Pharmacotherapy for Nonalcoholic Fatty Liver Disease

Abstract

Lifestyle modifications and optimization of the management of cardiometabolic comorbidities are currently the mainstay of treatment for patients with nonalcoholic fatty liver disease. Pharmacotherapy to halt or reverse hepatic histological injury and prevent the development of end-stage liver disease is specifically offered to patients with nonalcoholic steatohepatitis (NASH) and those with advanced fibrosis. In this review, the authors discuss the state of the art of various pharmacological agents for NASH. The efficacy of vitamin E and pioglitazone is reasonably well established in a selected group of patients with NASH. Current data do not offer convincing evidence for efficacy of pentoxifylline, long-chain polyunsaturated fatty acids, angiotensin receptor blockers, metformin, or ursodeoxycholic acid. They also discuss the state of several emerging agents for treating NASH including the farsenoid X receptor ligand, obeticholic acid.

Keywords

nonalcoholic fatty liver disease - nonalcoholic steatohepatitis - vitamin E - thiazolidinedione - obeticholic acid

• References

• 1 Wong RJ, Aguilar M, Cheung R , et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148 (3) 547-555
• 2 Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141 (4) 1249-1253
• 3 Pais R, Charlotte F, Fedchuk L , et al; LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013; 59 (3) 550-556
• 4 McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62 (5) 1148-1155
• 5 Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116 (6) 1413-1419
• 6 Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22 (6) 1714-1719
• 7 Dam-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P, Bendtsen F. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol 2009; 44 (10) 1236-1243
• 8 Ekstedt M, Hagström H, Nasr P , et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61 (5) 1547-1554
• 9 Ekstedt M, Franzén LE, Mathiesen UL , et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44 (4) 865-873
• 10 Angulo P, Machado MV, Diehl AM. Fibrosis in nonalcoholic Fatty liver disease: mechanisms and clinical implications. Semin Liver Dis 2015; 35 (2) 132-145
• 11 Younossi ZM, Stepanova M, Rafiq N , et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011; 53 (6) 1874-1882
• 12 Angulo P, Kleiner DE, Dam-Larsen S , et al. Liver fibrosis, but no other histologic features is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015; 149 (2) 389-397 e10
• 13 Sanyal AJ, Brunt EM, Kleiner DE , et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54 (1) 344-353
• 14 Chalasani N, Younossi Z, Lavine JE , et al; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterologyh. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142 (7) 1592-1609
• 15 Chung MY, Yeung SF, Park HJ, Volek JS, Bruno RS. Dietary α- and γ-tocopherol supplementation attenuates lipopolysaccharide-induced oxidative stress and inflammatory-related responses in an obese mouse model of nonalcoholic steatohepatitis. J Nutr Biochem 2010; 21 (12) 1200-1206
• 16 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 (10) 1667-1672
• 17 Sanyal AJ, Mofrad PS, Contos MJ , et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004; 2 (12) 1107-1115
• 18 Guy CD, Suzuki A, Abdelmalek MF, Burchette JL, Diehl AM ; NASH CRN. Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology 2015; 61 (1) 98-107
• 19 Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98 (11) 2485-2490
• 20 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. Hepatology 2003; 38 (2) 413-419
• 21 Yakaryilmaz F, Guliter S, Ozenirler S, Erdem O, Akyol G. Vitamin E treatment in patients with nonalcoholic steatohepatitis: A six-month, open-label study of sixteen patients. Curr Ther Res Clin Exp 2004; 65 (3) 266-277
• 22 Dufour JF, Oneta CM, Gonvers JJ , et al; Swiss Association for the Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006; 4 (12) 1537-1543
• 23 Sanyal AJ, Chalasani N, Kowdley KV , et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
• 24 Pietu F, Guillaud O, Walter T , et al. Ursodeoxycholic acid with vitamin E in patients with nonalcoholic steatohepatitis: long-term results. Clin Res Hepatol Gastroenterol 2012; 36 (2) 146-155
• 25 Wang CL, Liang L, Fu JF , et al. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World J Gastroenterol 2008; 14 (10) 1598-1602
• 26 Lavine JE, Schwimmer JB, Van Natta ML , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305 (16) 1659-1668
• 27 Pacana T, Sanyal AJ. Vitamin E and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2012; 15 (6) 641-648
• 28 Berry D, Wathen JK, Newell M. Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality. Clin Trials 2009; 6 (1) 28-41
