RESUMO
BACKGROUND: Hemochromatosis is a genetic condition of iron overload caused by deficiency of hepcidin. In a previous stage of this study, patients with suspected hemochromatosis had their quality of life (QL) measured. We observed that QL scores differed among genotypic groups of patients. In this reported final phase of the study, the aims were to compare QL scores after a treatment period of approximately 3 years and to analyze a possible association of the serum ferritin values with QL scores. METHODS: Sixty-five patients were enrolled in this final phase and divided into group 1 (patients that showed primary iron overload and homozygous genotype for the HFE p.Cys282Tyr mutation) and group 2 (other kinds of genotypes). Short Form 36 (SF-36) was performed and consisted of eight domains with a physical and also a mental component. RESULTS: Both groups had a significant decrease in serum ferritin concentrations: group 1 had a variation from 1844 ± 1313 ng/mL to 281 ± 294 ng/mL, and group 2 had a variation from 1216 ± 631 ng/mL to 236 ± 174 ng/mL. Group 1 had a smaller mean value for these six SF-36 domains compared with group 2, indicating a worse QL. CONCLUSIONS: In this final stage, six domains demonstrated a difference among genotypic groups (role emotional and mental health, adding to the four of the initial phase), reassuring the impact of the identified genotype on the QL of hemochromatosis patients. Furthermore, despite that both patient groups demonstrated similar and significant decreases in serum ferritin values, no association was found between the decrease in this biological parameter and the SF-36 domains.
Assuntos
Ferritinas/sangue , Proteína da Hemocromatose/genética , Hemocromatose/diagnóstico , Hemocromatose/genética , Proteínas de Membrana/genética , Mutação , Qualidade de Vida , Predisposição Genética para Doença , Genótipo , Hemocromatose/sangue , HumanosRESUMO
AIM: Hereditary hemochromatosis (HH) is a group of inherited disorders that causes a slow and progressive iron deposition in diverse organs, particularly in the liver. Iron overload induces oxidative stress and tissue damage. Coenzyme Q10 (CoQ10) is a cofactor in the electron-transport chain of the mitochondria, but it is also a potent endogenous antioxidant. CoQ10 interest has recently grown since various studies show that CoQ10 supplementation may provide protective and safe benefits in mitochondrial diseases and oxidative stress disorders. In the present study we sought to determine CoQ10 plasma level in patients recently diagnosed with HH and to correlate it with biochemical, genetic, and histological features of the disease. METHODS: Plasma levels of CoQ10, iron, ferritin, transferrin and vitamins (A, C and E), liver tests (transaminases, alkaline phosphatase and bilirubin), and histology, as well as three HFE gene mutations (H63D, S654C and C282Y), were assessed in thirty-eight patients (32 males, 6 females) newly diagnosed with HH without treatment and in twenty-five age-matched normolipidemic healthy subjects with no HFE gene mutations (22 males, 3 females) and without clinical or biochemical signs of iron overload or liver diseases. RESULTS: Patients with HH showed a significant decrease in CoQ10 levels respect to control subjects (0.31⯱â¯0.03 µM vs 0.70⯱â¯0.06 µM, pâ¯<â¯0.001, respectively) independently of the genetic mutation, cirrhosis, transferrin saturation, ferritin level or markers of hepatic dysfunction. Although a decreasing trend in CoQ10 levels was observed in patients with elevated iron levels, no correlation was found between both parameters in patients with HH. Vitamins C and A levels showed no changes in HH patients. Vitamin E was significantly decreased in HH patients (21.1⯱â¯1.3 µM vs 29.9⯱â¯2.5 µM, pâ¯<â¯0.001, respectively), but no correlation was observed with CoQ10 levels. CONCLUSION: The decrease in CoQ10 levels found in HH patients suggests that CoQ10 supplementation could be a safe intervention strategy complementary to the traditional therapy to ameliorate oxidative stress and further tissue damage induced by iron overload.
Assuntos
Ataxia , Hemocromatose , Doenças Mitocondriais , Debilidade Muscular , Ubiquinona/deficiência , Ataxia/epidemiologia , Estudos de Casos e Controles , Feminino , Hemocromatose/sangue , Hemocromatose/epidemiologia , Hemocromatose/genética , Humanos , Masculino , Doenças Mitocondriais/epidemiologia , Debilidade Muscular/epidemiologia , Ubiquinona/análogos & derivados , Ubiquinona/sangueRESUMO
BACKGROUND: Hereditary hemochromatosis (HH) is a primary iron overload (IO) condition. Absolute telomere length (ATL) is a marker of cellular aging and DNA damage associated with chronic diseases and mortality. AIM: To evaluate the relationship between ATL and IO in patients with HH. METHODS: Cross-sectional study including 25 patients with HH: 8 with IO and 17 without IO (ferritin < 300 ng/ml) and 25 healthy controls. Inclusion criteria were: age > 18 years, male sex and HH diagnosis. Patients with diabetes or other endocrine and autoimmune diseases were excluded. ATL was measured by real-time PCR. RESULTS: HH patients with IO were older (P<0.001) and showed higher ferritin concentration (P<0.001). Patients with HH, disregarding the iron status, showed higher glucose and body mass index (BMI) than controls (both P<0.01). ATL was shorter in patients with IO than controls [with IO: 8 (6-14), without IO: 13 (9-20), and controls: 19 (15-25) kilobase pairs, P<0.01]; with a linear trend within groups (P for trend <0.01). Differences in ATL remained statistically significant after adjusting by age, BMI and glucose (P<0.05). DISCUSSION: Patients with IO featured shorter ATL while patients without IO showed only mild alterations vs. controls. Screening for IO is encouraged to prevent iron-associated cellular damage and early telomere attrition.
