Current and future treatment options in non-alcoholic steatohepatitis (NASH)

References

• Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124–131.
   PubMed Web of Science ®Google Scholar
• Chalasani N, Younossi Z, Lavine JE, et al.; American Association for the Study of Liver D, American College of G, American Gastroenterological A. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012;107:811–826.
   PubMed Web of Science ®Google Scholar
• EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–1402.
   PubMed Web of Science ®Google Scholar
• Adiels M, Taskinen MR, Boren J. Fatty liver, insulin resistance, and dyslipidemia. Curr Diab Rep. 2008;8:60–64.
   PubMed Web of Science ®Google Scholar
• Koehler EM, Plompen EP, Schouten JN, et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam study. Hepatology. 2016;63:138–147.
   PubMed Web of Science ®Google Scholar
• Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–1048.
   PubMed Web of Science ®Google Scholar
• Finkelstein EA, Khavjou OA, Thompson H, et al. Obesity and severe obesity forecasts through 2030. Am J Prev Med. 2012;42:563–570.
   PubMed Web of Science ®Google Scholar
• Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249–1253.
   PubMed Web of Science ®Google Scholar
• Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.
   PubMed Web of Science ®Google Scholar
• Kantartzis K, Thamer C, Peter A, et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut. 2009;58:1281–1288.
   PubMed Web of Science ®Google Scholar
• Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.
   PubMed Web of Science ®Google Scholar
• Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Harrison SA, Francque S, et al.; Group G-IS. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–59 e5.
   PubMed Web of Science ®Google Scholar
• Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–690.
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–965.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Abdelmalek MF, Suzuki A, et al.; Group E-AS. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147:377-84.e1.
   PubMed Web of Science ®Google Scholar
• Wong VW, Wong GL, Chan AW, et al. Treatment of non-alcoholic steatohepatitis with Phyllanthus urinaria: a randomized trial. J Gastroenterol Hepatol. 2013;28:57–62.
   PubMed Web of Science ®Google Scholar
• Torres DM, Jones FJ, Shaw JC, et al. 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;54:1631–1639.
   PubMed Web of Science ®Google Scholar
• Lavine JE, Schwimmer JB, van Natta ML, et al.; Nonalcoholic Steatohepatitis Clinical Research N. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–1668.
   PubMed Web of Science ®Google Scholar
• Malaguarnera M, Gargante MP, Russo C, et al. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis–a randomized and controlled clinical trial. Am J Gastroenterol. 2010;105:1338–1345.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.
   PubMed Web of Science ®Google Scholar
• Leuschner UF, Lindenthal B, Herrmann G, et al.; Group NS. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472–479.
   PubMed Web of Science ®Google Scholar
• Vilar Gomez E, Rodriguez de Miranda A, Gra Oramas B, et al. Clinical trial: a nutritional supplement Viusid, in combination with diet and exercise, in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2009;30:999–1009.
   PubMed Web of Science ®Google Scholar
• Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–1184.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology. 2008;135:100–110.
   PubMed Web of Science ®Google Scholar
• Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut. 2007;56:1760–1769.
   PubMed Web of Science ®Google Scholar
• Zein CO, Unalp A, Colvin R, et al.; Nonalcoholic Steatohepatitis Clinical Research N. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol. 2011;54:753–759.
   PubMed Web of Science ®Google Scholar
• Tsochatzis EA, Papatheodoridis GV. Smoking is associated with histological severity in nonalcoholic steatohepatitis. Hepatology. 2010;52:1522–1523.
   PubMed Web of Science ®Google Scholar
• Sookoian S, Castano GO, Pirola CJ. Modest alcohol consumption decreases the risk of non-alcoholic fatty liver disease: a meta-analysis of 43 175 individuals. Gut. 2014;63:530–532.
   PubMed Web of Science ®Google Scholar
• Dunn W, Sanyal AJ, Brunt EM, et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol. 2012;57:384–391.
   PubMed Web of Science ®Google Scholar
• Drenick EJ, Simmons F, Murphy JF. Effect on hepatic morphology of treatment of obesity by fasting, reducing diets and small-bowel bypass. N Engl J Med. 1970;282:829–834.
   PubMed Web of Science ®Google Scholar
• Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408–1413.
   PubMed Web of Science ®Google Scholar
• Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut. 2004;53:413–419.
   PubMed Web of Science ®Google Scholar
• Phelan S, Wadden TA, Berkowitz RI, et al. Impact of weight loss on the metabolic syndrome. Int J Obes. 2007;31:1442–1448.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Fecht W, Brunt EM, et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009;49:80–86.
   PubMed Web of Science ®Google Scholar
• Glass LM, Dickson RC, Anderson JC, et al. Total body weight loss of >/= 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2015;60:1024–1030.
