Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice

Hereditary hemochromatosis (HH) is a genetic condition that can lead to unregulated absorption of iron from the gut with resultant iron overload. The most common form of HH is caused by mutations in the HFE gene, with most cases of HH presenting in patients who are homozygous for the Cys282Tyr mutation. The prevalence of HFE gene mutations in persons of Northern European ancestry is fairly high (0.3-0.7% homozygous and 9-14% heterozygous for the Cys282Tyr mutation), but the penetrance of the disease is considered fairly low and is quite variable. While routine screening of the general population is not recommended, a targeted approach to screening in symptomatic patients and in those with a family member with iron overload is warranted. Untreated, iron overload can lead to considerable morbidity including liver cirrhosis, arthritis and diabetes mellitus, and increased mortality. The pathophysiology of diabetes mellitus in HH is thought to be due primarily to defects in the early insulin response to glucose. An Hfe(-/-) mouse model of HH has demonstrated defects in beta-cell function and beta-cell apoptosis that may be mediated by increased oxidative stress. Fortunately, these defects seem to be reversible if phlebotomy treatment is initiated before the development of cirrhosis or diabetes mellitus in patients. Further research into the long-term effects of treatment on prevention of diabetes mellitus in HH is needed.