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See article on page 836
Since the original discovery of the haemochromatosis gene (HFE) in 1996,1 there have been two genetic mutations that have dominated clinical studies. The C282Y mutation (845 G→A) has attracted the most attention as the majority of typical haemochromatosis patients are homozygotes for this mutation. This has increasingly led to the use of genetic testing for the diagnosis of haemochromatosis and in many cases has alleviated the need for liver biopsy. In comparison with most other genetic diseases, it remains a marvel that a single mutation explains most clinical cases. Furthermore, in vitro studies have demonstrated that the C282Y mutation disrupts the normal presentation of the HFE protein on the cell surface.2 The H63D mutation (187 G→C) was described in the original description of the HFE gene but has been relegated to a minor clinical role in comparison with the C282Y mutation. It is more prevalent than the C282Y mutation with approximately one in five of the European population carrying the mutation. Despite this high prevalence, it is not well represented in descriptions of large series of haemochromatosis patients defined on the basis of iron overload. The H63D mutation has also not been shown to cause the same intracellular processing defect as the C282Y mutation.
In this issue of Gut, Aguilar-Martinez and colleagues describe a series of 56 H63D homozygotes with varying degrees of iron abnormalities (see page 836).3Although this is not the first description of iron overload in H63D homozygotes, it represents a large series in a referred sample of 968 cases. The authors have tried to eliminate known risk factors such as alcoholism and viral hepatitis and searched for other genetic mutations associated with iron overload. Fifty of their cases had iron abnormalities which ranged from slight elevations in transferrin saturation to six cases of cirrhosis and two with hepatocellular carcinoma. The presence of liver dysfunction is an unexpected observation as in compound heterozygotes (C282Y/H63D) liver damage is uncommon in the absence of another risk factor. The authors acknowledge the effects of referral or ascertainment bias in their study and suggest that population based studies are required to establish the clinical significance of the H63D homozygote. In fact, many of these population studies have been done and many more are in progress. In the screening of 10 198 patients at a health appraisal clinic in San Diego, there were 203 H63D homozygotes. Mean serum ferritin in these homozygotes was 71 μg/l in women and 133 μg/l in men.4 Population studies in Australia5 and Canada6 in which over 8222 people were screened did not detect any H63D homozygotes in cases of iron overload.
Why are there so many iron loaded H63D homozygotes in Montpelier, France, that have not been described in other countries? If a referral bias was the sole explanation, it would be expected that other iron overload referral centres would have a large number of cases. At our own clinic, we have evaluated 25 referred H63D homozygotes with a mean serum ferritin of 760 μg/l (range 7– 8142). The study of siblings of these H63D proband cases would be another approach to reduce referral bias effects. This approach has recently been reported in C282Y homozygous siblings.7 Is it possible that the H63D mutation in these patients is on a haplotype containing another iron loading gene? Different haplotypes with the H63D mutation have been described in Sri Lanka.8 If a regional variation was the explanation, we would expect to see many iron loaded H63D cases in Spain and in screening studies in progress in Rennes, France. The authors point out that H63D homozygotes are very common in their community (3%) and also that 3% of their iron loaded cases carried noHFE mutations, and therefore some of the cases may incidentally be H63D homozygotes without a direct causal relationship. In clinical practice, it seems reasonable to test for both the C282Y and H63D mutations in iron loaded patients. Advances in diagnostic techniques have allowed for the rapid detection of bothHFE mutations. The use of H63D testing in population screening is less certain as it seems likely that most H63D homozygotes will not have iron overload, and so they should not be subjected to the potential risks of stigmatisation, labelling, and genetic discrimination. It continues to be important in all haemochromatosis genotyping studies to include control patients as attribution of symptoms to genotype or iron parameters can be difficult. This current study is provocative because it presents a large number of cases of iron overload in H63D homozygotes. It may stimulate the discovery of other genetic or environmental factors contributing to iron overload in these patients. The large population screening studies which are in progress in many countries should resolve the important issues surrounding the clinical relevance of the H63D homozygote.
See article on page 836
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