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PubMed2001

A primer for predicting risk of disease in HFE-linked hemochromatosis.

Since the discovery of the hemochromatosis gene (HFE) in 1996, there has been increasing interest in diagnostic testing for the C282Y and H63D mutations. The high frequency of these two alleles and their incomplete penetrance in homozygotes and compound heterozygotes make genetic counseling for hemochromatosis different from some other autosomal recessive conditions in that parents and children may also be at risk for iron overload, while homozygotes may remain asymptomatic. We provide a guideline for genetic counseling in HFE-linked hemochromatosis based on the genetic probability of inheriting HFE mutations and known information about expression of iron overload in various HFE genotypes. Genetic probabilities were based on allele frequencies derived from large population studies and Hardy-Weinberg equilibrium estimates. Expression of iron overload in those of various genotypes was based on available estimates of serum ferritin from population screening studies. Estimates for the likelihood of clinical iron overload requiring follow-up screening or treatment are provided by gender and genotype. The probability of inheriting HFE mutations and developing iron overload can be estimated in family members of a proband with HFE mutations. Many C282Y homozygotes will not have clinical iron overload. The risk is highest in men and their C282Y homozygous brothers and significantly lower in homozygous women. Iron overload is uncommon in compound heterozygotes and H63D homozygotes.

Female↗
PubMed2003

Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.

BACKGROUND: The HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. METHODS: Participants undergo testing for serum iron measures and common mutations of the hemochromatosis gene ( ) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. RESULTS: Of the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. CONCLUSIONS: Information from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.

Adult↗
PubMed1997

Clone-contig and STS maps of the hereditary hemochromatosis region on human chromosome 6p21.3-p22.

YAC-based and bacterial-clone based STS-content maps were constructed that served as the framework physical maps for the positional cloning of a candidate gene for hereditary hemochromatosis. The YAC-based map comprises 43 YACs and 86 STS and spans approximately 8 Mb of DNA between the class I region of the major histocompatibility complex on human chromosome 6p21.3 and D6S276 in 6p22. Comparison with published maps revealed a hole in the MIT/Whitehead and CEPH YAC maps that includes the immediate region around the hemochromatosis gene itself. Approximately 3 Mb of DNA was covered by a bacterial clone contig that consists of 38 BACs, 45 PACs, 26 PI clones and one lambda phage. The bacterial clone-based STS map comprises 153 STSs. A contiguous block of 8 STSs could be amplified from both human chromosome 6 and 5. Further characterization of selected STSs and bacterial clones by radiation hybrid mapping and fluorescence in situ hybridization, respectively, revealed the presence of a multicopy DNA segment, more than one bacterial clone length in size, which is duplicated near the chromosome-6 centromere and part of which is present in multiple copies on chromosome 5. Possible implications of the incomplete public YAC-contig map and of the multicopy segment for physical mapping and linkage disequilibrium studies of the hemochromatosis candidate region are discussed.

Bacteria↗
PubMed2004

Molecular diagnosis of hereditary hemochromatosis: application of a newly-developed reverse-hybridization assay in the South African population.

A recently developed strip-assay for hemochromatosis provides a rapid method for simultaneous detection of multiple mutations, which among others includes the HFE gene mutations V53M, V59M, H63D, H63H, S65C, Q127H, E168Q, and C282Y, previously detected in the general South African population using gel-based mutation-screening methods. The objective of the study was to determine the frequency of the relatively rare mutations in samples selected for altered iron parameters or a family history of hereditary hemochromatosis (HH) as part of the validation process of the assay for routine diagnostic purposes. The study population consisted of 451 individuals previously screened for mutations C282Y and H63D by restriction enzyme analysis in order to confirm or possibly exclude a diagnosis of HH. These individuals were subjected to mutation screening using the commercially available hemochromatosis strip-assay. Previous positive results for mutations C282Y and H63D in 233 individuals confirmed the accuracy of the reverse-hybridization assay. Mutation S65C was detected in 13 Caucasians, including three compound heterozygotes. These constituted 2% (13/600) of the chromosomes without mutations C282Y or H63D. The African-specific HFE mutation V53M was detected in one out of 11 (9%) African subjects screened. Mutation E168Q was detected in a single Caucasian individual together with mutation H63D. Our data demonstrate the value of the strip-based technology in providing a rapid and reliable comprehensive test for simultaneous analysis of multiple mutations.

DNA Mutational Analysis↗
PubMed2001

Hemochromatosis with HFE gene mutation in a Japanese patient.

A case of hemochromatosis associated with HFE gene mutation has never been previously reported in a Japanese patient. A 65-yr-old Japanese woman presenting with primary hemochromatosis underwent HFE mutation analyses, which demonstrated a C282Y mutation, this being the definitive gene mutation of Caucasian hemochromatosis.

