Opinion statement
Nonalcoholic fatty liver disease (NAFLD) is very common in the United States, and in some patients it may lead to cirrhosis, liver failure, and liver cancer. NAFLD encompasses a spectrum of liver injury, ranging from steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, histologically comprises steatosis, balloon degeneration, inflammation, and fibrosis in varying degrees. It is generally believed that simple steatosis is benign with minimal risk of progression, whereas NASH is progressive and can lead to cirrhosis. The commonly associated risk factors for NAFLD include obesity, hyperlipidemia, and diabetes mellitus. The pathogenesis of NAFLD and NASH is not fully known; however, current evidence suggests that insulin resistance and lipid peroxidation play a role in the pathogenesis of this condition. Currently, there are no proven effective therapies available for the treatment of NASH. Although there are numerous studies that have explored various treatments for NASH, these generally consist of small numbers of patients with suboptimal endpoints. Treatment strategies for NAFLD and NASH can be broadly divided into 1) treatment or control of underlying risk factors such as hyperlipidemia, diabetes mellitus, and obesity; and 2) specific pharmacologic therapy such as insulin sensitizers, antioxidants, or cytoprotective agents. Newer thiazolidinediones, such as rosiglitazone and pioglitazone, have shown promise in the treatment of NASH in pilot studies. However, these agents should not be used in clinical practice until their efficacy and safety are firmly established in larger studies. Despite encouraging initial studies, the recently completed multicenter, randomized, controlled trial failed to show any efficacy for ursodeoxycholic acid in the treatment of NASH. Other agents, such as vitamin E, betaine, probucol, and atorvastatin, have been explored as therapeutic agents for NASH. However, none of these studies have shown convincingly their utility in the treatment of NASH. Attempts to identify optimal therapy for patients with NASH are being vigorously pursued by the research community and important advances are expected within next several years. Until then, subjects should be advised to avoid alcohol, lose weight, and exercise regularly, and meticulous attention should be paid to the control of their risk factors such as diabetes and hyperlipidemia.
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References and Recommended Reading
Neuschwander-Tetri BA, Caldwell SH: Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003, 37:1202–1219. A comprehensive and well-summarized review of NASH based on the proceedings from a recent single-topic symposium sponsored by American Association for the Study of Liver Disease.
Clark JM, Brancati FL, Diehl AM: Nonalcoholic fatty liver disease. Gastroenterology 2002, 122:1649–1657.
Ballentani S, Saccoccio G, Masutti F, et al.: Prevalence of and risk factors for hepatic steatosis in northern Italy. Ann Intern Med 2000, 132:112–117.
Araujo LM, DeOliveira A, Nunes DS: Liver and biliary sonography in diabetic and non-diabetic obese woman. Diabetes Metab 1998, 24:458–462.
Hilden M, Christoffersen P, Juhle E, et al.: Liver histology in a ‘normal’ population-examination of 503 consecutive fatal traffic casualities. Scand J Gastroenterol 1977, 12:593–597.
McCullough AJ: Update on nonalcoholic fatty liver disease. J Clin Gastroenterol 2002, 34:255–262.
Itoh S, Yougel T, Kawagoe K: Comparison between nonalcoholic steatohepatitis and alcoholic steatohepatitis. Am J Gastroenterol 1987, 82:650–654.
Wanless IR, Lentz JS: Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy with analysis of risk factors. Hepatology 1990, 12:1106–1110.
Silverman JF, O’Brien KF, Long S, et al.: Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol 1990, 85:1349–1355.
Angulo P: Nonalcoholic fatty liver disease. N Engl J Med 2002, 346:1221–1231.
American Gastroenterological Association Medical Position Statement: Nonalcoholic fatty liver disease. Gastroenterology 2002, 123:1702–1704. Comprehensive and well-written summary and evidencebased position statement by the American Gastroenterological Association.
Clark JM, Diehl AM: Nonalcoholic fatty liver disease. An unrecognized cause of cryptogenic cirrhosis. JAMA 2003, 289:300–304.
Sanyal AJ, Campbell-Sargent C, Mirshani F, et al.: Nonalcoholic steatohepatitis association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001, 120:1183–1192.
Willner IR, Waters B, Patil SR, et al.: Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001, 96:2957–2961.
Marchesini G, Brizi M, Marsell-Labate AM, et al.: Association of nonalcoholic liver disease with insulin resistance. Am J Med 1999, 107:450–455.
Chalasani N, Deeg MA, Persohn S, et al.: Metabolic and anthropometric evaluation of insulin resistance in non-diabetic patients with non-alcoholic steatohepatitis. Am J Gastroentertol 2003, in press.
Esterbauer H, Schaur RJ, Zollner H: Chemistry and biochemistry of 4-hydroxynonenal, maloaldehyde and related aldehydes. Free Radic Biol Med 1991, 11:81–128.
Niemela O, Parkkila S, Juvonen RO, et al.: Cytochrome P450 2A6, 2E1, and 3A4 and production of protein aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver disease. J Hepatol 2000, 33:893–901.
Chalasani N, Gorski JC, Asghar MS, et al.: Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology 2003, 37:544–550.
Drenick EJ, Fisler J, Johnson D: Hepatic steatosis after intestinal bypass-prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology 1982, 82:535–548.
Koteish A, Diehl AM: Animal models of steatosis. Semin Liver Dis 2001, 21:89–104.
Tilg H, Diehl AM: Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000, 343:1467–1476.
