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More than 80% of people with a clinical diagnosis of the iron overload disease hereditary haemochromatosis are homozygous for the C282Y mutation in the HFE gene. As about 1 in 200 people in populations of European extraction are homozygous for this allele, there have been calls for population screening followed by prophylactic treatment (regular phlebotomy) for those identified. However, the penetrance of haemochromatosis-associated mutations has been unclear, with some studies suggesting that it is very low. Beutler et al now report a very large study, involving more than 41,000 people, who were tested for C282Y and a second haemochromatosis-associated mutation, H63D, and for symptoms of iron overload [Beutler, E. et al (2002) Lancet 359, 211-218]. A range of classical clinical signs and symptoms associated with haemochromatosis were no more frequent in the 152 individuals who were homozygous (C282Y/C282Y) or compound heterozygotes (C282Y/H63D) for haemochromatosis-associated mutations than they were in matched controls. One exception was a history of liver disease, but this feature was still observed in only 10% of those with genetically-defined haemochromatosis, and there was no evidence that the liver symptoms worsened with age or shortened lifespan. Only one individual had clinically-defined haemochromatosis.

Comment: This large study provides compelling evidence that the penetrance of haemochromatosis-associated genotypes is far lower than would be needed to justify a population screening programme.