Assuntos
Hemocromatose/imunologia , Ferro/metabolismo , Leucócitos/imunologia , Homeostase do Telômero/imunologia , Telômero/metabolismo , Adulto , Idoso , Envelhecimento/imunologia , Estudos Transversais , Ferritinas/sangue , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/genética , Proteína da Hemocromatose/genética , Humanos , Ferro/sangue , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Estresse Oxidativo/imunologiaRESUMO
INTRODUCTION AND AIM: Observations of hepatitis C virus (HCV) infection in adults with hemochromatosis are limited. MATERIALS AND METHODS: We determined associations of serum ferritin (SF) with anti-HCV in non-Hispanic white North American adults in a post-screening examination. Cases included p.C282Y homozygotes (regardless of screening transferrin saturation (TS) and SF) and participants (regardless of HFE genotype) with high screening TS/SF. Controls included participants without p.C282Y or p.H63D who had normal screening TS/SF. Participants with elevated alanine aminotransferase underwent anti-HCV testing. We determined prevalence of chronic HCV infection in consecutive Alabama and Ontario referred adults with HFE p.C282Y homozygosity. RESULTS: In post-screening participants, anti-HCV prevalence was 0.3% [95% CI: 0.02, 2.2] in 294 p.C282Y homozygotes, 9.5% [7.2, 12.3] in 560 Cases without p.C282Y homozygosity, and 0.7% [0.2, 2.3] in 403 Controls. Anti-HCV was detected in 7.2% of 745 participants with and 0.8% of 512 participants without elevated SF (odds ratio 9.9 [3.6, 27.6]; p<0.0001). Chronic HCV infection prevalence in 961 referred patients was 1.0% (10/961) [95% confidence interval (CI): 0.5, 2.0]. Ten patients with chronic HCV infection had median age 45y (range 29-67) and median SF 1163µg/L (range 303-2001). Five of eight (62.5%) patients had biopsy-proven cirrhosis. CONCLUSIONS: Odds ratio of anti-HCV was increased in post-screening participants with elevated SF. Prevalence of anti-HCV in post-screening participants with HFE p.C282Y homozygosity and chronic HCV infection in referred adults with HFE p.C282Y homozygosity in North America is similar to that of Control participants with HFE wt/wt and normal screening TS/SF.
Assuntos
Proteína da Hemocromatose/genética , Hemocromatose/genética , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/epidemiologia , Mutação , Adulto , Idoso , Alabama/epidemiologia , Alanina Transaminase/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Ferritinas/sangue , Predisposição Genética para Doença , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/epidemiologia , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Fenótipo , Prevalência , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: 373 black participants had elevated screening and post-screening serum ferritin (SF) (> 300 µg/L men; > 200 µg/L women). MATERIAL AND METHODS: We retrospectively studied SF and post-screening age; sex; body mass index; transferrin saturation (TS); ALT; AST; GGT; elevated C-reactive protein; ß-thalassemia; neutrophils; lymphocytes; monocytes; platelets; metacarpophalangeal joint hypertrophy; hepatomegaly; splenomegaly; diabetes; HFE H63D positivity; iron/alcohol intakes; and blood/erythrocyte transfusion units. Liver disease was defined as elevated ALT or AST. We computed correlations of SF and TS with: age; body mass index; ALT; AST; GGT; C-reactive protein; blood cell counts; and iron/alcohol. We compared participants with SF > 1,000 and ≤ 1,000 µg/L and performed regressions on SF. RESULTS: There were 237 men (63.5%). Mean age was 55 ± 13 (SD) y. 143 participants had liver disease (62 hepatitis B or C). There were significant correlations of SF: TS, ALT, AST, GGT, and monocytes (positive); and SF and TS with platelets (negative). 22 participants with SF > 1,000 µg/L had significantly higher median TS, ALT, and AST, and prevalences of anemia and transfusion > 10 units; and lower median platelets. Regression on SF revealed significant associations: TS; male sex; age; GGT; transfusion units (positive); and splenomegaly (negative) (p < 0.0001, 0.0016, 0.0281, 0.0025, 0.0001, and 0.0096, respectively). Five men with SF > 1,000 µg/L and elevated TS had presumed primary iron overload (hemochromatosis). Four participants had transfusion iron overload. CONCLUSION: Persistent hyperferritinemia in 373 black adults was associated with male sex, age, TS, GGT, and transfusion. 2.4% had primary iron overload (hemochromatosis) or transfusion iron overload.
