, Volume 63, Issue 22, pp 2379–2394 | Cite as

Advances in the Understanding and Treatment of Nonalcoholic Fatty Liver Disease

Leading Article


Nonalcoholic fatty liver disease (NAFLD) is a well recognised form of chronic liver disease that has recently gained greater recognition. Originally described in the late 1950s, NAFLD is currently considered the leading cause of abnormal liver enzyme levels in the US, closely paralleling the increase in obesity and diabetes mellitus. NAFLD has a worldwide distribution, affecting both adults and children, and typically is seen in association with obesity, diabetes, hypertension and hypertriglyceridaemia. Most patients are asymptomatic and usually present with mild elevations in aminotransferases.

The natural history of NAFLD is not clearly defined but progression to cirrhosis and end-stage liver disease is well recognised in some patients. The accumulation of hepatic steatosis is thought to occur initially, primarily through hepatic and peripheral insulin resistance, which leads to altered glucose and free fatty acid metabolism. The progression from simple fatty liver to more severe forms of NAFLD (nonalcoholic steatohepatitis and cirrhosis) is much less clear but evidence suggests that oxidative stress may preferentially enhance proinflammatory cytokines, which leads to cellular adaptations and dysfunction followed by development of inflammation, necrosis and fibrosis.

Therapeutic modalities remain limited and are largely focused on correcting the underlying insulin resistance or reducing oxidative stress. However, at the present time, there are several limitations to the current potential therapies, mainly because of the lack of large-scale, prospective, randomised studies, as well as clearly defined histological endpoints. Ultimately, the future for potential therapeutic modalities to treat this disease are quite promising, but further research is needed to clearly demonstrate which therapy or therapies will be effective at eliminating fatty liver disease and its potential complications.


  1. 1.
    Westwater JO, Fainer D. Liver impairment in the obese. Gastroenterology 1958; 34: 686–93PubMedGoogle Scholar
  2. 2.
    Peters RL, Gay T, Reynolds TB. Post-jejunoileal bypass hepatic disease: its similarity to alcoholic hepatic disease. Am J Clin Pathol 1975; 63(3): 318–31PubMedGoogle Scholar
  3. 3.
    Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med 1979; 67: 811–6PubMedCrossRefGoogle Scholar
  4. 4.
    Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experience with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434–8PubMedGoogle Scholar
  5. 5.
    Teli MR, James OFW, Burt AD, et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714–9PubMedCrossRefGoogle Scholar
  6. 6.
    Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 1413–9PubMedCrossRefGoogle Scholar
  7. 7.
    Lee RG. Nonalcoholic steatohepatitis: a study of 39 patients. Hum Pathol 1989; 20: 594–8PubMedCrossRefGoogle Scholar
  8. 8.
    Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11: 74–80PubMedCrossRefGoogle Scholar
  9. 9.
    Bacon BR, Farahvash MJ, Janney CG, et al. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107: 1103–9PubMedGoogle Scholar
  10. 10.
    Harrison SA, Torgerson S, Hayashi P. Natural history of NASH: a clinical histopathologic study. Am J Gastroenterol 2003; 98: 2042–7PubMedCrossRefGoogle Scholar
  11. 11.
    Willner IR, Waters B, Raj Patil S, et al. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001; 96: 2957–61PubMedCrossRefGoogle Scholar
  12. 12.
    Contos MJ, Cales W, Sterling RK, et al. Development of nonalcoholic fatty liver disease after orthotopic liver transplant for cryptogenic cirrhosis. Liver Transplant 2001; 7: 363–73CrossRefGoogle Scholar
  13. 13.
    Ong J, Younossi ZM, Reddy V, et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl 2001; 7: 797–801PubMedCrossRefGoogle Scholar
  14. 14.
    Shimada M, Hashimoto E, Taniai M, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2002; 37: 154–60PubMedCrossRefGoogle Scholar
  15. 15.
    Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134–40PubMedCrossRefGoogle Scholar
  16. 16.
    Ong JP, Younossi ZM. Is hepatocellular carcinoma part of the natural history of nonalcoholic steatohepatitis? Gastroenterology 2002; 123: 375–8PubMedCrossRefGoogle Scholar
  17. 17.
