison, S., Lomonaco, R., Bril, F., Orsak, B., et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 60 (2014), 167–174.
38. Ratziu, V., Sheikh, M.Y., Sanyal, A.J., Lim, J.K., Conjeevaram, H., Chalasani, N., et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 55 (2012), 419–428.
39. Friedman, S.L., Ratziu, V., Harrison, S.A., Abdelmalek, M.F., Aithal, G.P., Caballeria, J., et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology, 2017, 10.1002/hep.29477 [Epub ahead of print].
40. Ratziu, V., Harrison, S., Franque, S., Bedossa, P., Lehert, P., Serfaty, L., et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor alpha and delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150 (2016), 1146–1159.
41. Ratziu, V., de Ledinghen, V., Oberti, F., Mathurin, P., Wartelle-Bladou, C., Renou, C., et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 54 (2011), 1011–1019.
42. Leuschner, U.F., Lindenthal, B., Herrmann, G., Arnold, J.C., Rossle, M., Cordes, H.J., et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 52 (2010), 472–479.
43. Ratziu, V., Bedossa, P., Francque, S.M., Larrey, D., Aithal, G.P., Serfaty, L., et al. Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 12 (2014), 1724–1730.
44. Ratziu, V., Treatment of NASH with ursodeoxycholic acid: pro. Clin Res Hepatol Gastroenterol 36 (2012), S41–S45.
45. Takano, S., Ito, Y., Yokosuka, O., Ohto, M., Uchiumi, K., Hirota, K., et al. A multicenter randomized controlled dose study of ursodeoxycholic acid for chronic hepatitis C. Hepatology 20 (1994), 558–564.
46. Lindor, K.D., Kowdley, K.V., Heathcote, E.J., Harrison, M.E., Jorgensen, R., Angulo, P., et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39 (2004), 770–778.
47. Marcellin, P., Gane, E., Buti, M., Afdhal, N., Sievert, W., Jacobson, I.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 381 (2013), 468–475.
48. D'Ambrosio, R., Aghemo, A., Rumi, M.G., Ronchi, G., Donato, M.F., Paradis, V., et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 56 (2012), 532–543.
49. Nielsen, M.J., Veidal, S.S., Karsdal, M.A., Orsnes-Leeming, D.J., Vainer, B., Gardner, S.D., et al. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int 35 (2015), 429–437.
50. Karsdal, M.A., Henriksen, K., Nielsen, M.J., Byrjalsen, I., Leeming, D.J., Gardner, S., et al. Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy. Am J Physiol Gastrointest Liver Physiol 311 (2016), G1009–G1017.
51. Decaris, M.L., Li, K.W., Emson, C.L., Gatmaitan, M., Liu, S., Wang, Y., et al. Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood. Hepatology 65 (2017), 78–88.
52. Hezode, C., Castera, L., Roudot-Thoraval, F., Bouvier-Alias, M., Rosa, I., Roulot, D., et al. Liver stiffness diminishes with antiviral response in chronic hepatitis C. Aliment Pharmacol Ther 34 (2011), 656–663.
53. Singh, S., Facciorusso, A., Loomba, R., Falck-Ytter, Y.T., Magnitude and kinetics of decrease in liver stiffness after antiviral therapy in patients with chronic hepatitis C: a systematic review and meta-analysis. Clin Gastroenterol Hepatol, 2017, 10.1016/j.cgh.2017.04.038.
54. Sagir, A., Erhardt, A., Schmitt, M., Haussinger, D., Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 47 (2008), 592–595.
55. Park, C.C., Nguyen, P., Hernandez, C., Bettencourt, R., Ramirez, K., Fortney, L., et al. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology, 152, 2017, e592.
56. Kim, D., Kim, W.R., Talwalkar, J.A., Kim, H.J., Ehman, R.L., Advanced fibrosis in nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. Radiology 268 (2013), 411–419.
57. Loomba, R., Sirlin, C.B., Ang, B., Bettencourt, R., Jain, R., Salotti, J., et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 61 (2015), 1239–1250.
58. Loomba, R., Lawitz, E., Mantry, P.S., Jayakumar, S., Caldwell, S.H., Arnold, H., et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology, 2017, 10.1002/hep.29514.
59. Banerjee, R., Pavlides, M., Tunnicliffe, E.M., Piechnik, S.K., Sarania, N., Philips, R., et al. Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease. J Hepatol 60 (2014), 69–77.
60. Pavlides, M., Banerjee, R., Sellwood, J., Kelly, C.J., Robson, M.D., Booth, J.C., et al. Multiparametric magnetic resonance imaging predicts clinical outcomes in patients with chronic liver disease. J Hepatol 64 (2016), 308–315.
61. Pavlides, M., Banerjee, R., Tunnicliffe, E.M., Kelly, C., Collier, J., Wang, L.M., et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int 37 (2017), 1065–1073.
62. Ekstedt, M., Franzen, L.E., Mathiesen, U.L., Kechagias, S., Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression. Scand J Gastroenterol 47 (2012), 108–115.
63. Kleiner, D.E., Brunt, E.M., Belt, P., Wilson, L.A., Guy, C.D., Yeh, M.M., et al. Diagnostic pattern and disease activity are related to disease progression and regression in nonalcoholic fatty liver disease. Hepatology, 64, 2016, S247.
64. Sanyal, A.J., Friedman, S.L., McCullough, A.J., Dimick-Santos, L., Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 61 (2015), 1392–1405.
65. Yang, S., Lin, H.Z., Hwang, J., Chacko, V.P., Diehl, A.M., Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition?. Cancer Res 61 (2001), 5016–5023.
