Hereditary haemochromatosis: diagnosis and management in the gene era

Hereditary haemochromatosis is a common inherited disorder of iron metaboli sm in Caucasian populations. Two mutations in the HFE gene are strongly ass ociated with hereditary haemochromatosis. One of these mutations (Cys282--> Tyr; C282Y) is found homozygous in 90-95% of subjects with typical heredita ry haemochromatosis. A second mutation (His63-->Asp; H63D) has also been id entified but is not associated with the same degree of iron overload as wit h the C282Y mutation. About 20% of subjects who are heterozygous for both m utations (C282Y, H63D - compound heterozygotes) can express typical heredit ary haemochromatosis. A large number of patients with early disease are asy mptomatic, and prompt diagnosis and treatment can result in normal life exp ectancy. The diagnosis can readily be confirmed by serum iron studies and g enetic testing. For C282Y homozygotes or compound heterozygotes diagnosed u nder the age of 40 years and with no biochemical or clinical evidence of li ver disease, phlebotomy therapy can be initiated without the need for liver biopsy. Liver biopsy should still be considered in all other patients with iron overload. Screening of first degree relatives should now be based on genotype assessment and measurement of serum iron parameters in order to de termine phenotypic expression of the disease.