    Kopelman PG. Obesity as a medical problem. Nature 2000; 404: 635–43PubMedGoogle Scholar
  18. 18.
    Boyle JP, Honeycutt AA, Narayan KM, et al. Projection of diabetes burden through 2050: impact of changing demography and disease prevalence in the US. Diabetes Care 2001; 24: 1936–40PubMedCrossRefGoogle Scholar
  19. 19.
    Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002; 288: 1723–7PubMedCrossRefGoogle Scholar
  20. 20.
    National Center for Health Statistics. Plan and operation of the Third National Health and Nutrition Examination Survey 1988–1994. Vol. I. Vital Health Statistics. Hyattsville (MD): National Center for Health Statistics, 1994Google Scholar
  21. 21.
    Harrison SA, Diehl AM. Fat and the liver: a molecular overview. Semin Gastrointest Dis 2002; 13(1): 3–16PubMedGoogle Scholar
  22. 22.
    Nomura H, Kashiwagi S, Hayashi J, et al. Prevalence of fatty liver in the general population of Okinowa, Japan. Jpn J Med 1988; 27: 142–9PubMedCrossRefGoogle Scholar
  23. 23.
    Bellentani S, Tiribelli C, Saccoccio G, et al. Prevalence of chronic liver disease in the general population of northern Italy: the Dyonisos study. Hepatology 1994; 20: 1442–9PubMedCrossRefGoogle Scholar
  24. 24.
    Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002; 122: 1649–57PubMedCrossRefGoogle Scholar
  25. 25.
    Younossi ZM, Diehl AM, Ong JP. Nonalcoholic fatty liver disease: an agenda for clinical research. Hepatology 2002; 35: 746–52PubMedCrossRefGoogle Scholar
  26. 26.
    Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990; 12: 1106–10PubMedCrossRefGoogle Scholar
  27. 27.
    Garcia-Monson C, Martin-Perez E, Iacono OL, et al. Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity. J Hepatol 2000; 33: 716–24CrossRefGoogle Scholar
  28. 28.
    Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001; 121: 91–100PubMedCrossRefGoogle Scholar
  29. 29.
    Franzese A, Vajro P, Argenziano A, et al. 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: 1428–32PubMedCrossRefGoogle Scholar
  30. 30.
    Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity: an epidemiological ultrasonographic survey. Dig Dis Sci 1995; 40: 2002–9PubMedCrossRefGoogle Scholar
  31. 31.
    Manton ND, Lipsett J, Moore DJ, et al. Non-alcoholic steatohepatitis in children and adolescents. Med J Aust 2000; 173: 476–9PubMedGoogle Scholar
  32. 32.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221–30PubMedCrossRefGoogle Scholar
  33. 33.
    Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997; 126: 137–45PubMedGoogle Scholar
  34. 34.
    Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: 1117–23PubMedCrossRefGoogle Scholar
  35. 35.
    Harrison SA, Hayashi P. Clinical factors associated with fibrosis in 102 patients with nonalcoholic steatohepatitis [abstract]. Hepatology 2002; 36: 412AGoogle Scholar
  36. 36.
    Chitturi S, Weltman M, Farrell GC, et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 2002; 36: 142–9PubMedCrossRefGoogle Scholar
  37. 37.
    Santos L, Molina EG, Jeffers L, et al. Prevalence of nonalcoholic steatohepatitis among ethnic groups [abstract]. Gastroenterology 2001; 120: A117Google Scholar
  38. 38.
    Caldwell SH, Harris DM, Patrie JT, et al. Is NASH underdiagnosed among African-Americans. Am J Gastroenterol 2002; 97: 1496–500PubMedCrossRefGoogle Scholar
  39. 39.
    Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30: 1356–62PubMedCrossRefGoogle Scholar
  40. 40.
    Youssef W, McCullough AJ. Diabetes mellitus, obesity, and hepatic steatosis. Semin Gastrointest Dis 2002; 13: 17–30PubMedGoogle Scholar
  41. 41.
    Reaven G. Syndrome X: 10 years after [discussion appears in Drugs 1999; 58 Suppl. 1: 75–82]. Drugs 1999; 58 Suppl. 1: 19–20PubMedCrossRefGoogle Scholar
  42. 42.
