Dear Sir,

We read with interest the manuscript of Harper et al. [1], that analysed the presence of mutations of the haemochromatosis-associated gene (HFE) in patients of northern Europe with sporadic porphyria cutanea tarda (sPCT); the authors found that the presence of C282Y mutation of HFE was associated to iron overload and overt haemochromatosis. Nevertheless, it is already known that the polymorphism distribution of HFE may differ in different populations; in fact, the H63D and less S65C mutations are closely related to iron overload in patients with sPCT in Mediterranean areas. In Spain the specific HFE mutation associated to sPCT is H63D [2–4]. We were interested in the early detection of these HFE mutations in first-degree relatives of patients with sPCT, in order to identify those who could be susceptible, after hypothetical exposure to triggering factors like alcohol, oestrogens or liver viral infections [5], of developing overt PCT.

For this purpose we determined the three major HFE mutations (C282Y, H63D and S65C), porphyrins (uro-III and hepta-III) in a 24-h urine sample, as well as the iron load status in 25 first-degree relatives (16 were offspring, seven sibblings, and two parents) of 11 unrelated patients with sPCT. HFE mutations were analysed by polymerase chain reaction using RsaI, BclI, and HindI [6, 7].

The relatives were mainly women (n = 18); the mutation H63D was present in five (20%) of them, and two (8%) were heterozygous for the C282Y mutation. None of them showed elevated urine porphyrins, and iron metabolism alterations were also absent in those with different HFE mutations. A description of the HFE genotypes of the studied relatives is detailed in Table 1.

Table 1. HFE mutations, iron status, and biological characteristics in first-degree relatives of sporadic PCT patients
Genotypen (%)Sex (M/F)Ferritin (μg dL−1)Saturation index (%)Haemoglobin (g/L) ALT (U/L)
  1. ALT, alanine aminotransaminase.

C282Y/–2 (8)2/044.00 ± 26.8731.45 ± 18.32156.60 ± 24.6819.30 ± 23.1
H63D/–5 (20)1/458.00 ± 59.0229.50 ± 17.44154.50 ± 21.9322.25 ± 12.6
No mutations18 (72)4/1494.22 ± 113.7727.42 ± 7.54133.4 ± 21.7817.89 ± 7.2

In our study, in contrast to results of Harper et al. [1], the mainly observed genotype was H63D mutation. However, the presence this mutation in relatives of patients with sPCT was not correlated with iron overload nor with altered liver function, so this issue, in our opinion, remains to be elucidated.

A second finding of our study that bears consideration is the high frequency of heterozygous H63D overexpression in women (male 1/female 4), similar to that described by other authors [7]; this finding, together with the expanded use of oestrogens and increase in alcohol consumption by women, could induce changes in the features of PCT in the future. In fact a 53% of the evaluated women were receiving oestrogens, and a 67% drank alcohol every day.

We agree with Harper et al. that determination of iron load status and HFE mutations in patients with sPCT and their first-degree relatives could be useful in the early detection and treatment of iron overload; nevertheless we recommend this last determination only in those persons with iron overload (by means of a saturation index >50%), or demonstrated liver function abnormalities. In any case we think that future studies are needed to definitively establish the role of H63D mutation in the development of PCT in relatives of patients with sPCT of Mediterranean areas.

Conflict of interest statement

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  2. Conflict of interest statement
  3. References

No conflict of interest was declared.


  1. Top of page
  2. Conflict of interest statement
  3. References
  • 1
    Harper P, Floderus Y, Holmstrom P, Eggertsen G, Gafvels M. Enrichment of HFE mutations in Swedish patients with familial and sporadic form of porphyria cutanea tarda. J Inter Med 2004; 255: 6847.
  • 2
    Bulaj ZJ, Phillips JD, Aljoka RS et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 2000; 95: 156571.
  • 3
    Trombini P, Mauri V, Salvioni A, Corengia C, Arosio C, Piperno A. S65C frequency in Italian patients with hemochromatosis, porphyria cutanea tarda and chronic viral hepatitis with iron overload. Haemologica 2001; 86: 3167.
  • 4
    Enriquez de Salamanca R, Morales P, Castro MJ, Rojo R, Gonzalez M, Arraiz-Villena A. The most frequent HFE allele linked to porphyria cutanea tarda in Mediterranean is His63Asp. Hepatology 1999; 30: 81920.
  • 5
    Garcia Morillo JS, Carneado de la Fuente J, Stiefel P, Garcia-Donas MA, González Escribano MF, Nuñez Roldan A. Study of the gene of hemocromatosis in first degree relatives of patients with porphyria cutanea tarda. Med Clin (Barc) 1999; 112: 699701.
  • 6
    Feder JN, Gnirke A, Thomas W et al. A novel MHC class I-like gene is mutaded in patients with hereditary haemochromatosis. Nat Genet 1996; 13: 399408.
  • 7
    Bygum A, Christiansen L, Petersen NE, Horder M, Thomsem K, Brandrup B. Familial and sporadic porphyria cutanea tarda: clinical, biochemical and genetic features with emphasis on iron status. Acta Derm Venereol 2003; 83: 11520.