Hepatology International

, Volume 7, Supplement 2, pp 833–841 | Cite as

Pharmacological agents for nonalcoholic steatohepatitis

Review Article

Abstract

The rationale for specific pharmacologic therapy in nonalcoholic steatohepatitis (NASH) is determined by the potential for disease progression and the difficulties, in many patients, to successfully implement diet and lifestyle changes in the long term. Because they correct insulin resistance, insulin-sensitizing agents are attractive candidates for the treatment of NASH. However, two randomized studies have shown that vitamin E, despite having no effect on insulin sensitivity, achieves interesting histological and biochemical efficacy. This review provides an insight into the therapeutic efficacy and safety issues of different pharmacological agents tested in human NASH.

Keywords

Steatohepatitis Fibrosis Steatosis Glitazones Vitamin E Ursodesoxycholic acid Insulin resistance Oxidative stress Insulin sensitizers 

References

  1. 1.
    Kleiner D, Brunt E. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis 2012;32:3–13PubMedCrossRefGoogle Scholar
  2. 2.
    Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013;10:330–344PubMedCrossRefGoogle Scholar
  3. 3.
    White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10(1342–1359):e2PubMedGoogle Scholar
  4. 4.
    Adams LA, Lymp JF, St. Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113–121PubMedCrossRefGoogle Scholar
  5. 5.
    Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121–129PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. 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. Hepatology 2012;55:2005–2023PubMedCrossRefGoogle Scholar
  7. 7.
    Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51:1820–1832PubMedCrossRefGoogle Scholar
  8. 8.
    Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010;53:372–384PubMedCrossRefGoogle Scholar
  9. 9.
    Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137:532–540PubMedCrossRefGoogle Scholar
  10. 10.
    Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011;54:344–353PubMedCrossRefGoogle Scholar
  11. 11.
    Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000;49:749–758PubMedCrossRefGoogle Scholar
  12. 12.
    Bhalla K, Hwang BJ, Dewi RE, Twaddel W, Goloubeva OG, Wong KK, et al. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila) 2012;5:544–552CrossRefGoogle Scholar
  13. 13.
    Chen HP, Shieh JJ, Chang CC, Chen TT, Lin JT, Wu MS, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 2012;62:606–615PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012;97:2347–2353PubMedCrossRefGoogle Scholar
  15. 15.
    Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, 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 2009;50:1087–1093PubMedCrossRefGoogle Scholar
  16. 16.
    Bell LN, Wang J, Muralidharan S, Chalasani S, Fullenkamp AM, Wilson LA, et al. Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. Hepatology 2012;56:1311–1318PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Belfort R, Harrison SA, 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 2006;355:2297–2307PubMedCrossRefGoogle Scholar
  18. 18.
    Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135:1176–1184PubMedCrossRefGoogle Scholar
  19. 19.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–1685PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Ratziu V, Caldwell S, Neuschwander-Tetri BA. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology 2010;52:2206–2215PubMedCrossRefGoogle Scholar
  21. 21.
    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 2008;135:100–110PubMedCrossRefGoogle Scholar
  22. 22.
    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 2010;51:445–453PubMedCrossRefGoogle Scholar
  23. 23.
    Mahady SE, Wong G, Craig JC, George J. Pioglitazone and vitamin E for nonalcoholic steatohepatitis: a cost utility analysis. Hepatology 2012;56:2172–2179PubMedCrossRefGoogle Scholar
  24. 24.
    Balas B, Belfort R, Harrison SA, Darland C, Finch J, Schenker S, et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol 2007;47:565–570 Epub 2007 May 24PubMedCrossRefGoogle Scholar
  25. 25.
    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;298:1180–1188PubMedCrossRefGoogle Scholar
  26. 26.
    Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009;180:32–39PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Neumann A, Weill A, Ricordeau P, Fagot JP, Alla F, Allemand H. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia 2012;55:1953–1962PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda M. Metformin in nonalcoholic steatohepatitis. Lancet 2001;358:893–894PubMedCrossRefGoogle Scholar
  29. 29.
    Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082–1090PubMedCrossRefGoogle Scholar
  30. 30.
    Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537–544PubMedCrossRefGoogle Scholar
