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]
Medscape Gastroenterology © 2012
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Cite this: Rowen K. Zetterman. Hemochromatosis: More Common Than You Think? - Medscape - Oct 22, 2012.