    DeFronso RA, Ferranini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–94CrossRefGoogle Scholar
  43. 43.
    Marchesini G, Brizi M, Marsell-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107: 450–5PubMedCrossRefGoogle Scholar
  44. 44.
    Sanyal AJ, Campbell-Sargent C, Mirshani F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120: 1183–92PubMedCrossRefGoogle Scholar
  45. 45.
    Pagano G, Pacini G, Musso G, et al. Non-alcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002; 35: 367–72PubMedCrossRefGoogle Scholar
  46. 46.
    Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with insulin resistance syndrome. Hepatology 2002; 35: 373–9PubMedCrossRefGoogle Scholar
  47. 47.
    Marceau P, Biron S, Hould FS, et al. Liver pathology and metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513–7PubMedCrossRefGoogle Scholar
  48. 48.
    George DK, Goldwurm S, MacDonald GA, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114: 311–8PubMedCrossRefGoogle Scholar
  49. 49.
    Bonkovsky HL, Jawaid Q, Tortorelli K, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol 1999; 31: 421–9PubMedCrossRefGoogle Scholar
  50. 50.
    Younossi ZM, Gramlich T, Bacon BR, et al. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 1999; 30: 847–50PubMedCrossRefGoogle Scholar
  51. 51.
    Mendler M-H, Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117: 1155–63PubMedCrossRefGoogle Scholar
  52. 52.
    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: 931–9PubMedCrossRefGoogle Scholar
  53. 53.
    Graif M, Yanuka M, Baraz M, et al. Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease. Invest Radiol 2000; 35: 319–24PubMedCrossRefGoogle Scholar
  54. 54.
    Saadeh S, Zobair M, Younossi ZM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745–50PubMedCrossRefGoogle Scholar
  55. 55.
    Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histologic lesions. Am J Gastroenterol 1999; 94: 2468–73CrossRefGoogle Scholar
  56. 56.
    Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in NASH. J Hepatology 1999; 31: 430–4CrossRefGoogle Scholar
  57. 57.
    Day C, James O. Steatohepatitis: a tale of two “hits”? [editorial]. Gastroenterology 1998; 114: 842–5PubMedCrossRefGoogle Scholar
  58. 58.
    Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109: 1345–50PubMedGoogle Scholar
  59. 59.
    Seppala-Lindroos A, Vehkavaara S, Hakkinen A-M, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002; 87: 3023–8PubMedCrossRefGoogle Scholar
  60. 60.
    Garg A, Misra A. Hepatic steatosis, insulin resistance, and adipose tissue disorders. Clin Endocrinol Metab 2002; 87: 3019–22CrossRefGoogle Scholar
  61. 61.
    Kaplan LM. Leptin, obesity, and liver disease. Gastroenterology 1998; 115: 997–1001PubMedCrossRefGoogle Scholar
  62. 62.
    Rutter GA. Diabetes: the importance of the liver. Curr Biol 2000; 10: R736–8PubMedCrossRefGoogle Scholar
  63. 63.
    Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799–806PubMedCrossRefGoogle Scholar
  64. 64.
    Hug C, Lodish HF. Diabetes, obesity and acrp30/adiponectin. Biotechniques 2002; 33: 654–62PubMedGoogle Scholar
  65. 65.
    Zierath JR, Krook A, Wallberg-Henriksson H. Insulin action and insulin resistance in skeletal muscle. Diabetologia 2000; 43: 677–83CrossRefGoogle Scholar
  66. 66.
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109: 1125–31PubMedGoogle Scholar
  67. 67.
    Cummings MH, Watts GF, Umpleby AM, et al. Acute hyperinsulinemia decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM. Diabetes 1995; 44: 1059–65PubMedCrossRefGoogle Scholar
  68. 68.
    Charlton M, Sreekumar R, Rasmussen D, et al. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 2002; 35: 898–904PubMedCrossRefGoogle Scholar
  69. 69.
    Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001; 98: 7522–7PubMedCrossRefGoogle Scholar
  70. 70.
    Sun Z, Arendt CW, Ellmeier W, et al. PKC-theta is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 2000; 404: 402–7PubMedCrossRefGoogle Scholar
  71. 71.
    Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity-and diet-induced insulin resistance with salicylates or targeted disruption of IKKβ. Science 2001; 293: 1673–7PubMedCrossRefGoogle Scholar
  72. 72.
    Mensenkamp AR, van Luyn MJA, van Goor H, et al. Hepatic lipid accumulation, altered very low density lipoprotein formation and apolipoprotein E deposition in apolipoprotein E3-Leiden transgenic mice. J Hepatol 2000; 33: 189–98PubMedCrossRefGoogle Scholar
  73. 73.
    Bernard S, Touzet S, Personne I, et al. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes. Diabetologia 2000; 43: 995–9PubMedCrossRefGoogle Scholar
  74. 74.
    Bjorkegren J, Beigneux A, Bergo MO, et al. Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury. J Biol Chem 2002; 277: 5476–83PubMedCrossRefGoogle Scholar
  75. 75.
    Ceddia RB, Koistinen HA, Zierath JR, et al. Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 2002; 16: 1163–76PubMedCrossRefGoogle Scholar
  76. 76.
    Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive leptin concentrations in normal weight and obese humans. N Engl J Med 1996; 334: 292–5PubMedCrossRefGoogle Scholar
  77. 77.
    Uygun A, Kadayifci A, Yesilova Z, et al. Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2000; 95: 3584–9PubMedCrossRefGoogle Scholar
  78. 78.
    Reitman ML, Arioglu E, Gavrilova O, et al. Lipoatrophy revisited. Trends Endocrinol Metab 2000; 11: 410–6PubMedCrossRefGoogle Scholar
  79. 79.
    Barzilai N, Wang J, Massilon D, et al. Leptin selectively decreases visceral adiposity and enhances insulin action. J Clin Invest 1997; 100: 3105–10PubMedCrossRefGoogle Scholar
  80. 80.
    Sahu A. Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurons. J Neuroendocrinol 2002; 14: 796–804PubMedCrossRefGoogle Scholar
  81. 81.
    Hotamisligil GS, Peraldi P, Budavari A, et al. IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996; 271: 665–8PubMedCrossRefGoogle Scholar
  82. 82.
    Zanger R, Novak R. Effects of fatty acids and ketone bodies on cytochromes p4502B, 4A, 2E1 expression in primary cultured rat hepatocytes. Arch Biochem Biophys 1997; 337: 217–24CrossRefGoogle Scholar
  83. 83.
    Leclercq IA, Farrell GC, Field J, et al. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 2000; 105: 1067–75PubMedCrossRefGoogle Scholar
  84. 84.
    Weltman MD, Farrell GC, Hall P. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 1998; 27: 128–33PubMedCrossRefGoogle Scholar
  85. 85.
    Pessayre D, Berson A, Fromenty B, et al. Mitochondria in steatohepatitis. Semin Liver Dis 2001; 21: 57–69PubMedCrossRefGoogle Scholar
  86. 86.
    Rao MS, Reddy JK. Peroxisomal beta-oxidation and steatohepatitis. Semin Liver Dis 2001; 21: 43–55PubMedCrossRefGoogle Scholar
  87. 87.
    Baeuerle PA, Henkel T. Function and activation of NF-kB in the immune system. Annu Rev Immunol 1994; 12: 141–79PubMedCrossRefGoogle Scholar
  88. 88.
    Crespo J, Cayon A, Fernadez-Gil P, et al. Gene expression of TNF-α and TNF receptors, p55 and p 75. J Hepatol 2001; 34: 1158–63CrossRefGoogle Scholar
  89. 89.
    Loffreda S, Yang SQ, Lin HZ, et al. Leptin regulates proinflammatory immune responses. FASEB J 1998; 12: 57–65PubMedGoogle Scholar
  90. 90.
    Yang SQ, Lin HZ, Lane MD, et al. Obesity increases sensitivity to endotoxin liver injury: implications for pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997; 94: 2557–62PubMedCrossRefGoogle Scholar
  91. 91.
    Yang S, Zhu H, Li Y, et al. Mitochondrial adaptations to obesity-related oxidative stress. Arch Biochem Biophys 2000; 378: 259–68PubMedCrossRefGoogle Scholar
  92. 92.
