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1
Åsberg, Arne, Kristian Hveem, Kjell Kannelønning, and Wenche Øiestad Irgens. "Penetrance of the C28Y/C282Y genotype of theHFEgene." Scandinavian Journal of Gastroenterology 42, no. 9 (January 2007): 1073–77. http://dx.doi.org/10.1080/00365520701245488.
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Sandnes, Miriam, Marta Vorland, Rune J. Ulvik, and Håkon Reikvam. "HFE Genotype, Ferritin Levels and Transferrin Saturation in Patients with Suspected Hereditary Hemochromatosis." Genes 12, no. 8 (July 28, 2021): 1162. http://dx.doi.org/10.3390/genes12081162.
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HFE hemochromatosis is characterized by increased iron absorption and iron overload due to variants of the iron-regulating HFE gene. Overt disease is mainly associated with homozygosity for the C282Y variant, although the H63D variant in compound heterozygosity with C282Y (C282Y/H63D) contributes to disease manifestation. In this observational study, we describe the association between biochemical findings, age, gender and HFE genotype in patients referred from general practice to a tertiary care referral center for diagnostic workup based on suspected hemochromatosis due to persistent hyperferritinemia and HFE variants. C282Y and H63D homozygosity were, respectively, the most and least prevalent genotypes and we found a considerable variation in transferrin saturation and ferritin levels independent of HFE genotype, which may indeed represent a diagnostic challenge in general practice. While our results confirm C282Y homozygosity as the major cause of iron accumulation, non-C282Y homozygotes also displayed mild to moderate hyperferritinemia with median ferritin levels at 500–700 µg/L, well above the reference cut-off. Such findings have traditionally been ignored in the clinic, and initiation of iron depletion has largely been restricted to C282Y homozygotes. Nevertheless, superfluous iron can aggravate pathogenesis in combination with other diseases and risk factors, such as inflammation, cancer and hepatopathy, and this possibility should not be neglected by clinicians.
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Rossi, Enrico, John K. Olynyk, Digby J. Cullen, George Papadopoulos, Max Bulsara, Lesa Summerville, and Lawrie W. Powell. "Compound Heterozygous Hemochromatosis Genotype Predicts Increased Iron and Erythrocyte Indices in Women." Clinical Chemistry 46, no. 2 (February 1, 2000): 162–66. http://dx.doi.org/10.1093/clinchem/46.2.162.
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Abstract Background: Women who inherit heterozygosity for the C282Y mutation of the HFE gene may have increased serum iron indices and hemoglobin and are less likely to develop iron deficiency compared with women with the wild-type genotype. Methods: We performed a cross-sectional analysis of 497 women 20–44 years of age and 830 women >51 years of age drawn from the Busselton (Australia) population study to assess the effects of the HFE genotype on serum iron and hematology indices. Results: Heterozygosity for the C282Y mutation occurred in 13.8% of the study population, comprising 11.8% C282Y wild-type heterozygotes and 2.0% C282Y/H63D compound heterozygotes. In the younger age group, C282Y wild-type women did not have significantly increased serum iron, transferrin saturation, or hemoglobin values, and were not protected from developing iron deficiency, compared with women of the same age with the wild-type genotype. Young compound heterozygous women had higher means for serum iron (25.0 vs 16.9 μmol/L; P <0.001), transferrin saturation (42.0% vs 25.6%; P <0.05), hemoglobin (139.4 vs 132.3 g/L; P <0.05), and corpuscular volume (91.1 vs 87.7 fL; P <0.05), and a higher median ferritin (53 vs 44 μg/L; P <0.05) compared with the wild-type genotype. Similar results were observed for compound heterozygotes in the >51 years age group. Conclusions: Women with the compound heterozygous HFE genotype C282Y/H63D, but not the C282Y wild-type genotype, had increased values for serum iron and transferrin saturation, and the younger age group also had increased hemoglobin values. We conclude that the compound heterozygous genotype may have a beneficial effect in protecting women from iron deficiency.
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Adams, Paul, Albert Altes, Pierre Brissot, Barbara Butzeck, Ioav Cabantchik, Rodolfo Cançado, Sonia Distante, et al. "Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype." Hepatology International 12, no. 2 (March 2018): 83–86. http://dx.doi.org/10.1007/s12072-018-9855-0.
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Cançado, Rodolfo Delfini, Aline Cristiane de Oliveira Guglielmi, Carmen Silvia Vieitas Vergueiro, Ernani Geraldo Rolim, Maria Stella Figueiredo, and Carlos Sérgio Chiattone. "Analysis of HFE gene mutations and HLA-A alleles in Brazilian patients with iron overload." Sao Paulo Medical Journal 124, no. 2 (2006): 55–60. http://dx.doi.org/10.1590/s1516-31802006000200002.
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CONTEXT AND OBJECTIVE: Hemochromatosis is a common inherited disorder of iron metabolism and one of the most important causes of iron overload. The objective was to analyze the presence of C282Y, H63D and S65C mutations in the HFE gene and HLA-A alleles for a group of Brazilian patients with iron overload, and to correlate genotype with clinical and laboratory variables. DESIGN AND SETTING: Prospective study, in Discipline of Hematology and Oncology, Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo. METHODS: We studied 35 patients with iron overload seen at our outpatient unit between January 2001 and December 2003. Fasting levels of serum iron and ferritin, and total iron-binding capacity, were assayed using standard techniques. Determinations of C282Y, H63D and S65C mutations in the HFE gene and of HLA-A alleles were performed by polymerase chain reaction (PCR). RESULTS: Twenty-six out of 35 patients (74%) presented at least one of the HFE gene mutations analyzed. Among these, five (14%) were C282Y/C282Y, four (11%) C282Y/H63D, one (3%) H63D/H63D, six (17%) C282Y/WT and ten (29%) H63D/WT. No patients had the S65C mutation and nine (25%) did not present any of the three HFE mutations. Four out of five patients with C282Y/C282Y genotype (80%) and three out of four patients with C282Y/H63D genotype (75%) were HLA A*03. CONCLUSION: Analysis of HFE gene mutations constitutes an important procedure in identifying patients with hereditary hemochromatosis, particularly for patients with iron overload.
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Piperno, Alberto, Domenico Girelli, Elizabeta Nemeth, Paola Trombini, Claudia Bozzini, Erika Poggiali, Yen Phung, Tomas Ganz, and Clara Camaschella. "Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis." Blood 110, no. 12 (December 1, 2007): 4096–100. http://dx.doi.org/10.1182/blood-2007-06-096503.
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Abstract Inadequate hepcidin synthesis leads to iron overload in HFE-related hemochromatosis. We explored the regulation of hepcidin by iron in 88 hemochromatosis patients (61 C282Y/C282Y, 27 C282Y/H63D) and 23 healthy controls by analyzing urinary hepcidin before and 24 hours after a 65-mg oral iron dose. Thirty-four patients were studied at diagnosis and had iron overload, and 54 patients were iron depleted. At diagnosis, hepcidin values in C282Y homozygotes were similar to controls, whereas values in C282Y/H63D heterozygotes were higher (P = .02). However, the hepcidin/ferritin ratio was decreased in both homozygotes (P < .001) and heterozygotes (P = .017), confirming the inadequate hepcidin production for the iron load with both genotypes. In iron-depleted patients of both genotypes studied at a time remote from phlebotomy, basal hepcidin was still lower than in controls (P < .001 for C282Y/C282Y and P = .002 for heterozygotes). After an iron challenge, mean urinary hepcidin excretion increased in controls (P = .001) but not patients, irrespective of genotype and iron status. Significant hepcidin increase ( ≥ 10 ng/mg creatinine) was observed in 74% of controls, 15% of homozygotes, and 32% of heterozygotes. The hepcidin response to oral iron is blunted in HFE-related hemochromatosis and not improved after iron depletion. The findings support the involvement of HFE in iron sensing and subsequent regulation of hepcidin.
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Acton, Ronald T., Beverly M. Snively, James C. Barton, Paul C. Adams, John H. Eckfeldt, Emily L. Harris, Fitzroy W. Dawkins, et al. "Geographic and Racial/Ethnic Differences in HFE Mutation Frequencies and Iron Phenotypes in the Hemochromatosis and Iron Overload Screening (HEIRS) Study." Blood 104, no. 11 (November 16, 2004): 3211. http://dx.doi.org/10.1182/blood.v104.11.3211.3211.
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Abstract Designing an optimal screening approach for hemochromatosis and iron overload requires knowledge of racial/ethnic subpopulations and frequencies of HFE mutations and phenotypes in geographic areas. In the HEIRS Study, HFE C282Y and H63D genotypes and prevalences of participants who met biochemical criteria for further evaluation (transferrin saturation >50% and ferritin >300 ng/mL, men; >45% and >200 ng/mL, women) were compared in a primary care-based sample of ~100,000 adults ≥25 years from 5 Field Centers. There were different respective HFE C282Y and H63D genotype frequencies in Whites, Blacks, Asians, and Hispanics across geographic areas (all p<0.0001), but not in Native Americans or Pacific Islanders. In Whites, the C282Y/C282Y proportion was significantly higher in AL than in CA or OR/HI. AL also had a significantly higher proportion of C282Y/wt than CA or OR/HI. In Blacks, D.C. had a significantly higher proportion of C282Y and H63D genotypes than AL. ONT had a significantly higher H63D genotype proportion than AL. In Asians, CA had a significantly higher proportion of H63D genotypes than OR/HI or ONT. In Hispanics, there were significant differences between: AL and CA; AL and D.C.; CA and D.C.; CA and OR/HI; D.C. and OR/HI; and D.C. and ONT. We also observed: Prevalences of Participants Who Met Biochemical Criteria for Further Evaluation Race/Ethnicity Geographic Area Prevalence (%) 95% CI Asians California 5.54 4.98, 6.16 Oregon/Hawaii 5.06 4.29, 5.95 Ontario 4.25 3.69, 4.88 Alabama 1.41 0.25, 7.56 D.C. 0.96 0.26, 3.42 Pacific Islanders California 3.66 1.25, 10.21 Oregon/Hawaii 3.47 2.23, 5.36 Native Americans Alabama 2.65 0.91, 7.52 Oregon/Hawaii 2.50 0.69, 8.66 D.C. 0.99 0.17, 5.40 Ontario 0.75 0.21, 2.71 Whites Ontario 2.31 2.08, 2.56 California 1.93 1.56, 2.37 Oregon/Hawaii 1.52 1.34, 1.73 Alabama 1.48 1.26, 1.74 D.C. 1.40 0.80, 2.43 Hispanics Ontario 1.92 0.82, 4.41 California 1.52 1.28, 1.79 Oregon/Hawaii 1.34 0.73, 2.4 Alabama 0.84 0.23, 3.01 D.C. 0.74 0.48, 1.16 Blacks D.C. 1.75 1.56, 1.96 Ontario 1.55 0.52, 4.45 Alabama 1.09 0.90, 1.32 Oregon/Hawaii 0.92 0.31, 2.66 California 0.86 0.29, 2.51 The percentage of men who met biochemical criteria for further evaluation was greater than that of women. We conclude that 1) C282Y and H63D genotype frequencies vary significantly within a single racial/ethnic group across geographic regions; and 2) the percentage of participants who met biochemical criteria for further evaluation varies by racial/ethnic group.
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Bradley, L. A., D. D. Johnson, G. E. Palomaki, J. E. Haddow, N. H. Robertson, and R. M. Ferrie. "Hereditary haemochromatosis mutation frequencies in the general population." Journal of Medical Screening 5, no. 1 (March 1, 1998): 34–36. http://dx.doi.org/10.1136/jms.5.1.34.
