High prevalence of HFE gene mutations in patients with porphyria cutanea tarda in the Czech Republic.

BACKGROUND: Iron overload and hepatitis C virus (HCV) infection are independent factors which are thought to play a role in the pathogenesis of porphyria cutanea tarda (PCT). OBJECTIVES: To determine the prevalence of the HFE gene mutations p.Cys282Tyr (C282Y), p.His63Asp (H63D) and p.Ser65Cys (S65C), the p.Tyr250X (Y250X) mutation of the TFR2 gene, and HCV infection in patients with PCT in the Czech population, and to make comparison of the iron status among the respective genotypes. METHODS: Iron metabolism indices, results of mutational analysis and serological markers of HCV infection were examined in 63 patients with PCT. RESULTS: The HFE gene mutations were detected in 70% of patients with PCT compared with 35% in the control group (P < 0.001). Mean serum ferritin levels were increased in all genotypes, the highest being in homozygotes for the p.Cys282Tyr mutation. HCV infection was detected in only 8% of patients with PCT. CONCLUSIONS: There was a very high prevalence of the p.Cys282Tyr and p.His63Asp mutations observed in patients with PCT accompanied by mild degrees of iron overload, which was genotype dependent.

[Is tamoxifene porphyrinogenic?]. / Je tamoxifen porfyrinogenní?

BACKGROUND: As reported in previous studies, porphyria cutanea tarda (PCT) developed in several tamoxifene-treated patients with breast cancer. We studied the group of patients with cancer having only tamoxifene therapy after the initial surgery. We evaluated their clinical and laboratory results and compared them with the results of the group of patients suffering also from breast tumor, but treated after the surgery with other systemic therapies, mostly with chemotherapy. METHODS AND RESULTS: 20 patients were complexly studied, 10 of them with only tamoxifene therapy, and 10 without it. Diagnosis of the breast tumor was histologically confirmed in all of them. With the use of laboratory methods we examined their urinary excretion of diagnostically important porphyrins (uro- and coproporphyrin), then total blood count, liver function tests (ALT and AST), blood sugar, cholesterin, serum iron and ferritin, and performed also urinanalysis and detection of possible anti-HCV antibodies. The laboratory examination was repeated in the patient subgroup after three months, urinary uro- and coproporphyrin excretion also in the the control group, for to have an opportunity to follow the dynamics of laboratory changes. All the patients were examined during their regular laboratory controls performed so as not to be bothered with repeated additional phlebotomies. We did not confirm in our patients suffering from breast tumor the results of other autors, suggesting the connection between tamoxifene-therapy and development of porphyria cutanea tarda. CONCLUSIONS: Isolated cases of PCT can be induced through the effect of various hepatotoxic factors. However, the influence of common porphyrinogenically acting noxious substances (alcohol, HCV virus or iron overload as a result of the HFE gene mutations) were not found in our patients.

Autoantibodies in sporadic porphyria cutanea tarda.

In an investigation of autoimmune antibodies using indirect immunofluorescence and Western blot analysis in a group of porphyria cutanea tarda patients we did not find any cytosolic antibodies potentially able to inhibit uroporphyrinogen decarboxylase. Furthermore, no known etiological factors were present in any of our patients. We therefore consider the development of the recently reported autoantibody with a molecular weight of 40 kDa a reaction to infection with the hepatitis C virus. The origin of mostly antinuclear antibodies against liver antigens (50, 45 and 56 kDa), detected in seven patients, was not identified and their etiopathogenetic implications remain unknown.

[Porphyria cutanea tarda after antineoplastic drugs]. / Porphyria cutanea tarda po protinádorových lécích.

Chronic hepatic porphyria is in some cases a paraneoplasia, in others part of the neoplastic disease. Sometimes it is, on the other hand manifested during antineoplastic treatment. Its development may be associated with this therapy. The presented case-history describes a female patient with breast cancer treated with antineoplastic agents, who developed a sporadic form of late cutaneous porphyria with a classical clinical and laboratory picture. The authors contemplate on the possible porphyrinogenic effect of antineoplastic agents, in particular cyclophosphamide and tamoxifen, which in the latter preparation was not described so far.

[Significance and prevalence of the C282Y gene mutation of primary hemochromatosis in the pathogenesis of pophyria cutanea tarda]. / Význam a prevalence mutace C282Y genu primární hemochromatózy (HFE) v patogenezi pozdní kozní porfyrie (PCT).

BACKGROUND: Hitherto studies on the ethiopathogenesis of porphyria cutanea tarda (PCT) show that the major pathogenic factor is iron ion, which acts via inhibition of the uroporphyrinogen decarboxylase. New speculations have appeared on the possible relation of this role of iron and the occurrence of mutation of the recently discovered gene of the hereditary hemochromatosis HFE, which may cause the iron overloading of the organism. Our paper describes prevalence of the C282Y gene mutation (HFE) together with the clinical and laboratory record in PCT patients. METHODS AND RESULTS: PCT was diagnosed mostly on the basis of clinical finding of actinic-traumatic vesicular dermatitis and the typical laboratory record of elevated higher-carboxylic porphyrines in urine and stool. Other laboratory methods tested the liver functions, plasma iron level and its binding capacity, ferritine level. All patient underwent routine haematological testing. Presence of antibodies against hepatitis C was also assayed (Elisa test 2nd generation, Sanofi Pasteur). In patients with prominent laboratory alterations showing possibility of the hepatic structural lesion, histology from the liver punctate was done. Frequency data of the C282Y gene mutation (HFE) in PCT patients was estimated on the basis of the genetic testing using PCR reaction of our own system. Group of PCT patients had 69 persons (63 patients with the sporadic form and 6 patients with familiar form of the disease). Hereditary haemochromatosis C282Y gene mutation (HH) was found in 15 patients, three of them were homozygotes and twelve heterozygotes (three heterozygotes had the familiar form of the disease). Nobody in this group was positive in the HIV antibody testing. In all porphyria patients with the presence of mutated gene who underwent liver biopsy, siderosis of different degrees was identified. In three patients neither the phenotypic observation nor the laboratory testing have shown haemochromatosis. Prevalence of C282Y gene mutation HFE in patients with porphyria cutanea tarda was studied. Such mutation was found in 15 persons (12 heterozygotes and 3 homozygotes) from the group of 69 tested patients (21.7%). Such frequency is significantly higher than in the control--nonporphyric--persons (10%). Patients were without clinical symptoms. Laboratory haematological changes, typical for HH, manifested in some of them only (elevated level of ferritine was found in 10 from 15 porphyria patients, elevated sideremia in one of them). Red blood cell counts were in both homo- and heterozygotes normal. Concurrence of the two porphyrinogenic factors--presence of gene mutation HFE and hepatitis C infection--was not proved. Antibodies against hepatitis C virus were not identified in any of the patients. Siderosis was found to be only a symptomatic sign, which was pronounced in different degree in all 9 porphyria patients with C282Y gene mutation who underwent liver biopsy. CONCLUSIONS: Frequency of C282Y gene mutation in our patients with porphyria cutanea tarda appears similar to that in other Middle European countries. It differs significantly from the frequency found in South European and North European countries (British).