Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age-and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. N onalcoholic steatohepatitis (NASH) is characterized by morphological features indistinguishable from alcoholic liver disease in individuals who do not consume excess alcohol. 1 NASH can progress to cirrhosis, and death from liver failure is now the second-leading cause of death in these patients. 2 Although the prevalence of NASH appears to be increasing, the etiopathogenesis remains poorly understood.Associations with drug toxicity, weight-reducing operations, lipodystrophy, and other uncommon inherited syndromes are well documented but are rarely present in most patients with NASH. [1][2][3][4][5][6][7][8] Rather, attention has been drawn to the increased prevalence of common metabolic disorders in the "typical" patient with NASH. [1][2][3][4][5][6][7] Autopsy data indicate that NASH is at least 6 times more prevalent in obese individuals compared with lean subjects. 7 Type 2 diabetes mellitus or abnormalities of glucose tolerance are present in up to one third of patients with NASH, 8 often with hypertriglyceridemia and/or hypercholesterolemia. 9,10 The above metabolic disorders are also cardiovascular risk factors and often cluster together as syndrome X, which includes impaired glucose tolerance, dyslipidemia, and hypertension. 11 This disease cluster is also referred to as the metabolic or insulin resistance syndrome (IRS); the latter highlights a central role for insulin resistance (IR) in this disorder. 12,13 The expanded formulation of IRS includes central (visceral or truncal) adiposity, lipid abnormalities, hyperuricemia, polycystic ovarian syndrome, and...

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