    Acosta D, Wenzel DG. Injury produced by free fatty acids to lysosomes and mitochondria in cultured heart muscle and endothelial cells. Atherosclerosis 1974; 20: 417–26PubMedCrossRefGoogle Scholar
  93. 93.
    Chavin KD, Yang SQ, Lin HZ, et al. Obesity induces expression of UCP-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 1999; 274: 5692–700PubMedCrossRefGoogle Scholar
  94. 94.
    Baffy G, Zhang C-Y, Glickman JN, et al. Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. Hepatology 2002; 35: 753–61PubMedCrossRefGoogle Scholar
  95. 95.
    Cortez-Pinto H, Chatham J, Chacko V, et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282: 1659–64PubMedCrossRefGoogle Scholar
  96. 96.
    Diehl AM. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines. Am J Physiol Gastrointest Liver Physiol 2002; 282: G1–5PubMedGoogle Scholar
  97. 97.
    Li Z, Lin H, Yang S, et al. Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. Gastroenterology 2002; 123: 1304–10PubMedCrossRefGoogle Scholar
  98. 98.
    Matsui K, Yoshimoto T, Tsutsui H, et al. Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells. J Immunol 1997; 159: 97–106PubMedGoogle Scholar
  99. 99.
    Friedman SL. The cellular basis of hepatic fibrosis: mechanisms and treatment strategies. N Engl J Med 1993; 328: 1828–33PubMedCrossRefGoogle Scholar
  100. 100.
    Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol 2001; 35: 297–306PubMedCrossRefGoogle Scholar
  101. 101.
    Nieto N, Friedman SL, Greenwel P, et al. CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells. Hepatology 1999; 30: 987–96PubMedCrossRefGoogle Scholar
  102. 102.
    Svegliati-Baroni G, Saccomanno S, van Goor H, et al. Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells. Liver 2001; 21: 1–12PubMedCrossRefGoogle Scholar
  103. 103.
    Friedman SL. Cytokines and fibrogenesis. Semin Liver Dis 1999; 19: 129–40PubMedCrossRefGoogle Scholar
  104. 104.
    Leclercq IA, Farrell GC, Schriemer R, et al. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol 2002; 37: 206–13PubMedCrossRefGoogle Scholar
  105. 105.
    Saxena NK, Ikeda K, Rockey DC, et al. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 2002; 35: 762–71PubMedCrossRefGoogle Scholar
  106. 106.
    Ikejima K, Yoshiyuki T, Honda H, et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 2002; 122: 1399–410PubMedCrossRefGoogle Scholar
  107. 107.
    Ueno T, Sagawara H, Sujaka K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997; 27: 103–7PubMedCrossRefGoogle Scholar
  108. 108.
    Drenick EJ, 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: 829–34PubMedCrossRefGoogle Scholar
  109. 109.
    Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990; 99: 1408–13PubMedGoogle Scholar
  110. 110.
    Harrison SA, Ramrakhiani S, Brunt EM, et al. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol 2003; 98: 926–30PubMedCrossRefGoogle Scholar
  111. 111.
    Harrison SA, Fincke C, Helinski D, et al. Orlistat treatment in obese, non-alcoholic patients: a pilot study [abstract]. Hepatology 2002; 36: 406AGoogle Scholar
  112. 112.
    Caldwell SH, Hespenheide EE, Redick JA, et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96: 519–25PubMedCrossRefGoogle Scholar
  113. 113.
    Neuschwander-Tetri BA, Brunt EM, Bacon BR. Histological improvement in NASH following reduction in insulin resistance with 48-week treatment with PPAR agonist rosiglitazone [abstract]. Hepatology 2002; 36: 379AGoogle Scholar
  114. 114.
    Nair S, Diehl AM, Perrillo R. Metformin in non alcoholic steatohepatitis (NASH): efficacy and safety: a preliminary report [abstract]. Gastroenterology 2002; 1222: A621Google Scholar
  115. 115.
    Marchesini G, Brizi M, Blanchi G, et al. Metformin in nonalcoholic steatohepatitis. Lancet 2001; 358: 893–4PubMedCrossRefGoogle Scholar
  116. 116.
    Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C in the treatment of nonalcoholic steatohepatitis [abstract]. Gastroenterology 2002; 122: A669Google Scholar
  117. 117.
