Nonalcoholic fatty liver disease (NAFLD) encompasses both simple steatosis and nonalcoholic steatohepatitis (NASH). Differentiation of these two entities requires histopathologic evaluation. The aim of this study was to establish a reliable diagnostic model for differentiating steatosis from steatohepatitis utilizing both clinical characteristics and a panel of biochemical markers of lipid peroxidation and fibrosis. Eighty subjects with biopsy proven NAFLD were enrolled, 39 with simple steatosis and 41 with histopathologic evidence of NASH. Demographic and laboratory data to include serologic testing for 8-epi-PGF(2alpha), transforming growth factor-beta (TGF-beta), adiponectin, and hyaluronic acid (HA) were obtained and compared between the two groups. There were significant differences between the two groups with respect to age (P=0.004), female gender (P=0.024), aspartate aminotransferase (AST) (P=0.028), body mass index (BMI) (P=0.003), fasting insulin (0.018), AST/alanine aminotransferase (ALT) ratio (AAR) (P=0.017), quantitative insulin sensitivity check index (QUICKI) (P=0.002), and HA (P=0.029). A composite index for distinguishing steatosis from NASH was calculated by summing the risk factors of age >or=50 years, female gender, AST>or=45 IU/l, BMI >or=30 mg/kg2, AAR>or=0.80, and HA>or=55 microg/l, and its accuracy was determined by receiver operating characteristic (ROC) analysis to be 0.763 (95% CI: 0.650-0.876). The presence of three or more risk factors had a sensitivity, specificity, PPV, and NPV of 73.7%, 65.7%, 68.2%, and 71.4%, respectively. In addition, HA at a cutoff of 45.3 microg/l was a good predictor of advanced fibrosis. In conclusion, we propose a noninvasive screening model for distinguishing simple steatosis from NASH. Identifying patients at risk for NASH will allow clinicians to more accurately determine who may benefit from liver biopsy.