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Objectives This study aims to expand our knowledge of the general population frequency of two mutations, C282Y and H63D, identified in the candidate gene for hereditary haemochromatosis, and to determine whether the testing can be performed using routinely obtained cheek-brush (buccal) samples. Setting Banked buccal lysate samples, randomised and coded for anonymity, from a cohort of couples who underwent prenatal cystic fibrosis screening in Maine. Methods A multiplex ARMS test was performed on buccal cell lysates to identify the two mutations. Results Genotype frequencies found among the 1001 subjects studied (502 women, 499 men) were: seven C282Y homozygotes, 22 C282Y/H63D compound heterozygotes, 97 C282Y heterozygotes, 17 H63D homozygotes, 246 H63D heterozygotes, and 612 individuals with no detectable mutation. The allele frequencies for C282Y and H63D were 0.066 and 0.151, respectively. Conclusions Observed genotype frequencies in Maine are consistent with expectations and with consensus data from five smaller studies. Combined mutational analysis data indicate that homozygosity for C282Y (the genotype found in about 85% of subjects with diagnosed hereditary haemochromatosis) occurs in 51 per 10 000 white subjects of northern European heritage; the corresponding total hereditary haemochromatosis prevalence of about 60 per 10 000 is consistent with previous estimates. The study also confirms that H63D would not be useful in general population screening for hereditary haemochromatosis.
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Vantyghem, Marie-Christine, Isabelle Fajardy, Florence Dhondt, Caroline Girardot, Michèle D’Herbomez, Pierre-Marie Danze, Jean Rousseaux, and Jean-Louis Wemeau. "Phenotype and HFE genotype in a population with abnormal iron markers recruited from an Endocrinology Department." European Journal of Endocrinology 154, no. 6 (June 2006): 835–41. http://dx.doi.org/10.1530/eje.1.02152.
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Objective: The aim of this study was to describe HFE genotype in a population of patients with altered iron markers recruited in an Endocrinology Department and to define the possible phenotype–genotype relationships. Methods: A total of 156 patients with high serum ferritin concentrations (>300 ng/ml) or transferrin saturation (>45%) (I group), and a control group of 106 healthy subjects (C group) underwent HFE genotyping (classical C282Y and H63D mutations). We also examined the main genetic features of subgroups in I according to the presence (D) or the absence (ND) of diabetes. Results: (1) The genotypes were significantly different in the I and C groups (P<0.001), with an increased frequency of major 282Y allele in the I group (35% vs 7.5%), but not of minor 63D allele (17 vs 18.5%). (2) The genotype of D and ND groups also differed (P<0.0001), with a lower frequency of C282 heterozygosity (P<0.0001) in the D group, and a higher prevalence of H63D heterozygosity in the D vs ND groups (P<0.01). (3) The phenotypic comparison of D and ND groups also showed a higher mean body mass index, age, and serum ferritin concentration, as well as an increased proportion of males with increased liver enzymes in the D group. Conclusion: This population harboring abnormal iron markers had a different HFE genotype and a higher 282Y allele frequency than the control population. This suggests that blood iron markers could be checked in etiological investigations of metabolic disturbances to identify patients who should undergo genotyping, since approximately 20% were diagnosed with C282Y homozygosity.
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Rossi, Enrico, Max K. Bulsara, John K. Olynyk, Digby J. Cullen, Lesa Summerville, and Lawrie W. Powell. "Effect of Hemochromatosis Genotype and Lifestyle Factors on Iron and Red Cell Indices in a Community Population." Clinical Chemistry 47, no. 2 (February 1, 2001): 202–8. http://dx.doi.org/10.1093/clinchem/47.2.202.
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Abstract Background: Heterozygotes for the C282Y mutation of the HFE gene may have altered hematology indices and higher iron stores than wild-type subjects. Methods: We performed a cross-sectional analysis of 1488 females and 1522 males 20–79 years of age drawn from the Busselton (Australia) population study to assess the effects of HFE genotype, age, gender, and lifestyle on serum iron and hematology indices. Results: Male C282Y heterozygotes had increased transferrin saturation compared with the wild-type genotype. Neither male nor female heterozygotes had significantly increased ferritin values compared with the wild-type genotype. Younger (20–29 years) wild-type males, but not heterozygous males, had significantly lower ferritin values than wild-type males in the older age groups. Compound heterozygous subjects had increased means for serum iron, transferrin saturation, corpuscular volume, and corpuscular hemoglobin compared with the wild-type genotype, and the males also had increased ferritin values (medians 323 vs 177 μg/L; P = 0.003). In both male and female wild-type subjects, an increased body mass index was associated with decreased serum iron and transferrin saturation and increased ferritin values. There was a significant increase in ferritin concentrations in both genders with increasing frequency of red meat consumption above a baseline of 1–2 times per week and alcohol intakes >10 g/day. Conclusions: Male C282Y heterozygotes had significantly increased transferrin saturation values. Compound heterozygous (C282Y/H63D) subjects formed a separate category of C282Y heterozygotes in whom both iron and red cell indices were significantly increased compared with the wild-type genotype.
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Beutler, Ernest, Terri Gelbart, and Pauline Lee. "Haptoglobin Polymorphism and Iron Homeostasis." Clinical Chemistry 48, no. 12 (December 1, 2002): 2232–35. http://dx.doi.org/10.1093/clinchem/48.12.2232.
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Abstract Background: There is a marked difference in the degree of expression of the homozygous C282Y HFE genotype that is associated with hereditary hemochromatosis. It has been reported that individuals with the haptoglobin 2-2 type manifest increased iron concentrations, including serum iron, transferrin saturation, and ferritin. Methods: We studied 232 patients, 115 homozygous for the c.845G→A (C282Y) mutation and 117 matched controls with the wild-type HFE genotype, for haptoglobin phenotypes. Haptoglobin types were determined by electrophoresis of the denatured protein. The HFE genotype was determined by allele-specific oligonucleotide hybridization. Ferritin and transferrin saturation were measured by standard methods. Results:There was no relationship between haptoglobin type and ferritin concentration or transferrin saturation. Conclusions: The effect of haptoglobin type on iron homeostasis cannot account for the marked phenotypic variation that is seen in patients homozygous for the HFE C282Y mutation.
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Evangelista, Andreia Silva, Maria Cristina Nakhle, Thiago Ferreira de Araújo, Clarice Pires Abrantes-Lemos, Marta Mitiko Deguti, Flair José Carrilho, and Eduardo Luiz Rachid Cançado. "HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/164671.
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Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS) > 45%, and serum ferritin (SF) > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n=16) were the HFE hereditary hemochromatosis (HFE-HH) group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n=92). Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population.
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Cancado, Rodolfo D., Paulo CJL Santos, Samuel Rostelato, Cristiane T. Terada, Iris Gonzales, Rosário DC Hirata, Mario H. Hirata, Carlos Chiattone, and Elvira M. Guerra-Shinohara. "Interaction Between Genotypes for HFE and TFR2 Genes Mutations and Iron Status in Brazilian Blood Donors." Blood 112, no. 11 (November 16, 2008): 5382. http://dx.doi.org/10.1182/blood.v112.11.5382.5382.
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Abstract Hereditary hemochromatosis (HH) is a disorder characterized by increased intestinal iron absorption, which leads to a progressive accumulation of iron in the body. This iron overload has been associated with mutations in HFE gene (C282Y, H63D and S65C) and other genes. The objectives of this study were to assess the frequencies of functional mutations in HFE and TFR2 genes and to investigate their relationship with the iron status in a sample of blood donors. Blood donors (n=542) were recruited at the Hemocenter of the Santa Casa Hospital, Sao Paulo, Brazil. The genotypes for HFE (C282Y, H63D and S65C) TFR2 (Y250X and Q690P) gene mutations were evaluated by PCR-RFLP. The concentrations of serum iron and total iron-binding capacity (TIBC) were measured by automation system Advia®(Bayer Diagnostics) and serum ferritin by Axsym System®(Abbott Laboratories). The frequencies of HFE 282Y, HFE 63D and HFE 65C alleles were 2.1, 13.6 and 0.6%, respectively. The frequency C282Y allele (2.1%) in Brazilian blood donors is lower than that observed in blood donors from Northern Europe (5.1 to 8.2%, P<0.05). The TFR2 250X and TFR2 690P alleles were not found in these subjects. The iron status was similar between HFE genotypes in women. However, men carrying HFE 282CY genotype had higher serum ferritin and lower TIBC concentrations when compared to the HFE 282CC genotype carriers. HFE 282CY genotype was also associated with higher transferrin saturation in men who donated blood at the first time. Moreover, male donors with HFE 63DD plus 63HD genotypes had higher serum iron and transferrin saturation when compared to those with HFE 63HH genotype. A relationship between HFE CY/HH/SS haplotype and lower TIBC concentrations was also found in men. The HFE 282Y and HFE 65C alleles were rare while the HFE 63D was frequent in blood donors. The mutations in TFR2 gene were not found in this study. The HFE 282Y and HFE 63D alleles were associated with alterations on iron status only in male blood donors.
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Barton, James C., Ronald T. Acton, Fitzroy W. Dawkins, Paul C. Adams, Laura Lovato, Cathy Leiendecker-Foster, Christine E. McLaren, et al. "Initial Screening Transferrin Saturations, Serum Ferritin Concentrations, and HFE Genotypes in Whites and Blacks in the Hemochromatosis and Iron Overload Screening (HEIRS) Study." Blood 104, no. 11 (November 16, 2004): 3202. http://dx.doi.org/10.1182/blood.v104.11.3202.3202.
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Abstract We compared initial screening data of 44,149 whites (17,043 men; 27,106 women) and 26,947 blacks (9,788 men; 17,159 women) who reported no previous diagnosis of hemochromatosis or iron overload from a primary care-based sample of ~100,000 adults ≥25 years recruited from 5 Field Centers. Each underwent transferrin saturation (TfSat) and serum ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. We observed these mean TfSat and SF values and percentages of participants with elevated biochemical measurements (TfSat >50% and SF >300 ng/mL, men; TfSat >45% and SF >200 ng/mL, women): Participants Mean % TfSat (95% CI) Elevated TfSat, % Participants Mean SF, ng/mL (95% CI) Elevated SF, % Participants White men 32.4 (32.3, 32.6) 7.05 150.9 (149.1, 152.8) 19.49 Black men 29.3 (29.1, 29.5) 4.03 178.4 (175.5, 181.3) 25.95 p Value <0.0001 <0.0001 <0.0001 <0.0001 White women 27.5 (27.3, 27.6) 6.62 63.0 (62.3, 63.7) 8.74 Black women 23.3 (23.1, 23.4) 3.04 68.3 (67.2, 69.4) 15.43 p Value <0.0001 <0.0001 <0.0001 <0.0001 In participants grouped by decade, mean TfSat was greater in white men than in black men, and in white women than in black women (all p<0.0001). Mean SF was greater in black men than in white men in all decades except 25–34 years, and in black women than in white women in decades ≥45 years. SF increased with age to ~45 years in white men and ~50 years in black men, and then decreased. In white women, SF rose with age until ~62 years and less rapidly to age ≥80. In black women, SF rose with age until ~62 years and then decreased. C282Y allele frequency was 0.0700 (95% CI: 0.0683, 0.0717) in whites and 0.0119 (0.0110, 0.0129) in blacks. H63D allele frequency was 0.1532 (0.1509, 0.1556) in whites and 0.0299 (0.0284, 0.0313) in blacks. Frequencies of genotypes with C282Y or H63D were greater in whites than in blacks (all p<0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y was 0.003 in whites and 0.00004 in blacks (p<0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y, C282Y/H63D, or H63D/H63D was 0.006 in whites and 0.0003 in blacks (p<0.0001). We conclude that: 1) the prevalence of elevated TfSat is higher in whites and the prevalence of elevated SF is higher in blacks; 2) SF levels increase with age; 3) HFE C282Y and H63D alleles occur more frequently in whites than in blacks; and 4) the prevalence of elevated TfSat and SF plus genotypes with two common HFE mutations is greater in whites than in blacks.
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Mikhail, Sameh E., and Pradyumna D. Phatak. "Elevated MCV in Patients with Hereditary Hemochromatosis." Blood 108, no. 11 (November 16, 2006): 3733. http://dx.doi.org/10.1182/blood.v108.11.3733.3733.
