Hereditary haemochromatosis: diagnosis and management in the gene era

Hereditary haemochromatosis is a common inherited disorder of iron metabolism in Caucasian populations. Two mutations in the HFE gene are strongly associated with hereditary haemochromatosis. One of these mutations (Cys282-->Tyr; C282Y) is found homozygous in 90-95% of subjects with typical hereditary haemochromatosis. A second mutation (His63-->Asp; H63D) has also been identified but is not associated with the same degree of iron overload as with the C282Y mutation. About 20% of subjects who are heterozygous for both mutations (C282Y, H63D - compound heterozygotes) can express typical hereditary haemochromatosis. A large number of patients with early disease are asymptomatic, and prompt diagnosis and treatment can result in normal life expectancy. The diagnosis can readily be confirmed by serum iron studies and genetic testing. For C282Y homozygotes or compound heterozygotes diagnosed under the age of 40 years and with no biochemical or clinical evidence of liver 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 determine phenotypic expression of the disease.