Abstract
Hereditary hemochromatosis (HH) refers to several inherited disorders of iron metabolism leading to tissue iron overload. Classical HH is associated with mutations in HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) and is almost exclusively found in populations of northern European descent. Non-HFE associated HH is caused by mutations in other recently identified genes involved in iron metabolism. Hepcidin is an iron regulatory hormone that inhibits ferroportin-mediated iron export from enterocytes and macrophages. Defective hepcidin gene expression or function may underlie most forms of HH. Target organs and tissues affected by HH include the liver, heart, pancreas, joints, and skin, with cirrhosis and diabetes mellitus representing late signs of disease in patients with markedly elevated liver iron concentration. Compound heterozygotes have milder disease than C282Y homozygotes and clinical signs of HH in these patients are usually associated with other factors such as alcoholism and the dysmetabolic syndrome. The most frequent causes of death in HH are liver cancer, cirrhosis, cardiomyopathy, and diabetes, but patients who undergo successful iron depletion before the development of cirrhosis or diabetes can have normal survival. Classical HH is characterized by incomplete penetrance and variable expressivity, and women are less affected than men by iron overload and iron overload-related disease. The diagnosis of HH is established by genetic testing in patients with elevated transferrin saturation values. Patients with an established diagnosis of HH and iron overload should be treated with phlebotomy to achieve body iron depletion followed by maintenance phlebotomy. Population screening for HH is controversial principally because of incomplete penetrance, but screening of selected, high risk populations and first-degree relatives of affected probands may be cost effective.
