scholarly journals Reference Centiles for Serum Ferritin and Percentage of Transferrin Saturation, with Application to Mutations of the HFE Gene

2001 ◽  
Vol 47 (10) ◽  
pp. 1804-1810 ◽  
Author(s):  
James A Koziol ◽  
Ngoc J Ho ◽  
Vincent J Felitti ◽  
Ernest Beutler
Keyword(s):  
Serum Ferritin ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Reference Population ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Wild Type ◽  
C282y Mutation ◽  
Compound Heterozygotes ◽  
Healthy Females

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.

scholarly journals Compound Heterozygous Hemochromatosis Genotype Predicts Increased Iron and Erythrocyte Indices in Women

2000 ◽  
Vol 46 (2) ◽  
pp. 162-166 ◽  
Author(s):  
Enrico Rossi ◽  
John K Olynyk ◽  
Digby J Cullen ◽  
George Papadopoulos ◽  
Max Bulsara ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Age Group ◽  
Wild Type ◽  
C282y Mutation ◽  
Younger Age ◽  
Compound Heterozygotes

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.

Iron Overload in C282Y Heterozygotes: Identification of New Rare HFE Gene Mutants and a Step Strategy for Diagnosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1859-1859
Author(s):  
Patricia Aguilar-Martinez ◽  
Severine Cunat ◽  
Fabienne Becker ◽  
Francois Blanc ◽  
Marlene Nourrit ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Genetic Defect ◽  
Transferrin Saturation ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Exon 2 ◽  
High Iron ◽  
Iron Parameters

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.

Interaction Between Genotypes for HFE and TFR2 Genes Mutations and Iron Status in Brazilian Blood Donors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5382-5382
Author(s):  
Rodolfo D Cancado ◽  
Paulo CJL Santos ◽  
Samuel Rostelato ◽  
Cristiane T Terada ◽  
Iris Gonzales ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Serum Iron ◽  
Blood Donors ◽  
Binding Capacity ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
The Body ◽  
Hfe Gene ◽  
Automation System

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.

scholarly journals Discrepancy between Serum Ferritin and Liver Iron Concentration in a Patient with Hereditary Hemochromatosis – The Value of T2* MRI

2020 ◽  
Vol 13 (2) ◽  
pp. 712-715
Author(s):  
Mustafa A. Al-Tikrity ◽  
Mohamed A. Yassin
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Ferritin Level ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Hfe Gene ◽  
Liver Iron Concentration ◽  
C282y Mutation ◽  
Liver Iron ◽  
T2 Mri

Primary hemochromatosis is an inherited disorder, and the homeostatic iron regulator (HFE) gene C282Y mutation is a common cause of hemochromatosis in Europe. We are reporting a case of a 56-year-old female known to have hemochromatosis with the HFE gene C282Y mutation with a serum ferritin level of 482 μg/L who underwent heart and liver T2* MRI which showed no evidence of iron overload – neither in the heart nor in the liver. This indicates that there is a discrepancy between serum ferritin and liver iron concentration by MRI and the superiority of T2* MRI in diagnosis and follow-up of iron overload in patients with hereditary hemochromatosis.

scholarly journals 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?

1998 ◽  
Vol 44 (12) ◽  
pp. 2429-2432 ◽  
Author(s):  
Christian Datz ◽  
Thomas Haas ◽  
Heinrich Rinner ◽  
Friedrich Sandhofer ◽  
Wolfgang Patsch ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Young Women ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Protective Role ◽  
Hfe Gene ◽  
Wild Type Allele ◽  
Wild Type ◽  
C282y Mutation ◽  
Type Allele

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.

Screening for Hemochromatosis by Measuring Ferritin Levels: A More Effective Approach.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2673-2673 ◽  
Author(s):  
Jill Waalen ◽  
Ernest Beutler
Keyword(s):  
Serum Ferritin ◽  
Screening Program ◽  
Ferritin Level ◽  
Severe Disease ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Cost Effective ◽  
Population Screening ◽  
Compound Heterozygous ◽  
Missed Opportunities

