HFE

About HFE

HFE on chromosome 6p22.2 encodes an MHC class I like protein that associates with beta 2 microglobulin and transferrin receptor 1 and helps the liver sense body iron stores and regulate hepcidin, the master hormone of iron balance. The C282Y variant disrupts a disulfide bond, preventing the protein from reaching the cell surface. People homozygous for C282Y can develop HFE related hereditary hemochromatosis, one of the most common genetic disorders in people of Northern European ancestry, although penetrance is incomplete and many homozygotes never develop iron overload disease. The H63D variant is common but much less penetrant. Low hepcidin leads to increased intestinal iron absorption and iron deposition in organs, causing liver fibrosis and cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, arthritis classically of the second and third metacarpophalangeal joints, skin bronzing, and hypogonadism. Symptoms appear later in women because of menstrual and pregnancy related iron loss. The gene was identified in 1996. Diagnosis involves blood tests of iron status and genetic testing, and therapeutic phlebotomy, the regular removal of blood, is the standard treatment. Complications are largely preventable when iron overload is recognized early.