Assuntos
Ferritinas/sangue , Hemocromatose/sangue , Sobrecarga de Ferro/sangue , Adulto , Negro ou Afro-Americano/genética , Idoso , Alabama/epidemiologia , Biomarcadores/sangue , Transfusão de Sangue , Comorbidade , Feminino , Hemocromatose/etnologia , Hemocromatose/genética , Hemocromatose/terapia , Humanos , Sobrecarga de Ferro/etnologia , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/terapia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Transferrina/metabolismo , Resultado do Tratamento , Regulação para Cima , gama-Glutamiltransferase/sangueRESUMO
BACKGROUND AND AIM: HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. MATERIAL AND METHODS: Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrhosis. RESULTS: GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. CONCLUSIONS: Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.
Assuntos
Aciltransferases/genética , Doadores de Sangue , Proteína da Hemocromatose/genética , Hemocromatose/genética , Ferro/sangue , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Ferritinas/sangue , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/enzimologia , Heterozigoto , Homozigoto , Humanos , Itália , Fígado/metabolismo , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/enzimologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de RiscoRESUMO
BACKGROUND: Previous studies in high and low expressors has demonstrated that a variant in the GNPAT gene (D519G, Rs11558492, chromosome 1, exon 11) has been associated with severe iron overload in C282Y homozygotes for hemochromatosis. In this study, a GNPAT variant was assessed prospectively in patients referred for HFE testing over a range of serum ferritin levels. MATERIAL AND METHODS: Consecutive patients sent for HFE testing were studied for the GNPAT variant using a TaqMan kit assay (Life Technologies, Burlington, ON). Serum ferritin and iron removed by phlebotomy was compared in C282Y homozygotes with and without the GNPAT variant. The frequency of the GNPAT variant in referred patients was compared to a control population of voluntary blood donors without HFE mutations. RESULTS: There were 533 patients that had GNPAT analysis. The allele frequency for the GNPAT variant in C282Y homozygotes (n = 75) was 0.226 and in wild type control patients (n = 458) was 0.213 (p = .07). Forty-eight percent (of the C282Y homozygotes were heterozygous (n = 28) or homozygous (n = 8) for the GNPAT variant. The mean (log)ferritin and iron removed did not significantly differ between C282Y homozygous with GNPAT homozygotes, GNPAT heterozygotes, and without the GNPAT variant (p = 0.84). CONCLUSIONS: C282Y homozygotes referred for HFE testing commonly have a GNPAT variant. This GNPAT variant does not appear be a co-modifying gene affecting expression of HFE related hemochromatosis in this population. The GNPAT variant does not predict the severity of iron overload.
Assuntos
Aciltransferases/genética , Ferritinas/sangue , Proteína da Hemocromatose/genética , Hemocromatose/genética , Ferro/sangue , Flebotomia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/terapia , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Índice de Gravidade de Doença , Regulação para CimaRESUMO
BACKGROUND: We identified no reports of long-term follow-up of participants in hemochromatosis screening programs. We evaluated causes of death and survival in non-C282Y homozygous Canadian participants in the primary care-based hemochromatosis and iron overload screening (HEIRS) study. MATERIAL AND METHODS: Initial screening (IS) included transferrin saturation (TS), serum ferritin (SF), HFE genotyping (C282Y, H63D), and health questionnaire responses. By definition, participants without C282Y or H63D had HFE wt/wt. We linked 20,306 Canadian participants to the Ontario Death Registry for dates and causes of death 9 y after IS. We computed Cox proportional hazards to identify factors with increased death risks and Kaplan-Meier curves to estimate survival of non-C282Y homozygous participants with SF ≤ 1,000 µg/L and > 1,000 µg/dL. RESULTS: There were 19,052 evaluable participants (IS mean age 49 y; 60% women; 93 C282Y homozygotes). There were 988 deaths. Significantly increased hazard ratios for all-cause mortality were positively associated with TS, SF, men, and C282Y homozygosity, and liver disease, diabetes, and heart failure reports. Non-C282Y homozygous participants with SF > 1,000 µg/L had lower survival than those with SF ≤ 1,000 µg/L (p < 0.0001). CONCLUSIONS: Nine years after initial screening, non-C282Y homozygous participants and SF > 1,000 µg/L was associated with decreased survival.
