A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation

Gochee, Peter A.; Powell, Lawrie W.; Cullen, Digby J.; Sart, Desirée du; Rossi, Enrico; Olynyk, John K.

doi:10.1016/s0016-5085(02)80116-0

Cited by 226 publications

(157 citation statements)

References 26 publications

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“…Such an association has been observed in homozygosity studies [38,39] , and also with the findings that serum transferrin saturation is significantly increased in H63D homozygotes and heterozygotes as compared with wild-type individuals [40] . To reinforce the importance of the HFE mutations as risk factors for liver disease, the presence of these mutations should be associated with significantly higher iron parameters.…”

Section: Discussionsupporting

confidence: 71%

Iron homeostasis and H63D mutations in alcoholics with and without liver disease

Machado¹,

Ravasco²,

Martins³

et al. 2009

WJG

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AIM:To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS:One hundred and fifty-three heavy drinkers (defined as alcohol consumption > 80 g/d for at least 5 years) were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics (LDA)] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics (NLDA)], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS:Gender ratio was similar in both study groups. LDA patients were older than NLDA patients (52 ± 10 years vs 48 ± 11 years, P = 0.03). One third and one fifth of the study population had serum transferrin saturation (TS) greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS (51 ± 27 vs 36 ± 13, P < 0.001) and ferritin levels (559 ± 607 ng/mL vs 159 ± 122 ng/mL, P < 0.001), and lower total iron binding capacity (TIBC) (241 ± 88 µg/dL vs 279 ± 40 µg/dL, P = 0.001). The odds ratio for having liver disease with TS greater than 45% was 2.20 (95% confidence interval (CI): 1.37-3.54). There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients (0.25 vs 0.16, P = 0.03). LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients (49.5% vs 31.6%, P = 0.02). The odds ratio for LDA in patients with H63D mutation was 1.57 (95% CI: 1.02-2.40). CONCLUSION:The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease, in parallel with an increased frequency of H63D HFE mutation.

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Section: Discussionsupporting

confidence: 71%

Iron homeostasis and H63D mutations in alcoholics with and without liver disease

Machado¹,

Ravasco²,

Martins³

et al. 2009

WJG

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“…25 Our present failure to find an increased rate of the H63D mutation in persons with NASH compared with healthy controls is consistent with the findings of George et al 10 The overall implications of H63D heterozygosity or homozygosity mutation to increased body iron stores are much less important than initially proposed. 26 The present study on associations between HFE mutations and fibrotic severity in NASH is the first to take into account the ethnicity of the cohort and controls. The issue of ethnicity is particularly relevant when HFE mutations are evaluated.…”

Section: Discussionmentioning

confidence: 99%

HFE mutations, hepatic iron, and fibrosis: Ethnic-specific association of NASH with C282Y but not with fibrotic severity

et al. 2002

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There is conflicting evidence regarding inheritance of hemochromatosis gene (HFE) mutations and influence of hepatic iron deposition as cofactors for development of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We studied hepatic iron content (Perls' stain grade), frequency of HFE mutations, and serum iron indices in 93 patients with NASH from a multiethnic background; 59 (63%) were of Anglo-Celtic origin. Data on C282Y mutations were available for all 93 patients and on H63D for 69 patients. Respective controls were 206 (for C282Y, 141 [69%] of whom were Anglo-Celtic) and 180 (for H63D) blood donors. Hyperferritinemia was present in 38 patients (40%) with NASH, but transferrin saturation was increased (>55%) in only 5 (5%). Liver biopsy specimens showed advanced fibrosis in 31 (33%) (cirrhosis in 20%). Altogether, 9 biopsy specimens (10%) showed increased iron: 7 (8%) with grade 2 and 2 (2%) with grade 3 iron staining. Only 1 biopsy specimen with increased iron showed advanced fibrosis. The frequency of C282Y heterozygosity was increased in Anglo-Celtic patients with NASH compared with ethnic blood donor controls (22% vs. 9.2%; P ‫؍‬ .035); there were no C282Y homozygotes in the NASH cohort. Although there was a trend toward higher serum ferritin levels among C282Y heterozygotes with NASH, there were no differences in histologic grades of steatosis, inflammation, or fibrosis between individuals with and without C282Y. The frequencies of compound C282Y/H63D heterozygotes (n ‫؍‬ 1) or H63D heterozygotes (n ‫؍‬ 10) were not increased in NASH. Multivariate analysis identified female sex, diabetes mellitus, and more severe liver inflammation but not HFE mutations, serum ferritin, iron saturation, or hepatic iron staining as independent predictors of hepatic fibrosis. In conclusion, hepatic iron is not a factor linked to hepatic fibrogenesis in patients with NASH. HFE mutations do not confer an additional risk of hepatic fibrosis in this disorder. (HEPATOLOGY 2002;36:142-149.)

