Revisiting hemochromatosis: genetic vs. phenotypic manifestations

Iron overload disorders represent an important class of human diseases. Of the primary iron overload conditions, by far the most common and best studied is HFE-related hemochromatosis, which results from homozygosity for a mutation leading to the C282Y substitution in the HFE protein. This disease is characterized by reduced expression of the iron-regulatory hormone hepcidin, leading to increased dietary iron absorption and iron deposition in multiple tissues including the liver, pancreas, joints, heart and pituitary. The phenotype of HFE-related hemochromatosis is quite variable, with some individuals showing little or no evidence of increased body iron, yet others showing severe iron loading, tissue damage and clinical sequelae. The majority of genetically predisposed individuals show at least some evidence of iron loading (increased transferrin saturation and serum ferritin), but a minority show clinical symptoms and severe consequences are rare. Thus, the disorder has a high biochemical penetrance, but a low clinical prevalence. Nevertheless, it is such a common condition in Caucasian populations (1:100–200) that it remains an important clinical entity. The phenotypic variability can largely be explained by a range of environmental, genetic and physiological factors. Men are far more likely to manifest significant disease than women, with the latter losing iron through menstrual blood loss and childbirth. Other forms of blood loss, immune system influences, the amount of bioavailable iron in the diet and lifestyle factors such as high alcohol intake can also contribute to iron loading and disease expression. Polymorphisms in a range of genes have been linked to variations in body iron levels, both in the general population and in hemochromatosis. Some of the genes identified play well known roles in iron homeostasis, yet others are novel. Other factors, including both co-morbidities and genetic polymorphisms, do not affect iron levels per se, but determine the propensity for tissue pathology.