66. Gallagher, E.J., LeRoith, D., Minireview: IGF, insulin, and cancer. Endocrinology 152 (2011), 2546–2551.
67. Calvisi, D.F., Wang, C., Ho, C., Ladu, S., Lee, S.A., Mattu, S., et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 140 (2011), 1071–1083.
68. Park, E.J., Lee, J.H., Yu, G.Y., He, G., Ali, S.R., Holzer, R.G., et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140 (2010), 197–208.
69. Paradis, V., Albuquerque, M., Mebarki, M., Hernandez, L., Zalinski, S., Quentin, S., et al. Cullin7: a new gene involved in liver carcinogenesis related to metabolic syndrome. Gut 62 (2013), 911–919.
70. Bedossa, P., Dargere, D., Paradis, V., Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 38 (2003), 1449–1457.
71. Charlotte, F., Naour, G.L., Bernhardt, C., Poynard, T., Ratziu, V., A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C☆. Hum Pathol 41 (2010), 1178–1185.
72. Younossi, Z.M., Stepanova, M., Rafiq, N., Makhlouf, H., Younoszai, Z., Agrawal, R., et al. Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver-related mortality. Hepatology 53 (2011), 1874–1882.
73. Angulo, P., Kleiner, D.E., Dam-Larsen, S., Adams, L.A., Bjornsson, E.S., Charatcharoenwitthaya, P., et al. Liver fibrosis, but no other histologic features, associates with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149 (2015), 389–397.
74. Hagstrom, H., Nasr, P., Ekstedt, M., Hammar, U., Stal, P., Hultcrantz, R., et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol 67 (2017), 1265–1273.
75. Dulai, P.S., Singh, S., Patel, J., Soni, M., Prokop, L.J., Younossi, Z., et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65 (2017), 1557–1565.
76. Calvaruso, V., Burroughs, A.K., Standish, R., Manousou, P., Grillo, F., Leandro, G., et al. Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient. Hepatology 49 (2009), 1236–1244.
77. Sethasine, S., Jain, D., Groszmann, R.J., Garcia-Tsao, G., Quantitative histological-hemodynamic correlations in cirrhosis. Hepatology 55 (2012), 1146–1153.
78. Manousou, P., Burroughs, A.K., Tsochatzis, E., Isgro, G., Hall, A., Green, A., et al. Digital image analysis of collagen assessment of progression of fibrosis in recurrent HCV after liver transplantation. J Hepatol 58 (2013), 962–968.
79. Sanyal, A., Harrison, S., Ratziu, V., Abdelmalek, M., Diehl, A., Caldwell, S., et al. Changes in fibrosis, but not the NAFLD Activity Score (NAS), are associated with disease progression in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis. J Hepatol 66 (2017), S2–S3.
80. Goodman, Z.D., Becker, R.L. Jr., Pockros, P.J., Afdhal, N.H., Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis. Hepatology 45 (2007), 886–894.
81. McHutchison, J., Goodman, Z., Patel, K., Makhlouf, H., Rodriguez-Torres, M., Shiffman, M., et al. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology 138 (2010), 1365–1373 [1373; e1361–e1362].
82. Ekstedt, M., Franzen, L.E., Mathiesen, U.L., Thorelius, L., Holmqvist, M., Bodemar, G., et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44 (2006), 865–873.
83. Marchesini, G., Bugianesi, E., Forlani, G., Cerrelli, F., Lenzi, M., Manini, R., et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37 (2003), 917–923.
84. Sanyal, A.J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W.B., Contos, M.J., Sterling, R.K., et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120 (2001), 1183–1192.
85. Neuschwander-Tetri, B.A., Clark, J.M., Bass, N.M., Van Natta, M.L., Unalp-Arida, A., Tonascia, J., et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 52 (2010), 913–924.
86. Pais, R., Charlotte, F., Fedchuk, L., Bedossa, P., Lebray, P., Poynard, T., et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 59 (2013), 550–556.
87. McPherson, S., Hardy, T., Henderson, E., Burt, A.D., Day, C.P., Anstee, Q.M., Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 62 (2015), 1148–1155.
88. Argo, C.K., Northup, P.G., Al-Osaimi, A.M., Caldwell, S.H., Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 51 (2009), 371–379.
89. Singh, S., Allen, A.M., Wang, Z., Prokop, L.J., Murad, M.H., Loomba, R., Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 13 (2015), 643–654 [e641–e649; quiz e639–e640].
90. Ratziu, V., Francque, S., Harrison, S.H., Anstee, Q.M., Bedossa, P., Hum, D.W., et al. Improvement in NASH histological activity highly correlates with fibrosis regression. Hepatology, 64, 2016, LB21.
91. Randomized global phase 3 study to evaluate the impact on NASH with fibrosis of obeticholic acid treatment (REGENERATE). 2017 [cited Accessed November 3rd 2017]; Available from: https://clinicaltrials.gov/ct2/show/NCT02548351?term=Obeticholic+acid&cond=NASH&rank=1.
92. Phase 3 study to evaluate the efficacy and safety of elafibranor vs. placebo in patients with nonalcoholic steatohepatitis (NASH) (RESOLVE-IT). 2017 [cited Accessed on November 3rd 2017]; Available from: https://clinicaltrials.gov/ct2/show/NCT02704403?term=elafibranor&cond=NASH&rank=1.
93. Neuschwander-Tetri, B.A., Loomba, R., Sanyal, A.J., Lavine, J.E., Van Natta, M.L., Abdelmalek, M.F., et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385 (2015), 956–965.