Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis

Background/Aims: Non-alcoholic steatohepatitis (NASH) is increasingly recog nized, and its pathogenesis is believed to involve increased oxidative stre ss. Elevated levels of serum ferritin and positive liver iron stains are of ten observed in patients with NASH, and the pathogenesis of liver injury du e to iron is also thought to involve oxidative stress. The aim of this stud y was to determine whether there is an association of NASH and mutations in the HFE gene associated with hereditary hemochromatosis (HHC). Methods: clinical, laboratory and histopathological data on all 57 subjects with a final diagnosis of NASH seen between August 1990 and August 1997 at our Liver Center were analyzed. Thirty-six Caucasian subjects (23 men) wit h NASH underwent mutational analyses of HFE gene mutations performed. The p revalence of HFE gene mutations was compared to that in 348 Caucasian norma l controls. Data were analyzed by both parameteric and non-parametric metho ds with similar results. Results: One subject (2.8%) with NASH was homozygous for the C282Y mutation and six (16.7%) mere heterozygous, compared with 0% and 11.2%, respectivel y, of controls. Two (5.6%) subjects with NASH were homozygous for the H63D mutation and 16 (44.4%) were heterozygous, whereas 2.9% and 26.4%, respecti vely, of controls had these genotypes. The prevalence of heterozygosity (61 .1%) for either mutation was significantly higher in subjects with NASH tha n in controls (38%) (p=0.008), and the prevalence of homozygosity or hetero zygosity combined in NASH subjects (69.4%) was significantly higher than fo r controls (40.5%, p=0.001). Sex (63-67% male) and age at diagnosis of NASH did not differ between those with or without HFE mutations, but men with N ASH were significantly more likely than women to have the H63D mutation (15 /23 vs. 3/13, p<0.05) Levels of serum ferritin, iron, transferrin saturatio n levels, and the degree of hepatic iron staining were significantly higher (p<0.05) in subjects with NASH who carried an HFE mutation than in those w ithout. Differences in hepatic iron concentrations or hepatic iron indices between NASH subjects with and without HFE mutations were not significant. Those with C282Y mutations had significantly more hepatic fibrosis than tho se without (p<0.05). Those with HFE mutations had significantly higher leve ls of serum ALT (90+/-11 [mean+/-SE]) than those without (55+/-6; p=0.02). Conclusion: The prevalences of the HFE gene mutations associated with hered itary hemochromatosis are increased among North American subjects with NASH .