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Abstract Background: Previous studies have reported that patients with Hereditary Hemochromatosis have higher red cell volumes than normal controls. The relationship of this abnormality to the degree of iron overload and to HFE genotype has not been systematically studied. Method: We retrospectively compared the mean corpuscular volume (MCV) of patients with Hereditary Hemochromatosis with that of an age-, race- and sex-matched control population from the primary care clinic at our institution. We studied the relationship of MCV at diagnosis with serum transferrin saturation, serum ferritin level, phlebotomy-mobilizable iron stores and HFE genotype in our patients. Results: The study population included 290 patients who were treated for Hereditary Hemochromatosis at our center. 122/290 were homozygous for C282Y; the mean MCV of this group was significantly elevated at 95.2 fL (control group was 89.2 fL; p<0.001) Among all patients with phlebotomy-mobilizable iron greater than four grams, regardless of HFE genotype, the mean MCV was 94.8 fL (significantly greater than control, p<0.001); there was no significant difference between those who are homozygous for the C282Y HFE mutation and those who are not. Among C282Y homozygous individuals, there was no significant correlation between the MCV versus serum transferrin saturation, serum ferritin and phlebotomy-mobilizable iron (r= 0.07, 0.207 and −0.005 respectively). In patients with mobilizable iron greater than four grams who were not C282Y homozygous there was weak correlation between the MCV versus serum transferrin saturation and serum ferritin (r= 0.39 and 0.37 respectively) and no significant correlation versus phlebotomy-mobilizable iron (r= 0.04). Conclusion: Our study confirms the presence of elevated MCV levels in patients with Hereditary Hemochromatosis. The mean MCV was high in both C282Y homozygous individuals as well as those with elevated levels of body iron (>4 g) who were not homozygous for the C282Y HFE mutation. For the most part, the elevated MCV did not correlate with measures of body iron stores although there was a weak correlation with serum transferrin saturation and serum ferritin among iron-loaded individuals who were not homozygous for C282Y. Further studies of the factors that influence MCV in these patients may provide insights into the derangements of iron utilization that may occur in iron overload syndromes.
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Acton, Ronald T., James C. Barton, Leah Passmore, Paul C. Adams, Mark R. Speechley, Fitzroy W. Dawkins, Phyliss Sholinsky, et al. "Relationships of Serum Ferritin, Transferrin Saturation, and HFE Mutations and Self-Reported Diabetes Mellitus in the Hemochromatosis and Iron Overload Screening (HEIRS) Study." Blood 106, no. 11 (November 16, 2005): 3713. http://dx.doi.org/10.1182/blood.v106.11.3713.3713.
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Abstract Mean serum ferritin concentration (SF) has been positively associated with diabetes mellitus in some racial/ethnic groups. We evaluated the associations of self-reported diabetes mellitus with SF, serum transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five Field Centers in the multi-center, primary care-based HEIRS Study. Analyses were conducted on the 97,470 participants for whom pertinent data were available. Participants who reported that they had been previously diagnosed with diabetes mellitus and/or hemochromatosis or iron overload were compared to participants who did not report a previous diagnosis. The overall prevalence of diabetes mellitus was 13.8%; the highest prevalence was observed in Native Hawaiian/Pacific Islanders (20.1%). 2.0% of all participants with diabetes mellitus and 2.2% of whites with diabetes mellitus reported that they also had hemochromatosis or iron overload. Mean SF was elevated in women with diabetes mellitus in all racial/ethnic groups and in American Indian/Alaska Native men with diabetes mellitus. Mean SF was significantly lower in Asian men with diabetes mellitus. Mean TfSat was lower (or not increased) in participants with diabetes mellitus than in those without diabetes mellitus. There was no significant association of diabetes mellitus with HFE genotype. Mean SF was greater (p <0.0001) in women with diabetes mellitus than in those without diabetes mellitus for HFE genotypes except C282Y/C282Y and C282Y/H63D. There was a significant positive association of log SF and diabetes mellitus in a logistic regression analysis after adjusting for age, gender, racial/ethnic group, HFE genotype, and Field Center. We conclude that SF is significantly associated with diabetes mellitus, even at levels of SF below those typically associated with hemochromatosis or iron overload.
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McLaren, C. E., J. C. Barton, G. D. McLaren, R. T. Acton, P. C. Adams, L. F. Henkin, V. R. Gordeuk, et al. "Heritability of Iron Status Phenotype in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study." Blood 112, no. 11 (November 16, 2008): 115. http://dx.doi.org/10.1182/blood.v112.11.115.115.
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Abstract Hereditary hemochromatosis (HH) is a common iron overload (IO) disorder of people of western European descent. HH, defined using biochemical criteria, occurs in 0.2%–0.5% of US whites. Some HH patients absorb excessive dietary iron and develop consequent liver fibrosis and cirrhosis, hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, and hypogonadotrophic hypogonadism. Most whites with HH have common mutations (C282Y and H63D) in HFE; this gene encodes HFE, which regulates iron absorption by modulating hepatic expression of hepcidin. The spectrum of HH phenotypes is broad, and mutations in known iron-related genes do not account for most phenotype variability. Thus, it is assumed that HH phenotypes are affected by other genetic and environmental factors. Gender and age are two important factors known to affect HH phenotypes. Putative genetic factors may influence dietary choices or modulate iron absorption or loss via mechanisms presently undefined. The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. We examined familial aggregation and genetic contributions to iron- and HH-related phenotypes in the HEIRS Family Study and hypothesized that both genetic and environmental factors influence serum iron measures after adjustment for gender, age, HFE C282Y and H63D genotype, and other clinical and demographic characteristics. Heritability (h2), defined as the proportion of total variation due to variability in genetic values, measures the fraction of variation between individuals in a population attributable to additive effects of their genotypes. We estimated heritability of TS, SF, and unbound iron-binding capacity (UIBC) in participants from the HEIRS Family Study (N=180 families, mean size 5.5). Eligible probands (aged >24 y) had both TS and SF values above gender-specific thresholds (TS>50% and SF >300 μg/L in men; TS >45% and SF >200 μg/L in women), or were C282Y homozygotes. Family members, 19 years of age or older, were eligible. There were 77% Caucasians, 3% African Americans, 8% Hispanics, and 10% Asians; average age (SD) was 49 (16) y; 56% were female. The distribution of HFE genotypes was 22% C282Y/C282Y, 7% C282Y/H63D, 2% H63D/H63D, 34% C282Y/+, 8% H63D/+, and 26% +/+. A variance component approach using SOLAR software estimated residual heritability, adjusting for age, gender, their interaction (age × gender), race/ethnicity, and HFE genotype (model 1). In another model, study site, body mass index, menopausal status, phlebotomy treatment, hepatitis, average daily intake of alcohol, and level of C-reactive protein were added to the core set of covariates (model 2). Log transformation of serum ferritin was performed prior to analysis. In model 1 (N=938 individuals), h2 was 0.40 (SE 0.060) for UIBC, 0.26 (0.055) for log SF, and 0.25 (0.056) for TS; P < 0.0001 for each test of h2=0. Age, gender, race/ethnicity, and HFE genotype accounted for 38%, 38%, and 36% of the variability in UIBC, log SF, and TS, respectively. In model 2, based on complete data from N=828 individuals, adjusted for the full set of covariates, h2 was 0.31 (0.067) for UIBC, 0.26 (0.067) for log SF, and 0.16 (0.061) for TS; P < 0.0013 for each. The proportion of variance due to age, gender, HFE gene and all measured environmental factors was 0.43 for UIBC, 0.44 for log SF, and 0.41 for TS. We conclude that quantitative serum iron measures in HEIRS Family Study participants have significant heritability components, even after accounting for effects of HFE C282Y and H63D genotypes. This suggests that other genetic variants contribute to the variability in TS, SF, and UIBC, and indicates the need for gene discovery studies to provide insight into clinical disorders in which morbidity and mortality are affected by perturbations of iron metabolism.
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Moen, Ingrid W., Helle K. M. Bergholdt, Thomas Mandrup-Poulsen, Børge G. Nordestgaard, and Christina Ellervik. "Increased Plasma Ferritin Concentration and Low-Grade Inflammation—A Mendelian Randomization Study." Clinical Chemistry 64, no. 2 (February 1, 2018): 374–85. http://dx.doi.org/10.1373/clinchem.2017.276055.
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Abstract BACKGROUND It is unknown why increased plasma ferritin concentration predicts all-cause mortality. As low-grade inflammation and increased plasma ferritin concentration are associated with all-cause mortality, we hypothesized that increased plasma ferritin concentration is genetically associated with low-grade inflammation. METHODS We investigated whether increased plasma ferritin concentration is associated with low-grade inflammation [i.e., increased concentrations of C-reactive protein (CRP) and complement component 3 (C3)] in 62537 individuals from the Danish general population. We also applied a Mendelian randomization approach, using the hemochromatosis genotype C282Y/C282Y as an instrument for increased plasma ferritin concentration, to assess causality. RESULTS For a doubling in plasma ferritin concentration, the odds ratio (95% CI) for CRP ≥2 vs <2 mg/L was 1.12 (1.09–1.16), with a corresponding genetic estimate for C282Y/C282Y of 1.03 (1.01–1.06). For a doubling in plasma ferritin concentration, odds ratio (95% CI) for complement C3 >1.04 vs ≤1.04 g/L was 1.28 (1.21–1.35), and the corresponding genetic estimate for C282Y/C282Y was 1.06 (1.03–1.12). Mediation analyses showed that 74% (95% CI, 24–123) of the association of C282Y/C282Y with risk of increased CRP and 56% (17%–96%) of the association of C282Y/C282Y with risk of increased complement C3 were mediated through plasma ferritin concentration. CONCLUSIONS Increased plasma ferritin concentration as a marker of increased iron concentration is associated observationally and genetically with low-grade inflammation, possibly indicating a causal relationship from increased ferritin to inflammation. However, as HFE may also play an immunological role indicating pleiotropy and as incomplete penetrance of C282Y/C282Y indicates buffering mechanisms, these weaknesses in the study design could bias the genetic estimates.
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Jacobs, Esther M. G., Jan C. M. Hendriks, Herman G. Kreeftenberg, Richard A. de Vries, Joannes J. M. Marx, Cees Th B. M. van Deursen, Anton F. H. Stalenhoef, Andre L. M. Verbeek, and Dorine W. Swinkels. "Determinants for Iron Overload-Related Disease in Siblings of Probands with Clinically Detected HFE Hereditary Hemochromatosis: The Hemochromatosis Family Study." Blood 112, no. 11 (November 16, 2008): 1857. http://dx.doi.org/10.1182/blood.v112.11.1857.1857.
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Abstract The clinical expression of HFE-associated hereditary hemochromatosis (HH) gen is highly variable and may be influenced by nongenetic factors and coinherited genetic modifiers, complicating early screening options to prevent iron-overload related disease. The aim of this study was to verify the existence of HH-related disease in C282Y homozygous siblings of C282Y homozygous probands with clinically detected HFE-related HH and to identify factors predictive for the iron-related disease within these siblings. To this end, C282Y homozygous (n=110, males n=53) and non-homozygous siblings (n=318, males n=145) of 224 probands were compared for levels of serum iron parameters, and self-reported environmental and lifestyle factors and previously diagnosed HH-related diseases. Compared to non-homozygous C282Y siblings, C282Y homozygous siblings more often mentioned to have been diagnosed with arthropathy (Odds Ratio [OR] 2.76, 95% Confidential Interval [CI] 1.71–4.46) and liver disease (OR 2.90, 95%CI 1.27– 6.62). Using multivariate logistic regression modelling, genotype (OR 2.29, 95%CI 1.04– 5.02), age (OR 1.07, 95% CI 1.04–1.09) and gender (OR 1.71, 95%CI 1.04–2.80) were found predictive for the development of iron-associated organ disease. With genotype in the model, there was neither an additive predictive value of the serum iron parameters, nor of body mass index (BMI) or alcohol intake. However, when the predictive value of the iron parameters was analyzed in siblings above 55 yrs, the input of the serum ferritin levels was also significant, with a less prominent influence of gender. In conclusion, our results show that the prevalence of hemochromatosis-attributed morbid conditions is increased in the C282Y homozygous siblings compared to their non-homozygous counterparts. Results furthermore suggest that age and gender, but not BMI and alcohol intake, add to the identification of C282Y homozygous siblings most at risk to develop hemochromatosis-associated disease. These findings will be instrumental in the definition of a high-risk group for iron overload-related disease among siblings of clinically detected C282Y homozygous probands and may contribute to the cost-effectiveness of family screening.
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Coelho-Borges, Silvia, Hugo Cheinquer, Fernando Herz Wolff, Nelson Cheinquer, Luciano Krug, and Patricia Ashton-Prolla. "Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin." Arquivos de Gastroenterologia 49, no. 1 (March 2012): 9–13. http://dx.doi.org/10.1590/s0004-28032012000100003.
