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Nonalcoholic Fatty Liver Disease as a Complication of Insulin Resistance

      Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and rarely, progression to cirrhosis. The pathogenesis of NAFLD is thought to be related to insulin resistance and oxidant stress. Truncal obesity, dyslipidema, hypertension, and hyperglycemia are strongly associated with NAFLD; therefore, management of NAFLD entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defenses in the liver. This article briefly summarizes advances in our understanding of the relationship between NAFLD and the insulin resistance (metabolic) syndrome, its prevalence, natural history, and treatment.
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      References

        • Angulo P.
        Nonalcoholic fatty liver disease.
        N Engl J Med. 2002; 346: 1221-1231
        • Sanyal A.J.
        AGA technical review on nonalcoholic fatty liver disease.
        Gastroenterology. 2002; 123: 1705-1725
        • Neuschwander-Tetri B.A.
        • Caldwell S.H.
        Nonalcoholic steatohepatitis: summary of an AASLD single topic conference.
        Hepatology. 2003; 37: 1202-1219
        • Teli M.R.
        • James O.F.
        • Burt A.D.
        • et al.
        The natural history of nonalcoholic fatty liver: a follow-up study.
        Hepatology. 1995; 22: 1714-1719
        • Brunt E.M.
        Pathology of nonalcoholic steatohepatitis.
        Hepatol Res. 2005; 33: 68-71
        • Marchesini G.
        • Forlani G.
        NASH: from liver disease to metabolic disorders and back to clinical hepatology.
        Hepatology. 2002; 35: 497-499
        • Browning J.D.
        • Szczepaniak L.S.
        • Dobbins R.
        • et al.
        Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
        Hepatology. 2004; 40: 1387-1395
        • Clark J.M.
        • Brancati F.L.
        • Diehl A.M.
        The prevalence and etiology of elevated aminotransferase levels in the United States.
        Am J Gastroenterol. 2003; 98: 960-967
        • Weston S.R.
        • Leyden W.
        • Murphy R.
        • et al.
        Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease.
        Hepatology. 2005; 41: 372-379
        • Poonawala A.
        • Nair S.P.
        • Thuluvath P.J.
        Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.
        Hepatology. 2000; 32: 689-692
        • Clark J.M.
        • Diehl A.M.
        Hepatic steatosis and type 2 diabetes mellitus.
        Curr Diab Rep. 2002; 2: 210-215
        • Gupte P.
        • Amarapurkar D.
        • Agal S.
        • et al.
        Non-alcoholic steatohepatitis in type 2 diabetes mellitus.
        J Gastroenterol Hepatol. 2004; 19: 854-858
        • Ioannou G.N.
        • Boyko E.S.
        • Less S.P.
        The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999–2002.
        Am J Gastroenterol. 2006; 101: 76-82
        • Boza C.
        • Riquelme A.
        • Ibanez L.
        • et al.
        Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass.
        Obes Surg. 2005; 15: 1148-1153
        • Srivastava S.
        • Younossi Z.M.
        Morbid obesity, nonalcoholic fatty liver disease, and weight loss surgery.
        Hepatology. 2005; 42: 490-492
        • Oliveira C.P.
        • Faintuch J.
        • Rascovski A.
        • et al.
        Lipid peroxidation in bariatric candidates with non-alcoholic fatty liver disease (NAFLD)—preliminary findings.
        Obes Surg. 2005; 15: 502-505
        • Adams L.A.
        • Lymp J.F.
        • St Sauver J.
        • et al.
        The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
        Gastroenterology. 2005; 129: 113-121
        • Hashimoto E.
        • Yatsuji S.
        • Kaneda H.
        • et al.
        The characteristics and natural history of Japanese patients with nonalcoholic fatty liver disease.
        Hepatol Res. 2005; 33: 72-76
        • Bugianesi E.
        • Leone N.
        • Vanni E.
        • et al.
        Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
        Gastroenterology. 2002; 123: 134-140
        • Powell E.E.
        • Cooksley W.G.
        • 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: 74-80
        • Matteoni C.A.
        • Younossi Z.M.
        • Gramlich T.
        • et al.
        Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
        Gastroenterology. 1999; 116: 1413-1419
        • Ratziu V.
        • Bonyhay L.
        • Di Martino V.
        • et al.
        Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis.
        Hepatology. 2002; 35: 1485-1493
        • Jepsen P.
        • Vilstrup H.
        • Mellemkjaer L.
        • et al.
        Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study.
        Hepatogastroenterology. 2003; 50: 2101-2104
        • Contos M.J.
        • Cales W.
        • Sterling R.K.
        • et al.
        Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis.
        Liver Transpl. 2001; 7: 363-373
        • Silverman J.F.
        • O'Brien K.F.
        • Long S.
        • et al.
        Liver pathology in morbidly obese patients with and without diabetes.
        Am J Gastroenterol. 1990; 85: 1349-1355
        • Andersen T.
        • Christoffersen P.
        • Gluud C.
        The liver in consecutive patients with morbid obesity: a clinical, morphological, and biochemical study.
        Int J Obes. 1984; 8: 107-115
        • Assy N.
        • Kaita K.
        • Mymin D.
        • et al.
        Fatty infiltration of liver in hyperlipidemic patients.
        Dig Dis Sci. 2000; 45: 1929-1934
        • Berkovitz D.
        Metabolic changes associated with obesity before and after weight reduction.
        JAMA. 1964; 187: 399-403
        • Donati G.
        • Stagni B.
        • Piscaglia F.
        • et al.
        Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance.
        Gut. 2004; 53: 1020-1023
        • Marchesini G.
        • Natale S.
        • Manini R.
        • et al.
        Review article: the treatment of fatty liver disease associated with the metabolic syndrome.
        Aliment Pharmacol Ther. 2005; 22: 37-39
        • Reaven G.M.
        Banting Lecture 1988. Role of insulin resistance in human disease.
        Diabetes. 1988; 37: 1595-1607
        • Ford E.S.
        • Giles W.H.
        • Mokdad A.H.
        Increasing prevalence of the metabolic syndrome among U.S. adults.
        Diabetes Care. 2004; 27: 2444-2449
        • Hamaguchi M.
        • Kojima T.
        • Takeda N.
        • et al.
        The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.
        Ann Intern Med. 2005; 143: 722-728
      1. World Health Organization Western Pacific Region, International Association for the Study of Obesity/International Obesity Task Force. The Asia-Pacific perspective: Redefining obesity and its treatment. Melbourne (Australia). Health Communications Australia; 2000.

        • Bellentani 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
        • Akbar D.H.
        • Kawther A.H.
        Nonalcoholic fatty liver disease in Saudi type 2 diabetic subjects attending a medical outpatient clinic: prevalence and general characteristics.
        Diabetes Care. 2003; 26 ([Letter]): 3351-3352
        • Chitturi S.
        • Farrell G.C.
        • George J.
        Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock?.
        J Gastroenterol Hepatol. 2004; 19: 368-374
        • Kojima S.
        • Watanabe N.
        • Numata M.
        • et al.
        Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background.
        J Gastroenterol. 2003; 38: 954-961
        • Mofrad P.
        • Contos M.J.
        • Haque M.
        • et al.
        Clinical and histologic spectrum of non-alcoholic fatty liver disease associated with normal ALT values.
        Hepatology. 2003; 37: 1286-1292
        • Angulo P.
        • Keach J.C.
        • Batts K.P.
        • et al.
        Independent predictors of liver fibrosis in patients with non-alcoholic steatohepatitis.
        Hepatology. 1999; 30: 1356-1362
        • Szczepaniak L.S.
        • Nurenberg P.
        • Leonard D.
        • et al.
        Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.
        Am J Physiol Endocrinol Metab. 2005; 288: E462-E468
        • Joy D.
        • Thava V.R.
        • Scott B.B.
        Diagnosis of fatty liver disease: is biopsy necessary?.
        Eur J Gastroenterol Hepatol. 2003; 15: 539-543
        • Saadeh S.
        • Younossi Z.M.
        • Remer E.M.
        • et al.
        The utility of radiological imaging in non-alcoholic fatty liver disease.
        Gastroenterology. 2002; 123: 745-750
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321
        • Van Ness M.M.
        • Diehl A.M.
        Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes?.
        Ann Intern Med. 1989; 111: 473-478
        • Adams L.A.
        • Lindor K.D.
        • Angulo P.
        The prevalence of autoantibodies and autoimmune hepatitis in patients with non-alcoholic fatty liver disease.
        Am J Gastroenterol. 2004; 99: 1316-1320
        • Younossi Z.M.
        • Gramlich T.
        • Matteoni C.A.
        • et al.
        Nonalcoholic fatty liver disease in patients with type 2 diabetes.
        Clin Gastroenterol Hepatol. 2004; 2: 262-265
        • Diehl A.M.
        Lessons from animal models of NASH.
        Hepatol Res. 2005; 33: 138-144
        • Chaldakov G.N.
        • Stankulov I.S.
        • Hristova M.
        • et al.
        Adipobiology of disease: adipokines and adipokine-targeted pharmacology.
