C282Y and H63D mutation of the hemochromatosis gene in German porphyria cutanea tarda patients

Tannapfel, Andrea; Stölzel, Ulrich; Köstler, E; Melz, Steffi; Richter, Matthias; Keim, Volker; Schuppan, Detlef; Wittekind, Christian

doi:10.1007/s004280100401

Cited by 52 publications

(41 citation statements)

References 22 publications

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“…(18) encontraron en Norteamérica que el 73% de los pacientes con PCT tenían una o más mutaciones en el gen HFE (23% heterocigotos, 19% homocigotos C282Y; para H63D 23% heterocigotos y 8% homocigotos). Se han publicado hallazgos similares por otros autores (16,(26)(27)(28). En contraste Sampietro y cols.…”

Section: Discussionunclassified

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Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco

Castiella¹,

Zapata²,

Juan

et al. 2008

Rev. esp. enferm. dig.

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RESUMENObjetivo: estudiar la frecuencia de las mutaciones en el gen HFE (C282Y, H63D, S65C) en un grupo de 54 pacientes con porfiria cutánea tarda (PCT) y en un grupo de controles sanos (donantes de sangre) en Guipúzcoa. También analizar su relación con los virus de la hepatitis B y C (VHB, VHC), alcohol y otros factores de riesgo reconocidos.Métodos: el análisis de las mutaciones se hizo mediante PCR. Se compararon las frecuencias alélicas y genotípicas. Se determinaron la probabilidad y el test de Chi cuadrado.Resultados: no encontramos asociación entre C282Y y PCT (5,76 vs. 5% controles). Se observó una alta frecuencia alélica en la mutación H63D en PCT (34,25%), pero sin ser estadísticamen-te significativa (controles 29,31%), debido a la alta prevalencia de esta mutación en la población vasca. La mutación S65C fue menor en PCT que en controles. Encontramos una idéntica presencia de H63D en heterocigosis en ambos grupos (38,8 vs. 38,8%). La asociación con el VHC se objetivó en el 35,18% de los pacientes y la infección por VHB en el 7,4%. Un 55,55% de los pacientes tenía un hábito alcohólico de más de 60 g etanol día. Todos eran negativos para el virus de la inmunodeficiencia humana (VIH) y 1 de las 5 mujeres con PCT tomaba estrógenos.Conclusión: las mutaciones C282Y y H63D no tienen un papel relevante en los pacientes con PCT en Guipúzcoa. Los factores externos (consumo importante de alcohol y VHC) parecen jugar un papel fundamental en el desarrollo de la PCT en nuestra población.Palabras clave: Porfiria cutánea tarda. Enfermedades hepáticas. Gen HFE. ABSTRACTAim: to study the frequency of HFE gene mutations (C282Y, H63D, S65C) in a group of 54 sporadic PCT patients and in a group of healthy controls (blood donors) from Guipúzcoa, Spain. We studied the association of PCT with HCV, HBV, alcohol abuse, and other established risk factors.Methods: the analysis of mutations was made by PCR. Allelic and genotypic frequencies were compared. Probability was determined and a Chi-squared test was performed.Results: no association was observed between C282Y mutation and PCT (5.76 vs. 5% in controls). A high H63D mutation frequency was observed in PCT (34.25%) but was not statistically significant (controls 29.31%) because of the high prevalence of this mutation in the Basque general population. The S65C mutation was lower in PCT than in controls. There is a similar presence for H63D heterozygosis in PCT (38.8 vs. 38.8%). HCV association was observed in 35.18% of patients with PCT. HBV infected 7.4% of patients. Heavy alcohol intake (> 60 g/day) was present in 55.55% of patients. No HIV-infected patients were detected. The study of other risk factors revealed only one of the five women with PCT taking estrogens.Conclusion: our results found no relevant role for C282Y and H63D mutations. External factors such as HCV and alcohol could be determinant in the development of PCT in the Basque population.

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Section: Discussionunclassified

“…La relación entre mutaciones HFE con los índices séricos férricos, la concentración férrica hepática y la fibrosis varía de unos trabajos a otros (2,4,16,18,25,26,28,30,31). En nuestra serie el 80% de los pacientes presentaron elevación de ferritina.…”

Section: Discussionunclassified

Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco

Castiella¹,

Zapata²,

Juan

et al. 2008

Rev. esp. enferm. dig.