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CONTEXT: Abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis C and are associated with a lower response rate to interferon therapy. OBJECTIVE: To determine if the presence of HFE gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis C patients with elevated serum ferritin. METHODS: A total of 44 treatment naÏve patients with histologically demonstrated chronic hepatitis C, all infected with hepatitis C virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/mL were treated with interferon (3 MU, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. RESULTS: Sustained virological response was defined as negative qualitative HCV-RNA more than 24 weeks after the end of treatment. Serum HCV-RNA was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 IU/mL. HFE gene mutation was detected using restriction-enzyme digestion with RsaI (C282Y mutation analysis) and BclI (H63D mutation analysis) in 16 (37%) patients, all heterozygous (11 H63D, 2 C282Y and 3 both). Sustained virological response was achieved in 0 of 16 patients with HFE gene mutations and 11 (41%) of 27 patients without HFE gene mutations (P = 0.002; exact Fisher test). CONCLUSION: Heterozigozity for H63D and/or C282Y HFE gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis C, non-1 genotype and serum ferritin levels above 500 ng/mL.
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Busti, Fabiana, Annalisa Castagna, Giacomo Marchi, Oliviero Olivieri, Peter Pramstaller, and Domenico Girelli. "Altered Iron Parameters and Hepcidin Levels in a General Population: Lessons from the CHRIS Study." Blood 134, Supplement_1 (November 13, 2019): 2239. http://dx.doi.org/10.1182/blood-2019-127098.
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Introduction Environmental and genetic factors may lead to iron accumulation, causing irreversible organ damage. Homozygosity for the C282Y (C282Y +/+) and compound heterozygosity for the C282Y and H63D (C282Y-H63D) mutations of the HFE gene are associated with susceptibility to iron overload (IO). However, their clinical and biochemical expression is heterogeneous, with some patients showing only an increase of transferrin saturation (TSAT) for life, and others developing severe liver disease at a young age. Rarely, IO occurs in subjects without HFE-mutations or other acquired factors (e.g. alcohol intake, hemolysis, etc.). In these cases, non-HFE hemochromatosis is suspected, but the diagnosis is challenging, based on invasive (i.e., liver biopsy) or poorly available (i.e., Next-Generation Sequencing) approaches. A defective production of the iron regulatory hormone hepcidin is the key pathogenetic factor in hereditary hemochromatosis, irrespective of the gene involved, but extensive studies evaluating its potential diagnostic role are still lacking. This project evaluated hepcidin levels in a large subpopulation from the Cooperative Health Research In South Tyrol (CHRIS) study. Here we explored in particular hepcidin levels in subjects with altered iron status parameters, and their role in the identification of subjects at major risk of developing IO. Patients and Methods Study Population. The CHRIS study is a population-based study carried out in South Tyrol (Northern Italy), whose general aims are reported in detail elsewhere (Pattaro C, J Transl Med 2015). Blood samples were tested for several biochemical and genetic parameters, including those related to iron status, such as TSAT, ferritin, and C282Y and H63D mutations. Hepcidin was measured in stored aliquots by a recently updated and validated mass spectrometry-based method in tandem with liquid chromatography (LC-MS/MS), able to distinguish the active hepcidin-25 isoform (Diepeveen LE, Clin Chem Lab Med 2019). Results Among 4,642 participants, 6 were C282Y +/+ and 30 were C282Y-H63D (hereinafter defined as "HFE-H subjects"). HFE-H subjects showed ferritin levels only slightly higher than those with apparent wild-type HFE-H genotype (92.7 vs. 76.0 ng/ml, p=0.29), significantly higher TSAT (46.6 vs. 28.9%, p<0.0001) and lower hepcidin levels (1.41 vs. 2.30 nmol/l, p=0.016) (Table 1). Defective production of hepcidin was suggested by the reduced hepcidin:ferritin ratio (1.53 vs. 3.02 pmol/ng, p<0.0001), which was particularly low in C282Y +/+ (0.65 pmol/ng). Table 2 shows the prevalence of subjects with altered iron parameters (hyperferritinemia and/or increased TSAT), according to the HFE genotype. As concern HFE-H subjects, hyperferritinemia (i.e. >200 or >300 ng/ml in females and males, respectively) was detected in 16.7%, increased TSAT (>45%) in 52.8% and both in 11.1%. A biochemical pattern suggestive of IO (ferritin>500 ng/ml and TSAT>50%) was seen only in 33.3% of C282Y +/+ and in 6.7% of C282Y-H63D, while 41.7% neither had hyperferritinemia nor increased TSAT, confirming the low penetrance of such genotype. Although HFE-H subjects displayed a tendency to increase hepcidin production according to iron deposits (mean level of 1.10 nmol/l in subjects without hyperferritinemia/increased TSAT vs. 3.5 nmol/l of subjects with IO), the hepcidin:ferritin ratio was significantly lower in phenotypically expressed HFE-H subjects (0.49 vs. 2.04 pmol/ng, p=0.014) (Table 3). On the other hand, 540 participants (11.7 percent) without HFE-H genotype had hyperferritinemia, 64 (1.4%) had both hyperferritinemia and increased TSAT, and 12 (0.3 percent) had biochemical signs strongly suggestive of IO (ferritin>500 ng/ml and TSAT>50%). The latters had reduced hepcidin:ferritin ratio (0.92 pmol/ng), a value comparable to that of HFE-H iron loaded subjects (p=0.048). Whole Exome Sequencing data are available for the majority of CHRIS subjects included in this project and will be analyzed in detail in these subpopulations. Conclusions Our data suggest that the hepcidin:ferritin ratio may actually represent a useful indicator of hemochromatosis irrespective of the HFE genotype, possibly driving an optimal use of second level genetic test. Disclosures Girelli: Vifor Pharma: Other: honoraria for lectures; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; La Jolla Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.
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Koziol, James A., Ngoc J. Ho, Vincent J. Felitti, and Ernest Beutler. "Reference Centiles for Serum Ferritin and Percentage of Transferrin Saturation, with Application to Mutations of the HFE Gene." Clinical Chemistry 47, no. 10 (October 1, 2001): 1804–10. http://dx.doi.org/10.1093/clinchem/47.10.1804.
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Abstract Background: The gene that causes most cases of hereditary hemochromatosis is designated HFE. Individuals with mutations in the HFE gene may have increased serum iron, transferrin saturation, and ferritin concentrations relative to individuals with the wild-type genotype. Methods: We generated reference centiles for percentage of transferrin saturation and serum ferritin concentrations in normal (wild-type), healthy Caucasian adults. We then examined transferrin and ferritin concentrations relative to these centiles in 81 individuals homozygous for the major hemochromatosis mutation C282Y and 438 individuals with the compound heterozygous HFE genotype C282Y/H63D. Results: Serum ferritin concentrations, but not percentage of transferrin saturation, in normal, healthy women tended to increase sharply as they progressed through menopause. Transferrin and serum ferritin centiles for normal, healthy females were lower than the corresponding centiles in normal, healthy males. C282Y homozygotes had abnormally high transferrin saturation and serum ferritin values relative to the wild types. Compound heterozygotes appeared to be a mixture of individuals with unexceptional transferrin and ferritin values and those with abnormally large values similar to the homozygotes, with equal proportions of each. Conclusions: There are age- and sex-related differences in reference centiles for the percentage of transferrin saturation and serum ferritin concentrations in normal, healthy adults. Individuals homozygous for the C282Y mutation in the HFE gene have abnormal transferrin saturation and serum ferritin values relative to the reference population; penetrance with the compound heterozygotes, as reflected by abnormal transferrin and ferritin values, is less than with the homozygotes.
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Aguilar-Martinez, Patricia, Severine Cunat, Fabienne Becker, Francois Blanc, Marlene Nourrit, Philippe Pouderoux, and Jean-Francois Schved. "Iron Overload in C282Y Heterozygotes: Identification of New Rare HFE Gene Mutants and a Step Strategy for Diagnosis." Blood 112, no. 11 (November 16, 2008): 1859. http://dx.doi.org/10.1182/blood.v112.11.1859.1859.
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Abstract Introduction: Homozygozity for the p.Cys282Tyr (C282Y) mutation of the HFE gene is the main genotype associated with the common form of adult hereditary hemochromatosis. C282Y carriers do not usually develop iron overload, unless they have additional risk factors such as liver diseases, a dysmetabolic syndrome or an associated genetic defect. The commonest is the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele. However, a few rare HFE mutations can be found on the 6th chromosome in trans, some of which are of clinical interest to fully understand the disorder. Patients and Methods: We recently investigated four C282Y carrier patients with unusually high iron parameters, including increased levels of serum ferritin (SF), high transferrin saturation (TS) and high iron liver content measured by MRI. They were males, aged 37, 40, 42, 47 at diagnosis. Two brothers (aged 40 and 42) were referred separately. The HFE genotype, including the determination of the C282Y, H63D and S65C mutations was performed using PCR-RFLP. HFE sequencing was undertaken using the previously described SCA method (1). Sequencing of other genes (namely, HAMP, HJV/HFE2, SLC40A1, TFR2) was possibly performed in a last step using the same method. Results: We identified three rare HFE mutant alleles, two of which are undescribed, in the four studied patients. One patient bore a 13 nucleotide-deletion in exon 6 (c.[1022_1034del13], p.His341_Ala345>LeufsX119), which is predicted to lead to an abnormal, elongated protein. The two brothers had a substitution of the last nucleotide of exon 2 (c.[340G>A], p.Glu114Lys) that may modify the splicing of the 2d intron. The third patient, who bore an insertion of a A in exon 4 (c.[794dupA],p.[trp267LeufsX80]), has already been reported (1). Discussion: A vast majority of C282Y carriers will not develop iron overload and can be reassured. However, a careful step by step strategy at the clinical and genetic levels may allow to correctly identify those patients deserving further investigation. First, clinical examination and the assessment of iron parameters (SF and TS) allow identifying C282Y heterozygotes with an abnormal iron status. Once extrinsic factors such as heavy alcohol intake, virus or a dysmetabolic syndrome have been excluded, MRI is very useful to authenticate a high liver iron content. Second, HFE genotype must first exclude the presence of the H63D mutation. Compound heterozygozity for C282Y and H63D, a very widespread condition in our area, is usually associated with mild iron overload. Third, HFE sequencing can be undertaken and may identify new HFE variants as described here. The two novel mutations, a frameshift modifying the composition and the length of the C terminal end of the HFE protein and a substitution located at the last base of an exon, are likely to lead to an impaired function of HFE in association with the C282Y mutant. However, it is noteworthy that three of the four patients were diagnosed relatively late, after the 4th decade, as it is the case for C282Y homozygotes. Three further unrelated patients are currently under investigation in our laboratory for a similar clinical presentation. Finally, it can be noted that in those patients who will not have a HFE gene mutant identified, analysis of other genes implicated in iron overload must be performed to search for digenism or multigenism. None of our investigated patients had an additional gene abnormality.
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Aguilar-Martinez, Patricia, Michael Bismuth, Francois Blanc, Pierre Blanc, Severine Cunat, Olivier Dereure, Pierre Dujols, et al. "The Southern French Registry of Genetic Hemochromatosis, a Tool for Determination of Clinical Prevalence and Genotype Penetrance of the Disorder." Blood 114, no. 22 (November 20, 2009): 4055. http://dx.doi.org/10.1182/blood.v114.22.4055.4055.