Abstract Population screening for hereditary hemochromatosis has traditionally been performed by determining the serum transferrin saturation. With the recognition that the penetrance of HFE hemochromatosis is extremely low, it has become apparent that population screening with transferrin saturation is unlikely to be cost effective as the vast majority of individuals detected neither have clinical disease nor are likely to develop it. Although the factors that cause a subset of patients to develop the severe disease phenotype have not been identified, it is clear from at least three independent studies that only patients with serum ferritin concentrations of over 1000 ng/ml are at risk. We have utilized data from the Scripps-Kaiser hemochromatosis study to model results of a screening program using this ferritin cut-off value. Among 29,699 white subjects screened, only 59 had serum ferritin levels of greater than 1000 ng/ml. Twenty-four of these had homozygous mutant or compound heterozygous mutant HFE genotypes that could account for the ferritin levels. Among the remaining patients, the main causes of elevated ferritin levels were excessive alcohol intake, cancer, or liver disease. Causes for the hyperferritinemia were found in all but 8% of the 59 patients. We conclude that screening for hemochromatosis with serum ferritin levels will detect the vast majority of patients who will be clinically affected, and may detect other clinically significant disease in patients who do not have hemochromatosis phenotypes. Since it is clear from other longitudinal studies that the ferritin level of the vast majority of adult homozygotes for HFE mutations does not rise over long periods of time, excluding subjects with serum ferritin levels <1000 ng/ml should not result in missed opportunities for early treatment of patients who could benefit.

Hereditary Haemochromatosis in Two Cousins with Cluster Headache

Cephalalgia ◽  
2002 ◽  
Vol 22 (4) ◽  
pp. 317-319 ◽  
Author(s):  
LJ Stovner ◽  
K Hagen ◽  
A Waage ◽  
KS Bjerve
Keyword(s):  
Cluster Headache ◽  
Serum Ferritin ◽  
Causal Relation ◽  
Transferrin Saturation ◽  
Headache Disorder ◽  
Normal Serum ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Hereditary Haemochromatosis ◽  
Iron Stores

A 60-year-old woman with secondary chronic cluster headache had increased serum ferritin and serum transferrin saturation and was homozygous for the C282Y mutation in the HFE gene, which is indicative of hereditary haemochromatosis. Treatment with venesection that normalized her iron stores led to a radical improvement of her headache complaints that had been daily for several years. Later, the headache returned to some degree in spite of normal serum ferritin levels. Her cousin, a 33-year-old man who had had episodic cluster headache for several years, also had increased transferrin saturation and was compound heterozygous for two mutations, a genotype known to be associated with a slightly increased frequency of haemochromatosis. This is the first report of a headache disorder in a patient with hereditary haemochromatosis. The coexistence of the two disorders may be a mere coincidence, but the temporary improvement of headache from depletion of iron stores may indicate a causal relation, possibly mediated by iron deposits in pain-modulating centres in the brainstem.

scholarly journals Kinetics of Iron Depletion in Hereditary Hemochromatosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3630-3630
Author(s):  
Cristina Sanz ◽  
Anna Garcia-Carulla ◽  
Arturo Pereira
Keyword(s):  
Body Weight ◽  
Serum Ferritin ◽  
Hereditary Hemochromatosis ◽  
Mathematical Expression ◽  
Categorical Variables ◽  
Compound Heterozygous ◽  
Inflammatory Disorder ◽  
C282y Mutation ◽  
Iron Depletion ◽  
Kinetics Of

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.

scholarly journals Effect of Hemochromatosis Genotype and Lifestyle Factors on Iron and Red Cell Indices in a Community Population

2001 ◽  
Vol 47 (2) ◽  
pp. 202-208 ◽  
Author(s):  
Enrico Rossi ◽  
Max K Bulsara ◽  
John K Olynyk ◽  
Digby J Cullen ◽  
Lesa Summerville ◽  
...  
Keyword(s):  
Serum Iron ◽  
Transferrin Saturation ◽  
Age Groups ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Red Cell ◽  
Wild Type ◽  
Cross Sectional ◽  
Red Cell Indices ◽  
Sectional Analysis

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 &gt;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.

scholarly journals Haptoglobin Polymorphism and Iron Homeostasis

2002 ◽  
Vol 48 (12) ◽  
pp. 2232-2235 ◽  
Author(s):  
Ernest Beutler ◽  
Terri Gelbart ◽  
Pauline Lee
Keyword(s):  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Wild Type ◽  
C282y Mutation ◽  
Ferritin Concentration ◽  
Denatured Protein ◽  
Oligonucleotide Hybridization ◽  
Allele Specific ◽  
Haptoglobin Polymorphism

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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