C282Y and H63D mutations of the haemochromatosis gene in patients with iron overload.

OBJECTIVE: To determine the relevance of C282Y and H63D mutations of HEF gene in patients with iron overload. PATIENTS AND METHODS: Patients with iron overload referred to our Liver Unit were included in the study. The association of mutations to different diagnosis and their impact on the severity of the hepatopathy were explored. Sensitivity, specificity and positive and negative predictive values of mutations for the diagnosis of haemochromatosis were determined. RESULTS: The study included 78 patients with iron overload. The control group included 21 patients of similar age and sex ratio without iron overload nor hepatopathy. Twenty three patients had haemochromatosis, 22 alcoholic liver disease and 33 other diseases unrelated to iron metabolism. Seventy three per cent of patients with haemochromatosis were homozygous for the C282Y mutation. All the C282Y homozygous subjects had also haemochromatosis. Fifty three per cent of patients with alcoholic hepatopathy had some kind of mutation. This has been also observed in 70% of patients with iron-unrelated diseases. Such percentage was significantly greater than in the control group (24% with H63D mutation). C282Y homozygosity in patients with iron overload had a sensitivity of 73.9%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 89.6%. CONCLUSIONS: In our population, as in all the Western countries, haemochromatosis is mainly associated to homozygous C282Y mutation. The high frequency of mutations in patients with iron overload and without haemochromatosis suggests the involvement of such mutations in iron overload.     

Association of HFE mutations (C282Y and H63D) with iron overload in blood donors from Mexico City

Background and objective: Iron overload has been associated with HFE mutations (C282Y and H63D). We investigated the association between these mutations and high serum ferritin in a sample of healthy adult men.Design and methods: We enrolled unrelated blood donors from three hospitals in Mexico City in a cross-sectional study. Serum ferritin (SF) was determined to define iron overload, and HFE gene mutations were identified by PCR–RFLP.Results: We evaluated 2524 male blood donors and included 246 individuals for each group. We identified 108 individuals with HFE gene mutation, 20.5 % were heterozygote (wt/H63D or wt/C282Y) and the remaining homozygote (H63D/ H63D). The genotype wt/C282Y was observed in two cases, none cases with C282Y/C282Y. The allelic frequency of H63D and C282Y was 0.115 and 0.002, respectively. We observed different association for H63D allele with iron overload (OR 1.54, CI 95 %1.16-2.03) and none in allele C282Y. Although values averages were different, the extreme dispersion of serum ferritin not showed statistically significant differences between H63D and C282Y alleles and ferritin concentrations.Conclusions: The male unrelated blood donors from Mexico City with iron overload prevalence of 13.8% hold similarities with other populations from Europe o America continent, respecting the allele frequency H63D. Nevertheless, allele frequency C282Y is lower than that observed in descendents from northern Europe. We have not observed statistic difference of SF or iron overload frequency by effect of both alleles.     

C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease.

OBJECTIVE: To test the hypothesis that the heterozygous state for HFE gene mutations involved in the pathogenesis of hemochromatosis, that may induce an increase of hepatic iron content, may aggravate the liver damage induced by prolonged and excessive use of ethanol. PATIENTS AND METHODS: C282Y and H63D mutations of HFE gene were identified through polymerase chain reaction (PCR) on leukocyte DNA, in 125 consecutive patients diagnosed of advanced alcoholic liver disease (109 men, mean age 54 years, SD 11) and 181 healthy controls. All subjects were white Spaniards. RESULTS (CASES/CONTROLS): 1. Genotype distribution: a) mutation C282Y: no homozygotes, 10/23 heterozygotes, 115/158 normal (p = 0.60); b) mutation H63D: 9/5 homozygotes, 46/52 heterozygotes, 70/124 normal (Chi square 6.51, p = 0.039). 2. Allele frequencies: a) mutation C282Y: 240/339 normal, 10/23 mutated (p = 0.21); b) mutation H63D: 186/300 normal, 64/62 mutated (odds ratio 1.66, 95% CI 1.10-2.52, p = 0.01). CONCLUSIONS: Our results suggest that H63D mutation of the HFE gene, but not the C282Y mutation, is associated to the risk of developing advanced liver alcoholic disease.     

