Hepatic iron metabolism gene expression profiles in HFE associated Hereditary Hemochromatosis

Background:Individuals with pathogenic mutations in HFE, hemojuvelin (HJV) and transferrin receptor 2 (TfR2) have low levels of hepcidin, but little is known about the hepatic expression of these molecules in patients with physiological iron overload or HFE associated Hemochromatosis (HH).Aims:To examine the hepatic mRNA expression of iron homeostasis genes in patients with HH, physiological iron overload and healthy controls.Patients:Untreated C282Y homozygous HH patients (n = 20) with elevated serum ferritin (SF) and patients with physiological iron overload (n = 12) with positive hepatocellular iron staining and negative HFE mutation analysis were evaluated. The control cohort (n = 10) had normal iron parameters, negative HFE mutation analysis and negative hepatocellular iron staining.Methods:Hepcidin, HJV (hemojuvelin), TfR2 (transferrin receptor 2), HFE, IL6 (interleukin 6) and ferroportin mRNA expression patterns were evaluated using quantitative real-time PCR.Results:Physiological iron overload led to significantly upregulated hepcidin, HJV and ferroportin mRNA expression while TfR2 expression was not significantly different to controls. In contrast, HFE associated iron overload failed to induce hepcidin or HJV. TfR2 mRNA expression was significantly reduced when compared to controls. Ferroportin expression in HH was comparable to that found in physiological iron overload. Neither HFE nor IL6 expression was altered by variation in iron status.Conclusions:These findings suggest that patients with HH, in contrast to those with physiological iron overload, have a weakened TfR2 sensing mechanism that leads to the lack of induction of hepcidin and HJV. The C282Y HFE mutation does not appear to impede the hepatocellular iron export function of ferroportin.