Aged↗
PubMed2005

Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging.

OBJECTIVES: Hepatic fibrosis is a complication of hereditary hemochromatosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis. METHODS: Receiver-operating characteristic curve analysis to determine the utility of hepatic iron concentration (HIC) and age in the diagnosis of low- or high-grade fibrosis was undertaken retrospectively in 60 subjects who had undergone liver biopsy for assessment of hereditary hemochromatosis. A prospective pilot study was then conducted in 10 additional subjects to evaluate utility of magnetic resonance imaging (MRI) measurements of HIC to predict fibrosis. RESULTS: Eighteen subjects had high-grade fibrosis while 42 subjects had low-grade fibrosis. Hepatic iron concentration alone was highly sensitive (100%) but of limited specificity (67%) in diagnosis of high-grade fibrosis. The product of [HIC x age] had a sensitivity and specificity of 100% and 86%, respectively, for diagnosis of high-grade fibrosis. Magnetic resonance imaging measurements also provided accurate assignment of subjects into fibrosis severity groups. CONCLUSIONS: Duration of exposure to iron is important in the development of hepatic fibrosis in hereditary hemochromatosis. The product of HIC and age is highly sensitive and specific for diagnosis of high-grade fibrosis and can be obtained using MRI.

Adult↗
PubMed2006

Hemochromatosis: genetics and pathophysiology.

A number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.

Antimicrobial Cationic Peptides↗
PubMed1999

Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation : a prospective cohort study in men in eastern Finland.

Background-Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated (HFE) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study. Methods and Results-Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1. 1 to 4.8; P=0.03) risk of acute myocardial infarction compared with noncarriers. Conclusions-Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.

Adult↗
PubMed2001

Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.

Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.

Amino Acid Substitution↗
PubMed2004

Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin.

Juvenile hemochromatosis is an early-onset form of iron storage disease characterized by hypogonadotrophic hypogonadism and cardiomyopathy. Recently, the putative causative gene (LOC148738) encoding a protein designated hemojuvelin was cloned. The previously proposed designation of this gene as HFE2 is contrary to established convention, because it is not a member of the HFE family. We suggest that it be designated HJV. We sequenced this gene in members of 2 previously reported kinships that manifest typical juvenile hemochromatosis. In one kinship, 2 previously undescribed mutations of HJV were identified, c.238T>C (C80R) and c.302T>C (L101P). In the second kinship, 2 previously identified mutations, G320V and I222N, were found. These studies confirm that mutations in HJV cause juvenile hemochromatosis.

Adolescent↗
PubMed2006

Effect of Native American ancestry on iron-related phenotypes of Alabama hemochromatosis probands with HFE C282Y homozygosity.

BACKGROUND: In age-matched cohorts of screening study participants recruited from primary care clinics, mean serum transferrin saturation values were significantly lower and mean serum ferritin concentrations were significantly higher in Native Americans than in whites. Twenty-eight percent of 80 Alabama white hemochromatosis probands with HFE C282Y homozygosity previously reported having Native American ancestry, but the possible effect of this ancestry on hemochromatosis phenotypes was unknown. METHODS: We compiled observations in these 80 probands and used univariate and multivariate methods to analyze associations of age, sex, Native American ancestry (as a dichotomous variable), report of ethanol consumption (as a dichotomous variable), percentage transferrin saturation and loge serum ferritin concentration at diagnosis, quantities of iron removed by phlebotomy to achieve iron depletion, and quantities of excess iron removed by phlebotomy. RESULTS: In a univariate analysis in which probands were grouped by sex, there were no significant differences in reports of ethanol consumption, transferrin saturation, loge serum ferritin concentration, quantities of iron removed to achieve iron depletion, and quantities of excess iron removed by phlebotomy in probands who reported Native American ancestry than in those who did not. In multivariate analyses, transferrin saturation (as a dependent variable) was not significantly associated with any of the available variables, including reports of Native American ancestry and ethanol consumption. The independent variable quantities of excess iron removed by phlebotomy was significantly associated with loge serum ferritin used as a dependent variable (p < 0.0001), but not with reports of Native American ancestry or reports of ethanol consumption. Loge serum ferritin was the only independent variable significantly associated with quantities of excess iron removed by phlebotomy used as a dependent variable (p < 0.0001) (p < 0.0001; ANOVA of regression). CONCLUSION: We conclude that the iron-related phenotypes of hemochromatosis probands with HFE C282Y homozygosity are similar in those with and without Native American ancestry reports.

Adolescent↗
PubMed2004

Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis.