Frequency of primary iron overload and HFE gene mutations （C282Y, H63D and S65C） in chronic liver disease patients in north India

AIM:To identify the frequency of iron overload and study the three mutations in the HFE gene (C282Y,H63D,and S65C) in patients with chronic liver disorders (CLD) and controls. METHODS:To identify patients with iron overload (transferrin saturation > 45% in females and > 50% in males and serum ferritin > 1000 ng/mL) we evaluated 236 patients with CLD,including 59 with non-alcoholic steatohepatitis (NASH),22 with alcoholic liver disease (ALD),19 of cirrhosis due to viruses (HBV,HCV),and 136 with cryptogenic cirrhosis. Mutations of the HFE gene were analyzed by PCR-RE. hundred controls were screened for iron status and the mutations. RESULTS:Seventeen patients with CLD showed evidence of iron overload. Fifteen cases of iron overload had cryptogenic cirrhosis and two had ALD. None of the controls showed iron overload. We did not find any individual with 282Y or 65C either in the cases or in the controls. The prevalence of H63D heterozygosity was 12% in normal individuals,14.8% in 236 patients (16.9% in NASH,13.6% in ALD,26.3% in viral and 12.5% in cryptogenic cirrhosis) and the overall prevalence was 13.98%. Only two of the 17 patients with primary iron overload were heterozygous for H63D. One patient with NASH and one normal individual who were homozygous for H63D showed no iron overload.CONCLUSION:Primary iron overload in Indians is nonHFE type,which is different from that in Europeans and further molecular studies are required to determine the defect in various iron regulatory genes.     

Analysis of HFE gene mutations (C282Y, H63D, and S65C) in the Ecuadorian population

Type 1 hemochromatosis is a disorder of iron metabolism mostly related to the HFE gene mutations. In the present study, we performed a mutation analysis to determine the frequencies of the HFE gene mutations (C282Y, H63D, and S65C) in DNA samples of 100 healthy Ecuadorian individuals. We used the polymerase chain reaction (PCR) to amplify exons 2 and 4 of the HFE gene and then the restriction fragment length polymorphism (RFLP) method to detect the mutations. The results revealed that the mutations in the normal Ecuadorian population have frequencies of 0.0, 0.035, and 0.04 for C282Y, H63D, and S65C, respectively. We also searched for these mutations in 12 hemochromatosis patients, and the frequencies that we found were 0.0 for C282Y, 0.167 for H63D, and 0.042 for S65C. We found differences [using the chi-square (²) test] in the frequency of the H63D mutation between the control group and the group of hemochromatosis patients (p<0.01). This suggests that in Ecuador, type 1 hemochromatosis is more influenced by the H63D mutation than the other two mutations that we analyzed. Given that in a Caucasian population hereditary hemochromatosis is mostly related to the C282Y mutation, it is possible that the findings for the Ecuadorian population are due to geographical differences between the populations.     

Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in 2501 ethnic Danes

The aim of the study was to assess the frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in ethnic Danes. The series comprised 2501 subjects (1284 men) of Danish heritage who were drawn at random from the Census Registry in age cohorts of 30, 40, 50, and 60 years. The frequency of the C282Y and H63D mutations was assessed on blood samples by genotyping using a polymerase chain reaction (PCR) technique. The HFE genotype distribution was in Hardy–Weinberg equilibrium (p=0.85). C282Y mutation: 9 subjects (0.36%) were homozygous and 265 subjects (10.6%) were heterozygous. H63D mutation: 40 subjects (1.6%) were homozygous and 584 subjects (23.4%) were heterozygous. C282Y/H63D compound heterozygosity was found in 36 subjects (1.4%). The C282Y allele frequency was 5.7% [95% confidence interval (CI) 5.0–6.3%] and the H63D allele frequency was 13.3% (95% CI 12.3–14.2%). In conclusion, the C282Y frequency is relatively high in the Danes, being close to the frequency in other Scandinavian countries, i.e., Iceland 5.1%, the Faroe Islands 6.6%, and Sweden 5.7%, but significantly lower than in Norway 6.6% (p=0.02). Also, the H63D frequency in Danes is close to and not significantly different from the frequency in Iceland 10.9%, Norway 11.2%, and Sweden 12.4%, but significantly lower than in the Faroe Islands 15.4% (p=0.046).     