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Abstract Abstract 4055 Poster Board III-990 Background Hereditary hemochromatosis (HH) is a monogenic disorder, mainly due to the HFE C282Y homozygous mutation. This genotype is very widespread, with a prevalence of nearly 1 out of 200, among individuals of North European descent. However, despite great progress in our knowledge during the last decade, there are still debates about the true clinical prevalence and about the penetrance of the disorder, with penetrance estimates ranging from 50-60% to less than 1% depending on the adopted definition of penetrance. Design and methods A registry of patients with HH (systematic record of patients with HH in a defined administrative area) was implemented in South France and a regional health network was developed to allow including all the diagnosed patients living in the area. C282Y homozygous patients were classified into stages according to the French National Authority for Health (HAS) (Brissot P, de Bels F. Hematology Am Soc Hematol Educ Program 2006:36-41). Patients stage 2 (biological iron overload), 3 and 4 (clinical stages, stage 4 including the most severely affected patients with live threatening conditions with impact on survival, such as diabetes, chronic liver disease, cirrhosis or cardiopathy) were included in the registry during a 6 year- period. A yearly follow-up was performed in order to update the registry (particularly removal of patients either deceased or who migrated from the region). Frequency of the C282Y genotypes in this region (homozygotes: 15.7 per 10,000) was known from previous studies, allowing to calculated the penetrance of the different stages. Results A total of 352 symptomatic C282Y homozygotes were identified, resulting in a prevalence of 1.83 per 10,000 subjects over 20 years [CI95%: 1.63-2.02]. The total calculated penetrance was 11.6%, slightly higher in males (13.8%) than in females (9.7%). A markedly lower penetrance at 5.3% was found in patients under 40, and a maximum at 22.9% in patients aged 50-54. Among 249 patients with full record, the majority (58%) was stage 3, 24% stage 2 and 18% stage 4. The penetrance was 2.8%, 7.0% and 2.2% for stages 2, 3 and 4 respectively. There was a higher proportion of males and excessive alcohol intake was more frequent in stage 4 than stage 2 and 3 combined. Conclusions A regional genetic hemochromatosis registry with strict design and inclusion criteria is a useful tool for characterizing the disease history and the prevalence of the clinical manifestations using the proposed HAS classification into stages. The total penetrance of the C282Y homozygous genotype for the three stages with either biological or clinical iron overload was around 12%. Overall, the clinical penetrance (stage 3 and 4) was 9.2%, whereas the penetrance of the most severe manifestations (stage 4) was low, at only 2.2%, with a predominance of men. These results strengthen the need for new biological markers which can help define prognostic criteria in C282Y homozygous subjects diagnosed at an early stage. Disclosures: No relevant conflicts of interest to declare.
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McLaren, Gordon D., and Victor R. Gordeuk. "Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study." Hematology 2009, no. 1 (January 1, 2009): 195–206. http://dx.doi.org/10.1182/asheducation-2009.1.195.
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Abstract Hemochromatosis comprises a group of inherited disorders resulting from mutations of genes involved in regulating iron metabolism. The multicenter, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study screened ~100,000 participants in the US and Canada, testing for HFE mutations, serum ferritin and transferrin saturation. As in other studies, HFE C282Y homozygosity was common in Caucasians but rare in other ethnic groups, and there was a marked heterogeneity of disease expression in C282Y homozygotes. Nevertheless, this genotype was often associated with elevations of serum ferritin and transferrin saturation and with iron stores of more than four grams in men but not in women. If liver biopsy was performed, in some cases because of evidence of hepatic dysfunction, fibrosis or cirrhosis was often found. Combined elevations of serum ferritin and transferrin saturation were observed in non-C282Y homozygotes of all ethnic groups, most prominently Asians, but not often with iron stores of more than four grams. Future studies to discover modifier genes that affect phenotypic expression in C282Y hemochromatosis should help identify patients who are at greatest risk of developing iron overload and who may benefit from continued monitoring of iron status to detect progressive iron loading.
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Barton, James C., Ronald T. Acton, Laura Lovato, Mark R. Speechley, Christine E. McLaren, Emily L. Harris, David M. Reboussin, et al. "Initial Screening Transferrin Saturation Values, Serum Ferritin Concentrations, and HFE Genotypes in Native Americans and Whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study." Blood 106, no. 11 (November 16, 2005): 3712. http://dx.doi.org/10.1182/blood.v106.11.3712.3712.
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Abstract There are few reports of transferrin saturation (TfSat) and serum ferritin (SF) phenotypes and HFE C282Y and H63D genotypes in native Americans. We compared initial screening data of 645 native American and 43,453 white HEIRS Study participants who reported a single race/ethnicity and who did not report a previous diagnosis of hemochromatosis or iron overload. Each underwent TfSat and SF measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat >50% (men), >45% (women); and SF >300 ng/mL (men), >200 ng/mL (women). Mean TfSat was lower in native American men than in white men (31% vs. 32%, respectively; p = 0.0337), and lower in native American women than in white women (25% vs. 27%, respectively; p <0.0001). Mean SF was similar in native American and white men (153 μg/L vs. 151 μg/L; p = 0.8256); mean SF was lower in native American women than in white women (55 μg/L vs. 63 μg/L, respectively; p = 0.0015). The respective percentages of native American men and women with elevated TfSat or elevated SF were similar to those of white men and women. The respective mean TfSat and SF values of native American and white participants with genotype HFE wt/wt were similar. The C282Y allele frequency was 0.0340 in native Americans and 0.0683 in whites (p <0.0001). The H63D allele frequency was 0.1150 in native Americans and 0.1532 in whites (p = 0.0001). We conclude that the screening TfSat and SF phenotypes of native Americans do not differ greatly from those of whites. The respective allele frequencies of HFE C282Y and H63D are significantly lower in native Americans than in whites.
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Pericleous, Marinos, and Claire Kelly. "The clinical management of hereditary haemochromatosis." Frontline Gastroenterology 9, no. 2 (September 23, 2017): 110–14. http://dx.doi.org/10.1136/flgastro-2017-100872.
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Hereditary haemochromatosis is an autosomal recessive disorder with variable penetrance. Most patients are C282Y homozygotes while heterozygotes or patients who are homozygous with other mutations are uncommonly affected. The true genotype to phenotype expression remains unclear. Treatment with phlebotomy is highly effective and cost-efficient while liver transplantation confers a curative option.
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Datz, Christian, Thomas Haas, Heinrich Rinner, Friedrich Sandhofer, Wolfgang Patsch, and Bernhard Paulweber. "Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency?" Clinical Chemistry 44, no. 12 (December 1, 1998): 2429–32. http://dx.doi.org/10.1093/clinchem/44.12.2429.
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Abstract Genetic hemochromatosis (GH) is the most common autosomal-recessive disorder (1 in 300 in populations of Celtic origin). Homozygosity for a C282Y mutation in the hemochromatosis (HFE) gene is the underlying defect in ∼80% of patients with GH, and 3.2–13% of Caucasians are heterozygous for this gene alteration. Because the high frequency of this mutation may result from a selection advantage, the hypothesis was tested that the C282Y mutation confers protection against iron deficiency in young women. To address this question the genotype of codon 282 was determined in a cohort of 468 unrelated female healthcare workers, ages 18–40 years. In all study participants, a complete blood count was obtained, and erythrocyte distribution width, serum iron, transferrin, transferrin saturation, and ferritin were measured. Two individuals were homozygous for the C282Y mutation, 44 were heterozygous, and 416 were homozygous for the wild-type allele. Heterozygous women had significantly higher values for hemoglobin (P = 0.006), serum iron (P = 0.013), and transferrin saturation (P = 0.006) than women homozygous for the wild-type allele. Our data provide evidence for a protective role of the C282Y mutation in the HFE gene against iron deficiency in young women and suggest that a more efficient utilization of nutritional iron may have contributed to the high prevalence of the mutation in Caucasian populations.
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Camacho, António, Thomas Funck-Brentano, Márcio Simão, Leonor Cancela, Sébastien Ottaviani, Martine Cohen-Solal, and Pascal Richette. "Effect of C282Y Genotype on Self-Reported Musculoskeletal Complications in Hereditary Hemochromatosis." PLOS ONE 10, no. 3 (March 30, 2015): e0122817. http://dx.doi.org/10.1371/journal.pone.0122817.
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Rainero, I., E. Rubino, C. Rivoiro, W. Valfrè, E. Binello, E. Zampella, P. De Martino, et al. "Haemochromatosis Gene (HFE) Polymorphisms and Migraine: An Association Study." Cephalalgia 27, no. 1 (January 2007): 9–13. http://dx.doi.org/10.1111/j.1468-2982.2006.01231.x.
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Several studies have suggested that iron metabolism may be involved in the pathogenesis of migraine. Using a case-control design, we performed an association study in a cohort of Italian migraine patients to evaluate whether a particular allele or genotype of the haemochromatosis gene ( HFE) would modify the occurrence and clinical features of the disease. We genotyped 256 migraine patients and 237 healthy age-, sex- and ethnicity-matched controls for the C282Y and H63D polymorphisms of the HFE gene. Phenotype and allele frequencies of both polymorphisms were similarly distributed in migraine patients and controls. The patients carrying the DD genotype of the H63D polymorphism showed a later age at onset of the disease and an increased number of migraine attacks. Our data suggest that the HFE gene is not a major disease gene for migraine. However, the H63D polymorphism of the HFE gene may be considered a modifying genetic factor in migraine.
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OGOUMA-AWORET, Ludmilla, Jean-Pierre RABES, and Philippe de MAZANCOURT. "A Simple RFLP-Based Method for HFE Gene Multiplex Amplification and Determination of Hereditary Hemochromatosis-Causing Mutation C282Y and H63D Variant with Highly Sensitive Determination of Contamination." BioMed Research International 2020 (December 28, 2020): 1–6. http://dx.doi.org/10.1155/2020/9396318.
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Hereditary hemochromatosis is an autosomal recessive disorder with incomplete penetrance that results from excess iron absorption and can lead to chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma. The most common form of hereditary hemochromatosis in Western Europe is due to a homozygous mutation (p.(Cys282Tyr) or C282Y), in the HFE gene which encodes hereditary haemochromatosis protein. In the general European population, the frequency of the homozygous genotype is 0.4%, and this mutation explains up to 95% of hereditary hemochromatosis in France. We report here an improved PCR and restriction endonuclease assay based on multiplex amplification of HFE exon 4 (for C282Y detection), HFE exon 2 (for H63D detection), FZD1 gene (for digestion controls), and two Short Tandem Repeats (SE33 and FGA) for identity monitoring and contamination tracking. Fluorescent primers allow capillary electrophoresis, accurate allele tagging, and sensitive contamination detection.
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Nearman, Zachary P., Bianca Serio, Hadrian Szpurka, Ilka Warshawsky, Alan Lichtin, Mikkael A. Sekeres, and Jaroslaw P. Maciejewski. "Hemochromatois-Associated Gene Mutations in Patients with Myelodysplastic Syndromes with Refractory Anemia and Ringed Sideroblasts." Blood 108, no. 11 (November 16, 2006): 1541. http://dx.doi.org/10.1182/blood.v108.11.1541.1541.
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Abstract Complex interaction between a multitude of genetic variants may be responsible for differential susceptibility to specific diseases, and be responsible for phenotypic variability and heterogeneity of clinical presentations. Such a variability in clinical features confounded for many years investigations into the pathogenesis of myelodysplastic syndromes (MDS). We made a curious observation of increased ferritin levels in some newly diagnosed patients with MDS RARS (refractory anemia with ringed sideroblasts) in whom transfusional iron-overload was unlikely due to very low transfusion burden. Hence, we hypothesized that RARS patients may harbor hemochromatosis-related mutations, which could contribute to the pathophysiology of this particular subset of MDS. We studied a cohort of 109 MDS patients; 42 with RARS, and 67 with other forms of MDS (18 RA, 12 RAEB, 7 RAEB-T, 1 CMML, and 29 MDS/MPD overlap). All patients were genotyped using restriction fragment length polymorphism (RFLP) method, designed to detect presence of C282Y and H63D mutations of the HFE gene. We found significantly higher frequency of heterozygozity for the C282Y mutation in 21% of RARS patients (vs 9% in control population, n=2016, p= 0.017) while H63D genotype was not increased. The possible pathogenic role of this finding in RARS was supported by the normal distribution of mutant HFE alleles in patients with other forms of MDS (5% vs. 9%, p =0.35). Interestingly, 3/7 patients with RA not fulfilling the RARS criteria, but having increased numbers of ringed sideroblasts (<15%) also showed heterozygozity for either C282Y or H63D allele. To correlate the presence of C282Y allele with clinical features of RARS patients, we have performed a subset analysis. Within this group we have included patients with a rather nebulous and rare form of MDS, provisionally subclassified by WHO as RARS with thrombocytosis (RARSt); 7 of these patients (n=10) were found to have either C282Y or H63D allele resulting in a frequency of 30% and 40% of C282Y or H63D allele, respectively. The combined prevalence of either of these alleles in the control population is 33% (vs. 70% in RARSt, p=.01). Previously, we have demonstrated that RARSt patients are characterized by a high prevalence of the V617F JAK2 mutation (Szpurka et al, Blood 2006) suggestive of the pathophysiologic derivation of this syndrome from MPD rather than MDS. Consequently, we have tested the frequency of HFE gene variants associated with hemochromatosis in patients with MPD and Jak2 mutations. Of note is that patients with RARS harbored more C282Y alleles than those with other forms of MDS or MPD with Jak2 mutation (except for those with RARSt; (21% vs 5% and 3%, p =0.036 and .012, respectively). We conclude that hemochromatosis associated mutations may contribute to the pathogenesis of RARS. In patients with MPD and Jak2 mutation, concomitant presence of hemachromatosis-predisposing HFE variants may result in the unusual presentation associated with ringed sideroblasts.