Assuntos
Ferritinas/sangue , Hemocromatose/sangue , Sobrecarga de Ferro/sangue , Programas de Rastreamento , Biomarcadores/sangue , Causas de Morte/tendências , Feminino , Hemocromatose/mortalidade , Humanos , Sobrecarga de Ferro/mortalidade , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Taxa de Sobrevida/tendênciasRESUMO
BACKGROUND AND AIMS: There are limited data on clinical and phenotypic characteristics of outpatients referred for hyperferritinemia (HF). To determine the causes of HF in outpatients referred to a secondary hospital. MATERIAL AND METHODS: A prospective study of 132 consecutive patients with HF (> 200 µg/L, women; > 300 µg/L, men) was conducted from January-December 2010. RESULTS: Mean age, 54.42 years (SD: 13.47, range: 23-83); body mass index (BMI), 28.80 (SD: 3.96, 17-39); ferritin (SF), 579.54 ng/mL (SD: 296.575, 206-1668); transferrin saturation (TSI), 43.87% (SD: 14.09, 12-95); iron (Fe), 134 µg/dL (SD: 49.68, 55-322); overweight: 48.31%, and obese: 40.44% (89%), and most patients were men (108/132). Regarding HFE mutations, H63D/H63D genotype and H63D allele frequencies were 17.5% (vs. 7.76% in controls); and 36% (31% in controls) respectively. While 63.6% consumed no alcohol, 18.1% consumed ≥ 60 g/day, the mean being 20.83 (SD: 33.95, 0-140). Overall, 6/132 (4.5%) patients were positive for B or C hepatitis. Mean LIC by MRI was 36.04 (SD: 32.78, 5-210), 53 patients having normal concentrations (< 36 µmol/g), 22 (33%) iron overload (37-80), and 4 (5%) high iron overload (> 80). Metabolic syndrome (MS) was detected in 44/80 men (55%) and 10/17 women (59%). In this group, the genotype frequency of the H63D/H63D mutation was significantly higher than in controls-21.56% vs. 7.76%- (p = 0.011); the H63D allelic frequency was 42.15% in MS group and 31% in controls (p = 0.027). CONCLUSION: The H63D/H63D genotype and H63D allele predispose individuals to HF and MS. MRI revealed iron overload in 33% of patients.
Assuntos
Ferritinas/sangue , Antígenos de Histocompatibilidade Classe I/genética , Imageamento por Ressonância Magnética/métodos , Proteínas de Membrana/genética , Síndrome Metabólica/genética , Mutação , Pacientes Ambulatoriais , Centros de Cuidados de Saúde Secundários , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA/genética , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Hemocromatose/sangue , Hemocromatose/epidemiologia , Hemocromatose/genética , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Incidência , Masculino , Proteínas de Membrana/metabolismo , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Estudos Prospectivos , Espanha/epidemiologia , Adulto JovemRESUMO
BACKGROUND & AIMS: Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder characterized by severe early-onset iron overload, caused by mutations in hemojuvelin (HJV), hepcidin (HAMP), or a combination of genes regulating iron metabolism. Here we describe two JH cases associated with simple heterozygosity for novel HJV mutations and unknown genetic factors. Case 1: A 12 year-old male from Central Italy with beta-thalassemia trait, increased aminotransferases, ferritin 9035 ng/ml and transferrin saturation 84%, massive hepatocellular siderosis and hepatic bridging fibrosis. Case 2: A 12 year-old female from Northern Italy with ferritin 467 ng/ml, transferrin saturation 87-95%, and moderate hepatic iron overload. MATERIAL AND METHODS: Direct sequencing of hemochromatosis genes (HFE-TfR2-HJV-HAMP-FPN-1) was performed in the children and siblings. RESULTS: In case 1, we detected heterozygosity for a novel HJV mutation (g.3659_3660insG), which was inherited together with the beta thalassemia trait from the father, who (as well as the mother) had normal iron parameters. In case 2, we detected another novel HJV mutation (g.2297delC) in heterozygosity, which was inherited from the mother, affected by mild iron deficiency. The father had normal iron stores. Both mutations are frameshifts determining premature stop codons. No other disease causing variant was detected. CONCLUSION: Although beta-thalassemia trait was a possible cofactor of iron overload in case 1, iron overload cannot be explained by simple heterozygosity for HJV mutations in both cases. Other genetic factors should be investigated, and further studies are needed to understand genotype-phenotype correlations in JH.