Prevalence of HFE genotypes, C282Y and H63D, in patients with hematologic disorders

BACKGROUND AND OBJECTIVES: Iron status has implications for normal erythrocyte and leukocyte function and for platelet count, size and activation. Increased storage of iron is considered a potential risk factor participating in the pathogenesis of malignant diseases. Since HFE gene mutations have recently been implicated in unbalanced iron homeostasis, we set out to examine the prevalence of these mutations in patients with hematologic disorders. DESIGN AND METHODS: C282Y and H63D mutations were determined in 232 patients with various hematologic disorders treated at Oulu University Hospital between 1987 and 2000. DNA samples extracted from either the peripheral blood or bone marrow of these patients were amplified by a polymerase chain reaction (PCR) method using sequence-specific primers, and the products were analyzed on agarose gels. RESULTS: There was a slight tendency towards lower frequencies of the C282Y allele in patients with acute myeloid leukemia (AML) (3.8%, n=53) and higher frequencies in those with essential thrombocythemia (ET) (16.2%, n=37). Contrary to some expectations, however, the frequency of the C282Y allele in acute lymphoblastic leukemia turned out to be normal (7.0%, n=43). Our data showed no significant deviations in H63D mutation frequency in any of the categories of patients. INTERPRETATION AND CONCLUSIONS: Our results do not show any significant association between HFE gene mutations and hematologic malignancies. The divergent frequencies observed for the C282Y mutation in patients with AML and ET highlight the need for larger population studies of HFE mutations in patients with hematologic diseases.     

H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers

BACKGROUND AND OBJECTIVES. Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism. The HFE gene implicated in this disorder has been identified on chromosome 6 (6p21.3). The most prevalent mutation in HH patients changes the 282 cysteine residue to tyrosine (C282Y). The role of a second mutation which changes the 63 histidine to aspartic acid (H63D) in iron overload has been controversial. The aim of this study was to evaluate the effect of the H63D mutation on the ferritin levels of beta-thalassemia carriers. DESIGN AND METHODS. beta-thalassemia carriers have a tendency to increase iron absorption because of mild anemia and slightly increased erythropoiesis. Differences in ferritin levels between homozygotes for H63D and wild type may indicate a modulator effect of the HFE mutation on iron absorption. We studied 152 healthy males, heterozygous for beta-thalassemia. Serum ferritin was measured by chemiluminescence. H63D genotypes were determined by digestion of polymerase chain reaction (PCR) products with MboI restriction enzyme. RESULTS. Forty-five subjects were H63D heterozygotes and four subjects were H63D homozygotes. Ferritin levels were (mean +/- SD): 250 +/- 138 microg/L in homozygotes for the wild type H/H; 295 +/- 186 microg/L in H/D heterozygotes; and 389 +/- 75 microg/L in homozygotes for the mutation D/D. The difference in ferritin values between H/H and D/D is statistically significant (p=0.022). INTERPRETATION AND CONCLUSIONS. beta-thalassemia carriers who are homozygotes for the H63D mutation have higher ferritin levels than beta-thalassemia carriers with the H/H genotype, suggesting that the H63D mutation may have a modulating effect on iron absorption.     

Hereditary hemochromatosis gene (HFE) mutations C282Y, H63D and S65C in patients with idiopathic dilated cardiomyopathy

BACKGROUND: Hereditary hemochromatosis (HH), a common autosomal recessive disease, leads to excessive iron accumulation in some organs, including the heart. It is therefore not surprising that cardiomyopathy is one of the most severe complications of HH. The HFE gene defects have been thought to contribute to idiopathic dilated cardiomyopathy (IDCM) in some patients, even though the results of genotype analyses have so far been contradictory. Hence we set out here to evaluate the prevalence and potential role of HFE mutations in patients with IDCM. METHODS: A total of 91 IDCM patients and 102 controls were subjected to HFE mutation analyses, in which C282Y, H63D and S65C mutations were determined for each patient. We also analyzed the impact of the C282Y and H63D mutations on the left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional classes. RESULTS: The prevalences of heterozygosity for the C282Y, H63D and S65C mutations in the IDCM patients were 13.2%, 22.0% and 2.2%, respectively. LVEDD was significantly higher (P=0.037) in those with the C282Y mutation at the end of the follow-up period than in those with no mutation. CONCLUSIONS: Our data showed no significant deviations in C282Y, H63D and S65C mutation frequencies between the IDCM patients and controls, suggesting that these mutations do not increase the risk of IDCM. Heterozygosity for the C282Y mutation may nevertheless be a modifying factor contributing to LV dilatation and remodeling.     

Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy

BACKGROUND/AIMS: The actual prevalence of the main hemochromatosis (HFE) mutations in the Italian adult population and their phenotypic expression have not yet been established. This information is key to advocate a mass-screening program. METHODS: Two thousand one hundred adults were tested for the C282Y/H63D HFE gene mutations by an automated genotyping assay as well as transferrin saturation (TS) and serum ferritin levels. RESULTS: No homozygotes for the C282Y mutation were found. Heterozygosity for the C282Y mutation was 3.1%, while heterozygosity and homozygosity for the H63D mutation were 21.5% and 2.5%, respectively. TS was significantly higher in C282Y heterozygotes and H63D homozygotes as compared to wild-type individuals (P < 0.01). Interestingly, of the HFE wild-type subjects 5.9% had a TS value above the 45% threshold. CONCLUSIONS: This study shows that (i) the predicted prevalence for C282Y homozygosity in Italy is 1:3900; (ii) the C282Y/H63D wild-type population has an increased baseline of iron parameters possibly due to genetic factors not linked to the C282Y/H63D mutations; (iii) since in the latter population the actual tissue iron burden cannot be assessed, phenotypic (TS) screening in Italy is not recommended until the true prevalence of all mutations in the HFE gene and in other hemochromatosis genes will be established.     

Prevalence of the C282Y and H63D mutations in the HFE gene in patients with hereditary haemochromatosis and in control subjects from Northern Germany

Mutation analysis was performed for two HFE mutations (C282Y, H63D) in unrelated patients with hereditary haemochromatosis (n = 92), family members of patients (n = 34), and unrelated controls (n = 157) from Northern Germany. 87/92 patients (94.6%) revealed the C282Y mutation in homozygous form, five were heterozygous. No H63D mutation was found in 174 chromosomes of patients homozygous for C282Y, whereas four of the heterozygote patients also carried the H63D mutation. Among the control group, 9.6% were heterozygotes for C282Y. 2/157 subjects were homozygous, 37/157 were heterozygous for the H63D mutation, but showed no signs of iron overload.     

Frequency of the hemochromatosis HFE mutations C282Y, H63D, and S65C in blood donors in the Faroe Islands

The aim of the study was to assess the frequencies of the hereditary hemochromatosis HFE mutations C282Y, H63D, and S65C in the population in the Faroe Islands. The series comprised 200 randomly selected blood donors of Faroese heritage. The frequency of the C282Y, H63D, and S65C mutations on the HFE gene was assessed by genotyping using the polymerase chain reaction (PCR) technique and calculated from direct allele counting. We found no C282Y homozygous subjects; 28 (14.0%) subjects were C282Y heterozygous and four subjects were C282Y/H63D compound heterozygous (2.0%). The C282Y allele frequency was 8.0% (95% CI 5.3–10.7%). The series contained three (1.5%) H63D homozygous subjects and 60 (30.0%) H63D heterozygous subjects. The H63D allele frequency was 17.5% (95% CI 13.8–21.2%). There were four (2.0%) S65C heterozygous subjects. The S65C allele frequency was 1.0% (95% CI 0.3–2.5%). The frequency of the C282Y mutation is high in Faroese blood donors, being close to and not significantly different from the frequencies reported in other Scandinavian countries: Denmark 5.7%, Norway 6.6%, Iceland 5.1%, and Sweden 6.1%. The frequency of the H63D mutation in Faroese subjects is significantly higher than the frequency in Denmark 12.8% (p=0.007), Iceland 10.9% (p=0.003), and Sweden 12.4% (p=0.015), but not from the frequency in Norway 11.2% (p=0.063). The frequency of the S65C mutation in Faroese subjects is not significantly different from the frequencies in Denmark 1.5% and Sweden 1.6%. Screening of larger groups of the Faroese population for HFE mutations especially C282Y should be considered in order to establish the penetrance.     