    Hasegawa T, Yoneda M, Nakamura K, et al. Plasma transforming growth factor-1 level and efficacy of α-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001; 15: 1667–72PubMedCrossRefGoogle Scholar
  118. 118.
    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: 2711–7PubMedCrossRefGoogle Scholar
  119. 119.
    Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis [letter]. J Hepatol 1999; 31: 384PubMedCrossRefGoogle Scholar
  120. 120.
    Laurin J, Lindor KD, Crippen JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of nonalcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 1464–7PubMedCrossRefGoogle Scholar
  121. 121.
    Horlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH [abstract]. Gastroenterology 2001; 120: A544Google Scholar
  122. 122.
    Ceriani R, Bunati S, Morini L, et al. Effect of ursodeoxycholic acid plus diet in patients with non-alcoholic steatohepatitis [abstract]. Hepatology 1998; 28: 386AGoogle Scholar
  123. 123.
    Guma G, Viola L, Thome M, et al. Ursodeoxycholic acid in the treatment of nonalcoholic steatohepatitis: results of a prospective clinical controlled trial [abstract]. Hepatology 1997; 26: 387ACrossRefGoogle Scholar
  124. 124.
    Desai TK. Phlebotomy reduces transaminase levels in patients with non-alcoholic steatohepatitis [abstract]. Gastroenterology 2000; 118: A1071Google Scholar
  125. 125.
    Nitecki J, Jackson FW, Allen ML, et al. Effect of phlebotomy on non-alcoholic steatohepatitis (NASH) [abstract]. Gastroenterology 2000; 118: A6679CrossRefGoogle Scholar
  126. 126.
    Lin HZ, Yang S, Chuckaree C, et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000; 6: 998–1003PubMedCrossRefGoogle Scholar
  127. 127.
    Rozental P, Biava C, Spencer H, et al. Liver morphology and function tests in obesity and during total starvation. Am J Dig Dis 1967; 12: 198–208PubMedCrossRefGoogle Scholar
  128. 128.
    Anderson T, Gluud C, Franzmann MB, et al. Hepatic effects of dietary weight loss in morbidly obese patients. J Hepatol 1991; 12: 224–9CrossRefGoogle Scholar
  129. 129.
    Despres J-P, Lemieux I, Prud'homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 2001; 322: 716–20PubMedCrossRefGoogle Scholar
  130. 130.
    Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy 2000; 20: 270–9PubMedCrossRefGoogle Scholar
  131. 131.
    Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-acitivated receptor gamma (PPAR gamma). J Biol Chem 1995; 270: 12953–6PubMedCrossRefGoogle Scholar
  132. 132.
    Mayerson AB, Hundal RS, Dufour S, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002; 51: 797–802PubMedCrossRefGoogle Scholar
  133. 133.
    Fryer LGD, Parbu-Patel A, Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 2002; 277: 25226–32PubMedCrossRefGoogle Scholar
  134. 134.
    Kim Y-B, Ciaraldi TP, Kong A, et al. Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110 protein levels in skeletal muscle of type 2 diabetic subjects. Diabetes 2002; 51: 443–8PubMedCrossRefGoogle Scholar
  135. 135.
    Galli A, Crabb DW, Cerri E, et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 2002; 122: 1924–40PubMedCrossRefGoogle Scholar
  136. 136.
    Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002; 51: 2074–81PubMedCrossRefGoogle Scholar
  137. 137.
    Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167–74PubMedGoogle Scholar
  138. 138.
    Lu SC. S-adenosylmethionine. Int J Biochem Cell Biol 2000; 32: 391–5PubMedCrossRefGoogle Scholar
  139. 139.
    Mato JM, Camara J, Ortiz P, et al. Spanish collaborative group for the study of alcoholic liver cirrhosis. S-adenosylmethionine in the treatment of alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind mutlicentre clinical trial. J Hepatol 1999; 30: 1081–9Google Scholar
  140. 140.
    Angulo P, Lindor KD. Treatment of nonalcoholic fatty liver: present and emerging therapies. Semin Liver Dis 2001; 21: 81–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Stephen A. Harrison
    • 1
  • Adrian M. Di Bisceglie
    • 1
  1. 1.Division of Gastroenterology and HepatologySaint Louis University School of MedicineSt LouisUSA

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