in Iron Absorption

PATHOPHYSIOLOGY AND GENETIC OF HEREDITARY HEMOCHOROMATOSIS

THE HFE PROTEIN

THE C282Y MUTANT

THE H63D MUTANT

Most Americans ingest approximately 15 to 20 mg of elemental iron daily. Of this amount, only about 1 to 2 mg are actually absorbed in the gut. For those with normal iron metabolism, daily loss of iron (menstrual losses, stool, and sweat) roughly equals absorption. Because humans have no physiologic mechanism to alter iron excretion to meet demand or availability, iron balance in the normal state is maintained through mechanisms that control absorption. Iron in the circulation is bound to the protein, transferrin, which maintains it in a non-toxic state. Cells contain receptors for transferrin on their plasma membranes which mediate cellular iron uptake. Transferrin receptors bind iron-transferrin complexes which are taken into endosomes. Iron is separated from transferrin in the endosome, and is shuttled into the interior of the cell. The iron-free transferrin (apotransferrin) is recycled into the circulation and is free to bind and transport additional iron atoms.

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Pathophysiology and Genetics of Hereditary Hemochromatosis

The HFE protein

In 1996, the gene responsible for hereditary hemochromatosis, HFE gene, resides on chromosome 6 (6p21.3) was discovered. The HFE protein is a 348 residue type 1 transmembrane protein that associated with class 1 light chain beta2-microglobulin. The HFE protein acts as a major regulator of iron absorption by binding to the transferrin receptor thus decreasing the affinity of the transferrin receptor for iron-loaded transferrin. HFE protein production is regulated in response to iron stores by an unknown mechanism. Iron regulatory proteins or a number of other proteins known to be involved in cellular iron metabolism might be involved.

The C282Y mutant HFE protein

The clinical disease of hereditary hemochromatosis is usually caused by a homozygous autosomal recessive mutation in the HFE gene. In approximately 60% to 90% of cases, the defect is a single missense mutation at position 282 where cysteine is replaced by tyrosine (C282Y). The C282Y mutant HFE protein is unable to bind to beta2-microglobulin, with the result being unregulated transferrin receptor-mediated iron uptake in the gut.

The prevalence of the homozygous C282Y mutation ranges from 1 in 200 for whites to 1 in 4,000 for those of African-American heritage. There appears to be variable expression of iron overload in persons with the homozygous C282Y mutation, with as many as 30% to 50% of those homozygous for the defect showing no signs of phenotypic expression at the time of discovery. As much as 10% of the US white population is heterozygous for the C282Y mutation.

Persons affected with hereditary hemochromatosis absorb 3 to 4 mg/d of iron, instead of the normal 1 to 2 mg/d. The net result is a positive iron balance in the range of 400 to 1,000 mg/y. Ninety percent of the excess iron stores are retained in the liver. As ferrous iron accumulates in the parenchymal tissues, the intracellular iron-binding sites are overwhelmed, which results in lipid peroxidation, cellular injury, and fibrosis.

The H63D mutant HFE protein

In addition to the mutation at the 282 position, a second mutation has been found at position 63, where histidine is replaced by aspartate (H63D). The H63D mutation, while able to bind to transferrin receptors, appears to lack the normal high degree of inhibitory effect on the transferrin receptor. Persons homozygous for the H63D mutation and those who are compound heterozygotes (with the C282Y mutation) have a low rate of phenotypic expression, accounting for approximately 5% and 15% cases of hereditary hemochromatosis, respectively.