Relations among serum ferritin, C282Y and H63D mutations in the HFE gene and type 2 diabetes mellitus in the Czech population.

Aims of the study were: (i) to determine the prevalence of mutations C282Y and H63D in the HFE gene causing hereditary hemochromatosis in patients with type 2 diabetes mellitus and non-diabetics, (ii) to investigate the relationship among HFE genotypes, serum ferritin and glucose intolerance and (iii) to assess possible association of HFE mutations with the susceptibility to develop late diabetic complications in the Czech population. Two approaches were employed - the case-control study comprising diabetics and non-diabetic controls (n = 326) and the cross-sectional study comprising subjects with a previously unknown defect of glucose tolerance (n = 113, oral glucose tolerance test performed in each subject). Allele frequencies of C282Y and H63D did not differ between diabetic and control groups nor among subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes. Ferritin levels significantly differed between diabetic and non-diabetic women (P<1.10 (-3)) and among subjects with NGT, IGT and diabetes (P<0.05). Differences in ferritin levels related to particular genotypes of C282Y and H63D were not detected. Prevalence of diabetes in the first and second quartiles of ferritin distribution differed highly significantly from the prevalence in the third and fourth quartiles in women (P = 0.000037), OR = 3.50 (95% CI, 1.89-6.48). The extent of diabetic late complications did not correlate with ferritin plasma levels.     

Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular carcinoma developed in non-cirrhotic liver

BACKGROUND/AIMS: Histological and biochemical iron overload has been reported in non-tumoral liver of most patients presenting an hepatocellular carcinoma (HCC) developed in non-cirrhotic liver (NCL). The aim of our study was to investigate HFE mutations in patients with HCC in NCL. METHODS: Thirty-five patients with HCC in NCL were included either retrospectively or prospectively. Clinical data, iron and viral status, and HFE gene mutations were compared between groups with (I+, n = 19) or without histological iron overload (I-, n = 16). RESULTS: Twenty per cent of patients were HBV or HCV positive. Fifty-four per cent had hepatocytic iron overload at histology. Mean hepatic iron concentration was 100.2 +/- 14.6 micromol/g in I+ versus 23.2 +/- 2.1 micromol/g in I- (p<0.001). Among the 19 I+ patients, eight mutations were found: two C282Y/C282Y, three C282Y/WT, two C282Y/H63D and one H63D/H63D. None of these mutations was found in the I- group. There was no significant difference concerning the H63D heterozygous mutation between I+ or I- patients. CONCLUSIONS: In patients with HCC in NCL, HBV and HCV markers are rare (20%), and mild iron overload is frequent (54%). In patients with HCC in NCL and iron overload, C282Y mutations are frequent (36.8% of cases) and significantly increased (p<0.009) compared to HCC in NCL without iron overload; these mutations are mostly heterozygous. H63D heterozygosity is not associated with liver iron overload. Because of the small size of the series, HFE C282Y mutation should be investigated on a larger scale in patients with HCC in NCL with iron overload in order to confirm this association.     

Frequency of the HFE C282Y and H63D mutations in Danish patients with clinical haemochromatosis initially diagnosed by phenotypic methods

AIM: To assess the frequency of the C282Y and H63D mutations on the HFE gene in Danish patients with clinical hereditary haemochromatosis initially diagnosed by phenotypic methods. METHODS: In the period 1950-1985, an epidemiological survey in Denmark identified 179 patients with clinical idiopathic haemochromatosis diagnosed by phenotypic methods (serum transferrin saturation, serum ferritin, liver biopsy and mobilisable body iron stores). In 32 unrelated patients, frozen blood samples were available for genetic analysis. In a subsequent series of 26 unrelated Danish patients, a phenotypic diagnosis of clinical idiopathic haemochromatosis was made before blood samples were taken for HFE genotyping. The total series consisted of 58 patients (40 men and 18 women) with a median age of 60 yrs (range 18-74). HFE genotyping was performed by the polymerase chain reaction (PCR) technique. RESULTS: Among the patients, 55 of 58 (94.8%) were C282Y/C282Y homozygous. One 63-year-old woman (1.7%) was compound C282Y/H63D heterozygous. Two women (3.4%), aged 42 and 43 yrs were negative for both the C282Y and the H63D mutation. CONCLUSION: In the Danish population, homozygosity for the C282Y mutation appears to be the prevailing cause of clinically overt genetic haemochromatosis. This finding has implications both for the evaluation of patients with iron overload disorders and for the strategy in future population screening surveys.     