Assuntos
Proteínas Ligadas por GPI/genética , Hemocromatose/congênito , Heterozigoto , Ferro/sangue , Fígado/metabolismo , Mutação , Biomarcadores/sangue , Biópsia , Criança , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/genética , Proteína da Hemocromatose , Hereditariedade , Humanos , Fígado/patologia , Masculino , Linhagem , Fenótipo , Fatores de Risco , Talassemia beta/genéticaRESUMO
In patients with porphyria cutanea tarda (PCT), hepatic iron accumulation associated to hereditary hemochromatosis (HH) could play a role in the etiology and in the clinical expression of the disease. The H63D and C282Y mutations of the HFE gene frequency were studied in a PCT group of patients and compared with the frequency observed in a group of volunteer blood donors. PCT patients were cataloged as hereditary or acquired PCT carriers, whether or not they presented uroporphyrinogen decarboxilase gene mutations. Fifty percent of PCT patients were carriers of the disease's genetic type. Such percentage is significantly higher than what other authors have previously informed. H63D and C282Y mutations were present in 23% and 2.4% of the volunteer blood donors, respectively. Similar frequencies were informed by others authors in Chilean white ethnic populations, and also in Spaniard and Argentinean populations, but significantly higher than that observed in Chile's Araucanean aboriginal population. Probably the frequency of H63D and C283Y mutations are related to the Spaniard ascendancy dominance of Chile's white ethnic population. The frequency of HFE gene mutations in PCT patients was not different than what was observed in volunteer blood donors. Similarly, there was no statistical difference in the frequency of these mutations among patients with acquired or genetic PCT disease. With the obtained results, it is not possible postulate an association between PCT and the hereditary hemochromatosis of HFE gene mutations carrier conditions.
Assuntos
Doadores de Sangue , Hemocromatose/genética , Mutação , Porfiria Cutânea Tardia/genética , Chile/etnologia , Feminino , Frequência do Gene , Triagem de Portadores Genéticos , Genótipo , Hemocromatose/sangue , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Sobrecarga de Ferro , Masculino , Proteínas de Membrana/genética , Porfiria Cutânea Tardia/sangue , Uroporfirinogênio Descarboxilase/sangue , Uroporfirinogênio Descarboxilase/genéticaRESUMO
La acumulación de hierro hepático asociada a mutaciones en el gen HFE de la hemocromatosis hereditaria (HH) en los pacientes con porfiria cutánea tarda (PCT) podría tener un papel en la etiología y en la expresión clínica de esta enfermedad. Se estudió la frecuencia de las mutaciones H63D y C282Y en un grupo de pacientes con PCT y se la comparó con la observada en un grupo de donantes voluntarios desangre. Los pacientes con PCT fueron catalogados como portadores de la forma hereditaria o adquirida de laenfermedad, según presentaran o no mutaciones en el gen uroporfirinógeno decarboxilasa (UROD). El 50% delos pacientes con PCT eran portadores de la forma genética de la enfermedad, porcentaje significativamentemayor que lo informado en otras series. El 23% de los donantes voluntarios de sangre eran portadores de lamutación H63D y 2.4% lo era de la mutación C282Y. Frecuencias similares a lo encontrado por otros autoresen población chilena de etnia blanca, en población argentina y española, pero significativamente más alta quelo encontrado en estudios en población aborigen araucana. Esto tiene, probablemente, relación con el predominio de ascendencia española en la población blanca chilena. La frecuencia de mutación en el gen HFE en pacientes con PCT no fue significativamente diferente que la observada en donantes voluntarios de sangre. Tampoco hubo diferencias significativas en la frecuencia de estas mutaciones entre los casos con PCT adquirida respecto de aquellos en que ésta era de origen genético. Los resultados obtenidos no permiten afirmar que exista asociación entre la PCT y la condición de portador de mutaciones del gen HFE de la hemocromatosis hereditaria
In patients with porphyria cutanea tarda (PCT), hepatic iron accumulation associated to hereditary hemochromatosis (HH) could play a role in the etiology and in the clinical expression of the disease. The H63D and C282Y mutations of the HFE gene frequency were studied in a PCT group of patients and compared with the frequency observed in a group of volunteer blood donors. PCT patients were cataloged as hereditary or acquired PCT carriers, whether or not they presented uroporphyrinogen decarboxilase gene mutations. Fifty percent of PCT patients were carriers of the diseases genetic type. Such percentage is significantlyhigher than what other authors have previously informed. H63D and C282Y mutations were present in23% and 2.4% of the volunteer blood donors, respectively. Similar frequencies were informed by others authors in Chilean white ethnic populations, and also in Spaniard and Argentinean populations, but significantly higherthan that observed in Chiles Araucanean aboriginal population. Probably the frequency of H63D and C283Y mutations are related to the Spaniard ascendancy dominance of Chiles white ethnic population. The frequency of HFE gene mutations in PCT patients was not different than what was observed in volunteer blood donors.Similarly, there was no statistical difference in the frequency of these mutations among patients with acquired or genetic PCT disease. With the obtained results, it is not possible postulate an association between PCT and the hereditary hemochromatosis of HFE gene mutations carrier conditions
Assuntos
