The aim of this study was to evaluate the frequency of hepatic iron overload in insulin resistance (IR) states and in nonalcoholic steatohepatitis to determine if the association is due to a distinct metabolic entity. A total of 161 patients with non-C282Y-homozygotes with unexplained iron overload were studied. Age, sex, body mass index > 25, hyperlipidemia or diabetes (indicating IR states), serum iron tests, liver iron concentration, liver function tests, liver histology and C282Y and H63D mutations were assessed. Patients were mostly male and middle aged, 94% had IR, transferrin saturation was increased in 35%, liver iron concentration (LIC) revealed modest increases (median 90mgm), C282Y mutation was seen in 20% compared to 9% in controls and H63D in 30% versus 17% in controls. Patients with mutations had similar degrees of iron overload compared to those without except in the H63D group where levels were slightly higher. Steatosis was present in 25% and non-alcoholic steatohepatitis (NASH) in 27%. In 62% of patients, portal fibrosis was mild (0-3 grade) and in 12% fibrosis was grade 2 or 3. Sex ratio, IR, iron saturation and LIC were not correlated with extent of liver damage. Although serum ferritin, liver tests and hepatic fibrosis were more marked in patients with steatosis and NASH, LIC and genotypic mutations were no different when compared to patients without fat in the liver. These authors conclude that in patients with unexplained hepatic iron overload, a constant association with IR and moderate iron burden may suggest an unique metabolic defect. Further studies to characterize this abnormality are needed. [Dr. Mendler is currently a member of the USC Liver /GI Division.]