   PubMed Web of Science ®Google Scholar
• Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–5.
   PubMed Web of Science ®Google Scholar
• Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27:103–107.
   PubMed Web of Science ®Google Scholar
• Huang MA, Greenson JK, Chao C, et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2005;100:1072–1081.
   PubMed Web of Science ®Google Scholar
• Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;47:711–717.
   PubMed Web of Science ®Google Scholar
• Abdelmalek MF, Suzuki A, Guy C, et al.; Nonalcoholic Steatohepatitis Clinical Research N. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–1971.
   PubMed Web of Science ®Google Scholar
• Haufe S, Engeli S, Kast P, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology. 2011;53:1504–1514.
   PubMed Web of Science ®Google Scholar
• Ryan MC, Itsiopoulos C, Thodis T, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013;59:138–143.
   PubMed Web of Science ®Google Scholar
• Goodpaster BH, Delany JP, Otto AD, et al. Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial. JAMA. 2010;304:1795–1802.
   PubMed Web of Science ®Google Scholar
• Church TS, Kuk JL, Ross R, et al. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology. 2006;130:2023–2030.
   PubMed Web of Science ®Google Scholar
• Johnson NA, Sachinwalla T, Walton DW, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology. 2009;50:1105–1112.
   PubMed Web of Science ®Google Scholar
• Hallsworth K, Fattakhova G, Hollingsworth KG, et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut. 2011;60:1278–1283.
   PubMed Web of Science ®Google Scholar
• Keating SE, Hackett DA, George J, et al. Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;57:157–166.
   PubMed Web of Science ®Google Scholar
• Keating SE, Hackett DA, Parker HM, et al. Effect of aerobic exercise training dose on liver fat and visceral adiposity. J Hepatol. 2015;63:174–182.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Ramrakhiani S, Brunt EM, et al. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol. 2003;98:926–930.
   PubMed Web of Science ®Google Scholar
• Zelber-Sagi S, Kessler A, Brazowsky E, et al. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:639–644.
   PubMed Web of Science ®Google Scholar
• Haines NW, Baker AL, Boyer JL, et al. Prognostic indicators of hepatic injury following jejunoileal bypass performed for refractory obesity: a prospective study. Hepatology. 1981;1:161–167.
   PubMed Web of Science ®Google Scholar
• Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007340. doi:10.1002/14651858.CD007340.pub2.
   Web of Science ®Google Scholar
• Berzigotti A, Saran U, Dufour JF. Physical activity and liver diseases. Hepatology. 2016;63:1026–1040.
   PubMed Web of Science ®Google Scholar
• Dixon JB, Bhathal PS, Hughes NR, et al. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–1654.
   PubMed Web of Science ®Google Scholar
• Mathurin P, Hollebecque A, Arnalsteen L, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137:532–540.
   PubMed Web of Science ®Google Scholar
• Taitano AA, Markow M, Finan JE, et al. Bariatric surgery improves histological features of nonalcoholic fatty liver disease and liver fibrosis. J Gastrointest Surg. 2015;19:429–7.
   PubMed Web of Science ®Google Scholar
• Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–6.
   PubMed Web of Science ®Google Scholar
• Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082–1090.
   PubMed Web of Science ®Google Scholar
• Shields WW, Thompson KE, Grice GA, et al. 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;2:157–163.
   PubMedGoogle Scholar
• Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013;62:606–615.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Charlotte F, Bernhardt C, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51:445–453.
   PubMed Web of Science ®Google Scholar
• Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–2471.
   PubMed Web of Science ®Google Scholar
• Home PD, Pocock SJ, Beck-Nielsen H, et al.; Team RS. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125–2135.
   PubMed Web of Science ®Google Scholar
• Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–196.
   PubMed Web of Science ®Google Scholar
• Lutchman G, Modi A, Kleiner DE, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46:424–429.
   PubMed Web of Science ®Google Scholar
• Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307.
   PubMed Web of Science ®Google Scholar
• Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–1188.
   PubMed Web of Science ®Google Scholar
• Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370:1129–1136.
   PubMed Web of Science ®Google Scholar
• Shah P, Mudaliar S. Pioglitazone: side effect and safety profile. Expert Opin Drug Saf. 2010;9:347–354.
   PubMed Web of Science ®Google Scholar
• Jb B, Rosenstock J, Sesti G, et al.; Group L-S. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39–47.
   PubMed Web of Science ®Google Scholar
• Astrup A, Rossner S, van Gaal L, et al.; Group NNS. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–1616.
   PubMed Web of Science ®Google Scholar
• Kim JH, Hong HN, Choi HH, et al. YH25724, a novel long-acting GLP-1/FGF21 dual agonist improves hepatic steatosis, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH) animal models. Hepatology. 2016;64:1136A–7A.