        Curr Pharm Des. 2003; 9: 1023-1031
        • Klaus S.
        Adipose tissue as a regulator of energy balance.
        Curr Drug Targets. 2004; 5: 241-250
        • Rajala M.W.
        • Scherer P.E.
        Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis.
        Endocrinology. 2003; 144: 3765-3773
        • Kershaw E.E.
        • Flier J.S.
        Adipose tissue as an endocrine organ.
        J Clin Endocrinol Metab. 2004; 89: 2548-2556
        • Arner P.
        The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones.
        Trends Endocrinol Metab. 2003; 14: 137-145
        • Farrell G.C.
        • Larter C.Z.
        Nonalcoholic fatty liver disease: from steatosis to cirrhosis.
        Hepatology. 2006; 43: S99-S112
        • Tilg H.
        • Hotamisligil G.S.
        Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance.
        Gastroenterology. 2006; 131: 934-945
        • Nomura F.
        • Ohnishi K.
        • Suzuki T.
        • et al.
        Fatty liver in rats induced by excessive intake of a nutritionally adequate liquid diet.
        Int J Obes. 1987; 11: 603-608
        • Assy N.
        • Grozovski M.
        • Bersudsky I.
        • et al.
        Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease.
        World J Gastroenterol. 2006; 12: 4369-4376
        • Schattenberg J.M.
        • Wang Y.
        • Singh R.
        • et al.
        Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling.
        J Biol Chem. 2005; 280: 9887-9894
        • Alexia C.
        • Fourmatgeat P.
        • Delautier D.
        • et al.
        Insulin-like growth factor-I stimulates H4II rat hepatoma cell proliferation: dominant role of PI-3′K/Akt signaling.
        Exp Cell Res. 2006; 312: 1142-1152
        • Florez J.C.
        • Jablonski K.A.
        • Bayley N.
        • et al.
        TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program.
        N Engl J Med. 2006; 355: 241-250
        • Pessayre D.
        • Mansouri A.
        • Fromenty B.
        Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis.
        Am J Physiol Gastrointest Liver Physiol. 2002; 282: G193-G199
        • Hui J.M.
        • Hodge A.
        • Farrell G.C.
        • et al.
        Beyond insulin resistance in NASH: TNF-alpha or adiponectin?.
        Hepatology. 2004; 40: 46-54
        • Feldstein A.E.
        • Werneburg N.W.
        • Canbay A.
        • et al.
        Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.
        Hepatology. 2004; 40: 185-194
        • Arkan M.C.
        • Hevener A.L.
        • Greten F.R.
        • et al.
        IKK-beta links inflammation to obesity-induced insulin resistance.
        Nat Med. 2005; 11: 191-198
        • Garg A.
        Lipodystrophies.
        Am J Med. 2000; 108: 143-152
        • Backhed F.
        • Ding H.
        • Wang T.
        • et al.
        The gut microbiota as an environmental factor that regulates fat storage.
        Proc Natl Acad Sci USA. 2004; 101: 15718-15723
        • Chitturi S.
        • Farrell G.C.
        Etiopathogenesis of nonalcoholic steatohepatitis.
        Semin Liver Dis. 2001; 21: 27-41
        • Green R.M.
        Hepatic metabolism and not simply the metabolic syndrome.
        Hepatology. 2003; 38: 14-17
        • Koteish A.
        • Diehl A.M.
        Animal models of steatosis.
        Semin Liver Dis. 2001; 21: 89-104
        • Tsukamoto H.
        • Gaal K.
        • French S.W.
        Insights into the pathogenesis of alcoholic liver necrosis and fibrosis: status report.
        Hepatology. 1990; 12: 599-608
        • Mottin C.C.
        • Moretto M.
        • Padoin A.V.
        • et al.
        Histological behavior of hepatic steatosis in morbidly obese patients after weight loss induced by bariatric surgery.
        Obes Surg. 2005; 15: 788-793
        • Bataller R.
        • Brenner D.A.
        Liver fibrosis.
        J Clin Invest. 2005; 115: 209-218
        • Friedman S.L.
        Stellate cells: a moving target in hepatic fibrogenesis.
        Hepatology. 2004; 40: 1041-1043
        • Kamada Y.
        • Tamura S.
        • Kiso S.
        • et al.
        Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin.
        Gastroenterology. 2003; 125: 1796-1807
        • Lijnen H.R.
        Pleiotropic functions of plasminogen activator inhibitor-1.
        J Thromb Haemost. 2005; 3: 35-45
        • Fujikawa K.
        • Ohata K.
        • Honda T.
        • et al.
