Semin Liver Dis 2001; 21(1): 081-088
DOI: 10.1055/s-2001-12931
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Treatment of Nonalcoholic Fatty Liver: Present and Emerging Therapies

Paul Angulo, Keith D. Lindor
  • Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
Further Information

Publication History

Publication Date:
31 December 2001 (online)

ABSTRACT

Treatment of patients with nonalcoholic fatty liver has typically been focused on the management of associated conditions such as obesity, diabetes mellitus, and hyperlipidemia as well as discontinuation of potentially hepatotoxic drugs. Nonalcoholic fatty liver associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate metabolic control for patients with diabetes mellitus or hyperlipidemia is always recommended but not always effective in reversing nonalcoholic fatty liver. Promising results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, and α-tocopherol suggest that these medications may be of potential benefit in the treatment of patients with nonalcoholic fatty liver. These medications, however, need first to be tested in well-controlled trials with clinically relevant end points and extended follow-up. A better understanding of the pathogenesis and natural history of this condition will help to identify the subset of patients with nonalcoholic fatty liver at risk of progressing to advanced liver disease and, hence, the subgroup of patients who should derive the most benefit from medical therapy. In this article, we review (1) the existing medical therapy for patients with nonalcoholic fatty liver, (2) the emerging data from clinical trials evaluating potentially useful medications, and (3) the potential therapeutic implications of recent studies on the pathogenesis of this liver disease.