The pathogenesis of diabetes associated with hemochromatosis is not known. We therefore examined glucose homeostasis and beta-cell function in mouse models of hemochromatosis. Mice with targeted deletion of the hemochromatosis gene (Hfe(-/-)) on the 129/Sv genetic background exhibited a 72% increase in iron content in the islets of Langerhans compared with wild-type controls. Insulin content was decreased in Hfe(-/-) mice by 35%/pancreas and 25%/islet. Comparable decreases were seen in the mRNA levels of beta-cell-specific markers, ins1, ins2, and glucose transporter 2. By 6-8 months, islets from Hfe(-/-) mice were 45% smaller, associated with increased staining for activated caspase 3 and terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling. Islets from Hfe(-/-) mice were also desensitized to glucose, with half-maximal stimulation of insulin secretion seen at 16.7 +/- 0.9 mm glucose in perifused islets from Hfe(-/-) mice compared with 13.1 +/- 0.6 mm glucose in wild-type animals. Carbonyl protein modification, a marker for oxidative stress, was increased by 58% in Hfe(-/-) islets. Despite decreased islet size, Hfe(-/-) mice exhibited enhanced glucose tolerance. Fasting serum insulin levels were comparable between Hfe(-/-) and Hfe(+/+) mice, but were 48% lower in the Hfe(-/-) mice 30 min after challenge. Similar results were seen in mice carrying an Hfe mutation analogous to the common human mutation (C282Y) and in mice fed excess dietary iron. Hfe(-/-)mice on the C57BL6 background exhibited decreased glucose tolerance at 10-12 months due to an inability to increase insulin levels as they aged. We conclude that iron excess results in beta-cell oxidant stress and decreased insulin secretory capacity secondary to beta-cell apoptosis and desensitization of glucose-induced insulin secretion. This abnormality alone, however, is insufficient to cause diabetes.

Age Factors↗
PubMed2002

The "anemic" enterocyte in hereditary hemochromatosis: molecular insights into the control of intestinal iron absorption.

Studies of the molecular function of HFE, the protein defective in hereditary hemochromatosis, have provided important insights into the control of intestinal iron absorption. A recent study suggests that HFE controls the recycling rate of the transferrin receptor and thereby ultimately controls the iron status of the enterocyte. In hereditary hemochromatosis, a defect in HFE causes relative iron starvation in the enterocyte leading paradoxically to the development of an "anemic" enterocyte phenotype in the midst of bountiful body iron stores. Despite ever-increasing stores of body iron, the inappropriately low iron status of the hereditary hemochromatosis enterocyte continues to drive the hyper-absorption of dietary iron, eventually leading to iron overload.

Enterocytes↗
PubMed2001

Idiopathic hemochromatosis with the mutation of Ala176Val heterozygous for HFE gene.

Most patients with hereditary hemochromatosis are homozygous for C282Y in the HFE gene in populations of Celtic origin, but the genetic cause of this disease is unknown in Japan because of its rarity. A 48-year-old Japanese patient was recently diagnosed with idiopathic hemochromatosis. Analysis of the entire coding region of the patient's HFE by RT-PCR showed a heterozygous nucleotide substitution at nucleotide 527 from C to T, which resulted in A176V amino acid substitution. Another mutation at nucleotide 942 from T to C was observed, but this was a nonsense mutation. C282Y and another mutation, H63D, were not found in the patient. The mutation may have a possible role on the cause of hemochromatosis in this Japanese case.

Alanine↗
PubMed1999

Update on hereditary hemochromatosis and the HFE gene.

Hereditary hemochromatosis (HHC) is the most common inherited single gene disorder in people of northern European descent. Hereditary hemochromatosis is characterized by increased intestinal absorption of iron leading to its deposition into multiple organs. The classic description of HHC is bronze diabetes in a patient with cirrhosis. Hereditary hemochromatosis is increasingly being diagnosed at an earlier, less symptomatic stage. Diagnosis is based on an elevated fasting early morning transferrin saturation. Treatment is by phlebotomy, which, if initiated before the development of cirrhosis or diabetes, is associated with a normal life expectancy. Recently, a gene associated with HHC was discovered and named HFE. Two point mutations of this gene have been referred to as C282Y and H63D. Several US and European studies have found that 60% to 93% of patients with suspected HHC are homozygous for C282Y. Positive results of HFE gene testing may eliminate the need for a liver biopsy in selected cases. The greatest utility of HFE gene testing will likely be in screening family members of an identified proband and in helping to resolve ambiguous cases.

Diagnosis, Differential↗
PubMed1999

Hereditary hemochromatosis: impact of molecular and iron-based testing on the diagnosis, treatment, and prevention of a common, chronic disease.