  31. 31.
    Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004;20:23–28PubMedCrossRefGoogle Scholar
  32. 32.
    Haukeland JW, Konopski Z, Eggesbo HB, von Volkmann HL, Raschpichler G, Bjoro K, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009;44:853–860PubMedCrossRefGoogle Scholar
  33. 33.
    Tiikkainen M, Hakkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen 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;53:2169–2176PubMedCrossRefGoogle Scholar
  34. 34.
    Trevaskis JL, Griffin PS, Wittmer C, Neuschwander-Tetri BA, Brunt EM, Dolman CS, et al. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 2012;302:G762–772PubMedCrossRefGoogle Scholar
  35. 35.
    Kim YO, Schuppan D. When GLP-1 hits the liver: a novel approach for insulin resistance and NASH. Am J Physiol Gastrointest Liver Physiol 2012;302:G759–761PubMedCrossRefGoogle Scholar
  36. 36.
    Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 2011;31:1285–1297PubMedCrossRefGoogle Scholar
  37. 37.
    Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004;2:1107–1115PubMedCrossRefGoogle Scholar
  38. 38.
    Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006;4:1537–1543PubMedCrossRefGoogle Scholar
  39. 39.
    Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659–1668PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Nobili V, Manco M, Devito R, Di Ciommo V, Comparcola D, Sartorelli MR, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 2008;48:119–128PubMedCrossRefGoogle Scholar
  41. 41.
    Miller ER 3rd, 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;142:37–46PubMedCrossRefGoogle Scholar
  42. 42.
    Schurks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 2010;341:c5702PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 2011;306:1549–1556PubMedCrossRefGoogle Scholar
  44. 44.
    Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464–1467PubMedCrossRefGoogle Scholar
  45. 45.
    Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770–778PubMedCrossRefGoogle Scholar
  46. 46.
    Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M, Cordes HJ, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010;52:472–479PubMedCrossRefGoogle Scholar
  47. 47.
    Ratziu V. Treatment of NASH with ursodeoxycholic acid: pro. Clin Res Hepatol Gastroenterol 2012;36(Suppl 1):S41–45PubMedCrossRefGoogle Scholar
  48. 48.
    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 2011;54:1011–1019PubMedCrossRefGoogle Scholar
  49. 49.
    Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:2365–2368PubMedCrossRefGoogle Scholar
  50. 50.
    Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54:1610–1619PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Zein CO, Lopez R, Fu X, Kirwan JP, Yerian LM, McCullough AJ, et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology 2012;56:1291–1299PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004;40:1222–1225PubMedCrossRefGoogle Scholar
  53. 53.
    Rosselli MS, Burgueno AL, Carabelli J, Schuman M, Pirola CJ, Sookoian S. Losartan reduces liver expression of plasminogen activator inhibitor-1 (PAI-1) in a high fat-induced rat nonalcoholic fatty liver disease model. Atherosclerosis 2009;206:119–126PubMedCrossRefGoogle Scholar
  54. 54.
    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;54:1631–1639PubMedCrossRefGoogle Scholar
  55. 55.
    Sookoian S, Castano G, Garcia SI, Viudez P, Gonzalez C, Pirola CJ. A1166C angiotensin II type 1 receptor gene polymorphism may predict hemodynamic response to losartan in patients with cirrhosis and portal hypertension. Am J Gastroenterol 2005;100:636–642PubMedCrossRefGoogle Scholar
  56. 56.
    Ekstedt M, Franzen 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;47:135–141PubMedCrossRefGoogle Scholar
  57. 57.
    Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R. 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;46:1453–1463PubMedCrossRefGoogle Scholar
  58. 58.
    Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. 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;376:1916–1922PubMedCrossRefGoogle Scholar
  59. 59.
    Loria P, Lonardo A, Anania F. Liver and diabetes. A vicious circle. Hepatol Res 2013;43:51–64PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Yilmaz Y, Colak Y, Kurt R, Senates E, Eren F. Linking nonalcoholic fatty liver disease to hepatocellular carcinoma: from bedside to bench and back. Tumori 2013;99:10–16PubMedGoogle Scholar
  61. 61.
    Lai SW, Liao KF, Lai HC, Muo CH, Sung FC, Chen PC. Statin use and risk of hepatocellular carcinoma. Eur J Epidemiol 2013;28:485–492PubMedCrossRefGoogle Scholar
  62. 62.
    Pradelli D, Soranna D, Scotti L, Zambon A, Catapano A, Mancia G, et al. Statins and primary liver cancer: a meta-analysis of observational studies. Eur J Cancer Prev 2013;22:229–234PubMedCrossRefGoogle Scholar
  63. 63.
