Haemochromatosis an adult onset disorder, characterised by inappropriately high iron absorption resulting in progressive iron overload. Increases in the body’s iron levels may be acquired by for example, blood transfusion or may be due to inherited disturbances to the mechanisms regulating intestinal iron absorption. Hereditary Haemochromatosis is an autosomal recessive disease with estimated prevalence of 2 in 1,000 in the Caucasian population, with lower incidence in other races. It is characterised by cirrhosis of the liver, diabetes, cardiomyopathy, arthritis, testicular failure and tanning or bronzing of the skin.
Haemochromatosis is usually related to the deficient synthesis or reduced activity of the peptide hormone Hepcidin (coded for by the ‘Hepcidin Anti-Microbial Peptide’ gene – HAMP), which is produced in the liver. Hepcidin normally down-regulates the entry of iron into the blood stream and therefore regulates iron homeostasis. Mutations in the gene for Hepcidin or in the genes which regulate Hepcidin synthesis such as the Human Haemochromatosis gene (HFE) and ‘Transferrin Receptor 2’ gene – (TFR2) can affect Hepcidin activity. More than 80% of Hereditary Haemochromatosis is due to mutations in such regulatory genes. In addition, mutations in HFE can affect the ability of HFE to bind the transferrin receptor, thereby affecting ferritin levels.
Hereditary Haemochromatosis caused by mutations in the HFE gene is the most common and is termed Type 1 haemochromatosis. Type 2 haemochromatosis is caused by mutations to HAMP and Type 3 by mutations to TFR2. Other types exist.
The HFE gene is located on the short arm of chromosome 6. It codes for a HFE protein which is homologous to MHC class I and is composed of alpha 1 and 2 domains and an immunoglobulin like alpha 3 domain which associates with beta-2 microglobulin. HFE does not however present peptide to T-cells.
Several mutations in the HFE gene have been described. The cysteine to tyrosine substitution at position 282 (C282Y) is present in the homozygous state in over 80% of Hereditary Haemochromatosis cases. In a further 5% of cases, the C282Y mutation is present as a compound heterozygous with a histidine to aspartic acid substitution at position 63 (H63D). These mutations result in excessive, chronic iron absorption in the gut, as well as a relative inability to store iron in macrophages.
Hereditary Haemochromatosis is an excellent example of a disorder that meets the WHO criteria for genetic screening programs. These criteria require that the disorder is common, has a long asymptomatic period, if untreated results in serious morbidity and mortality and has a simple, sensitive and highly specific test. HFE genetic screening for Hereditary Haemochromatosis meets all these criteria. Treatment of Hereditary Haemochromatosis consists of the use of chelating agents and/or regular phlebotomy to reduce body iron load.
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