REFERENCES

  • 1 Ludwig J, Viggiano R T, McGill D B. Nonalcoholic steatohepatitis: Mayo Clinic experience with a hitherto unnamed disease.  Mayo Clin Proc . 1980;  55 342-348
  • 2 Matteoni C A, Younossi Z M, Gramlich T L. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.  Gastroenterology . 1999;  116 1413-1419
  • 3 Powell E E, Cooksley W G, Hanson R. The natural history of nonalcoholic steatohepatitis: a follow up study of forty-two patients for up to 21 years.  Hepatology . 1990;  11 74-80
  • 4 Teli M, Oliver F W, Burt A D. The natural history of nonalcoholic fatty liver: a follow up study.  Hepatology . 1995;  22 1714-1717
  • 5 Brunt E M, Janney C G, DiBisceglie A M. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.  Am J Gastroenterol . 1999;  94 2467-2474
  • 6 Diehl A M, Goodman Z, Ishak K G. Alcohol-like liver disease in nonalcoholic. A clinical and histological comparison with alcohol-induced liver injury.  Gastroenterology . 1989;  95 1056-1060
  • 7 Lee R G. Nonalcoholic steatohepatitis. A study of 49 patients.  Hum Pathol . 1989;  20 594-599
  • 8 Laurin J, Lindor K D, Crippin J S. Ursodeoxycholic acid or clofibrate in the treatment of nonalcohol-induced steatohepatitis: a pilot study.  Hepatology . 1996;  23 1464-1467
  • 9 Angulo P, Keach J C, Batts K P. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.  Hepatology . 1999;  30 1356-1362
  • 10 Eriksson S, Eriksson K F, Bondesson L. Nonalcoholic steatohepatitis in obesity: a reversible condition.  Acta Med Scand . 1986;  220 83-88
  • 11 Rozental P, Biava C, Spencer H. Liver morphology and function tests in obesity and during total starvation.  Am J Dig Dis . 1967;  12 198-208
  • 12 Drenick E J, Simmons F, Murphy J. Effect on hepatic morphology of treatment of obesity by fasting, reducing diets, and small bowel bypass.  N Engl J Med . 1970;  282 829-834
  • 13 Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients.  Gastroenterology . 1990;  99 1408-1413
  • 14 Andersen T, Gluud C, Franzmann M B. Hepatic effects of dietary weight loss in morbidly obese patients.  J Hepatol . 1991;  12 224-229
  • 15 Ueno T, Sugawara H, Sujaku K. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver.  J Hepatol . 1997;  27 103-107
  • 16 Vajro P, Fontanella A, Perna C. Persistent hyperaminotransferasemia resolving after weight reduction in obese children.  J Pediatr . 1994;  125 239-241
  • 17 Franzese A, Vajro P, Argenziano A. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population.  Dig Dis Sci . 1997;  42 1428-1432
  • 18 Rashid M, Roberts E. Nonalcoholic steatohepatitis in children.  Journal of Pediatric Gastroenterology and Nutrition . 2000;  30 48-53
  • 19 Kanders B S, Blackburn G L. Very-low-calorie diets for the treatment of obesity. In: Blackburn GL, Kanders BS (eds) Obesity: Pathophysiology, Psychology and Treatment. New York: Chapman & Hall 1994: 197-215
  • 20 Kolanowski J. A risk-benefit assessment of anti-obesity drugs.  Drug Saf . 1999;  20 119-131
  • 21 Abenhaim L, Moride Y, Brenot F. Appetite-suppressant drugs and the risk of primary pulmonary hypertension.  N Engl J Med . 1996;  335 609-616
  • 22 Lin H Z, Yang S Q, Chuckaree C. Metformin reverses fatty liver disease in obese, leptin-deficient mice.  Nat Med . 2000;  6 998-1003
  • 23 DeWind L T, Payne J H. Intestinal bypass surgery for morbid obesity. Long term results.  JAMA . 1976;  236 2298-2301
  • 24 Campbell J M, Hung T K, Karam J H. Jejunoileal bypass as a treatment of morbid obesity.  Arch Intern Med . 1977;  137 602-610
  • 25 Ackerman N B. Protein supplementation in the management of degenerating liver function after jejunoileal bypass.  Surg Gynecol Obstet . 1979;  149 8-14
  • 26 Drenick E J, Fisler J, Johnson D. Hepatic steatosis after intestinal bypass. Prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition.  Gastroenterology . 1982;  82 535-548
  • 27 Buchman A L, Dubin M, Jenden D. Lecithin increases plasma free choline and decreases hepatic steatosis in long-term total parenteral nutrition in rats.  Gastroenterology . 1992;  102 1363-1370
  • 28 Buchman A L, Dubin M D, Moukarzel A A. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation.  Hepatology . 1995;  22 1390-1403
  • 29 Pappo I, Becovier H, Berry E m. Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in rat.  J Clin Res . 1991;  51 106-112
  • 30 Freud H R, Muggia-Sullan M, LaFrance R. A possible beneficial effect of metronidazole in reducing TPN- associated liver function derangements.  J Surg Res . 1985;  38 356-363
  • 31 Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis.  J Hepatol . 1999;  31 384
  • 32 Guma G, Viola L, Thome M. Ursodeoxycholic acid in the treatment of nonalcoholic steatohepatitis: results of a prospective clinical controlled trial (Abstract).  Hepatology . 1997;  26 387A
  • 33 Ceriani R, Bunati S, Morini L. Effect of ursodeoxycholic acid plus diet in patients with non-alcoholic steatohepatitis (Abstract).  Hepatology . 1998;  28 386A
  • 34 Barak A J, Beckenhauer H C, Junnila M. Dietary betaine promotes generation of hepatitic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration.  Alcohol Clin Exp Res . 1993;  17 552-555
  • 35 Abdelmalek M, Angulo P, Jorgensen R A. Betaine for patients with nonalcoholic steatohepatitis: a promising new agent.  Gastroenterology . 2000;  118 A973
  • 36 Gulbahar O, Karasu Z A, Ersoz G. Treatment of non- alcoholic steatohepatitis with N-acetylcysteine (Abstract).  Gastroenterology . 2000;  118 A1444
  • 37 Hasegawa T, Yoneda M, Nakamura K. Long- and short-term d-alpha-tocopherol supplementation inhibits liver collagen alpha-1(I) gene expression (Abstract).  Hepatology . 1997;  26 250A
  • 38 Lavine J E. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study.  J Pediatrics . 2000;  136 734-738
  • 39 Letterson P, Fromenty B, Terris B. Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice.  J Hepatol . 1996;  24 200-208
  • 40 Jaeschke H, Wang Y, Essani N A. Reactive oxygen species activate the transcription factor NF-kB in the liver by induction of lipid peroxidation (Abstract).  Hepatology . 1996;  24 238A
  • 41 Acosta D, Wenzel D G. Injury produce by free fatty acids to lysosomes and mitochondria in cultures heart muscle and endothelial cells.  Atherosclerosis . 1974;  20 417-426
  • 42 Weltman M D, Farrell G C, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation.  Gastroenterology . 1996;  111 1645-1653
  • 43 Schuppan D, Jia J D, Brinkhaus B. Herbal products for liver diseases. A therapeutic challenge for the new millennium.  Hepatology . 1999;  30 1099-1104
  • 44 Yang S Q, Lin H Z, Lane M D. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis.  Proc Natl Acad Sci U S A . 1997;  94 2557-2562
  • 45 Chavin K, Yang S Q, Lin H Z. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.  J Biol Chem . 1999;  274 5692-5700
  • 46 Cortez-Pinto H, Chatham J, Chacko V P. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis. A pilot study.  JAMA . 1999;  282 1659-1664
  • 47 Weltman M D, Farrel G C, Hall P. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis.  Hepatology . 1998;  27 128-133
  • 48 George D K, Goldwurm S, MacDonald G A. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology . 1998;  114 311-318
  • 49 Boncovsky H L, Jawaid Q, Tortorelli K. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol . 1999;  31 421-429
  • 50 Younossi Z M, Gramlich T, Bacon B R. Hepatic iron and nonalcoholic fatty liver disease.  Hepatology . 1999;  30 847-850
  • 51 Desai T K. Phlebotomy reduces transaminase levels in patients with non-alcoholic steatohepatitis (Abstract).  Gastroenterology . 2000;  118 A975
  • 52 Nitecki J, Jackson F W, Allen M L. Effect of phlebotomy on non-alcoholic steatohepatitis (NASH) (Abstract).  Gastroenterology . 2000;  118 A1474
  • 53 Bonora E, Kiechi S, Willeit J. Prevalence of insulin resistance in metabolic disorders.  Diabetes . 1998;  47 1643-1649
  • 54 Mendler M H, Turlin B, Moirand R. Insulin resistance- associated hepatic iron overload.  Gastroenterology . 1999;  117 1155-1163
  • 55 Battle E H, Hespenheiden E E, Caldwell S H. Pilot study of troglitazone (Rezulin) for nonalcoholic steatohepatitis (Abstract).  Hepatology . 1998;  28 304A
  • 56 Watkins P B, Whitcomb R W. Hepatic dysfunction associated with troglitazone.  N Engl J Med . 1998;  338 908-909
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