• 29 Dietrich M, Jacques PF, Pencina MJ , et al. Vitamin E supplement use and the incidence of cardiovascular disease and all-cause mortality in the Framingham Heart Study: Does the underlying health status play a role?. Atherosclerosis 2009; 205 (2) 549-553
• 30 Miller III ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142 (1) 37-46
• 31 Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007; 297 (8) 842-857
• 32 Gerss J, Köpcke W. The questionable association of vitamin E supplementation and mortality—inconsistent results of different meta-analytic approaches. Cell Mol Biol (Noisy-le-grand) 2009; 55 (Suppl): OL1111-OL1120
• 33 Klein EA, Thompson Jr IM, Tangen CM , et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011; 306 (14) 1549-1556
• 34 Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351 (11) 1106-1118
• 35 Sharma AM, Staels B. Review: Peroxisome proliferator-activated receptor gamma and adipose tissue—understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab 2007; 92 (2) 386-395
• 36 Libby P, Plutzky J. Inflammation in diabetes mellitus: role of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma agonists. Am J Cardiol 2007; 99 (4A): 27B-40B
• 37 Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003; 144 (6) 2201-2207
• 38 Orasanu G, Ziouzenkova O, Devchand PR , et al. The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol 2008; 52 (10) 869-881
• 39 Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003; 38 (4) 1008-1017
• 40 Tiikkainen M, Häkkinen AM, Korsheninnikova E, Nyman T, Mäkimattila S, Yki-Järvinen H. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004; 53 (8) 2169-2176
• 41 Ratziu V, Giral P, Jacqueminet S , et al; LIDO Study Group. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008; 135 (1) 100-110
• 42 Ratziu V, Charlotte F, Bernhardt C , et al; LIDO Study Group. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51 (2) 445-453
• 43 Omer Z, Cetinkalp S, Akyildiz M , et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2010; 22 (1) 18-23
• 44 Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial. Hepatology 2011; 54 (5) 1631-1639
• 45 Promrat K, Lutchman G, Uwaifo GI , et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004; 39 (1) 188-196
• 46 Belfort R, Harrison SA, Brown K , et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355 (22) 2297-2307
• 47 Aithal GP, Thomas JA, Kaye PV , et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135 (4) 1176-1184
• 48 Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012; 35 (1) 66-75
• 49 Lutchman G, Modi A, Kleiner DE , et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 2007; 46 (2) 424-429
• 50 Cusi K, Orsak B, Lomonaco R , et al. Extended treatment with pioglitazone improves liver histology in patients with prediabetes or type 2 diabetes mellitus and NASH. Hepatology 2013; 58 : Abstract 82
• 51 Azoulay L, Yin H, Filion KB , et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344: e3645
• 52 Bennett WL, Maruthur NM, Singh S , et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011; 154 (9) 602-613
• 53 Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298 (10) 1180-1188
• 54 Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci (Lond) 2009; 116 (1) 1-16
• 55 Flachs P, Rossmeisl M, Kopecky J. The effect of n-3 fatty acids on glucose homeostasis and insulin sensitivity. Physiol Res 2014; 63 (Suppl. 01) S93-S118
• 56 Wu JH, Cahill LE, Mozaffarian D. Effect of fish oil on circulating adiponectin: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2013; 98 (6) 2451-2459
• 57 López-Vicario C, González-Périz A, Rius B , et al. Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis. Gut 2014; 63 (2) 344-355
• 58 Capanni M, Calella F, Biagini MR , et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006; 23 (8) 1143-1151
• 59 Spadaro L, Magliocco O, Spampinato D , et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 2008; 40 (3) 194-199
• 60 Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol 2008; 42 (4) 413-418
• 61 Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 2008; 14 (41) 6395-6400
• 62 Sofi F, Giangrandi I, Cesari F , et al. Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food Sci Nutr 2010; 61 (8) 792-802
• 63 Nobili V, Alisi A, Della Corte C , et al. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutr Metab Cardiovasc Dis 2013; 23 (11) 1066-1070
• 64 Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012; 56 (4) 944-951
• 65 Scorletti E, Bhatia L, McCormick KG , et al; WELCOME Study. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology 2014; 60 (4) 1211-1221
• 66 Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M ; EPE-A Study Group. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 2014; 147 (2) 377-384.e1
• 67 Argo CK, Patrie JT, Lackner C , et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol 2015; 62 (1) 190-197
• 68 DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 1991; 73 (6) 1294-1301
