Hepatic iron overload in patients with alcoholic liver disease is due to inadequate hepcidin induction

Aims: Alcoholic liver disease (ALD) leads to secondary iron overload in more than 50% patients that is considered a major factor in the progression of fibrosis and the development of hepatocellular carcinoma. Hepcidin is the major systemic iron sensor in mammals and typically induced under conditions of iron overload. Hepcidin blocks duodenal iron absorption and the release of iron by inflammatory cells. Suppressed hepcidin levels have been recently reported from animals chronically exposed to alcohol.

Methods and results: Using cDNA microarray platform containing over 250 iron relevant genes (IRON CHIP), we first screened liver tissue of a control group and patients with ALD with or without histological deposition of iron for significantly regulated iron-associated gene expression (each group n=4). However, none of the classical iron genes (hepcidin, transferrin receptor, transferrin, ferroportin, hemojuvelin) were significantly regulated when ALD patients with and without iron overload were compared. These results were validated by qRT-PCR in an extended group of patients with ALD (n=30) with or without iron overload (serum ferritin as serological marker and Prussian Blue staining in liver biopsies). Patients were also matched for age, alcohol consumption and fibrosis stage. Thus, ALD patients with iron accumulation showed an inadequate induction of hepcidin. Serum analysis of hepcidin also showed no difference in circulating hepcidin in both groups. In vitro exposure of human hepatoma cells (Hep3B) to contiuous flux of non-toxic H₂O₂ a central reactive oxygen species, significantly suppresses hepcidin levels.

Conclusion: ALD patients with increased hepatic iron deposits show an inadequate secretion of hepcidin. Ethanol-mediated oxidative stress mechanisms could be pivotal in the suppression of hepcidin despite iron overload.