Clinical penetrance

Before the discovery of the HFE gene, it was assumed that every family member who was homozygous for haemochromatosis would eventually accumulate sufficient iron to cause tissue damage. Recent studies, in which subjects homozygous for HFE C282Y have been compared with 'wild-type' subjects, have shown that the frequencies of lethargy, arthralgia and diabetes are the same. There is, however, a small but significant increase in the percentage of subjects with either raised serum transaminase activity or fibrosis/cirrhosis in the C282Y homozygous group. Furthermore, population surveys have shown that less than 5% of subjects homozygous for C282Y ever receive a diagnosis of haemochromatosis. Despite much debate about ascertainment bias in family and population surveys, it is becoming clear that most men who are homozygous for C282Y will have a raised transferrin saturation before the age of 30 years; a proportion will have an elevated serum ferritin concentration, but only a minority will eventually develop fibrosis and cirrhosis of the liver. Only about 50% of homozygous women have a raised transferrin saturation, and progression through iron accumulation and tissue damage is usually, but not always, slower. In one population study in the USA, the clinical penetrance was estimated to be as low as 1%.

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