Morbidity risk in HFE associated hereditary hemochromatosis C282Y heterozygotes

Abstract

Hereditary hemochromatosis (HHC) is a late-onset, autosomal recessive disorder leading to a chronic iron overload syndrome, finally causing diabetes, cardiomyopathy and liver disease. HHC is the most common single gene disorder in northern Europeans that occurs with a frequency of approximately 0.5%, and most of these patients carry the C282Y and H63D mutation in the HFE gene on chromosome 6p21.3. The vast majority of HHC patients are homozygous for the C282Y mutation, but HHC phenotypes are observed in other genotypes. Expression of the disease, in those homozygous for the C282Y mutation, is highly variable depending on the various features of the population studied. C282Y heterozygotes have slightly increased iron stores and in absence of other genetic and/or environmental factors do usually not develop the HHC phenotype. It is currently a matter of debate whether C282Y heterozygotes may have an increased risk for morbidity. Different studies investigating the association of C282Y heterozygocity with morbidity have given conflicting results, as is exemplified by extrahepatic cancers, cardiovascular diseases, alcoholic liver disease, and diabetes. However, there are examples of clear and unambiguous disease associations, such as with sporadic pophyria cutanea tarda. It remains to be seen whether a strong correlation between the C282Y heterozygous state and distinct pathological conditions will exist and large-scale genotyping studies will help to identify such potential risk groups in the future.