   PubMed Web of Science ®Google Scholar
• Trevaskis J, Beaton ML, Bednarek M, et al. The dual glucagon-like peptide-1 (GLP-1)/Glucagon receptor agonist MEDI0382 improves metabolic and hepatic indices of NASH in mice. Hepatology. 2016;64:751A.
   Web of Science ®Google Scholar
• Yamamoto T, Nakade Y, Yamauchi T, et al. Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice. World J Gastroenterol. 2016;22:2512–2523.
   PubMed Web of Science ®Google Scholar
• Jung YA, Choi YK, Jung GS, et al. Sitagliptin attenuates methionine/choline-deficient diet-induced steatohepatitis. Diabetes Res Clin Pract. 2014;105:47–57.
   PubMed Web of Science ®Google Scholar
• Yilmaz Y, Yonal O, Deyneli O, et al. Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol Belg. 2012;75:240–244.
   PubMed Web of Science ®Google Scholar
• Cui J, Philo L, Nguyen P, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2016;65:369–376.
   PubMed Web of Science ®Google Scholar
• Athyros VG, Tziomalos K, Gossios TD, et al.; Group GSC. 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;376:1916–1922.
   PubMed Web of Science ®Google Scholar
• Nelson A, Torres DM, Morgan AE, et al. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43:990–994.
   PubMed Web of Science ®Google Scholar
• Hyogo H, Ikegami T, Tokushige K, et al. Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res. 2011;41:1057–1065.
   PubMed Web of Science ®Google Scholar
• Kargiotis K, Athyros VG, Giouleme O, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol. 2015;21:7860–7868.
   PubMed Web of Science ®Google Scholar
• Simon TG, Bonilla H, Yan P, et al. Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and HCC, among patients with HCV results from ERCHIVES. Hepatology. 2016;64:47–57.
   PubMed Web of Science ®Google Scholar
• El-Serag HB, Johnson ML, Hachem C, et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 2009;136:1601–1608.
   PubMed Web of Science ®Google Scholar
• Loomba R, Sirlin CB, Ang B, et al.; San Diego Integrated NRC. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology. 2015;61:1239–1250.
   PubMed Web of Science ®Google Scholar
• Di Minno MN, Russolillo A, Lupoli R, et al. Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease. World J Gastroenterol. 2012;18:5839–5847.
   PubMed Web of Science ®Google Scholar
• Dasarathy S, Dasarathy J, Khiyami A, et al. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2015;49:137–144.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485–2490.
   PubMed Web of Science ®Google Scholar
• Kawanaka M, Nishino K, Nakamura J, et al. Treatment of nonalcoholic steatohepatitis with vitamins E and C: a pilot study. Hepat Med. 2013;5:11–16.
   PubMedGoogle Scholar
• 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;2:1107–1115.
   PubMed Web of Science ®Google Scholar
• Han Y, Shi JP, Ma AL, et al. Randomized, vitamin E-controlled trial of bicyclol plus metformin in non-alcoholic fatty liver disease patients with impaired fasting glucose. Clin Drug Investig. 2014;34:1–7.
   PubMed Web of Science ®Google Scholar
• Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297:842–857.
   PubMed Web of Science ®Google Scholar
• Klein EA, Thompson IM Jr., Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306:1549–1556.
   PubMed Web of Science ®Google Scholar
• Schurks M, Glynn RJ, Rist PM, et al. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702.
   PubMed Web of Science ®Google Scholar
• Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147–191.
   PubMed Web of Science ®Google Scholar
• Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145:574-82.e1.
   PubMed Web of Science ®Google Scholar
• Traussnigg S, Kienbacher C, Halilbasic E, et al. Efficacy and safety of the non-steroidal farnesoid X receptor agonist PX-104 in patients with non-alcoholic fatty liver disease (NAFLD). Hepatology. 2016;64:536A–7A.
   Web of Science ®Google Scholar
• Djedjos CS, Kirby B, Billin A, et al. Pharmacodynamic effects of the oral, non-steroidal farnesoid X receptor agonist GS-9674 in healthy volunteers. Hepatology. 2016;64:543A.
   Web of Science ®Google Scholar
• Cariou B, Zair Y, Staels B, et al. Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care. 2011;34:2008–2014.
   PubMed Web of Science ®Google Scholar
• Cariou B, Hanf R, Lambert-Porcheron S, et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care. 2013;36:2923–2930.
   PubMed Web of Science ®Google Scholar
• Francque S, Verrijken A, Caron S, et al. PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015;63:164–173.
   PubMed Web of Science ®Google Scholar
• 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;58:1941–1952.