    Lonardo A, Loria P. Potential for statins in the chemoprevention and management of hepatocellular carcinoma. J Gastroenterol Hepatol 2012;27:1654–1664PubMedCrossRefGoogle Scholar
  64. 64.
    Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013;144:323–332PubMedCrossRefGoogle Scholar
  65. 65.
    Merat S, Malekzadeh R, Sohrabi MR, Sotoudeh M, Rakhshani N, Sohrabpour AA, et al. Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J Hepatol 2003;38:414–418PubMedCrossRefGoogle Scholar
  66. 66.
    Merat S, Aduli M, Kazemi R, Sotoudeh M, Sedighi N, Sohrabi M, et al. Liver histology changes in nonalcoholic steatohepatitis after one year of treatment with probucol. Dig Dis Sci 2008;53:2246–2250PubMedCrossRefGoogle Scholar
  67. 67.
    Capanni M, Calella F, Biagini MR, Genise S, Raimondi L, Bedogni G, 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;23:1143–1151PubMedCrossRefGoogle Scholar
  68. 68.
    Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids—a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2010;31:679–692PubMedCrossRefGoogle Scholar
  69. 69.
    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;56:944–951PubMedCrossRefGoogle Scholar
  70. 70.
    Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 2009;49:80–86PubMedCrossRefGoogle Scholar
  71. 71.
    Zoppini G, Targher G, Bonora E. The role of serum uric acid in cardiovascular disease in type 2 diabetic and non-diabetic subjects: a narrative review. J Endocrinol Invest 2011;34:881–886PubMedGoogle Scholar
  72. 72.
    Loria P, Lonardo A, Targher G. Is liver fat detrimental to vessels?: intersections in the pathogenesis of NAFLD and atherosclerosis. Clin Sci (Lond) 2008;115:1–12CrossRefGoogle Scholar
  73. 73.
    Valbusa F, Bertolini L, Bonapace S, Zenari L, Zoppini G, Arcaro G, et al. Relation of elevated serum uric acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus. Am J Cardiol 2013. doi:10.1016/j.amjcard.2013.04.012 PubMedGoogle Scholar
  74. 74.
    Li Y, Xu C, Yu C, Xu L, Miao M. Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. J Hepatol 2009;50:1029–1034PubMedCrossRefGoogle Scholar
  75. 75.
    Sirota JC, McFann K, Targher G, Johnson RJ, Chonchol M, Jalal DI. Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism 2013;62:392–399PubMedCrossRefGoogle Scholar
  76. 76.
    Afzali A, Weiss NS, Boyko EJ, Ioannou GN. Association between serum uric acid level and chronic liver disease in the United States. Hepatology 2010;52:578–589PubMedCrossRefGoogle Scholar
  77. 77.
    Xu CF, Yu CH, Xu L, Sa XY, Li YM. Hypouricemic therapy: a novel potential therapeutic option for nonalcoholic fatty liver disease. Hepatology 2010;52:1865–1866PubMedCrossRefGoogle Scholar
  78. 78.
    Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol 2011;55:920–932PubMedCrossRefGoogle Scholar
  79. 79.
    Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012;55:77–85PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Dongiovanni P, Valenti L, Fracanzani AL, Gatti S, Cairo G, Fargion S. Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. Am J Pathol 2008;172:738–747PubMedCrossRefGoogle Scholar
  81. 81.
    Fargion S, Dongiovanni P, Guzzo A, Colombo S, Valenti L, Fracanzani AL. Iron and insulin resistance. Aliment Pharmacol Ther 2005;22(Suppl 2):61–63PubMedCrossRefGoogle Scholar
  82. 82.
    Equitani F, Fernandez-Real JM, Menichella G, Koch M, Calvani M, Nobili V, et al. Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations. Diabetes Care 2008;31:3–8PubMedCrossRefGoogle Scholar
  83. 83.
    Valenti L, Moscatiello S, Vanni E, Fracanzani AL, Bugianesi E, Fargion S, et al. Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling–a propensity score-adjusted observational study. QJM 2011;104:141–149PubMedCrossRefGoogle Scholar
  84. 84.
    Valenti L, Fracanzani AL, Dongiovanni P, Bugianesi E, Marchesini G, Manzini P, et al. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol 2007;102:1251–1258PubMedCrossRefGoogle Scholar
  85. 85.
    Facchini FS, Hua NW, Stoohs RA. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 2002;122:931–999PubMedCrossRefGoogle Scholar
  86. 86.
    Valenti L, Dongiovanni P, Fracanzani AL, Fargion S. Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations: response to Equitani et al. Diabetes Care 2008;31:e18 author reply e19PubMedCrossRefGoogle Scholar
  87. 87.
    Riquelme A, Soza A, Nazal L, Martinez G, Kolbach M, Patillo A, et al. Histological resolution of steatohepatitis after iron depletion. Dig Dis Sci 2004;49:1012–1015PubMedCrossRefGoogle Scholar
  88. 88.
    Valenti L, Dongiovanni P, Fargion S. Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease. World J Gastroenterol 2012;18:3782–3786PubMedCrossRefGoogle Scholar
  89. 89.
    Lirussi F, Mastropasqua E, Orando S, Orlando R. Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev 2007;21:CD005165Google Scholar