Wigg AJ, Robert-Thompson IC, Dymock RB, et al.: The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumor necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001, 48:206–211.
Sanyal AJ: AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002, 123:1705–1725.
Luyckx FH, Desaive C, Thiry A, et al.: Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord 1998, 22:222–226.
Ranlov I, Hardt F: Regression of liver steatosis following gastroplasty or gastric bypass for morbid obesity. Digestion 1990, 47:208–214.
Eriksson S, Eriksson KF, Bondesson L: Nonalcoholic steatohepatitis in obesity: a reversible condition. Acta Med Scand 1986, 220:83–88.
Luyckx FH, Lefebvre PJ, Scheen AJ: Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Diabetes Metab 2000, 26:98–106.
Palmer M, Schaffner F: Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990, 99:1408–1413.
Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med 1998, 158:1855–1867.
Barlow SE, Dietz WH: Obesity evaluation and treatment: expert committee recommendations. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics 1998, 102:E29.
Anderson T, Gluud C, Franzmann MB, et al.: Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol 1991, 12:224–229.
Okita M, Hayashi M, Sasagawa T, et al.: Effect of a moderate energy-restricted diet on obese patients with fatty liver. Nutrition 2001, 17:542–547.
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.
Assy N, Svalb S, Hussein O: Orlistat (Xenical) reverses fatty liver disease and improved hepatic fibrosis in obese patients with NASH. Hepatology 2001, 34(suppl):458A.
Harrison SA, Fincke C, Helinski D, et al.: Orlistat treatment in obese, non-alcoholic steatohepatitis patients: a pilot study. Hepatology 2002, 36:406A.
Harrison SA, Ramrakhiani S, Brunt EM, et al.: Orlistat in the treatment of NASH: a case series. Am J Gastroenterol 2003, 98:926–930.
Laurin J, Lindor KD, Crippin JS, et al.: Ursodeoxycholic acid or clofibrate in the treatment of non-alcoholicinduced steatohepatitis: a pilot study. Hepatology 1996, 23:1464–1467.
Basaranoglu M, Acbay O, Sonsuz A: A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999, 31:384.
Horlander JC, Kwo PY, Cummings OW: Atorvastatin for the treatment of NASH. Gastroenterology 2001, 120:A544.
Marchesini G, Brizi M, Bianchi G, et al.: Metformin in non-alcoholic steatohepatitis. Lancet 2001, 358:893–894.
Nair S, Diehl AM, Perillo R: Metformin in nonalcoholic steatohepatitis: efficacy and safety: a preliminary report. Gastroenterology 2002, 122:A621.
Neuschwander-Tetri BA, Brunt EM, Wehmeier, et al.: Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with nonalcoholic steatohepatitis. J Hepatol 2003, 38:434–440. Interim data on rosiglitazone in NASH patients. The study is now completed and final results are awaited.
Caldwell SH, Hespenheide EE, Redick JA, et al.: A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 2001, 96:519–525.
Azuma T, Tomita K, Kato S, et al.: A pilot study of thiazolidinedione, pioglitazone, in nonalcoholic steatohepatitis. Hepatology 2002, 36:406A.
Acosta RC, Molina EG, O’Brien CB, et al.: The use of pioglitazone in nonalcoholic steatohepatitis. Gastroenterology 2001, 120:A546.
Sanyal AJ, Contos AJ, Sargeant C, et al.: A randomized controlled pilot study of pioglitazone and vitamin E versus vitamin E for nonalcoholic steatohepatitis. Hepatology 2002, 36:A382.
Promrat K, Luchman G, Kleiner DE, et al.: Pilot study of pioglitazone in nonalcoholic steatohepatitis. Gastroenterology 2003, 124:A708.
Lavine JE: Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000, 136:734–738. This is the only study to date looking at a cytoprotective agent, vitamin E, in pediatric patients with NASH.
Hasegawa T, Yoneda M, Nakamura K, et al.: Plasma transforming growth factor-beta 1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001, 15:1667–1672.
Kugelmas M, Hill DB, Vivian B, et al.: Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 2003, 38:413–419.
Kowdley KV: Ursodeoxycholic acid therapy in hepatobiliary disease. Am J Med 2000, 108:481–486.
Guma G, Viola L, Thome M, et al.: Ursodeoxycholic acid in the treatment on nonalcoholic steatohepatitis: results of a prospective clinical trial. Hepatology 1997, 26:A387.
Ceriani R, Brunati S, Morini L, et al.: Effect of ursodeoxycholic acid plus diet in patients with nonalcoholic steatohepatitis. Hepatology 1998, 28:A386.
Lindor KD (UDCA/NASH study group): Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized, placebo-controlled trial. Gastroenterology 2003, 124:A708.
Merat S, Malekzadeh R, Sohrabi MR, et al.: Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J Hepatol 2003, 38:414–418.
Barak AJ, Beckenhauer HC, Junnila M, et al.: Dietary betaine promotes generation of hepatitis S-adenosylmethionine and protects the liver from ethanolinduced fatty infiltration. Alcohol Clin Exp Res 1993, 17:552–555.
Abdelmalek MF, Angulo P, Jorgensen RA, et al.: Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001, 96:2711–2717.
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Liangpunsakul, S., Chalasani, N. Treatment of nonalcoholic fatty liver disease. Curr Treat Options Gastro 6, 455–463 (2003). https://doi.org/10.1007/s11938-003-0047-0
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DOI: https://doi.org/10.1007/s11938-003-0047-0