   PubMed Web of Science ®Google Scholar
• Loomba R, Lawitz E, Mantry PS, et al. GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized, phase 2 trial. Hepatology. 2016;64:1119A–20A.
   Google Scholar
• Musso G, Cassader M, Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov. 2016;15:249–274.
   PubMed Web of Science ®Google Scholar
• Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut. 2017;66:180–190. doi:10.1136/gutjnl-2016-312431.
   PubMed Web of Science ®Google Scholar
• Safadi R, Konikoff FM, Mahamid M, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085–91 e1.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Ramiro I, Vauzour D, Minihane AM. Polyphenols and non-alcoholic fatty liver disease: impact and mechanisms. Proc Nutr Soc. 2016;75:47–60.
   PubMed Web of Science ®Google Scholar
• Loffredo L, Del Ben M, Perri L, et al. Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2016;44:279–286.
   PubMed Web of Science ®Google Scholar
• Koukias N, Buzzetti E, Tsochatzis EA. Intestinal hormones, gut microbiota and nonalcoholic fatty liver disease (NAFLD). Minerva Endocrinol. 2016 Nov 23. [Epub ahead of print]. PMID: 27879962.
   PubMedGoogle Scholar
• Wong VW, Won GL, Chim AM, et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol. 2013;12:256–262.
   PubMed Web of Science ®Google Scholar
• Rysz J, Gluba-Brzozka A, Mikhailidis DP, et al. Fibroblast growth factor 19-targeted therapies for the treatment of metabolic disease. Expert Opin Investig Drugs. 2015;24:603–610.
   PubMed Web of Science ®Google Scholar
• Saboo B, Prajapati A, Joshi S, et al. To assess the effect of 4mg saroglitazar on patients of diabetes dyslipidemia with nonalcoholic fatty liver disease for 24 weeks at diabetes care centre (712-P-2015). Available from: https://ada.scientificposters.com/epsAbstractADA.cfm?id=1: American Diabetes Association [online]; 2015.
   Google Scholar
• Joshi S, Ghosh S, Shah P, et al. Saroglitazar in diabetic dyslipidemia: 1 year data. (126-LB-2015). Available from: https://ada.scientificposters.com/epsAbstractADA.cfm?id=1: American Diabetes Association [online]; 2015.
   Google Scholar
• Sanyal AJ, Cusi K, Patel S, et al. Effect of pradigastat, a diacylglycerol acyltransferase 1 inhibitor, on liver fat content in nonalcoholic fatty liver disease. Hepatology. 2015;62:1253A.
   Web of Science ®Google Scholar
• Ratziu V, Bedossa P, Francque SM, et al. Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2014;12:1724-30.e5.
   PubMed Web of Science ®Google Scholar
• Barreyro FJ, Holod S, Finocchietto PV, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35:953–966.
   PubMed Web of Science ®Google Scholar
• Shiffman M, Freilich B, Vuppalanchi R, et al. A placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases (LP37). J Hepatology. 2015;62:S282.
   Web of Science ®Google Scholar
• Friedman S, Sanyal A, Goodman Z, et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR phase 2b study design. Contemp Clin Trials. 2016;47:356–365.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Ratziu V, Harrison S, et al. Cenicriviroc placebo for the treatment of non-alcoholic steatohepatitis with liver fibrosis: results from the year 1 primary analysis of the phase 2b CENTAUR study. Hepatology. 2016;64:1118A–9A.
   Web of Science ®Google Scholar
• Lalazar G, Mizrahi M, Turgeman I, et al. Oral administration of OKT3 MAb to patients with NASH, promotes regulatory T-cell Induction, and alleviates insulin resistance: results of a phase IIa blinded placebo-controlled trial. J Clin Immunol. 2015;35:399–407.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Miller V. Regulatory science and drug approval for alcoholic and nonalcoholic steatohepatitis. Gastroenterology. 2016;150:1723–1727.
   PubMed Web of Science ®Google Scholar
• Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.
   PubMed Web of Science ®Google Scholar
• Ekstedt M, Hagstrom 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;61:1547–1554.
   PubMed Web of Science ®Google Scholar
• Tsochatzis E, Bruno S, Isgro G, et al. Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis. J Hepatol. 2014;60:948–954.
   PubMed Web of Science ®Google Scholar
• Manousou P, Dhillon AP, Isgro G, et al. Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation. Liver Transpl. 2011;17:178–188.
   PubMed Web of Science ®Google Scholar
• Calvaruso V, Dhillon AP, Tsochatzis E, et al. Liver collagen proportionate area predicts decompensation in patients with recurrent hepatitis C virus cirrhosis after liver transplantation. J Gastroenterol Hepatol. 2012;27:1227–1232.
   PubMed Web of Science ®Google Scholar