        Nonalcoholic steatohepatitis with improved hepatic fibrosis after weight reduction.
        Intern Med. 2004; 43: 289-294
        • 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
        • Brolin R.E.
        Bariatric surgery and long-term control of morbid obesity.
        JAMA. 2002; 288: 2973-2976
        • Andersen T.
        • Gluud C.
        • Franzmann M.B.
        • et al.
        Hepatic effects of dietary weight loss in morbidly obese subjects.
        J Hepatol. 1991; 12: 224-229
        • Goldstein D.J.
        Beneficial health effects of modest weight loss.
        Int J Obes Relat Metab Disord. 1992; 16: 397-415
        • O'Leary V.B.
        • Marchetti C.M.
        • Krishnan R.K.
        • et al.
        Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat.
        J Appl Physiol. 2006; 100: 1584-1589
        • Anonymous
        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
        • Muzio F.
        • Mondazzi L.
        • Sommariva D.
        • et al.
        Long-term effects of low-calorie diet on the metabolic syndrome in obese nondiabetic patients.
        Diabetes Care. 2005; 28: 1485-1486
        • Minehira K.
        • Tappy L.
        Dietary and lifestyle interventions in the management of the metabolic syndrome: present status and future perspective.
        Eur J Clin Nutr. 2002; 56: 1264-1269
        • Viviani G.L.
        • Carta G.
        • Berri F.
        • et al.
        Effects of normoglycemia after a low carbohydrate diet in NIDDM. Insulin secretion and effectiveness.
        Minerva Endocrinol. 1984; 9: 229-232
        • Arora S.K.
        • McFarlane S.I.
        The case for low carbohydrate diets in diabetes management.
        Nutr Metab (Lond). 2005; 2: 16-25
        • Niskanen L.
        • Uusitupa M.
        • Sarlund H.
        • et al.
        The effects of weight loss on insulin sensitivity, skeletal muscle composition and capillary density in obese non-diabetic subjects.
        Int J Obes Relat Metab Disord. 1996; 20: 154-160
        • Kriska A.
        Can a physically active lifestyle prevent type 2 diabetes?.
        Exerc Sport Sci Rev. 2003; 31: 132-137
        • Duncan G.E.
        • Perri M.G.
        • Theriaque D.W.
        • et al.
        Exercise training, without weight loss, increases insulin sensitivity and postheparin plasma lipase activity in previously sedentary adults.
        Diabetes Care. 2003; 26: 557-562
        • Uusitupa M.
        • Lindi V.
        • Louheranta A.
        • et al.
        Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study.
        Diabetes. 2003; 52: 2532-2538
        • Lean M.E.
        Is long-term weight loss possible?.
        Br J Nutr. 2000; 83: S103-S111
        • Eden K.B.
        • Orleans C.T.
        • Mulrow C.D.
        • et al.
        Does counseling by clinicians improve physical activity? A summary of the evidence for the U.S. Preventive Services Task Force.
        Ann Intern Med. 2002; 137: 208-215
        • Jones N.L.
        • Killian K.J.
        Exercise limitation in health and disease.
        N Engl J Med. 2000; 343: 632-641
        • van Baak M.A.
        Exercise training and substrate utilization in obesity.
        Int J Obes Relat Metab Disord. 1999; 23: S11-S17
        • Hoppeler H.
        Skeletal muscle substrate metabolism.
        Int J Obes Relat Metab Disord. 1999; 23: S7-S10
        • Palmer M.
        • Schaffner F.
        Effect of weight reduction on hepatic abnormalities in overweight patients.
        Gastroenterology. 1990; 99: 1408-1413
        • Drenick E.J.
        • Simmons F.
        • Murphy J.F.
        Effect on hepatic morphology of treatment of obesity by fasting, reducing diets and small bowel bypass.
        N Engl J Med. 1970; 282: 829-834
        • Vajro P.
        • Fontanella A.
        • Perna C.
        • et al.
        Persistent hyperaminotransferasemia resolving after weight reduction in obese children.
        J Pediatr. 1994; 125: 239-241
        • Sjostrom L.
        • Lindroos A.K.
        • Peltonen M.
        • et al.
        Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery.
        N Engl J Med. 2004; 351: 2683-2693
        • Dixon J.B.
        • Bhathal P.S.
        • Hughes N.R.
        • et al.
        Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss.
        Hepatology. 2004; 39: 1647-1654
        • Blackburn G.L.
        • Mun E.C.
        Effects of weight loss surgeries on liver disease.
        Semin Liver Dis. 2004; 24: 371-379
        • Klein S.
        • Mittendorfer B.
        • Eagon C.