Humanos , Masculino , Feminino , Doadores de Sangue , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Mutação , Proteínas de Membrana/genética , Porfiria Cutânea Tardia/genética , Chile/etnologia , Frequência do Gene , Genótipo , Triagem de Portadores Genéticos , Hemocromatose/sangue , Sobrecarga de Ferro , Porfiria Cutânea Tardia/sangue , Uroporfirinogênio Descarboxilase/sangue , Uroporfirinogênio Descarboxilase/genéticaRESUMO
La acumulación de hierro hepático asociada a mutaciones en el gen HFE de la hemocromatosis hereditaria (HH) en los pacientes con porfiria cutánea tarda (PCT) podría tener un papel en la etiología y en la expresión clínica de esta enfermedad. Se estudió la frecuencia de las mutaciones H63D y C282Y en un grupo de pacientes con PCT y se la comparó con la observada en un grupo de donantes voluntarios desangre. Los pacientes con PCT fueron catalogados como portadores de la forma hereditaria o adquirida de laenfermedad, según presentaran o no mutaciones en el gen uroporfirinógeno decarboxilasa (UROD). El 50% delos pacientes con PCT eran portadores de la forma genética de la enfermedad, porcentaje significativamentemayor que lo informado en otras series. El 23% de los donantes voluntarios de sangre eran portadores de lamutación H63D y 2.4% lo era de la mutación C282Y. Frecuencias similares a lo encontrado por otros autoresen población chilena de etnia blanca, en población argentina y española, pero significativamente más alta quelo encontrado en estudios en población aborigen araucana. Esto tiene, probablemente, relación con el predominio de ascendencia española en la población blanca chilena. La frecuencia de mutación en el gen HFE en pacientes con PCT no fue significativamente diferente que la observada en donantes voluntarios de sangre. Tampoco hubo diferencias significativas en la frecuencia de estas mutaciones entre los casos con PCT adquirida respecto de aquellos en que ésta era de origen genético. Los resultados obtenidos no permiten afirmar que exista asociación entre la PCT y la condición de portador de mutaciones del gen HFE de la hemocromatosis hereditaria (AU)
In patients with porphyria cutanea tarda (PCT), hepatic iron accumulation associated to hereditary hemochromatosis (HH) could play a role in the etiology and in the clinical expression of the disease. The H63D and C282Y mutations of the HFE gene frequency were studied in a PCT group of patients and compared with the frequency observed in a group of volunteer blood donors. PCT patients were cataloged as hereditary or acquired PCT carriers, whether or not they presented uroporphyrinogen decarboxilase gene mutations. Fifty percent of PCT patients were carriers of the diseaseãs genetic type. Such percentage is significantlyhigher than what other authors have previously informed. H63D and C282Y mutations were present in23% and 2.4% of the volunteer blood donors, respectively. Similar frequencies were informed by others authors in Chilean white ethnic populations, and also in Spaniard and Argentinean populations, but significantly higherthan that observed in Chileãs Araucanean aboriginal population. Probably the frequency of H63D and C283Y mutations are related to the Spaniard ascendancy dominance of Chileãs white ethnic population. The frequency of HFE gene mutations in PCT patients was not different than what was observed in volunteer blood donors.Similarly, there was no statistical difference in the frequency of these mutations among patients with acquired or genetic PCT disease. With the obtained results, it is not possible postulate an association between PCT and the hereditary hemochromatosis of HFE gene mutations carrier conditions (AU)
Assuntos
Humanos , Masculino , Feminino , Doadores de Sangue , Mutação , Hemocromatose/genética , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Classe I/genética , Porfiria Cutânea Tardia/genética , Chile/etnologia , Frequência do Gene , Genótipo , Hemocromatose/sangue , Triagem de Portadores Genéticos , Sobrecarga de Ferro , Porfiria Cutânea Tardia/sangue , Uroporfirinogênio Descarboxilase/sangue , Uroporfirinogênio Descarboxilase/genéticaRESUMO
La acumulación de hierro hepático asociada a mutaciones en el gen HFE de la hemocromatosis hereditaria (HH) en los pacientes con porfiria cutánea tarda (PCT) podría tener un papel en la etiología y en la expresión clínica de esta enfermedad. Se estudió la frecuencia de las mutaciones H63D y C282Y en un grupo de pacientes con PCT y se la comparó con la observada en un grupo de donantes voluntarios desangre. Los pacientes con PCT fueron catalogados como portadores de la forma hereditaria o adquirida de laenfermedad, según presentaran o no mutaciones en el gen uroporfirinógeno decarboxilasa (UROD). El 50% delos pacientes con PCT eran portadores de la forma genética de la enfermedad, porcentaje significativamentemayor que lo informado en otras series. El 23% de los donantes voluntarios de sangre eran portadores de lamutación H63D y 2.4% lo era de la mutación C282Y. Frecuencias similares a lo encontrado por otros autoresen población chilena de etnia blanca, en población argentina y española, pero significativamente más alta quelo encontrado en estudios en población aborigen araucana. Esto tiene, probablemente, relación con el predominio de ascendencia española en la población blanca chilena. La frecuencia de mutación en el gen HFE en pacientes con PCT no fue significativamente diferente que la observada en donantes voluntarios de sangre. Tampoco hubo diferencias significativas en la frecuencia de estas mutaciones entre los casos con PCT adquirida respecto de aquellos en que ésta era de origen genético. Los resultados obtenidos no permiten afirmar que exista asociación entre la PCT y la condición de portador de mutaciones del gen HFE de la hemocromatosis hereditaria (AU)