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“…In contrast, Beutler argued that the H63D is a disease-related mutation having very low clinical penetrance (28). Subsequent population studies have supported the argument that H63D has a mild effect on parameters of iron homeostasis (16)(17)(18). Scarce data are available on the effect of the H63D mutation on hepatic iron concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, normal iron parameters are observed in approximately half of individuals compound heterozygous for H63D and C282Y (15). Homozygosity for the H63D mutation is associated with increased serum transferrin saturations and ferritin levels in some populations (16)(17)(18). However, the majority of individuals homozygous for H63D have normal iron parameters.…”

Section: H Ereditary Hemochromatosis (Hh) Is An Autosomal Recessivementioning

confidence: 99%

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis

Tomatsu

Orii

Fleming

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by iron accumulation in several organs, followed by organ damage and failure. The C282Y mutation in the HFE gene explains 80 -90% of all diagnosed cases of HH in populations of northwestern European ancestry. Targeted disruption of the mouse Hfe gene (or introduction of the murine mutation analogous to the C282Y human mutation) produces a murine model of HH. Another mutation in the HFE gene, H63D, is more prevalent than C282Y. However, the physiological consequences of the H63D mutation (as well as C282Y͞H63D compound heterozygosity) on iron homeostasis are less well established. To evaluate the phenotypic consequences of the C282Y͞H63D and H63D͞H63D genotypes, we produced H67D (corresponding to H63D in humans) and C294Y (corresponding to C282Y in humans) knock-in mice. H67D homozygous mice, C294Y homozygous mice, and H67D͞ C294Y compound heterozygous mice each demonstrated hepatic iron loading. Even on a standard diet, by 10 weeks of age, hepatic iron levels in mice of these three genotypes were significantly higher than those of wild-type littermates. The relative severity of hepatic iron loading was C294Y͞C294Y > C294Y͞H67D > H67D͞ H67D. We conclude that the H67D allele, when homozygous or combined with a more consequential mutation like C294Y, leads to hepatic iron loading. These observations indicate that the H67D mutation leads to partial loss of Hfe function and can contribute to murine HH.knock-in mice ͉ C282Y mutation ͉ H63D mutation ͉ Cre-loxP H ereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by elevated transferrin saturations, hepatic iron overload, and variable clinical manifestations including liver cirrhosis, hypogonadism, heart failure, and arthropathy. Prevalence of mutations in the gene responsible for HH is estimated to be 2-5 per 1,000 in Caucasians. The gene mutated in HH, the hemochromatosis gene (HFE), encodes an MHC class I-like protein (1) that heterodimerizes with ␤ 2 -microglobulin (␤ 2 M). Most cases of HH arise from a founder mutation in HFE (845G to -A) that results in the amino acid substitution C282Y and prevents the association of HFE with ␤ 2 M (1-3). Functional significance of HFE-␤ 2 M complex in iron homeostasis was supported from the observations that HFE-␤ 2 M is physically associated with transferrin receptor 1 (TfR1) in human placenta (4), in crypt enterocytes of duodenum (5), and in cultured human cell lines (6, 7). The effect of HFE on transferrin-mediated iron uptake seems to depend on the particular cell type studied as well as the magnitude of expression of ␤ 2 M (8).Although the most common HFE mutation associated with HH is C282Y, the most common HFE mutation overall is H63D. Among Caucasian populations, the allele frequency of C282Y is 2-5% and that of H63D is 15-20% (9, 10). The H63D allele frequency has been reported to be as high as 30% in the Basque population of Spain (11). The H63D mutation seems to have evolutionarily predated C282Y and to have ar...

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A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation

Cited by 226 publications

References 26 publications

Iron homeostasis and H63D mutations in alcoholics with and without liver disease

Iron homeostasis and H63D mutations in alcoholics with and without liver disease

HFE mutations, hepatic iron, and fibrosis: Ethnic-specific association of NASH with C282Y but not with fibrotic severity

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis

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