Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Hemochromatosis, hereditary [E83.1]

OMIM numbers: 235200, 613609 (HFE)

Dr. rer. nat. Christoph Marschall, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso

Scientific Background

Hemochromatosis is caused by an acquired or inherited disorder of the iron metabolism. Increased absorption of iron in the small intestine causes accumulation of iron in various organs, mainly in the liver. If the diagnosis is established at an early stage, the disease can usually be treated well; if untreated, however, it frequently results in liver cirrhosis, liver tumors, diabetes mellitus and cardiac arrhythmia. The hereditary form, hereditary hemochromatosis (HH), follows an autosomal recessive inheritance pattern and is caused by homozygosity for the C282Y polymorphism (rs1800562) in the HFE gene in 85-90% of all cases. In Central Europe, the frequency of this genotype ranges between 1:400 and 1:100. The penetrance is incomplete; not every homozygous carrier will develop hemochromatosis.

Approximately 3-5% of all patients with hemochromatosis are compound heterozygous for the C282Y polymorphism and the H63D polymorphism (rs1800562). The penetrance, however, is low. Detection of this genotype in symptomatic patients can be considered a confirmation of hereditary hemochromatosis. Homozygosity for the H63D polymorphism confirms the clinical suspicion of hemochromatosis as well, although these patients exhibit only little accumulation of iron. Homozygosity for the less common S65C polymorphism (rs1800730) or combined heterozygosity for C282Y/S65C and H63D/S65C has been associated with a low risk of developing the disease. A mild course of the disease can be expected in most cases. Heterozygous carriers of the polymorphisms C282Y (5-10% of the population), H63D and S65C are not at an increased risk.

Full sequencing of the HFE gene can be carried out to detect rare mutations in patients diagnosed with hemochromatosis who have the C282Y or H63D polymorphism only in the heterozygous form and who are still suspected to have hereditary hemochromatosis (e.g. due to transferrin saturation >50%, serum ferritin level >200 µg/l or a positive liver biopsy).