In patients with porphyria cutanea tarda (PCT), hepatic iron accumulation associated to hereditary hemochromatosis (HH) could play a role in the etiology and in the clinical expression of the disease. The H63D and C282Y mutations of the HFE gene frequency were studied in a PCT group of patients and compared with the frequency observed in a group of volunteer blood donors. PCT patients were cataloged as hereditary or acquired PCT carriers, whether or not they presented uroporphyrinogen decarboxilase gene mutations. Fifty percent of PCT patients were carriers of the diseaseãs genetic type. Such percentage is significantlyhigher than what other authors have previously informed. H63D and C282Y mutations were present in23% and 2.4% of the volunteer blood donors, respectively. Similar frequencies were informed by others authors in Chilean white ethnic populations, and also in Spaniard and Argentinean populations, but significantly higherthan that observed in Chileãs Araucanean aboriginal population. Probably the frequency of H63D and C283Y mutations are related to the Spaniard ascendancy dominance of Chileãs white ethnic population. The frequency of HFE gene mutations in PCT patients was not different than what was observed in volunteer blood donors.Similarly, there was no statistical difference in the frequency of these mutations among patients with acquired or genetic PCT disease. With the obtained results, it is not possible postulate an association between PCT and the hereditary hemochromatosis of HFE gene mutations carrier conditions (AU)
Assuntos
Humanos , Masculino , Feminino , Doadores de Sangue , Mutação , Hemocromatose/genética , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Classe I/genética , Porfiria Cutânea Tardia/genética , Chile/etnologia , Frequência do Gene , Genótipo , Hemocromatose/sangue , Triagem de Portadores Genéticos , Sobrecarga de Ferro , Porfiria Cutânea Tardia/sangue , Uroporfirinogênio Descarboxilase/sangue , Uroporfirinogênio Descarboxilase/genéticaRESUMO
Patients with chronic renal insufficiency (CRI) have reduced hemoglobin levels, mostly as a result of decreased kidney production of erythropoietin, but the relation between renal insufficiency and the magnitude of hemoglobin reduction has not been well defined. Hereditary hemochromatosis is an inherited disorder of iron metabolism. The importance of the association of hemochromatosis with treatment for anemia among patients with CRI has not been well described. We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 201 Brazilian individuals with CRI undergoing hemodialysis. The analysis of the effects of HFE mutations on iron metabolism and anemia with biochemical parameters was possible in 118 patients of this study (hemoglobin, hematocrit, ferritin levels, transferrin saturation, and serum iron). A C282Y heterozygous mutation was found in 7/201 (3.4%) and H63D homozygous and heterozygous mutation were found in 2/201 (1.0%) and 46/201 (22.9%), respectively. The allelic frequencies of the HFE mutations (0.017 for C282Y mutation and 0.124 for H63D mutation) did not differ between patients with CRI and healthy controls. Regarding the biochemical parameters, no differences were observed between HFE heterozygous and mutation-negative patients, although ferritin levels were not higher among patients with the H63D mutation (P = 0.08). From what we observed in our study, C282Y/H63D HFE gene mutations are not related to degrees of anemia or iron stores in CRI patients receiving intravenous iron supplementation (P > 0.10). Nevertheless, the present data suggest that the H63D mutation may have an important function as a modulating factor of iron overload in these patients.
Assuntos
Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Estudos de Casos e Controles , Feminino , Genótipo , Hemocromatose/sangue , Proteína da Hemocromatose , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Diálise RenalRESUMO
Patients with chronic renal insufficiency (CRI) have reduced hemoglobin levels, mostly as a result of decreased kidney production of erythropoietin, but the relation between renal insufficiency and the magnitude of hemoglobin reduction has not been well defined. Hereditary hemochromatosis is an inherited disorder of iron metabolism. The importance of the association of hemochromatosis with treatment for anemia among patients with CRI has not been well described. We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 201 Brazilian individuals with CRI undergoing hemodialysis. The analysis of the effects of HFE mutations on iron metabolism and anemia with biochemical parameters was possible in 118 patients of this study (hemoglobin, hematocrit, ferritin levels, transferrin saturation, and serum iron). A C282Y heterozygous mutation was found in 7/201 (3.4 percent) and H63D homozygous and heterozygous mutation were found in 2/201 (1.0 percent) and 46/201 (22.9 percent), respectively. The allelic frequencies of the HFE mutations (0.017 for C282Y mutation and 0.124 for H63D mutation) did not differ between patients with CRI and healthy controls. Regarding the biochemical parameters, no differences were observed between HFE heterozygous and mutation-negative patients, although ferritin levels were not higher among patients with the H63D mutation (P = 0.08). From what we observed in our study, C282Y/H63D HFE gene mutations are not related to degrees of anemia or iron stores in CRI patients receiving intravenous iron supplementation (P > 0.10). Nevertheless, the present data suggest that the H63D mutation may have an important function as a modulating factor of iron overload in these patients.