  90. 90.
    Velayudham A, Dolganiuc A, Ellis M, Petrasek J, Kodys K, Mandrekar P, et al. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 2009;49:989–997PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–1103PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–1481PubMedCrossRefGoogle Scholar
  93. 93.
    Membrez M, Blancher F, Jaquet M, Bibiloni R, Cani PD, Burcelin RG, et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J 2008;22:2416–2426PubMedCrossRefGoogle Scholar
  94. 94.
    Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol 2008;48:983–992PubMedCrossRefGoogle Scholar
  95. 95.
    Cani PD, Lecourt E, Dewulf EM, Sohet FM, Pachikian BD, Naslain D, et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am J Clin Nutr 2009;90:1236–1243PubMedCrossRefGoogle Scholar
  96. 96.
    Parnell JA, Reimer RA. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr 2009;89:1751–1759PubMedCrossRefGoogle Scholar
  97. 97.
    Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 2008;49:821–830PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Mencarelli A, Cipriani S, Renga B, Bruno A, D’Amore C, Distrutti E, et al. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS ONE 2012;7:e45425PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005;39:540–543PubMedCrossRefGoogle Scholar
  100. 100.
    Solga SF, Buckley G, Clark JM, Horska A, Diehl AM. The effect of a probiotic on hepatic steatosis. J Clin Gastroenterol 2008;42:1117–1119PubMedCrossRefGoogle Scholar
  101. 101.
    Machado MV, Cortez-Pinto H. Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol 2012;11:440–449PubMedGoogle Scholar
  102. 102.
    Iacono A, Raso GM, Canani RB, Calignano A, Meli R. Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. J Nutr Biochem 2011;22:699–711PubMedCrossRefGoogle Scholar
  103. 103.
    Lam B, Younossi ZM. Treatment options for nonalcoholic fatty liver disease. Therap Adv Gastroenterol 2010;3:121–137PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Walter JH. l-Carnitine. Arch Dis Child 1996;74:475–478PubMedCrossRefGoogle Scholar
  105. 105.
    Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Avitabile T, 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;105:1338–1345PubMedCrossRefGoogle Scholar
  106. 106.
    Carulli L, Ballestri S, Lonardo A, Lami F, Violi E, Losi L, et al. Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels? Intern Emerg Med 2013;8:297–305PubMedCrossRefGoogle Scholar
  107. 107.
    Cachefo A, Boucher P, Vidon C, Dusserre E, Diraison F, Beylot M. Hepatic lipogenesis and cholesterol synthesis in hyperthyroid patients. J Clin Endocrinol Metab 2001;86:5353–5357PubMedCrossRefGoogle Scholar
  108. 108.
    Riis AL, Gravholt CH, Djurhuus CB, Norrelund H, Jorgensen JO, Weeke J, et al. Elevated regional lipolysis in hyperthyroidism. J Clin Endocrinol Metab 2002;87:4747–4753PubMedCrossRefGoogle Scholar
  109. 109.
    Cable EE, Finn PD, Stebbins JW, Hou J, Ito BR, van Poelje PD, et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 2009;49:407–417PubMedCrossRefGoogle Scholar
  110. 110.
    Arrese M. Burning hepatic fat: therapeutic potential for liver-specific thyromimetics in the treatment of nonalcoholic fatty liver disease. Hepatology 2009;49:348–351PubMedCrossRefGoogle Scholar
  111. 111.
    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;51:380–388PubMedCrossRefGoogle Scholar
  112. 112.
    Ratziu V, Sheikh MY, Sanyal AJ, Lim JK, Conjeevaram H, Chalasani N, et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 2012;55:419–428PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Cariou B, Zair Y, Staels B, Bruckert E. 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;34:2008–2014PubMedCrossRefGoogle Scholar
  114. 114.
    Tsuchiya H, Ikeda Y, Ebata Y, Kojima C, Katsuma R, Tsuruyama T, et al. Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice. Hepatology 2012;56:1319–1330PubMedCrossRefGoogle Scholar
  115. 115.
    Hoo RL, Lee IP, Zhou M, Wong JY, Hui X, Xu A, et al. Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice. J Hepatol 2013;58:358–364PubMedCrossRefGoogle Scholar
  116. 116.
    Lin CW, Zhang H, Li M, Xiong X, Chen X, Dong XC. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol 2013. doi:10.1016/j.jhep.2013.01.011 PubMedCentralGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2014

Authors and Affiliations

  1. 1.Service d’Hépatologie et Gastro-entérologie, INSERM 1048 and Université Paul Sabatier, Hôpital PurpanCentre Hospitalier Universitaire de ToulouseToulouseFrance
  2. 2.Service d’Hépatologie et Gastro-entérologieHôpital PurpanToulouse Cedex 9France
  3. 3.INSERM U938, Hospital Pitié SalpêtrièreCdR Saint-Antoine and Université Pierre et Marie CurieParisFrance
  4. 4.Service d’Hépatologie et Gastro-entérologieHôpital Pitié-SalpêtrièreParis Cedex 13France

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