Prevalence and clinical implications of HFE gene mutations (C282Y and H63D) in patients with chronic hepatitis B and C in Taiwan.

BACKGROUND/AIMS: The implication of hemochromatosis (HFE) gene mutations in chronic viral hepatitis remains controversial. We therefore studied the prevalence of HFE mutations and their impact on the progression of chronic viral hepatitis in Taiwan. PATIENTS & METHODS: H63D and C282Y mutations were screened by using polymerase chain reaction followed by restriction fragment length polymorphism in 152 chronic hepatitis B patients with various stages of liver disease, 87 chronic hepatitis C patients with various stages of liver disease, and 49 healthy controls. The distribution of each allele frequency was then compared among different groups of patients and in various stages of liver disease. RESULTS: All three groups of patients were C282Y wild type and the majority of H63D mutations were heterozygotes. Although statistically not significant, allele frequencies of H63D mutation in hepatitis B-related liver cirrhosis (6%) and hepatitis C-related liver cirrhosis (9.1%) were higher than those in healthy control (2%). After adjustment for age and sex, hepatitis B patients with H63D heterozygosity had a higher likelihood of cirrhosis than those with H63D wild type (odds ratios (OR): 3.2, confidence interval (CI): 0.49-20.5, P = 0.22). Similarly, hepatitis C patients with H63D homozygosity had a higher likelihood of cirrhosis compared with those with H63D wild type (OR: 2.35, CI : 0.19-28.5, P = 0.52). CONCLUSIONS: Almost all Taiwanese are C282Y wild type. H63D heterozygote and homozygote, occurring in less than 5% of the subjects, tended to be associated with the development of liver cirrhosis, irrespective of viral etiology. Screening for H63D mutation might be considered in patients with chronic viral hepatitis in Taiwan.     

HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis

BACKGROUND/AIMS: The impact of heterozygous HFE mutations on the course of chronic hepatitis C and iron indices was studied. METHODS: Ferritin, transferrin saturation (TS), serum iron, C282Y and H63D mutations were determined in 401 patients with chronic hepatitis C virus (HCV) infection and 295 healthy controls. Liver histologies were available in 217 and HCV genotypes in 339 patients. RESULTS: Allele frequencies of the C282Y and H63D mutation did not differ between HCV patients and healthy controls (6.95 vs. 6.2%; 14.75 vs. 16.4%; n.s.). HFE heterozygous HCV patients had higher ferritin (349+/-37 vs. 193+/-15 microg/l; P<0.0005), TS (38+/-2 vs. 32+/-1%; P<0.0005), serum iron (144+/-6 vs. 121+/-3 microg/dl; P<0.0005), semiquantitative liver iron staining (0.26+/-0.07 vs. 0.09+/-0.03; P<0.006) and fibrosis scores (1.9+/-0.2 vs. 1.4+/-0.1; P<0.003) compared to HFE wildtypes. By multivariate regression analysis odds ratios for liver cirrhosis were 5.9 (confidence interval (CI) 1.6-22.6; P<0.009) for C282Y heterozygotes and 2.9 (CI 1.0-8.4; P<0.05) for H63D heterozygotes compared to HFE wildtypes. Considering all HFE heterozygous HCV patients, odds ratios of 3.6 (CI 1.4-9.3; P<0.009) for cirrhosis and 3.1 (CI 1.3-7.3; P<0.009) for fibrosis were calculated. CONCLUSIONS: C282Y or H63D heterozygosity is an independent risk factor for liver fibrosis and cirrhosis in HCV infected individuals. Screening for HFE mutations should be considered in HCV infection.