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“…Additionally, induction of the δ-ALA-synthase increases the amount of δ-aminolevulinic acid, the primary product of the porphyrin synthesis pathway, thus accumulating intermediate products which provoke the symptoms of PCT. The high frequency of homo-and heterozygous allele carriers for the C282Y-and H63D-mutations of HHC among patients with sporadic PCT, as opposed to healthy controls, was demonstrated in several countries, such as Germany [12] , Great-Britain [13] , the Netherlands [14] and Australia [15] . Further studies confirmed the HFE mutations as a risk factor for PCT as well as additional risk factors like alcohol consumption, smoking and hepatitis C virus infection [16][17][18] .…”

Section: Discussionmentioning

confidence: 99%

An unhappy triad: Hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-A case report

Mogl

Pascher²,

Presser³

et al. 2007

WJG

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Liver fibrosis and cirrhosis are predisposing factors for the development of hepatocellular carcinoma (HCC). Hemosiderosis has also been described to trigger carcinogenesis. A significant iron overload, as found in hereditary hemochromatosis (HHC), is a risk factor for HCC and may also promote the symptoms of porphyria cutanea tarda (PCT). A 68-year old male patient presented to our clinic with a suspected HCC, elevated alpha-fetoprotein but normal liver function tests. He reported a 25 year-old history of vitiligo upon exposure to sunlight. The patient underwent an extended left hemihepatectomy, and the recovery was uneventful, with the exception of a persistent hyperbilirubinemia. Perfusion problems and extrahepatic cholestasis were ruled out by CT-scan with angiography and MR-cholangiopancreatography. However, MRI showed an iron overload. Histology confirmed the HCC (pT3, pN0, G3, R0) and revealed a portal fibrosis and hemosiderosis. Based on the skin lesions we suspected a PCT that was confirmed by laboratory tests showing elevated porphyrin, uroporphyrin, coproporphyrin and porphobilinogen. Concurrently, molecular diagnostics revealed homozygosity for the C282Y mutation within the hemochromatosis HFE gene. After phlebotomy and normalization of liver function tests the patient was discharged. This is the first case ever showing the unusual combination of HCC in a fibrotic liver with HHC and PCT. This diagnosis not only warrants oncological follow-up but also symptomatic therapy to normalize iron metabolism and thereby improve liver function and alleviate the symptoms of HHC and PCT. Thus progression of fibrosis may be prevented and liver regeneration supported.

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“…[1][2][3] PCT patients usually display hepatic siderosis, and the disease is responsive either to phlebotomy, which presumably acts through iron depletion, or a treatment with low-dose chloroquine or hydroxychloroquine. 1,2 In addition, some PCT patients have quite high levels of hepatic iron associated with the common mutations in the HFE gene (C282Y and H63D), 4,5 which are also found in hereditary hemochromatosis (type I).…”

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confidence: 99%

Effect of an oral iron chelator or iron-deficient diets on uroporphyria in a murine model of porphyria cutanea tarda

Gorman¹,

Zaharia²,

Trask³

et al. 2007

Hepatology

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Porphyria cutanea tarda is a liver disease characterized by elevated hepatic iron and excessive production of uroporphyrin (URO). Phlebotomy is an effective treatment that probably acts by reducing hepatic iron. Here we used Hfe(؊/؊) mice to compare the effects on hepatic URO accumulation of two different methods of hepatic iron depletion: iron chelation using deferiprone (L1) versus iron-deficient diets. Hfe(؊/؊) mice in a 129S6/SvEvTac background were fed 5-aminolevulinic acid (ALA), which results in hepatic URO accumulation, and increasing doses of L1 in the drinking water. Hepatic URO accumulation was completely prevented at low L1 doses, which partially depleted hepatic nonheme iron. By histological assessment, the decrease in hepatic URO accumulation was associated with greater depletion of iron from hepatocytes than from Kupffer cells. The L1 treatment had no effect on levels of hepatic cytochrome P4501A2 (CYP1A2). L1 also effectively decreased hepatic URO accumulation in C57BL/6 Hfe(؊/؊) mice treated with ALA and a CYP1A2 inducer. ALA-treated mice maintained on defined iron-deficient diets, rather than chow diets, did not develop uroporphyria, even when the animals were iron-supplemented either directly in the diet or by iron dextran injection. Conclusion: The results suggest that dietary factors other than iron are involved in the development of uroporphyria and that a modest depletion of hepatocyte iron by L1 is sufficient to prevent URO accumulation. (HEPATOLOGY

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C282Y and H63D mutation of the hemochromatosis gene in German porphyria cutanea tarda patients

Abstract: The high frequency of homo- and heterozygosity for the C282Y and H63D alleles strongly suggests that these mutations are important predisposing factors for PCT in German patients.

Cited by 52 publications

References 22 publications

Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco

Porfiria cutánea tarda: asociación con mutaciones HFE, hepatitis virales, alcohol y otros factores de riesgo en Guipúzcoa, País Vasco

An unhappy triad: Hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-A case report

Effect of an oral iron chelator or iron-deficient diets on uroporphyria in a murine model of porphyria cutanea tarda

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