OBJECTIVE: To review the current state-of-the-art regarding the role of iron- and DNA-based testing on the detection, treatment, and prevention of hereditary hemochromatosis (HH), the most common single-gene disorder in white people. SOURCES: Review of the medical literature, with particular emphasis on recent reports of the impact of DNA-based testing on the detection of symptomatic and presymptomatic patients with HH. CONCLUSIONS: Hereditary hemochromatosis, a common autosomal recessive iron overload disorder (with a population prevalence of 0.3%-0.8%), is a common cause of preventable liver, heart, joint, and endocrine disease. Since the associated clinical signs and symptoms are nonspecific, an accurate HH diagnosis demands both a high index of suspicion and the direct laboratory demonstration of elevated iron parameters. The substantial public health burden of HH as a common, deadly, detectable, and treatable chronic disease has led the College of American Pathologists to recommend that "systematic screening for hemochromatosis is warranted for all persons over the age of 20 years." The recent discovery that most HH cases are the result of a single well-conserved homozygous missense mutation (C282Y) within a novel transferrin-receptor binding protein (HFE) has given rise to diagnostic clinical tests for the DNA-based detection of this pathologic mutation. This direct HFE mutation test can now be used not only to confirm the diagnosis of HH in those with symptomatic disease, but also, perhaps more importantly, to detect those with presymptomatic iron overload in whom future disease manifestations may be prevented (with phlebotomy therapy).

Algorithms↗
PubMed2000

Screening for hereditary hemochromatosis in siblings and children of affected patients. A cost-effectiveness analysis.

BACKGROUND: Screening for hereditary hemochromatosis is traditionally done by using serum iron studies. However, mutation analysis of the hemochromatosis-associated HFE gene has recently become available. OBJECTIVE: To compare the cost-effectiveness of no screening with four screening strategies that incorporate HFE gene testing or serum iron studies. DESIGN: Cost-effectiveness analysis. DATA SOURCES: Published literature. TARGET POPULATION: Siblings and children of an affected proband. TIME HORIZON: Lifetime from 10 years of age (children) or 45 years of age (siblings). PERSPECTIVE: Societal. INTERVENTION: 1) Serum iron studies. 2) Gene testing of the proband. If the proband is homozygous (C82Y+/+), the spouse undergoes gene testing; if he or she is heterozygous (C82Y+/-), the children undergo gene testing. 3) Gene testing of the proband; if he or she is homozygous, relatives undergo gene testing. 4) Direct gene testing of relatives. OUTCOME MEASURES: Cost per life-year saved and incremental cost-effectiveness ratio. RESULTS OF BASE-CASE ANALYSIS: In children, HFE gene testing of the proband was the most cost-effective strategy for screening one child (incremental cost-effectiveness ratio, $508 per life-year saved). HFE gene testing of the proband followed by testing of the spouse was the most cost-effective strategy for screening two or more children (incremental cost-effectiveness ratio, $3665 per life-year saved). In siblings, all screening strategies were dominant compared with no screening. Strategies using HFE gene testing were less costly than serum iron studies. RESULTS OF SENSITIVITY ANALYSIS: Despite varying the prevalence of mutations and regardless of the cost of the genetic test in one- and two-way sensitivity analyses, HFE gene testing remained cost-effective. CONCLUSIONS: HFE gene testing for the C282Y mutation is a cost-effective method of screening relatives of patients with hereditary hemochromatosis.

Cost-Benefit Analysis↗
PubMed1999

[Hereditary hemochromatosis--new developments after discovery of the HFE gene].

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, resulting in an increased iron deposition and multiorgan failure. Recently a candidate gene of HH, termed HFE, has been identified on chromosome 6, coding for a protein homologous to major histocompatibility complex (MHC) class I molecules. Two mutations of the hemochromatosis gene leading to an exchange of cysteine to tyrosine at aminoacid 282 and histidine to asparagine at aminoacid 63, are retained responsible for the development of hereditary hemochromatosis. The Cys282Tyr-mutation disrupts a disulfid bond and thus abrogates binding of the mutant HFE-protein to beta 2-microglobulin and its presentation on the cell surface. The His63Asp-mutation seems to play a role in pH-regulated dissociation of the transferrin receptor/transferrin complex in the lysosome. Mutations of the HFE-protein alter the affinity of the transferrin receptor for its ligand transferrin and may thus cause an intracellular accumulation of iron. Knowledge of the responsible gene allows a molecular diagnosis of HH. The new genetic marker can be used for screening and confirmation of HH reducing the need for confirmatory liver biopsies. Compared to standard screening parameters like ferritin and transferrin saturation genetic testing will allow the diagnosis of HH in an early, asymptomatic state before iron accumulation has occurred. As a normal life expectancy of patients with HH can be achieved if iron reduction is initiated early, genetic testing may thus be of great benefit for patients with HH.

Algorithms↗