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• W2073485404 abstract "Dear Sir, Porphyria cutanea tarda (PCT) is caused by a strongly reduced activity of the hepatic enzyme uroporphyrinogen decarboxylase (UROD; EC 4.1.1.37). The reduced activity leads to accumulation of phototoxic porphyrins, primarily uroporphyrinogen and heptacarboxylated porphyrinogens that cause the characteristic clinical pattern with skin fragility and blisters on skin areas exposed to the sun [1, 2]. Iron seems to play a central role in the pathogenesis of PCT, because mild hepatic siderosis is present in most of the patients with overt disease [3, 4]. Removal of iron by repeated phlebotomies always leads to clinical and biochemical remission, even in patients without increased liver or total body iron [2, 5]. The disease process is enhanced by several heterogeneous factors such as alcohol abuse, estrogens and hepatic viral infections [for review see 6]. An association between hereditary haemochromatosis and PCT has been suspected for decades [3, 4, 7]. After the identification of the haemochromatosis-associated HFE gene [8], a high percentage of HFE mutations in patients with manifest PCT have been reported in many countries [9–16]. The present study was undertaken to retrospectively investigate the frequency of three HFE mutations (C282Y, H63D and S65C) in 117 unrelated Swedish PCT patients, with clinically and biochemically confirmed diagnosis [6]. The HFE allele frequencies in PCT patients were compared with the frequencies found in a control group of 250 Swedish healthy subjects and also to a group consisting of 296 patients with suspected clinical iron overload (elevated serum ferritin and/or transferrin saturation). The latter group has been characterized and reported before [17]. Written informed consent was obtained from all the patients and the study was approved by the local Ethics Committee of the Karolinska Institute (Dnr 167/99), Stockholm. Based on the UROD activity in erythrocyte lysates [18, 19], the PCT patients had been classified at the time of diagnosis as being either of familial (F-PCT, n = 53) or sporadic (S-PCT, n = 64) form of PCT [20]. Genomic DNA was extracted from peripheral blood, which had been kept frozen at −80 °C since the time of PCT diagnosis. The HFE genotypes were determined by sequencing two of the HFE gene regions flanking Cys282 (exon 4) and His63/Ser65 (exon 2). Comparisons of the frequencies of the HFE C282Y, H63D and S65C mutations in patients with PCT, healthy controls and patients with suspected clinical iron overload were performed with chi-square test, and P < 0.05 was considered statistically significant (Table 1). Of the 53 patients with F-PCT, six were homozygous for the C282Y mutation, five were C282Y/H63D compound heterozygous and one patient was homozygous for the H63D mutation. In the group of 64 S-PCT patients, 14 were homozygous for the C282Y mutation, six were compound heterozygous (C282Y/H63D) and three were homozygous for the H63D mutation. The presence of the third HFE mutation (S65C) was found in two S-PCT cases, one heterozygous and one compound heterozygous (S65C/H63D). Amongst PCT patients, there was a clear overrepresentation of C282Y homozygosity and C282Y/H63D compound heterozygosity compared with healthy controls (P < 0.001), which is in accordance with the results published by Bulaj et al. [16]. The HFE genotypes in PCT patients were not statistically different from those found in patients with suspected clinical iron overload (Table 1). The frequency of the carrier condition of the C282Y mutation in the S-PCT group was 44%, which is the same frequency as reported in British, Australian and North American S-PCT patients [9, 11, 13]. There was a significant difference in the HFE genotype patterns between familial and sporadic PCT. The C282Y/C282Y genotype and the presence of two HFE mutations was more frequent in the S-PCT group (P < 0.05), whilst the H63D/wildtype genotype was more frequent in F-PCT (P < 0.05), which also confirms the report from Bulaj et al. [16]. The increased prevalence of the H63D/wildtype genotype in the F-PCT group may indicate a possible importance of this HFE mutation in the pathogenesis of PCT. The H63D mutation has been associated with a mild iron overload [8], and as earlier pointed out by Sampietro et al. [12] it may contribute to an earlier precipitation of PCT symptoms. The rare S65C mutation was found in only two S-PCT patients. This mutation has a much lower carrier frequency compared with C282Y and H63D and has been considered of less significance in the pathogenesis of both PCT and haemochromatosis [17, 21]. The mean of the age at clinical onset for F-PCT patients was significantly lower than that for S-PCT patients (P < 0.001; Table 2). For these comparisons, four relatives (three offspring and one sibling) were added to the F-PCT group, i.e. the group increased to 57 F-PCT patients. The earlier clinical onset of F-PCT compared with S-PCT has in general been suspected [20, 22] and was recently established by Brady et al. [23]. The present study thus confirms this fact. The difference still remained when only the HFE mutation carriers from each group were compared (P < 0.001), and also when only the groups of homozygous and compound heterozygous patients were compared (P < 0.002). Even when only C282Y homozygous patients from each PCT group were compared, a difference was observed (P < 0.05; Table 2). There was no significant difference with regards to the age at clinical onset between carriers and noncarriers of HFE mutations within either form of PCT (Table 2). These results are in agreement with a study by Roberts et al. who found no difference regarding age at onset in a group of 41 S-PCT patients classified as carrying the C282Y mutation or not [9]. Neither was any statistically significant difference found when comparing only the homozygotes and compound heterozygotes from each PCT group to the respective group of non-HFE carriers. A lower UROD activity was recorded for F-PCT patients carrying no HFE mutation (48.6 ± 7.5%) compared with the mutation carriers in the same group (55.0 ± 8.5%; P < 0.01, Wilcoxon two-sample test). The difference was accentuated when only HFE homozygotes and compound heterozygotes (UROD 60.1 ± 6.5%) were compared with non-HFE carriers (P < 0.001, Wilcoxon two-sample test). This observation may indicate that, in the absence of HFE mutations, F-PCT carriers may need a lower baseline UROD activity to develop overt disease. There were no such differences between the corresponding S-PCT subgroups. We found that HFE mutations are clearly enriched in 117 unrelated Swedish PCT patients, to the same degree as in patients with suspected clinical iron overload (i.e. 62 and 69%, respectively). The C282Y homozygosity, which is the HFE genotype showing the strongest level of association with development of iron overload and overt haemochromatosis [8] was found to be more common in S-PCT patients (22%) when compared with patients with F-PCT (11%; P < 0.05). The age at clinical outbreak was much lower in F-PCT than in S-PCT independently of the presence of HFE mutations. Patients with overt PCT should be thoroughly investigated with respect to triggering factors, liver and iron metabolism before the choice of treatment, usually based on a regimen of phlebotomies or chloroquine phosphate (or a combination of both) [22]. The HFE genotyping may be helpful in deciding therapy choice, the frequency of phlebotomies and a follow-up programme [for review see 6]. No conflict of interest was declared. The authors thank Ms Pari Kabiri for excellent technical assistance. The study was supported by grants from the Karolinska Institute." @default.
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• W2073485404 date "2004-05-14" @default.
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• W2073485404 title "Enrichment of HFE mutations in Swedish patients with familial and sporadic form of porphyria cutanea tarda" @default.
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