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Leitman, Susan F. "Hemochromatosis: the new blood donor." Hematology 2013, no. 1 (December 6, 2013): 645–50. http://dx.doi.org/10.1182/asheducation-2013.1.645.
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Abstract Hereditary hemochromatosis (HH) due to homozygosity for the C282Y mutation in the HFE gene is a common inherited iron overload disorder in whites of northern European descent. Hepcidin deficiency, the hallmark of the disorder, leads to dysregulated intestinal iron absorption and progressive iron deposition in the liver, heart, skin, endocrine glands, and joints. Survival is normal if organ damage is prevented by early institution of phlebotomy therapy. HH arthropathy is the symptom most affecting quality of life and can be debilitating. Genotype screening in large population studies has shown that the clinical penetrance of C282Y homozygosity is highly variable and can be very low, with up to 50% of women and 20% of men showing a silent phenotype. Targeted population screening for the HFE C282Y mutation is not recommended at present, but might be reconsidered as a cost-effective approach to management if counseling and care were better organized and standardized. Referral of patients to the blood center for phlebotomy therapy and use of HH donor blood for transfusion standardizes treatment, minimizes treatment costs, and may benefit society as a whole. Physician practices should be amended such that HH subjects are more frequently referred to the blood center for therapy.
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Sanz, Cristina, Anna Garcia-Carulla, and Arturo Pereira. "Kinetics of Iron Depletion in Hereditary Hemochromatosis." Blood 132, Supplement 1 (November 29, 2018): 3630. http://dx.doi.org/10.1182/blood-2018-99-110457.
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Abstract Introduction: Hereditary hemochromatosis (HH) is a genetic disorder that results in an increased accumulation of dietary iron. The only effective treatment is iron depletion by phlebotomy or erytrocytapheresis (EA). The kinetics of iron depletion in response to these treatments has been little studied and its temporal profile and the influence of patient's factors are not fully known. Objective: To describe the kinetics of iron depletion in patients with HH on phlebotomy or EA. Material and methods: Patients in depletive treatment with phlebotomy (once per week) or EA (one every two weeks) were selected for this study if they had no associated inflammatory disorder, at least 3 ferritin determinations were available during treatment, and more than 70% of the established therapeutic schedule was fulfilled. The average reduction of serum ferritin was measured in ng/ml per ml of red blood cells (RBC) removed per Kg of patient's body weight, and was analyzed as natural logarithms (ln). Categorical variables were expressed as proportions and continuous variables, as median and interquartile range (IQR). Results: Median age of the 34 included patients was 51 (44-58) years and 32 (94%) were men. Initial and final ferritin values were 1035 (IQR: 777-1564) ng/ml and 83 (IQR: 50-123) ng/ml, respectively. Transaminase levels were high (ALT> 50 U/L) in 9 patients, and 2 of them had been diagnosed with liver cirrhosis secondary to HH. With regard to genotype, 27 patients were C282Y homozygous, 4 were compound heterozygous (C282Y/H63D), 1 had a TFR2 mutation, and no mutation was found in 2. The average reduction of serum ferritin was 1.04 (IQR: 1.03-1.05) ng/mL per mL of removed RBCs/Kg of patient's body weight. Figure 1 shows the mathematical expression that best described the kinetics of serum ferritin. The rate of serum ferritin reduction, as measured by this mathematical expression, was independent of the initial ferritin level, the total reduction of ferritin, the presence of high transaminase levels or cirrhosis, as well as the patient's age and body mass index. In contrast, the rate of ferritin reduction varied with the genotype; it was significantly lower in patients homozygous for the C282Y mutation than in patients with other genotypes (median: 1.03, IQR: 1.02-1.05 vs. 1.07, IQR: 1.06-1.11 ng/mL per mL of removed RBCs/Kg; p < 0.001; figure 2). Conclusions: In patients with HH and good adhesion to the therapeutic schedule, the reduction of serum ferritin is predictable as a function of the volume of removed RBCs and the patient's weight. Patients homozygous for the C282Y mutation have a slower kinetics of iron depletion. Disclosures No relevant conflicts of interest to declare.
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Nie, Ling, Lin Yang, Qinghua Li, Jianxiang Wang, and Zhijian Xiao. "Incidence of HFE Gene Mutations in Chinese Patients with Myelodysplastic Syndrome and Aplastic Anemia." Blood 112, no. 11 (November 16, 2008): 5085. http://dx.doi.org/10.1182/blood.v112.11.5085.5085.
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Abstract The C282Y and H63D mutations of HFE gene responsible for hereditary hemochromatosis lead to absorption of excess dietary iron, tissue iron deposition and occurrence of clinical complications such as congestive heart failure, arrhythmia, hepatocellular cirrhosis, insulin resistance and diabetes. Iron overload is one important clinical feature in patients with myelodysplastic syndrome (MDS) and aplastic anemia(AA). However, the conflict has been existing about influence of HFE gene mutations on iron overload in MDS patients. In the present study, we analyzed the incidence of the C282Y and H63D mutations of HFE gene in 271 MDS patients, 402 AA patients and 1615 healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No C282Y mutations and compound heterozygote were observed in the entire cohort. The genotype distribution of H63D heterozygous and homozygous did not differ significantly in AA cases from those in controls(9.7%vs. 10.2%, 0.25%vs. 0.24% respectively, Pearson Chi-square p both >0.05). While the frequency of the H63D heterozygous in MDS patients was significantly lower than controls (4.1%vs. 10.7%, Pearson Chi-square p=0.002). H63D homozygous was not found in MDS patients. The incidence of C282Y and H63D mutations of HFE gene in Chinese MDS cases is lower than those reported in the literature. Comparing the pretransfusion serum ferritin(SF), serum iron concentration(SI) and transferrin saturation values(TS) between HFE-mutation and HFE-wild MDS groups, we did not find a significant difference (all P>0.05); However, Only SI values were significantly higher in the HFE-mutation AA cases than those in HFE-wild ones[42.6(24.6–60.4)umol/Lvs. 32.0(8.4–63.3)umol/L, P=0.011]. We further estimated the function of important organs in MDS and AA patients. There is no significantly difference in Alanine amino transferase (ALT), Aspartate amino transferase (AST), fasting blood sugar, and electrocardiogram(ECG) between HFE-mutation and HFE-wild MDS and AA groups irrespective of the red blood cell transfusion history. The results suggest that the distribution of C282Y and H63D mutations has ethnic and genetic differences, and is very rare in Chinese population. The mutations of HFE gene are not main factors of iron overload in Chinese patients with myelodysplastic syndrome and aplastic anemia.
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Waalen, Jill, and Ernest Beutler. "A New Perspective on the Natural History of Hereditary Hemochromatosis." Blood 106, no. 11 (November 16, 2005): 3595. http://dx.doi.org/10.1182/blood.v106.11.3595.3595.
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Abstract A few homozygotes for the C282Y mutation of HFE manifest severe and even fatal iron-storage disease; most have only a modest increase in iron stores, show no clinical manifestations, and have no shortening of lifespan. Screening for hemochromatosis has been advocated so that therapeutic phlebotomy could be offered to the mildly affected subjects, often termed "pre-cirrhotic", presumably protecting them against progression of the disease. The rationale of this approach depends upon the implicit assumption that the natural history of the disease is one of progressive accumulation of iron and consequently ever-increasing tissue damage. In 1998 we began screening for the C282Y homozygous genotype among patients in the Kaiser Permanente Health Appraisal Clinic in San Diego. We have now followed 144 patients from this cohort of 156 C282Y homozygotes with medical records spanning up to 10 years, including 35 patients who declined phlebotomy. Data from this analysis and other sources now suggest that the natural history of the disease might be quite different than has heretofore been assumed. Our revised perspective is based upon both cross-sectional and longitudinal observations. Cross-sectional analysis of levels of serum ferritin, a surrogate for total body iron, shows little or no change with age in C282Y homozygotes. Neither are abnormal liver function tests, which occur in a small minority of homozygotes, age-related. In Denmark, longitudinal analyses of serum ferritin levels in untreated patients show no increase over as much as 20 years. Our own longitudinal data on serum ferritin levels in homozygotes who were not phlebotomized confirm this observation. Longitudinal analyses of abnormal ALT levels in homozygotes show no upward trend over a four-year period. Accordingly, it seems likely that in hemochromatosis the maximum extent of disease has been achieved in most patients by the time they reach adulthood, and that patients who are diagnosed with mild disease are unlikely to show progression.
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O'Toole, Rebecca, Collette Bromhead, and Kenneth R. Romeril. "Using Iron Studies to Target Testing for Hereditary Haemochromatosis in New Zealand." Blood 126, no. 23 (December 3, 2015): 2150. http://dx.doi.org/10.1182/blood.v126.23.2150.2150.
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Abstract Objective: Hereditary haemochromatosis (HH) follows a prolonged pre-symptomatic phase. The clinical features of HH are non-specific and subsequently, an accurate diagnosis may not be reached until the irreversible manifestations of the disease are apparent. Genetic testing for SNPs of the HFE gene is diagnostic of HH; however it is not economically viable in New Zealand to screen all patients with molecular testing unless there is sound clinical, familial or biochemical evidence to indicate testing. Abnormalities in iron biochemical assays are often the first indicator of HH and it has now become widely accepted that transferrin saturation (TS) and serum ferritin (SF) are the best initial tests for HH (Bacon et al 2011; King and Barton, 2006). These results however, particularly SF, may be affected by other conditions, making interpretation difficult and often misunderstood e.g. acute phase response. There is currently no national guideline for requesting HFE testing in New Zealand and existing recommendations are based on international data. This study evaluates the correlation between the iron phenotype and HFE genotype to inform future guidelines and cost-effective clinical pathways specific to our population. Materials and Methods: We audited the results from 2388 patients genotyped for HFE at Aotea Pathology Ltd; Wellington, between 2007 and 2013, and compared their C282Y, H63D and S65C genotypes to their iron status as quantified by SF and TS, as well as serum iron (SI) and serum transferrin (ST). The predictive power of the iron studies markers was evaluated by Receiver Operator Characteristic (ROC) curve analysis and if a statistically significant association for a variable was seen, the sensitivity, specificity, positive and negative predictive values were calculated at varying intervals. Results: Test ordering patterns showed that the majority (62%) of HFE genotyping tests were ordered on the basis of an elevated SF alone, without a full iron studies profile performed (which includes TS). Furthermore, only 11% of these patients had a C-Reactive Protein (CRP) test performed, which is a clinically useful marker of inflammatory states to establish if an elevated SF is acute phase in origin. In ROC curve analysis, the Area Under the Curve (AUC) of TS is larger than any other marker and a decision threshold of 45% produces the most favourable outcomes for patients in statistical analysis. Our results show that there is little association between SF and individual HFE genotypes and that SF values < 1000 µg/L are relatively insensitive to genotype. A SF of >1000 μg/L was found in one at-risk patient (C282Y homozygote) who had a TS < 45%, which provides some evidence to support the incorporation of SF into a diagnostic screening strategy for HH. AUCs for SI are analogous to that of TS, however, the sensitivity is poor at cut-offs above the normal range. ST showed no statistically significant association with any HFE genotype in ROC curve analysis. Using the thresholds of SF ≥ 1000 µg/L or TS ≥ 45% for consideration of HFE genotyping, any additional misidentified C282Y homozygotes in this study cohort were found to have a family history of HH, highlighting the importance of HFE testing on this basis. Conclusion: We conclude that an elevated SF of <1000 μg/L alone is not a predictor of HH since these levels are commonly encountered in the normal population. Our analysis of test ordering patterns however; proves that local primary care physicians rely heavily on SF as a predictor of HH, and suggest that there is little adherence to existing guidelines with regard to TS. Based on the lack of CRP testing requested, it also appears that HFE genotyping is being inappropriately requested without consideration of other causes of elevated SF. On the contrary, this study confirms that TS is a more accurate marker of HFE-related iron overload than SF. All C282Y homozygous patients would have been identified using a diagnostic algorithm requiring a TS ≥ 45%, a SF ≥ 1000 µg/L and/or a family history of HH. The data yielded by this study could be used by primary care physicians as a clinical guide for screening to identify appropriate candidates for genetic testing of the HFE gene which will facilitate earlier detection of a higher number of at-risk individuals. This strategy offers clinically appropriate solution which will enhance the accuracy of HFE genotyping requests and improve the cost effectiveness of molecular testing. Disclosures No relevant conflicts of interest to declare.