        • et al.
        Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease.
        Gastroenterology. 2006; 130: 1564-1572
        • Mathurin P.
        • Gonzalez F.
        • Kerdraon O.
        • et al.
        The evolution of severe steatosis after bariatric surgery is related to insulin resistance.
        Gastroenterology. 2006; 130: 1617-1624
        • Kral J.G.
        • THung S.N.
        • Biron S.
        • et al.
        Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis.
        Surgery. 2004; 135: 48-58
        • Lin H.Z.
        • Yang S.Q.
        • Chuckaree C.
        • et al.
        Metformin reverses fatty liver disease in obese, leptin-deficient mice.
        Nat Med. 2000; 6: 998-1003
        • Marchesini G.
        • Brizi M.
        • Bianchi G.
        • et al.
        Metformin in non-alcoholic steatohepatitis.
        Lancet. 2001; 358: 893-894
        • Magalotti D.
        • Marchesini G.
        • Ramilli S.
        • et al.
        Splanchnic haemodynamics in non-alcoholic fatty liver disease: effect of a dietary/pharmacological treatment. A pilot study.
        Dig Liver Dis. 2004; 36: 406-411
        • Schwimmer J.B.
        • Middleton M.S.
        • Deutsch R.
        • et al.
        A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric nonalcoholic steatohepatitis.
        Aliment Pharmacol Ther. 2005; 21: 871-879
        • Uygun A.
        • Kadayifci A.
        • Isik A.T.
        • et al.
        Metformin in the treatment of patients with nonalcoholic steatohepatitis.
        Aliment Pharmacol Ther. 2004; 19: 537-544
        • Nair S.
        • Diehl A.M.
        • Wiseman M.
        • et al.
        Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial.
        Aliment Pharmacol Ther. 2004; 20: 23-28
        • 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: 1082-1090
        • Caldwell S.H.
        • Hespenheide E.E.
        • Redick J.A.
        • et al.
        A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.
        Am J Gastroenterol. 2001; 96: 519-525
        • Neuschwander-Tetri B.A.
        • Brunt E.M.
        • Wehmeier K.R.
        • et al.
        Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.
        Hepatology. 2003; 38: 1008-1017
        • Promrat K.
        • Lutchman G.
        • Uwaifo G.I.
        • et al.
        A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.
        Hepatology. 2004; 39: 188-196
        • Sanyal A.J.
        • Mofrad P.S.
        • Contos M.J.
        • et al.
        A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis.
        Clin Gastroenterol Hepatol. 2004; 2: 1107-1115
        • Belfort R.
        • Harrison S.A.
        • Brown K.
        • et al.
        A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
        N Engl J Med. 2006; 355: 2297-2307
        • Basaranoglu M.
        • Acbay O.
        • Sonsuz A.
        A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis.
        J Hepatol. 1999; 31: 384
        • Gomez-Dominguez E.
        • Gisbert J.P.
        • Moreno-Monteagudo J.A.
        • et al.
        A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients.
        Aliment Pharmacol Ther. 2006; 23: 1643-1647
        • Kiyici M.
        • Gulten M.
        • Gurel S.
        • et al.
        Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis.
        Can J Gastroenterol. 2003; 17: 713-718
        • Hatzitolios A.
        • Savopoulos C.
        • Lazaraki G.
        • et al.
        Efficacy of omega-3 fatty acids, atorvastatin, and orlistat in non-alcoholic fatty liver disease with dyslipidemia.
        Indian J Gastroenterol. 2004; 23: 131-134
        • Rallidis L.S.
        • Drakoulis C.K.
        • Parasi A.S.
        Provastatin in patients with nonalcoholic steatohepatitis: results of a pilot study.
        Atherosclerosis. 2004; 174: 193-196
        • Nair S.
        • Wiseman M.
        HMG-CoA reductase inhibitors in nonalcoholic fatty liver disease: is potential hepatotoxicity an issue in these patients? A case-control study based on histology.
        Hepatology. 2002; 36 ([Abstract]): 409A
        • Chalasani N.
        • Aljadhey H.
        • Kesterson J.
        • et al.
        Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity.
        Gastroenterology. 2004; 126: 1287-1292
        • Laurin J.
        • Lindor K.D.
        • Crippin J.S.
        • et al.
        Ursodeoxycholic acid or clofibrate in the treatment of nonalcohol induced steatohepatitis: a pilot study.
        Hepatology. 1996; 23: 1464-1467
        • Bajaj M.
        • Suramornkul S.
        • Pratipanowatr T.
        • et al.
        Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes.
        Diabetes. 2003; 52: 1364-1370