• 69 Glueck CJ, Fontaine RN, Wang P , et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism 2001; 50 (7) 856-861
• 70 Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014; 10 (3) 143-156
• 71 Haukeland JW, Konopski Z, Eggesbø HB , et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44 (7) 853-860
• 72 Nair S, Diehl AM, Wiseman M, Farr Jr GH, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004; 20 (1) 23-28
• 73 Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The Effect of Metformin and Standard Therapy versus Standard Therapy alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial. Therap Adv Gastroenterol 2009; 2 (3) 157-163
• 74 Rakoski MO, Singal AG, Rogers MA, Conjeevaram H. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2010; 32 (10) 1211-1221
• 75 Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98 (19) 2088-2093
• 76 Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999; 31 (2) 384
• 77 Fernández-Miranda C, Pérez-Carreras M, Colina F, López-Alonso G, Vargas C, Solís-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2008; 40 (3) 200-205
• 78 Laurin J, Lindor KD, Crippin JS , et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23 (6) 1464-1467
• 79 Fabbrini E, Mohammed BS, Korenblat KM , et al. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2010; 95 (6) 2727-2735
• 80 Athyros VG, Mikhailidis DP, Didangelos TP , et al. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin 2006; 22 (5) 873-883
• 81 Han KH, Rha SW, Kang HJ , et al. Evaluation of short-term safety and efficacy of HMG-CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage). J Clin Lipidol 2012; 6 (4) 340-351
• 82 Hatzitolios A, Savopoulos C, Lazaraki G , et al. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol 2004; 23 (4) 131-134
• 83 Kiyici M, Gulten M, Gurel S , et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol 2003; 17 (12) 713-718
• 84 Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 2011; 106 (1) 71-77
• 85 Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 2007; 47 (1) 135-141
• 86 Hyogo H, Tazuma S, Arihiro K , et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008; 57 (12) 1711-1718
• 87 Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 2009; 43 (10) 990-994
• 88 Athyros VG, Tziomalos K, Gossios TD , et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756) 1916-1922
• 89 Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004; 126 (5) 1287-1292
• 90 Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R ; Pravastatin in Chronic Liver Disease Study Investigators. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007; 46 (5) 1453-1463
• 91 Oakley F, Teoh V, Ching-A-Sue G , et al. Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology 2009; 136 (7) 2334-2344.e1
• 92 Moreno M, Gonzalo T, Kok RJ , et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 2010; 51 (3) 942-952
• 93 Moreira de Macêdo S, Guimarães TA, Feltenberger JD, Sousa Santos SH. The role of renin-angiotensin system modulation on treatment and prevention of liver diseases. Peptides 2014; 62: 189-196
• 94 Goh GB, Pagadala MR, Dasarathy J , et al. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int 2015; 35 (3) 979-985
• 95 Fogari R, Maffioli P, Mugellini A, Zoppi A, Lazzari P, Derosa G. Effects of losartan and amlodipine alone or combined with simvastatin in hypertensive patients with nonalcoholic hepatic steatosis. Eur J Gastroenterol Hepatol 2012; 24 (2) 164-171
• 96 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 (8) 942-954
• 97 Koppe SW, Sahai A, Malladi P, Whitington PF, Green RM. Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet. J Hepatol 2004; 41 (4) 592-598
• 98 Strieter RM, Remick DG, Ward PA , et al. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun 1988; 155 (3) 1230-1236
• 99 Zein CO, Lopez R, Fu X , et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology 2012; 56 (4) 1291-1299
• 100 Satapathy SK, Garg S, Chauhan R , et al. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99 (10) 1946-1952
• 101 Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99 (12) 2365-2368
• 102 Zein CO, Yerian LM, Gogate P , et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54 (5) 1610-1619
• 103 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 (3) 277-286
• 104 Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’. J Hepatol 2001; 35 (1) 134-146
• 105 Ratziu V, de Ledinghen V, Oberti F , et al; FRESGUN. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011; 54 (5) 1011-1019
• 106 Leuschner UF, Lindenthal B, Herrmann G , et al; NASH Study Group. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010; 52 (2) 472-479
• 107 Lindor KD, Kowdley KV, Heathcote EJ , et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004; 39 (3) 770-778
