Hemochromatosis: More Common Than You Think?

Rowen K. Zetterman, MD


October 22, 2012

In This Article

Hereditary HFE Hemochromatosis

Hereditary HFE hemochromatosis accounts for most cases of excess body iron that result from increased iron absorption. Clinical disease in HFE hemochromatosis has variable penetrance; women are less likely to develop end-stage disease from hemochromatosis (1%-2%) than men (28%).[1]

The principal mutation accounting for type 1 HFE hemochromatosis is a substitution of tyrosine for cysteine at position 282 on chromosome 6, resulting in a mutation designated as C282Y.[2] Homozygous C282Y hemochromatosis is the cause of 85%-90% of cases of iron overload.[3] The other common HFE mutation is H63D, which has an approximate gene prevalence of 20% in European populations.[4] H63D mutation does not result in constitutional iron overload unless it occurs as a compound heterozygote with C282Y (C282Y/H63D). Rare mutations of the HFE gene also include G93R, I105T, R66C, R224G, S65C, V59M, and V295A.[5]

Other genetic mutations involved in iron homeostasis, which account for most of the remaining patients with inherited disorders of iron overload, include juvenile hemochromatosis (type 2), transferrin receptor 2 disease (type 3 hemochromatosis), and ferroportin disease (type 4 hemochromatosis). Without genetic predisposition, secondary iron overload can develop in patients who have undergone multiple blood transfusions, those with ineffective erythropoiesis coupled with oral iron supplementation, or patients in end-stage liver disease.

Iron Metabolism

Iron is absorbed from dietary sources through the proximal small intestine. Hepcidin, which is produced in the liver and to a smaller extent in adipocytes and macrophages, is a key regulator of iron absorption.[6] When iron levels are normal or elevated, hepcidin inhibits intestinal iron absorption. When iron levels are low (as in iron deficiency), hepcidin promotes iron absorption from the small intestine.[7,8] Hepcidin acts by binding to the iron exporter ferroportin, blocking the transport and release of iron, leading to retention of iron within enterocytes and reduced iron absorption.

Type 1 hemochromatosis results from reduced hepcidin expression and increased iron absorption, exceeding the capacity of transferrin to transport iron. Non-transferrin-bound circulating iron is readily taken up by hepatocytes, where it promotes the formation of free radical oxygen species that cause cell injury.[9] Chronic ethanol ingestion also reduces hepcidin transcription, thereby increasing iron absorption.[10] An excellent review of iron metabolism is available for those who desire more information.[6]