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Engberink, Mariëlle F., Cecile M. Povel, Jane Durga, Dorine W. Swinkels, Wim L. A. M. de Kort, Evert G. Schouten, Petra Verhoef, and Johanna M. Geleijnse. "Hemochromatosis (HFE) genotype and atherosclerosis: Increased susceptibility to iron-induced vascular damage in C282Y carriers?" Atherosclerosis 211, no. 2 (August 2010): 520–25. http://dx.doi.org/10.1016/j.atherosclerosis.2010.03.018.
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Eisfeld, Ann-Kathrin, Ralph Burkhardt, Daniel Teupser, Sabine Schroeder, Rainer Krahl, Andrea Junghans, Elvira Edel, et al. "HFE Genotype Is of Donor Origin and Does Not Correlate with Iron Overload Present in Patients after Allogeneic Stem Cell Transplantation." Blood 104, no. 11 (November 16, 2004): 3684. http://dx.doi.org/10.1182/blood.v104.11.3684.3684.
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Abstract Introduction: A substantial proportion of European populations (10–40%) are heterozygous carriers (het) and 0.1–0.3% homozygos (homo) for the hemochromatosis gene (HFE). Patients (pts) with hematologic malignancies often receive multiple blood transfusions (BT). 228 pts undergoing allogeneic stem cell transplantation (SCT) at the University of Leipzig and their donors were screened for HFE. Furthermore, HFE genotype after SCT and body iron stores were correlated with BT and GVHD. Pts and methods: 228 pts (125 m/103 f; median age 46 years) transplanted from Jan, 2001-May, 2004 and their donors [related, n=72 (31.6%); unrelated, n=156 (68.4%)] were screened for HFE. Diagnosis was acute leukemia and MDS in 126 (55%), chronic leukaemia in 51 (23%), lymphoma in 23 (10%), aplastic anemia in 5 (2%), and others in 23 (10%) pts. The majority of pts (n=120; 52.6%) received 12 gray TBI and Cyclophosphamid 120 mg/kg as preparative regimen. ATG 15 mg/kg for 3 days was given to recipients of unrelated SCT. 108 ( 47.4%) pts received Fludarabin 30 mg/m2 for 3 days and 2 gray TBI. 93 pts [36 (38.7%) had a related and 57 (61.3%) an unrelated donor] surviving SCT at least 4 months were further assessed. HFE analysis was performed before and after SCT by PCR techniques using LightCycler, Roche. Serum (s.) iron, transferrin, and ferritin were measured according to IFCC recommendations. Normal iron, transferrin, and ferritin values were 9.5–29.9 μmol/l, 1.9–3.6 g/l, 30–400 ng/ml respectively. Results: Before SCT, HFE mutations were found in 83 (36.4%) pts. 77 pts were het (52 for H63D, 16 for C282Y, 3 for S65C, 6 compound). 6 pts were homo for HFE (5 for H63D and 1 for C282Y). No correlation was found between HFE type and diagnosis. Similarly, mutations were demonstrated in 88 (38.6%) donors. 84 donors were het (50 for H63D, 18 for C282Y, 9 for S65C, 7compound). 4 donors were homo (2 for H63D, 2 for C282Y). After SCT, all 93 (100%) pts for whom data are available expressed donor HFE. Median s. iron, transferrin, and ferritin were 20 μmol/l (range 3.8 – 64.3 ), 1.7 g/l (0.6 – 3), and 952 ng/ml (32.7– 6832.4) respectively. 83 (89.2%) pts showed excess body iron. Median number (no.) of BT was 22 units (range 0–109). In multivariate analysis, median ferritin strongly correlated with the no.of BT (p<0.0001), older age (p=0.0001), and acute leukemia (p=0.0003). Body iron stores did not correlate with HFE genotype prior to or after SCT. Interestingly, acute GVHD of the liver grade I-III present in 8 (8.6%) and isolated SGPT/SGOT elevations seen in 51 (54.8%) pts tended to correlate with iron stores (p=0.06, p=0.1 respectively). Conclusions: 1)Mutations of the HFE were detected in a substantial proportion of donors and pts 2)HFE was always of donor origin after SCT 3)The majority of surviving pts after SCT have markedly increased body iron stores correlating with the no.of BT 4)There seems to be a correlation between iron stores and hepatic GVHD and abnormal liver function after SCT. The influence of iron stores on short- and long-term morbidity and mortality after SCT needs further study. 5)The effect of removal of excess iron by phlebotomy after SCT on GVHD and liver function is currently being assessed.
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Ajioka, Richard S., John D. Phillips, Robert B. Weiss, Diane M. Dunn, Maria W. Smit, Sean C. Proll, Michael G. Katze, and James P. Kushner. "Down-regulation of hepcidin in porphyria cutanea tarda." Blood 112, no. 12 (December 1, 2008): 4723–28. http://dx.doi.org/10.1182/blood-2008-02-138222.
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Abstract Hepatic siderosis is common in patients with porphyria cutanea tarda (PCT). Mutations in the hereditary hemochromatosis (hh) gene (HFE) explain the siderosis in approximately 20% patients, suggesting that the remaining occurrences result from additional genetic and environmental factors. Two genes known to modify iron loading in hh are hepcidin (HAMP) and hemojuvelin (HJV). To determine if mutations in or expression of these genes influenced iron overload in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes with marked hepatic iron overload. We also compared hepatic expression of these and other iron-related genes in a group of patients with PCT and hh. Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE C282Y homozygotes. No exonic polymorphisms were identified. Sequencing of HAMP revealed exonic polymorphisms in 2 patients with PCT: heterozygosity for a G→A transition (G71D substitution) in one and heterozygosity for an A→G transition (K83R substitution) in the other. Hepatic HAMP expression in patients with PCT was significantly reduced, regardless of HFE genotype, when compared with patients with hh but without PCT with comparable iron overload. These data indicate that the hepatic siderosis associated with PCT likely results from dysregulated HAMP.
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Eijkelkamp, Emmeke J., Thomas R. Yapp, and Lawrie W. Powell. "HFE-Associated Hereditary Haemochromatosis." Canadian Journal of Gastroenterology 14, no. 2 (2000): 121–25. http://dx.doi.org/10.1155/2000/360372.
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Hereditary hemochromatosis is a common inherited disorder of the iron metabolism. Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis gene (HFE) in 1996 and two candidate mutations; the C282Y mutation has been shown to be responsible for the majority of the hereditary hemochromatosis cases worldwide. The gene discovery has led to rapid advances in the field of iron metabolism. Although the basic defect is still not fully understood, much is known about the sequence of events leading to iron overload.Hereditary hemochromatosis is a major candidate for population screening and meets the screening criteria of the World Health Organization, and Wilson and Jungner. It is one of the most prevalent genetic diseases in white populations, and, importantly, early diagnosis and simple effective treatment allow normal life expectancy.The discovery of theHFEgene and the frequency of the single C282Y mutation as a cause of most cases of hereditary hemochromatosis allow the possibility of widespread genetic testing. However, the logistics, and the psychological and social consequence of this, coupled with incomplete expression of the genotype, necessitate further studies before population screening can be justified.
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Lanktree, Matthew B., Bruce B. Lanktree, John S. Waye, Guillaume Pare, Bekim Sadikovic, and Mark A. Crowther. "Retrospective Evaluation of Patients Referred for Hemochromatosis Genetic Testing." Blood 124, no. 21 (December 6, 2014): 4035. http://dx.doi.org/10.1182/blood.v124.21.4035.4035.
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Abstract Background: The common genetic test for hemochromatosis involves the genotyping of two polymorphisms in the HFE gene (C282Y and H63D). Current guidelines suggest testing of patients with ferritin greater than 300 µg/L and transferrin saturation greater than 45%. Testing of first degree relatives of confirmed HFE positive cases is also endorsed. However, the current test has poor sensitivity and specificity for iron overload causing end organ damage. We sought to evaluate biochemical parameters of patients referred for HFEtesting and identify those who received phlebotomy. Methods: After receiving ethics approval, electronic charts of patients referred to Hamilton Health Sciences, Hamilton, Ontario, Canada for HFE genetic testing between January 1, 2012 and December 31, 2012 were reviewed. Results: HFE genetic testing in 642 patients yielded 100 (15.6%) positive C282Y homozygote or C282Y/H63D compound heterozygote results. In patients with biochemical markers of iron overload available (n=160), patients with a risk HFE genotype had significantly higher iron saturation, serum iron, and hemoglobin (P<0.001), but did not have higher ferritin or liver enzymes. Only fifty percent of patients referred had biochemical evidence of iron overload (transferrin saturation [TS] > 45% and ferritin > 300). Of patients who required phlebotomy, only 27 of 40 (67.5%) were HFEpositive. Conclusion: Many factors affect the decision to phlebotomize a patient with suspected iron overload. However, it appears that most of the current HFE genetic testing being performed did not alter patient management. Disclosures Crowther: Asahi Kasai: Membership on an entity's Board of Directors or advisory committees; Bayer: Speakers Bureau; Celgene: Speakers Bureau; Shire: Speakers Bureau; Boehriniger Ingelheim: Consultancy; CSL Behring: Speakers Bureau; Leo Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Membership on an entity's Board of Directors or advisory committees; Viropharma: Membership on an entity's Board of Directors or advisory committees.
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Solov’eva, A. V., O. V. Kodyakova, I. N. Nikitina, N. P. Fomenko, and D. R. Rakita. "Clinical case of hereditary hemochromatosis." Kazan medical journal 99, no. 6 (December 15, 2018): 998–1003. http://dx.doi.org/10.17816/kmj2018-998.
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The article presents a clinical case demonstrating the difficulties of timely diagnosis of hereditary hemochromatosis, presents data on modern diagnosis and approaches to the treatment of the disease according to existing clinical guidelines. The described clinical case of hereditary hemochromatosis is associated with a homozygous mutation of C282Y in HFE gene in a 58-year-old patient and his twin brother. Initially, signs of iron deposition in the liver were found on MRI of the abdominal cavity. In laboratory analyses, the patient was found to have an increased level of serum iron - 40 µmol/l and ferritin - 1340 ng/ml. Subsequently, the investigation of HFE gene mutations was carried out and a mutation of C282Y in homozygous form (genotype A/A) was found, which is a molecular genetic confirmation of hereditary hemochromatosis of type 1. At the same time, the patient's twin brother at the targeted examination had the serum iron level of 36 µmol/l, the ferritin level of 600 ng/ml, and also the mutation of HFE gene, the allelic variant of A/A. The results of liver fibroelastometry of the patient correlate with the degree of fibrosis F1 by Metavir scale. Timely started therapeutic phlebotomies led to improved clinical and laboratory parameters of iron metabolism while maintaining normal levels of red blood cells and hemoglobin.
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Le Gac, Gerald, Catherine Mura, and Claude Férec. "Complete Scanning of the Hereditary Hemochromatosis Gene (HFE) by Use of Denaturing HPLC." Clinical Chemistry 47, no. 9 (September 1, 2001): 1633–40. http://dx.doi.org/10.1093/clinchem/47.9.1633.
