Hfe genotype, ferritin levels and transferrin saturation in patients with suspected hereditary hemochromatosis

HFE hemochromatosis is characterized by increased iron absorption and iron overload due to variants of the iron-regulating HFE gene. Overt disease is mainly associated with homozygosity for the C282Y variant, although the H63D variant in compound heterozygosity with C282Y (C282Y/H63D) contributes to disease manifestation. In this observational study, we describe the association between biochemical findings, age, gender and HFE genotype in patients referred from general practice to a tertiary care referral center for diagnostic workup based on suspected hemochromatosis due to persistent hyperferritinemia and HFE variants. C282Y and H63D homozygosity were, respectively, the most and least prevalent genotypes and we found a considerable variation in transferrin saturation and ferritin levels independent of HFE genotype, which may indeed represent a diagnostic challenge in general practice. While our results confirm C282Y homozygosity as the major cause of iron accumulation, non-C282Y homozygotes also displayed mild to moderate hyperferritinemia with median ferritin levels at 500–700 µg/L, well above the reference cut-off. Such findings have traditionally been ignored in the clinic, and initiation of iron depletion has largely been restricted to C282Y homozygotes. Nevertheless, superfluous iron can aggravate pathogenesis in combination with other diseases and risk factors, such as inflammation, cancer and hepatopathy, and this possibility should not be neglected by clinicians