Advances in Therapy

, Volume 31, Issue 1, pp 30–43

Effect of Metformin on Ballooning Degeneration in Nonalcoholic Steatohepatitis (NASH): When to Use Metformin in Nonalcoholic Fatty Liver Disease (NAFLD)

Review

Abstract

The key histologic feature of nonalcoholic steatohepatitis (NASH) is hepatocellular ballooning (HB). It plays an important role in NASH progression and is an independent predictor of liver mortality. In this review, we identified all studies using metformin in the treatment of nonalcoholic fatty liver disease (NAFLD) that included pre- and post-treatment liver biopsies. We specifically reviewed the effects of metformin on HB. Improved HB was noted in pediatric populations and in those adult patients who were able to lose weight and improve or normalize transaminases during therapy. Previous studies have supported the beneficial effects of metformin in reduction of body weight, improvement of insulin resistance, prevention of complications related to diabetes and chemo-preventive benefits in reducing hepatocellular carcinoma. All these effects make it an attractive treatment consideration for patients with diabetes, and prediabetes who have co-existing NAFLD. Future studies are warranted in order to confirm this effect of metformin on HB and its association with improving long-term outcomes in patients with NAFLD.

Keywords

Body mass index Hepatocellular ballooning Liver histology Metformin Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Type 2 diabetes mellitus 

Supplementary material

12325_2013_84_MOESM1_ESM.pdf (169 kb)
Supplementary material 1 (PDF 168 kb)

References

  1. 1.
    Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis. 2010;28:155–61.PubMedCrossRefGoogle Scholar
  2. 2.
    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;140:124–31.PubMedCrossRefGoogle Scholar
  3. 3.
    Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology. 2009;50:1282–93.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51:1820–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Lackner C. Hepatocellular ballooning in nonalcoholic steatohepatitis: the pathologist’s perspective. Expert Rev Gastroenterol Hepatol. 2011;5:223–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Guy CD, Suzuki A, Burchette JL, et al. Costaining for keratin 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Hum Pathol. 2012;43:790–800.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53:719–23.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Gramlich T, Kleiner DE, McCullough AJ, Matteoni CA, Boparai N, Younossi ZM. Pathologic features associated with fibrosis in nonalcoholic fatty liver disease. Hum Pathol. 2004;35:196–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987–1000.PubMedCrossRefGoogle Scholar
  12. 12.
    Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–25.PubMedCrossRefGoogle Scholar
  13. 13.
    Caldwell SH, de Freitas LA, Park SH, et al. Intramitochondrial crystalline inclusions in nonalcoholic steatohepatitis. Hepatology. 2009;49:1888–95.PubMedCrossRefGoogle Scholar
  14. 14.
    Diehl AM, Li ZP, Lin HZ, Yang SQ. Cytokines and the pathogenesis of non-alcoholic steatohepatitis. Gut. 2005;54:303–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148:852–71.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679–89.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Loomba R, Rao F, Zhang L, et al. Genetic covariance between gamma-glutamyl transpeptidase and fatty liver risk factors: role of beta2-adrenergic receptor genetic variation in twins. Gastroenterology. 2010;139:836–45.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Doycheva I, Patel N, Peterson M, Loomba R. Prognostic implication of liver histology in patients with nonalcoholic fatty liver disease in diabetes. J Diabetes Complicat. 2013;27:293–300.PubMedCrossRefGoogle Scholar
  19. 19.
    Loomba R, Abraham M, Unalp A, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56:943–51.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203.PubMedCrossRefGoogle Scholar
  21. 21.
    Adler AI, Shaw EJ, Stokes T, Ruiz F, Guideline Development Group. Newer agents for blood glucose control in type 2 diabetes: summary of NICE guidance. BMJ. 2009;338:b1668.PubMedCrossRefGoogle Scholar
  22. 22.
    Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6:998–1003.PubMedCrossRefGoogle Scholar
  23. 23.
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004;19:537–44.PubMedCrossRefGoogle Scholar
  25. 25.
    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;100:1082–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Duseja A, Das A, Dhiman RK, et al. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol. 2007;6:222–6.PubMedGoogle Scholar
  27. 27.
    Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29:172–82.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (London). 2012;122:253–70.CrossRefGoogle Scholar
  29. 29.
    Barbero-Becerra VJ, Santiago-Hernandez JJ, Villegas-Lopez FA, Mendez-Sanchez N, Uribe M, Chavez-Tapia NC. Mechanisms involved in the protective effects of metformin against nonalcoholic fatty liver disease. Curr Med Chem. 2012;19:2918–23.PubMedCrossRefGoogle Scholar
  30. 30.
    Idilman R, Mizrak D, Corapcioglu D, et al. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;28:200–8.PubMedCrossRefGoogle Scholar
  31. 31.
    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. Ther Adv Gastroenterol. 2009;2:157–63.CrossRefGoogle Scholar
  32. 32.
    Nobili V, Manco M, Ciampalini P, et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther. 2008;30:1168–76.PubMedCrossRefGoogle Scholar
  33. 33.
    Lavine JE, Schwimmer JB, Van Natta ML, 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;305:1659–68.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Omer Z, Centinkalp S, Akyldiz M, et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2010;22:18–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20:23–8.PubMedCrossRefGoogle Scholar
  36. 36.
    de Oliveira CP, Stefano JT, de Siqueira ER, et al. Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis. Hepatol Res. 2008;38:159–65.PubMedGoogle Scholar
  37. 37.
    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;44:853–60.PubMedCrossRefGoogle Scholar
  38. 38.
    Tikkainen 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;53:2169–76.CrossRefGoogle Scholar
  39. 39.
    Pamuk GE, Sonsuz A. N-acetylcysteine in the treatment of non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2003;18:1220–1.PubMedCrossRefGoogle Scholar
  40. 40.
    Samuhasaneeto S, Thong-Ngam D, Kulaputana O, Patumraj S, Klaikeaw N. Effects of N-acetycysteine on oxidative stress in rats with non-alcoholic steatohepatitis. J Med Assoc Thail. 2007;90:788–97.Google Scholar
  41. 41.
    Krakoff J, Clark JM, Crandall JP, et al. Effects of metformin and weight loss on serum alanine aminotransferase activity in the diabetes prevention program. Obesity (Silver Spring). 2010;18:1762–7.CrossRefGoogle Scholar
  42. 42.
    Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–9.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.PubMedCrossRefGoogle Scholar
  44. 44.
    Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.PubMedCrossRefGoogle Scholar
  45. 45.
    Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    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;135:100–10.PubMedCrossRefGoogle Scholar
  48. 48.
    Loomba R, Wesley R, Pucino F, Liang TJ, Kleiner DE, Lavine JE. Placebo in nonalcoholic steatohepatitis: insight into natural history and implications for future clinical trials. Clin Gastroenterol Hepatol. 2008;6:1243–8.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.PubMedCrossRefGoogle Scholar
  50. 50.
    Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis. 2012;32:3–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Patton HM, Yates K, Unalp-Arida A, et al. Association between metabolic syndrome and liver histology among children with nonalcoholic fatty liver disease. Am J Gastroenterol. 2010;105:2093–102.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Neuschwander-Tetri BA, Clark JM, Bass NM, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913–24.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    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;62:606–15.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Healthcare 2013

Authors and Affiliations

  1. 1.Division of Gastroenterology, Department of MedicineUniversity of California, San DiegoLa JollaUSA
  2. 2.Division of Epidemiology, Department of Family and Preventive MedicineUniversity of California, San DiegoLa JollaUSA

Personalised recommendations