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Abstract Background: Between 4% and 35% of hereditary hemochromatosis (HC) probands are C282Y or H63D heterozygotes or lack both of these two common HFE mutations, and 15 novel HFE mutations have been described recently. We evaluated denaturing HPLC (DHPLC) for screening of the whole HFE coding region and further defined whether HC probands with an incomplete HFE genotype carry uncommon mutations. Methods: Analytical conditions for each coding exon were determined by a combination of computer melting profile predictions and experimental melting curves. To test accuracy for scanning the complete HFE coding region and optimize DHPLC running conditions, each melting domain was investigated with at least one mutation or one polymorphism as reference. We tested 100 DNA samples harboring the C282Y, H63D, or S65C mutations and 17 artificially created positive controls that carried either 1 of the 14 other known HFE mutations or 3 selected polymorphisms. Results: Investigations on each of the coding exons 1, 2, 4, 5, and 6 could be performed at one analysis temperature. Coding exon 3 displayed a more complex melting profile and required two analysis temperatures. DHPLC detected all known HFE mutations as well as the three selected polymorphisms. Conclusions: DHPLC can be used to scan the HFE gene in HC probands in whom at least one chromosome lacks an assigned mutation.
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Schiepers, Olga J. G., Martin P. J. van Boxtel, Renate H. M. de Groot, Jelle Jolles, Wim L. A. M. de Kort, Dorine W. Swinkels, Frans J. Kok, Petra Verhoef, and Jane Durga. "Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study." Journals of Gerontology: Series A 65A, no. 12 (August 2, 2010): 1312–21. http://dx.doi.org/10.1093/gerona/glq149.
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Jacolot, Sandrine, Gerald Le Gac, Virginie Scotet, Isabelle Quere, Catherine Mura, and Claude Ferec. "HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype." Blood 103, no. 7 (April 1, 2004): 2835–40. http://dx.doi.org/10.1182/blood-2003-10-3366.
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Abstract Hereditary hemochromatosis is a genetically heterogeneous disease of iron metabolism. The most common form of the disorder is an adult-onset form that has mainly been associated with the HFE pC282Y/pC282Y genotype. The phenotypic expression of this genotype is very heterogeneous and could be modulated by both environmental factors and modifier genes. The non-HFE hereditary hemochromatosis forms include a juvenile onset form associated with mutations in HAMP. From a cohort of 392 C282Y homozygous patients, we found 5 carriers of an additional HAMP mutation at the heterozygous state (pR59G, pG71D, or pR56X). We found that iron indices of these 5 patients were among the most elevated of the cohort. Moreover, we specified that the HAMP mutations were not detected in 300 control subjects. These results revealed that mutations in HAMP might increase the phenotypic expression of the pC282Y/pC282Y genotype. From a cohort of 31 patients with at least one chromosome lacking an HFE mutation, we further identified 4 males carrying a heterozygous HAMP mutation (pR59G or pG71D). Based on a digenic model of inheritance, these data suggest that the association of heterozygous mutations in the HFE and HAMP genes could lead, at least in some cases, to an adult-onset form of primary iron overload. (Blood. 2004;103:2835-2840)
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El-Beshlawy, Amal, Manal Michel Wilson, Elwakeel Hanan, Mona Elghmarwy, Fadwa Said, and Mary Assaad. "Study of the Effect of HFE Gene Mutations on Iron Overload in Egyptian Thalassemia Patients." Blood 124, no. 21 (December 6, 2014): 1359. http://dx.doi.org/10.1182/blood.v124.21.1359.1359.
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Abstract Introduction: β-thalassemia is a common genetic disorder affecting the β-globin gene, characterized by ineffective erythropoiesis and iron overload. It is the most common hereditary hemolytic anemia in Egypt(85.1%)with a carrier rate of 5.3to 9% and annual birth of 1000/1.5million live births born with the disease. Mutations in the HFE gene have been shown to be responsible for hereditary hemochromatosis, an autosomal recessive disease of iron overloading. The effect of these mutations on iron load in β- thalassemia patients and carriers remains controversial. Interaction between β- thalassemia and hemochromatosis may increase the likelihood of developing iron overload in thalassemic patients and thus may require early iron chelation. Objectives:In this cross-sectional case-control study, we aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in β- thalassemia patients and carriers and to investigate the effect of these mutations on their serum ferritin levels. Patients and Methods: A total of100 β-thalassemia subjects; 75 β- thalassemia patients (homozygous or compound heterozygous) and 25 carriers were screened for HFE gene mutations (H63D and C282Y) by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Serum ferritin was measured for all subjects by enzyme-linked immunosorbant assay (ELISA) and β-globin gene mutations were determined by reverse hybridization technique. All β- thalassemia patients (45 males and 30 females with mean age 3.2 + 2.7 years) were diagnosed and followed at at our Pediatric Hematology Clinic. Their baseline serum ferritin at diagnosis was evaluated in relation to the HFE mutations. Twenty-five heterozygotes for β- thalassemia attending for genetic screening or parents or sibs of our patients were enrolled as carriers. All subjects and/or guardians gave informed consent before enrollment. Results: Twenty- eight of 75 β- thalassemia patients (37.3%) were heterozygotes for the H63D mutation (H/D), 8 (10.7%) were D/D homozygotes and 39 (52%) were negative for the mutation( H/H homozygotes). Among carriers, 4 (16%) were D/D homozygotes and 21 (84%) were H/H homozygotes(Fig1) . The C282Y mutant allele was not detected in any of patients or carriers. The median serum ferritin level was significantly higher in β- thalassemia patients compared to carriers (386 vs. 216 ng/ml; p=0.03). Serum ferritin levels were compared according to H63D genotypes in β- thalassemia patients and carriers (Table 1). There were significantly high levels of serum ferritin in β-thalassemia patients who were heterozygotes or homozygotes for the H63D mutation compared to those without the mutation (p=0.000).B-Thalassemia carriers homozygotes for the H63D mutation showed significantly higher serum ferritin levels compared to those without the mutation (P<0.001). The most prevalent underlying genetic mutation of β globin gene in our β-thalassemia patients was IVS 1.110 mutation followed by IVS 1.6. This study showed no correlation between these mutations and the H63D genotype. Conclusion:Homozygosity for the H63D mutation tend to be associated with higher ferritin levels in beta-thalassemia patients and carriers compared to the H/H genotype, suggesting that the H63D mutation may have a modulating effect on iron load. Screening of H63D mutation in β-thalassemia patients may predict patients with more tendency to develop early iron overload. Proper timely management of these patients prevents the hazard of iron overload. Figure (1): H63D polymorphism of the HFE gene in β-thalassemia patients and carriers Figure (1):. H63D polymorphism of the HFE gene in β-thalassemia patients and carriers Abstract 1359. Table 1: Serum ferritin levels in β-thalassemia patients and carriers according to their H63D genotype H63D Genotype β-thalassemia patients (n=75) β-thalassemia carriers (n=25) No. of subjects (%) Ferritin (ng/ml) Mean + SD P value No. of subjects (%) Ferritin (ng/ml) Mean + SD P value H/H H/D D/D 39(52%) 28 (37.3) 8(10.7%) 297.2 + 175.8 565.3 + 358 920.4 + 508.2 <0.001* 21(84%) - 4(16%) 221.9 + 142.9 - 969.8 + 290.3 <0.001* p-values: H/H vs. H/D; H/D vs. D/D;H/H vs. D/D < 0.001* Disclosures No relevant conflicts of interest to declare.
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Schwartz, Kenneth A., John Davis, Michael A. Scott, and Lana Kaiser. "Histopathologic Study of Livers From Chronic Iron Loaded C282Y Mice: Model of Hereditary Hemochromatosis?" Blood 118, no. 21 (November 18, 2011): 5288. http://dx.doi.org/10.1182/blood.v118.21.5288.5288.
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Abstract Abstract 5288 Introduction: The C282Y mouse model of hemochromatosis was developed to facilitate study of hereditary hemochromatosis in humans. We studied the liver histologic findings in mice that were iron loaded over at least 10 weeks to determine if the pathological changes in the mouse liver mirror the chronic iron overload condition observed in humans with genetic hemochromatosis. Methods: C282Y and wild-type mice (C57BL) were iron loaded over a minimum of 10 weeks using weekly intraperitoneal injections of 400 mg/kg of iron dextran. Animals were sacrificed at least 2 weeks after receiving their last iron injection. Hematoxylin and eosin, Masson's trichrome, and Perl's Prussian blue stains were used to assess the amount and distribution of liver iron and the presence or absence of inflammation and fibrosis. The slides were evaluated by a veterinary pathologist (MAS) without knowledge of genetic or iron load status. Specific histopathologic characteristics were evaluated and graded as the mean of 10 40x high power fields. These included: Hepatocyte iron distribution graded as either periportal or diffuse, amount of iron deposition in cells was graded for hepatocytes and Kupffer cells (graded 0–5), iron deposition in endothelial cells (graded 0–4), amount of fibrosis (graded 0–4), presence or absence of inflammation, periportal lymphocyte infiltration (graded 0–3), and hematopoiesis (present, present but mild, or absent). Livers from 24 mice (3 +/+, 9 +/Y and 12 Y/Y) were studied. Results: When compared with animals that were not iron loaded, animals iron loaded with at least 4 g/kg of iron had increased cellular deposition of iron. Of the two mice that were not iron loaded, the +/Y mouse had no increase in tissue iron and the Y/Y mouse had 2+ iron in hepatocytes, Kupffer cells, and endothelial cells. The highest two categories of cellular iron were observed in the four animals loaded with the highest doses of iron (5.6–6.8 g/kg): grade 4–5 for hepatocytes and Kupffer cells, and grade 3–4 for endothelial cells. Mice loaded with 4 g/kg of iron (7 Y/Y, 8 +/Y and 3 +/+) had similar but generally lower levels of iron deposition: grade 3–5 in hepatocytes, grade 3–4 in Kupffer cells, and grade 3 in endothelial cells. The three genotypes could not be differentiated based on the amount of iron deposition. However, the distribution of iron in hepatocytes of the 3 wild type animals (+/+) was clearly periportal which differed from the diffuse distribution pattern observed in the Y/Y and +/Y mice. One +/Y mouse had a mild periportal distribution of hepatocyte iron. Iron-loaded animals in all 3 genetic groups had grade 1 or 2 fibrosis in the periportal area and around the iron laden Kupffer cell aggregates. None of animals had bridging fibrosis or cirrhosis. In the iron-loaded Y/Y and +/Y mice, hematopoiesis was present in close association with intrasinusoidal iron laden Kupffer cell aggregates. In the non-iron loaded mice hematopoiesis was rare in the Y/Y animal, absent in the +/Y mouse. Hematopoiesis was present but mild in all 3 of the +/+ mice as well as in 1 mouse of each other genotype, and was present in the remaining 17 iron-loaded mice. No hepatocyte necrosis or regenerative nodules were detected in any mouse. Discussion: Histologic evaluation of the C282Y mice showed that the deposition of iron in the liver increased with increased iron loads. The distribution of iron between Kupffer cells and hepatocytes was similar in all 3 genetic groups. The periportal iron distribution observed in humans with genetic hemochromatosis was not seen in either the Y/Y or +/Y genotypes, but was observed in the iron-loaded wild type +/+ mice. Liver histology with chronic intraperitoneal iron loading in the C282Y C57BL mice is comparable to that observed in humans with secondary iron overload and not those observed in humans with hereditary hemochromatosis. Why the liver histology in the iron loaded C282Y knock-in mouse does not mirror the changes observed in human livers from patients with genetic hemochromatosis is not clear. It may be the dosing regimen or the strain of the mouse or that additional genetic or environmental factors are required. Disclosures: No relevant conflicts of interest to declare.
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Hermans, M. P., S. Van Lerberghe, and M. Buysschaert. "The [C282Y/wt] heterozygous HFE genotype is associated with lower blood pressure and HDL-cholesterol in Type 2 diabetes." Diabetic Medicine 19, no. 9 (September 2002): 796. http://dx.doi.org/10.1046/j.1464-5491.2002.00657_5.x.
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Barton, James C., Catherine Leiendecker-Foster, David M. Reboussin, Paul C. Adams, Ronald T. Acton, and John H. Eckfeldt. "Thyroid-Stimulating Hormone and Free Thyroxine Levels in Persons with HFE C282Y Homozygosity, a Common Hemochromatosis Genotype: The HEIRS Study." Thyroid 18, no. 8 (August 2008): 831–38. http://dx.doi.org/10.1089/thy.2008.0091.
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