• 108 Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012; 17 (17-18) 988-997
• 109 Mazuy C, Helleboid A, Staels B, Lefebvre P. Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci 2015; 72 (9) 1631-1650
• 110 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 (3) 574-582.e1
• 111 Neuschwander-Tetri BA, Loomba R, Sanyal AJ , et al; 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 2015; 385 (9972) 956-965
• 112 Kharitonenkov A, Shanafelt AB. FGF21: a novel prospect for the treatment of metabolic diseases. Curr Opin Investig Drugs 2009; 10 (4) 359-364
• 113 Kharitonenkov A, Shiyanova TL, Koester A , et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115 (6) 1627-1635
• 114 Coskun T, Bina HA, Schneider MA , et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 2008; 149 (12) 6018-6027
• 115 Xu J, Lloyd DJ, Hale C , et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58 (1) 250-259
• 116 Fisher FM, Chui PC, Nasser IA , et al. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 2014; 147 (5) 1073-83.e6
• 117 Gawrieh S, Alloosh M, Sheridan R , et al. Fibroblast growth factor 21 treatment improves atherogenic diet-induced liver injury and metabolic syndrome in Ossabaw miniature swine. Hepatology 2014; 60: 247A-249A
• 118 Kolterman OG, Buse JB, Fineman MS , et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88 (7) 3082-3089
• 119 Sathyanarayana P, Jogi M, Muthupillai R, Krishnamurthy R, Samson SL, Bajaj M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity (Silver Spring) 2011; 19 (12) 2310-2315
• 120 Samson SL, Sathyanarayana P, Jogi M , et al. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia 2011; 54 (12) 3093-3100
• 121 Li Y, Wong K, Giles A , et al. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 2014; 146 (2) 539-549.e7
• 122 Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 2011; 6 (9) e25269
• 123 Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, Harrison SA. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol 2010; 105 (12) 2707-2709
• 124 Eguchi Y, Kitajima Y, Hyogo H , et al; Japan Study Group for NAFLD (JSG-NAFLD). Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res 2015; 45 (3) 269-278
• 125 Armstrong MJGP, Aithal GP, Parker R , et al. Liraglutide is effective in the histological clearance of nonalcoholic steatohepatitis in a multicenter, double-blinded, randomized, placebo-controlled phase II trial. J Hepatol 2015; 62: S271
• 126 Prescott LF, Newton RW, Swainson CP, Wright N, Forrest AR, Matthew H. Successful treatment of severe paracetamol overdosage with cysteamine. Lancet 1974; 1 (7858) 588-592
• 127 Prescott LF, Sutherland GR, Park J, Smith IJ, Proudfoot AT. Cysteamine, methionine, and penicillamine in the treatment of paracetamol poisoning. Lancet 1976; 2 (7977) 109-113
• 128 Dohil R, Schmeltzer S, Cabrera BL , et al. Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011; 33 (9) 1036-1044
• 129 Van Bergen T, Marshall D, Van de Veire S , et al. The role of LOX and LOXL2 in scar formation after glaucoma surgery. Invest Ophthalmol Vis Sci 2013; 54 (8) 5788-5796
• 130 Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS ONE 2013; 8 (12) e83481
• 131 Traber PG, Chou H, Zomer E , et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS ONE 2013; 8 (10) e75361
• 132 Harrison S, Chalasani N, Lawitz E , et al. Early phase 1 clinical trial results of GR-MD-02, a galec-tin-3 inhibitor, in patients having non-alcoholic steato-hepatitis (NASH) with advanced fibrosis. Hepatology 2014; 60: 224A-227A
• 133 Lefebvre E, Hashiguchi T, Jenkins H , et al. Anti-fibrotic and anti-inflammatory activity of the dual CCR2 and CCR5 antagonist cenicriviroc in a mouse model of NASH. Hepatology 2013; 58: 219A-222A
• 134 Gilat T, Leikin-Frenkel A, Goldiner I , et al. Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC). Hepatology 2003; 38 (2) 436-442
• 135 Leikin-Frenkel A, Goldiner I, Leikin-Gobbi D , et al. Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents. Eur J Gastroenterol Hepatol 2008; 20 (12) 1205-1213
• 136 Safadi R, Konikoff FM, Mahamid M , et al; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12 (12) 2085-2091.e1
• 137 Cariou B, Staels B. GFT505 for the treatment of nonalcoholic steatohepatitis and type 2 diabetes. Expert Opin Investig Drugs 2014; 23 (10) 1441-1448
• 138 Quintero P, Arrese M. Nuclear control of inflammation and fibrosis in nonalcoholic steatohepatitis: therapeutic potential of dual peroxisome proliferator-activated receptor alpha/delta agonism. Hepatology 2013; 58 (6) 1881-1884
• 139 Staels B, Rubenstrunk A, Noel B , et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013; 58 (6) 1941-1952
• 140 Genfit. Press Release: New Proof of Efficacy of GFT505 in NASH and Positive Expert Opinion. Available at: http://www.genfit.com/wp-content/uploads/2015/04/2015.04.24-PR-GENFIT-EASL-Minutes.pdf . Accessed May 23, 2015