Proven: The causative role of homozygous H63D mutation in hereditary haemochromatosis

Dear Editor:

We have read with interest the scientific letter by Pinto-Pais et al.¹ “Is H63D a ‘minor’ HFE polymorphism?” They have studied 230 consecutive patients with hyperferritinemia and they have retrieved 16 H63D homozygotes. They have searched for the possible causes of hyperferritinemia, and in all the studied cases but in one there was a possible cause to explain the hyperferritinemia (NAFLD, chronic alcohol consumption, HBV, HBV). No liver iron concentration determination was determined in these patients and this was a very important point to know because of the possible causative role for hereditary hemochromatosis of this polymorphism.² Only in one patient, the study for other liver diseases was negative. Recently, we have published a work developed in 132 consecutive patients referred to a secondary hospital because of hyperferritinemia.³ Only 5% presented high liver iron overload (>80 μmol/g) and 33% of patients had liver iron surcharge (>36 μmol/g). The genotypic frequency of the H63D/H63D mutation was 21.56% in our series (6.96% for the Pinto-Pais et al. group),¹ and we concluded that H63D/H63D genotype and H63D allele predispose in our Region individuals to hyperferritinemia. Effectively, the H63D polymorphism is highly prevalent in Caucasian population (15–20%). The highest allele frequency (>30%), has been reported in the Basque Country, Spain.⁴ The significance of this mutation was in doubt and the EASL consensus do not consider it as a predisposing mutation, but there is evidence that contradicted this⁴: (a) excess of H63D alleles among Hemochromatosis patients; (b) C282Y/H63D have been found to express hemochromatosis with less penetrance that C282Y homocygotes; (c) in vitro evidence has been found; (d) murine evidence of H63D contributing to murine hemochromatosis. There is evidence that H63D mutation contributes to iron overload, increasing serum iron and transferrin, and also it has been demonstrated an independent relationship with hemochromatosis from the presence of C282Y.^5,6 The H63D/H63D genotype is responsible for hyperferritinemia.^2,5,6 It has been shown that H63D produces liver iron overload in homocygosis or in compound heterocygosis with C282Y. The causative role of H63D/H63D mutation in hereditary hemochromatosis or iron overload was demostrated,^4,7,8 but with less penetrance and a considerable variation of phenotypic expression. Mutations in other genes, gene penetrance, and environmental factors (alcohol abuse, steatosis, etc.) have been shown to explain the variable phenotypic expression of C282Y/H63D and H63D/H63D mutations. The search for other mutations in other genes or other unknown nongenetic factors will explain the development of hemochromatosis in these patients.⁴

Conflicts of interest

None declared.