Assuntos
Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Brasil , Estudos de Casos e Controles , Genótipo , Hemocromatose/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Mutação/genética , Diálise RenalRESUMO
The frequency of the C282Y, H63D and S65C alleles of the HFE gene was determined in a sample of the Venezuelan population. Two new sets of primers were tested for amplifying the regions mapping these mutations, and genotyping was performed by restriction fragment length polymorphism (RFLP). DNA sequencing was used to validate the RFLP analysis. Serum ferritin levels were also determined. Two hundred and fourteen individuals were tested, extracting DNA from whole blood cells (n=177) or from serum (n=37). The frequency of heterozygous subjects was 3.7, 18.2 and 1.7% for the C282Y, H63D and S65C mutations, respectively, and the allele frequencies were 0.019+/-0.01 for C282Y, 0.119+/-0.016 for H63D and 0.009+/-0.005 for S65C. The results suggest that the admixture of native populations with subjects of South European origin might have had an important role in the diffusion of HFE alleles in Venezuela. C282Y homozygous subjects were not found in this study. No HFE genotype studied here was associated with a significant elevation of serum ferritin concentrations, except for C282Y/H63D compound heterozygote found in one asymptomatic male. This finding supports the theory that the H63D mutation could be involved in alterations of iron parameters when inherited together with C282Y. Our results indicate that C282Y homozygotes will be rarely detected. Performance of HFE mutation analysis in individuals with high iron determinations would be recommended.
Assuntos
Substituição de Aminoácidos , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Mutação Puntual , Polimorfismo de Fragmento de Restrição , Adolescente , Adulto , Alelos , Criança , Análise Mutacional de DNA , Feminino , Ferritinas/sangue , Frequência do Gene , Hemocromatose/sangue , Proteína da Hemocromatose , Heterozigoto , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ferro/sangue , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Distribuição Aleatória , VenezuelaRESUMO
It has been proposed that iron overload may adversely affect liver disease outcome. The recent identification of 2 mutations in the HFE gene related to hereditary haemochromatosis (Cys282Tyr and His63Asp) provided an opportunity to test whether they are associated with hepatic iron accumulation and the activity and severity of liver disease in hepatitis C virus (HCV) infection. We investigated the prevalence of HFE mutations in 135 male patients with chronic HCV hepatitis, and correlated genotype distribution with different parameters of iron status and the activity and severity of liver disease. Of these 135 patients, 6 (4.4%) carried Cys282Tyr and 32 (23.7%) carried His63Asp, frequencies which were similar to those observed in healthy controls. Serum iron levels and transferrin saturation (but not ferritin levels or liver iron content) were significantly higher in carriers than in non-carriers of HFE mutations. No difference was observed in serum ALT, AST and GGT levels between carriers and non-carriers. Finally, scores for necroinflammatory activity and fibrosis in the liver were significantly higher in HFE carriers than in non-carriers. Patients with chronic HCV infection carrying HFE mutations tend to present more evident body iron accumulation and a higher degree of necroinflammatory activity and fibrosis in the liver. HFE gene mutations might be an additional factor to be considered among those implicated in the determination of a worse prognosis of the liver disease in chronic HCV infection.
Assuntos
Antígenos HLA/genética , Hemocromatose/genética , Hepatite C/complicações , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana , Adolescente , Adulto , Idoso , Ferritinas/sangue , Frequência do Gene , Hemocromatose/sangue , Hemocromatose/complicações , Proteína da Hemocromatose , Hepacivirus , Hepatite C/sangue , Hepatite C/fisiopatologia , Humanos , Ferro/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Índice de Gravidade de DoençaRESUMO
The distribution of lymphocyte subsets in blood, thymus, spleen, mesenteric lymph nodes, Peyer's patches and bone marrow was evaluated in an experimental model of secondary hemochromatosis in rats. The values of CD2, CD4, CD8, B and NK cells in these different lymphoid compartments did not differ between the control group and the experimental group. These results suggest that the abnormalities of lymphocyte subsets previously reported in patients with secondary hemochromatosis may be due to factors other than iron overload.